Malignant Liver Tumors, Third Edition: Current and Emerging Therapies

Malignant Liver Tumors Current and Emerging Therapies THIRD EDITION E D I T E D BY Pierre-Alain Clavien, MD, PhD, FACS...

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Malignant Liver Tumors Current and Emerging Therapies THIRD EDITION E D I T E D BY

Pierre-Alain Clavien, MD, PhD, FACS, FRCS Professor and Chairman Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

D E P U T Y E D ITOR

Stefan Breitenstein, MD Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

ASS O CI AT E E D I T O R S

Jacques Belghiti,

MD

Professor of Surgery Department of Hepatobiliary Surgery Hospital Beaujon Clichy, France

Ravi S. Chari,

MD, MBA

Professor of Surgery and Cancer Biology Vanderbilt University Medical Center Nashville, TN, USA

Josep M. Llovet,

MD

Associate Professor of Medicine Liver Cancer Program Division of Liver Diseases Mount Sinai School of Medicine New York, New York, USA; Professor of Research – ICREA BCLC Group, IDIBAPS, Liver Unit Hospital Clinic Barcelona, Spain

Chung-Mau Lo,

MS, FRCS (Edin),

FRACS, FACS Professor Divisions of Hepatobiliary/Pancreatic Surgery and Liver Transplantation Departments of Surgery The University of Hong Kong Queen Mary Hospital Hong Kong, China

Michael A. Morse,

MD, MHS

Associate Professor of Medicine Division of Medical Oncology, GI Oncology Molecular Therapeutics Program Duke University Medical Center Durham, NC, USA

A John Wiley & Sons, Ltd., Publication

Tadatoshi Takayama,

MD, PhD

Professor Department of Digestive Surgery Nihon University School of Medicine Tokyo, Japan

Jean-Nicolas Vauthey,

MD, FACS

Professor of Surgery Liver Service Department of Surgical Oncology The University of Texas M.D. Anderson Cancer Center Houston, TX, USA

Malignant Liver Tumors Current and Emerging Therapies

Third Edition

Malignant Liver Tumors Current and Emerging Therapies THIRD EDITION E D I T E D BY

Pierre-Alain Clavien, MD, PhD, FACS, FRCS Professor and Chairman Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

D E P U T Y E D ITOR

Stefan Breitenstein, MD Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

ASS O CI AT E E D I T O R S

Jacques Belghiti,

MD

Professor of Surgery Department of Hepatobiliary Surgery Hospital Beaujon Clichy, France

Ravi S. Chari,

MD, MBA

Professor of Surgery and Cancer Biology Vanderbilt University Medical Center Nashville, TN, USA

Josep M. Llovet,

MD

Associate Professor of Medicine Liver Cancer Program Division of Liver Diseases Mount Sinai School of Medicine New York, New York, USA; Professor of Research – ICREA BCLC Group, IDIBAPS, Liver Unit Hospital Clinic Barcelona, Spain

Chung-Mau Lo,

MS, FRCS (Edin),

FRACS, FACS Professor Divisions of Hepatobiliary/Pancreatic Surgery and Liver Transplantation Departments of Surgery The University of Hong Kong Queen Mary Hospital Hong Kong, China

Michael A. Morse,

MD, MHS

Associate Professor of Medicine Division of Medical Oncology, GI Oncology Molecular Therapeutics Program Duke University Medical Center Durham, NC, USA

A John Wiley & Sons, Ltd., Publication

Tadatoshi Takayama,

MD, PhD

Professor Department of Digestive Surgery Nihon University School of Medicine Tokyo, Japan

Jean-Nicolas Vauthey,

MD, FACS

Professor of Surgery Liver Service Department of Surgical Oncology The University of Texas M.D. Anderson Cancer Center Houston, TX, USA

This edition first published 2010, © 2010 by Blackwell Publishing Ltd Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell. Registered office: John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www. wiley.com/wiley-blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Malignant liver tumors : current and emerging therapies / edited by Pierre-Alain Clavien ; deputy editor, Stefan Breitenstein ; associate editors, Jacques Belghiti . . . [et al.]. – 3rd ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4051-7976-8 1. Liver–Cancer–Treatment. I. Clavien, Pierre-Alain. [DNLM: 1. Liver Neoplasms–therapy. WI 735 M251 2010] RC280.L5L578 2010 616.99′436–dc22 2009029874 ISBN: 9781405179768 A catalogue record for this book is available from the British Library. Set in 9/12 pt Meridien by Toppan Best-set Premedia Limited Printed and bound in Singapore 1

2010

Contents

Contributors, vii Preface, xi

9 Modalities for Imaging Liver Tumors, 76 Dominik Weishaupt and Thomas F. Hany

Acknowledgments, xiii Abbreviations, xiv

Section 1 Introduction, 1

Section 3 Systemic and Regional Therapies, 103 Introduction, 105 Ravi S. Chari

1 From Promethean to Modern Times, 3 Kuno Lehmann, Stefan Breitenstein, and Pierre-Alain Clavien

10 Systemic Treatment of Hepatobiliary Tumors, 107 Panagiotis Samaras, Michael A. Morse, and Bernhard C. Pestalozzi

2 Hepatic Anatomy and Terminology, 11 Steven M. Strasberg

11 External Beam Radiation Therapy for Liver Tumors, 122 Rakesh Reddy and A. Bapsi Chakravarthy

Section 2 Epidemiology and Diagnosis, 27 Introduction, 29 Chung-Mau Lo 3 Histology and Pathology of Normal and Diseased Liver, 30 Valérie Paradis and Achim Weber 4 Pathology of Primary and Secondary Malignant Liver Tumors, 40 Kay Washington 5 Epidemiology, Etiology, and Natural History of Hepatocellular Carcinoma, 52 Wei-Chen Lee and Miin-Fu Chen 6 Epidemiology, Etiology, and Natural History of Cholangiocarcinoma, 56 Peter Neuhaus, Ulf P. Neumann, and Daniel Seehofer 7 Epidemiology, Etiology, and Natural History of Colorectal Liver Metastases, 64 Robert J. Porte 8 Tumor Markers in Primary and Secondary Liver Tumors, 69 Ketsia B. Pierre and Ravi S. Chari

12 Internal Radiation Therapy for Liver Tumors, 131 Ahsun Riaz, Laura Kulik, Michael Abecassis, and Riad Salem 13 Transarterial Embolization for Patients with Hepatocellular Carcinoma, 139 Jordi Bruix, Carmen Ayuso, and Maria I. Real 14 Selective Continuous Intra-arterial Chemotherapy for Liver Tumors, 151 Fidel D. Huitzil-Melendez, Stefan Breitenstein, and Nancy Kemeny 15 Isolated Hepatic Perfusion and Percutaneous Hepatic Perfusion, 164 Charles K. Heller, III, James F. Pingpank, and Steven K. Libutti

Section 4 Resection, Ablation or Transplantation for Liver Tumors, 173 Introduction, 175 Jean-Nicolas Vauthey and Tadatoshi Takayama 16 Liver Resection of Primary Tumors: Hepatocellular Carcinoma, Cholangiocarcinoma, and Gallbladder Cancer, 177 Tadatoshi Takayama and Masatoshi Makuuchi

v

Contents 17 Liver Resection of Colorectal Liver Metastases, 192 Daria Zorzi, Yun Shin Chun, and Jean-Nicolas Vauthey 18 Laparoscopic Liver Resection, 203 Luca Viganò and Daniel Cherqui 19 Repeat Resection for Liver Tumors, 216 Mickael Lesurtel and Henrik Petrowsky 20 Cryoablation of Liver Tumors, 227 Sivakumar Gananadha and David L. Morris 21 Thermal Ablation of Liver Tumors by Radiofrequency, Microwave, and Laser Therapy, 244 M. B. Majella Doyle and David C. Linehan 22 Ethanol and Other Percutaneous Injection Modalities in the Treatment of Liver Tumors, 266 Michael A. Heneghan and Andrew D. Yeoman 23 Transplantation for Liver Tumors, 281 François Durand, Claire Francoz, and Jacques Belghiti 24 Preventing Recurrence of Hepatocellular Carcinoma after Curative Resection, 296 Stefan Breitenstein, Dimitris Dimitroulis, and Beat Müllhaupt

Section 5 Guidelines for Liver Tumor Treatment, 305 Introduction, 307 Stefan Breitenstein and Pierre-Alain Clavien 25 Strategies for Safer Liver Surgery, 308 Philipp Dutkowski, Olivier de Rougemont, and Pierre-Alain Clavien 26 Hepatocellular Carcinoma, 317 Tadatoshi Takayama 27 Cholangiocarcinoma, 324 Jacques Belghiti and Charles B. Rosen 28 Gallbladder Cancer, 333 Juan Hepp and Chung-Mau Lo 29 Colorectal Liver Metastases, 342 Phuong L. Doan, Jean-Nicolas Vauthey, Martin Palavecino, and Michael A. Morse

Section 6 Emerging Therapies, 347

31 Signaling Pathways and Rationale for Molecular Therapies in Hepatocellular Carcinoma, 368 Augusto Villanueva, Clara Alsinet, and Josep M. Llovet 32 Novel Therapies Targeted at Signal Transduction in Liver Tumors, 382 Fidel D. Huitzil-Melendez, Ghassan K. Abou-Alfa, and Michael A. Morse 33 Induction of Apoptosis in Liver Tumors, 393 Markus Selzner and Pierre-Alain Clavien 34 Antiangiogenic Agents for Liver Tumors, 400 Mathijs Vogten, Emile E. Voest, and Inne H.M. Borel Rinkes 35 Integrative Oncology: Alternative and Complementary Treatments, 414 Barrie R. Cassileth and Jyothirmai Gubili

Section 7 Special Tumors, Population, and Special Considerations, 421 Introduction, 423 Stefan Breitenstein and Pierre-Alain Clavien 36 Liver Metastases from Endocrine Tumors, 424 Clayton D. Knox and C. Wright Pinson 37 Uncommon Primary and Metastatic Liver Tumors, 439 Stefan Breitenstein, Ashraf Mohammad El-Badry, and Pierre-Alain Clavien 38 Liver Tumors in Special Populations, 454 Tadahiro Uemura, Akhtar Khan, and Zakiyah Kadry 39 Malignant Liver Tumors in Children, 475 Xavier Rogiers and Ruth De Bruyne 40 Liver Tumors in Asia, 487 Norihiro Kokudo, Sumihito Tamura, and Masatoshi Makuuchi 41 Liver Tumors in South America, 500 Lucas McCormack and Eduardo de Santibañes 42 Liver Tumors in Africa, 509 Michael C. Kew 43 Anesthetic Management of Liver Surgery, 519 Marco P. Zalunardo 44 Qualitative and Economic Aspects of Liver Surgery, 531 René Vonlanthen, Ksenija Slankamenac, and Christian Ernst

Introduction, 349 Michael A. Morse and Josep M. Llovet 30 Viral-Based Therapies for Primary and Secondary Liver Cancer, 352 Menghua Dai, Lorena Gonzalez, and Yuman Fong

vi

Index, 539

Contributors

Stefan Breitenstein,

Michael Abecassis,

Yun Shin Chun,

MD Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

MD Professor Division of Organ Transplantation Department of Surgery Northwestern University Chicago, IL, USA

MD Department of Surgical Oncology The University of Texas M.D. Anderson Cancer Center Houston, TX, USA

Pierre-Alain Clavien, Ghassan K. Abou-Alfa,

MD

Department of Medicine Division of Gastrointestinal Oncology Memorial Sloan-Kettering Cancer Center New York, NY, USA

Clara Alsinet,

PhD Barcelona-Clinic-Liver-Cancer (BCLC) Group, Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Centro de Investigaciones Biomédicas en Red (CIBEREHD) Liver Unit, Hospital Clínic Barcelona, Spain

Carmen Ayuso,

MD Senior Consultant Barcelona-Clinic-Liver-Cancer (BCLC) Group Department of Radiology Hospital Clínic, University of Barcelona Centro de Investigaciones Biomédicas en Red Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona, Spain

Jordi Bruix,

MD

Senior Consultant Barcelona-Clinic-Liver-Cancer (BCLC) Group Liver Unit Hospital Clínic, University of Barcelona Centro de Investigaciones Biomédicas en Red Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona, Spain

Barrie R. Cassileth,

MS, PhD Integrative Medicine Service Memorial Sloan-Kettering Cancer Center New York, NY, USA

A. Bapsi Chakravarthy,

MD

Associate Professor Department of Radiation Oncology Vanderbilt University Nashville, TN, USA

Inne H.M. Borel Rinkes, Professor of Surgery Department of Surgery University Medical Center Utrecht, The Netherlands

Menghua Dai,

MD Department of Surgery Memorial Sloan-Kettering Cancer Center New York, NY, USA

Olivier de Rougemont,

MD

Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

Eduardo de Santibañes,

MD Professor of Surgery and Cancer Biology Vanderbilt University Medical Center Nashville, TN, USA

MD, PhD, FACS Professor of Surgery Hepatobiliopancreatic and Liver Transplant Unit Hospital Italiano Buenos Aires, Argentina

Miin-Fu Chen,

MD, FACS Department of General Surgery Chang-Gung Memorial Hospital Chang-Gung University Medical School Taoyuan, Taiwan

Ruth De Bruyne,

Daniel Cherqui,

Dimitrios Dimitroulis,

Ravi S. Chari,

Jacques Belghiti,

MD Professor of Surgery Department of Hepatobiliary Surgery Hospital Beaujon Clichy, France

MD, Phd Professor Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

MD Department of Pediatrics Section of Pediatric Gastroenterology University Medical Center Ghent Ghent, Belgium

MD, PhD MD Professor of Surgery Chief Department of Digestive and Hepatobiliary Surgery Hôpital Henri Mondor – Université Paris Créteil, France

MD Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

vii

Contributors

Phuong L. Doan,

MD Department of Medicine Division of Medical Oncology Duke University Medical Center Durham, NC, USA

Jyothirmai Gubili,

MS, FACS Integrative Medicine Service Memorial Sloan-Kettering Cancer Center New York, NY, USA

Thomas F. Hany, M.B. Majella Doyle,

MD

Assistant Professor of Surgery Washington University School of Medicine Department of Surgery Section of Liver Transplant and Hepatobiliary Surgery St Louis, MO, USA

François Durand,

MD Hepatology and Liver Intensive Care Hospital Beaujon Clichy, France

Philipp Dutkowski,

MD Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

Ashraf Mohammad El-Badry MB.BCh, MCh, MD Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

Christian Ernst,

Prof Dr Economics and Management of Social Services University Hohenheim Stuttgart, Germany

Yuman Fong,

MD Murray F. Brennan Chair in Surgery Memorial Sloan-Kettering Cancer Center New York, NY, USA

MD Department of Nuclear Medicine University Hospital Zurich Zurich, Switzerland

Charles K. Heller III,

Sivakumar Gananadha Senior lecturer Department of Surgery The Canberra Hospital Australian National University Medical School Canberra, Australia

Lorena Gonzalez,

MD Department of Surgery Memorial Sloan-Kettering Cancer Center New York, NY, USA

viii

MD, FACS Assistant Professor of Surgery Division of Transplantation Department of Surgery Penn State Milton S. Hershey Medical Center Hershey, PA, USA

Clayton D. Knox,

MD, MBA Vanderbilt University School of Medicine Nashville, TN, USA

DO

Norihiro Kokudo,

MD, PhD Hepato-Biliary-Pancreatic Surgery Division Department of Surgery University of Tokyo Tokyo, Japan

Surgery Branch National Cancer Institute National Institutes of Health Bethesda, MD, USA

Michael A. Heneghan,

MD,

MMedSc, FRCPI Consultant Hepatologist & Lead Clinician for Hepatology Institute of Liver Studies King’s College Hospital London, UK

Juan Hepp,

MD, FACS Professor of Surgery Clínica Alemana – Universidad del Desarrollo School of Medicine Department of Surgery Clínica Alemana Santiago Santiago, Chile

Laura Kulik,

MD Assistant Professor Division of Hepatology Department of Medicine Robert H. Lurie Comprehensive Cancer Center Northwestern University Chicago, IL, USA

Wei-Chen Lee,

MD Department of General Surgery Chang-Gung Memorial Hospital Chang-Gung University Medical School Taoyuan, Taiwan

Kuno Lehmann,

MD Departamento de Hematología y Oncología Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán” Mexico, D. F. Mexico

MD Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

Zakiyah Kadry,

MD, FACS Professor of Surgery Division of Transplantation Department of Surgery Penn State Milton S. Hershey Medical Center Hershey, PA, USA

Mickael Lesurtel,

MD, PhD Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

Nancy Kemeny,

Steven K. Libutti,

Michael C. Kew,

David C. Linehan,

Fidel D. Huitzil-Melendez,

Claire Francoz,

MD Hepatology and Liver Intensive Care Hospital Beaujon Clichy, France

Akhtar Khan,

MD Memorial Sloan-Kettering Cancer Center Professor of Medicine Weill Medical College of Cornell University New York, NY, USA MD University of Cape Town; Emeritus Professor and Honorary Professor University of the Witwatersrand Johannesburg, South Africa

MD, FACS Professor of Surgery, Department of Surgery Montefiore Medical Center/Albert Einstein College of Medicine New York, NY, USA MD Section of Hepatobiliary, Pancreatic and Gastrointestinal Surgery Washington University School of Medicine Saint Louis, MO, USA

Contributors

Josep M. Llovet,

MD Associate Professor of Medicine Liver Cancer Program, Division of Liver Diseases Mount Sinai School of Medicine New York, New York, USA; Professor of Research – ICREA Barcelona-Clinic-Liver-Cancer (BCLC) Group Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Centro de Investigaciones Biomédicas en Red (CIBEREHD) Liver Unit, Hospital Clínic Barcelona, Spain

Ulf P. Neumann,

Martin Palavecino,

MD Department of Surgical Oncology The University of Texas M.D. Anderson Cancer Center Houston, TX, USA

FRACS, FACS Department of Surgery The University of Hong Kong Queen Mary Hospital Hong Kong, China

Valérie Paradis, MD, PhD Department of Pathology Beaujon Hospital Clichy, France INSERM U773 Centre de Recherche Bichat Beaujon Paris, France

Masatoshi Makuuchi,

Bernhard C. Pestalozzi,

Chung-Mau Lo,

MS, FRCS (Edin),

MD, PhD Department of Hepato-Biliary-Pancreatic Surgery President Japanese Red Cross Medical Center Tokyo, Japan

Maria I. Real,

MD Department of General, Visceral and Transplantation Surgery Charité – Universitätsmedizin Berlin Campus Virchow-Klinikum Berlin, Germany

MD Barcelona-Clinic-Liver-Cancer (BCLC) Group Department of Radiology Hospital Clínic, University of Barcelona Centro de Investigaciones Biomédicas en Red Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona, Spain

Rakesh Reddy,

MBBS Department of Radiation Oncology Vanderbilt University Nashville, TN, USA

Ahsun Riaz,

MD Section of Interventional Radiology Department of Radiology Robert H. Lurie Comprehensive Cancer Center Northwestern University Chicago, IL, USA MD, PhD Department of General and Hepatobiliary Surgery Transplantation Center University Medical Center Ghent Ghent, Belgium

Henrik Petrowsky,

MD The Dumont-UCLA Transplant Center Ronald Reagan Medical Center David Geffen School of Medicine at UCLA Los Angeles, CA, USA

Charles B. Rosen,

Professor of Surgery UNSW Department of Surgery St George Hospital Sydney, Australia

Ketsia B. Pierre,

Riad Salem,

Michael A. Morse,

James F. Pingpank,

Lucas McCormack,

MD

Xavier Rogiers,

Department of Oncology Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

MD

Liver Transplant Program General Surgery Service Hospital Aleman Buenos Aires, Argentina

MD Professor of Surgery Division of Transplantation Surgery Mayo Clinic Rochester, MN, USA

David Lawson Morris

MD, MHS Associate Professor of Medicine Division of Medical Oncology, Gl Oncology Molecular Therapeutics Program Duke University Medical Center Durham, NC, USA

Beat Müllhaupt,

MD Department of Gastroenterology and Hepatology Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

Peter Neuhaus,

MD Department of General, Visceral and Transplantation Surgery Charité – Universitätsmedizin Berlin Campus Virchow-Klinikum Berlin, Germany

MD, MSCI Department of Surgery Vanderbilt University Medical Center Nashville, TN, USA MD

Associate Professor of Surgery Department of Surgery University of Pittsburgh Pittsburgh, PA, USA

C. Wright Pinson

MD, MBA H. William Scott Professor of Surgery Deputy Vice-Chancellor for Health Affairs Vanderbilt University Medical Center Nashville, TN, USA

MD, MBA Professor Interventional Oncology Section of Interventional Radiology Department of Radiology Robert H. Lurie Comprehensive Cancer Center Northwestern University Chicago, IL, USA

Panagiotis Samaras,

MD Department of Oncology Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

Daniel Seehofer, Robert J. Porte,

MD, PhD

Professor of Surgery Department of Surgery Section Hepatobiliary Surgery and Liver Transplantation University Medical Center Groningen University of Groningen Groningen, The Netherlands

MD Department of General, Visceral and Transplantation Surgery Charité – Universitätsmedizin Berlin Campus Virchow-Klinikum Berlin, Germany

ix

Contributors

Markus Selzner,

MD Department of Surgery Multiorgan Transplant Program Toronto General Hospital Toronto, Ontario, Canada

MD Department of Hepatobiliary and Digestive Surgery Ospedale Mauriziano “Umberto I” Torino, Italy

Ksenija Slankamenac,

Augusto Villanueva,

MD Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

Steven M. Strasberg,

MD Pruett Professor of Surgery Section of Hepatobiliary-Pancreatic Surgery Washington University in Saint Louis Saint Louis, MO, USA

Luca Viganò,

MD Barcelona-Clinic-Liver-Cancer (BCLC) Group Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Centro de Investigaciones Biomédicas en Red (CIBEREHD) Liver Unit, Hospital Clínic Barcelona, Spain

Emile E. Voest,

MD, PhD Department of Medical Oncology University Medical Center Utrecht, The Netherlands

Tadatoshi Takayama,

MD, PhD Professor of Surgery Department of Digestive Surgery Nihon University School of Medicine Tokyo, Japan

Sumihito Tamura,

MD, PhD Hepato-Biliary-Pancreatic Surgery Division Department of Surgery University of Tokyo Tokyo, Japan

J. Mathijs Vogten

Jean-Nicolas Vauthey,

MD, FACS Professor of Surgery Liver Service Department of Surgical Oncology The University of Texas M.D. Anderson Cancer Center Houston, TX, USA

x

Dominik Weishaupt,

Department of Surgery Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

Kay Washington, MD, PhD Department of Pathology Vanderbilt University Medical Center Nashville, TN, USA

MD

Division of Radiology Triemli Hospital Zurich Zurich, Switzerland

Andrew D. Yeoman,

MB BCh,

MRCP Institute of Liver Studies King’s College Hospital London, UK MD

Institute of Anesthesiology University Hospital of Zurich Zurich, Switzerland

Daria Zorzi, MD

Tadahiro Uemura,

MD, Assistant Professor of Surgery Division of Transplantation Department of Surgery Penn State Milton S. Hershey Medical Center Hershey, PA, USA

MD Department of Pathology Institute of Surgical Pathology Swiss Hepato-Pancreato-Biliary and Transplantation Center University Hospital Zurich Zurich, Switzerland

Marco P. Zalunardo, MD, PhD

Department of Surgery University Medical Center Utrecht, The Netherlands

René Vonlanthen,

Achim Weber,

MD Department of Surgical Oncology The University of Texas M.D. Anderson Cancer Center Houston, TX, USA

Preface

Very few areas in medicine offer as many controversies as the management of liver tumors. Since the publication of the first two editions of the book, in 1999 and 2004 respectively, many novel diagnostic and therapeutic tools have become available. This has brought tremendous excitement and hope for curing previously lethal diseases. However, the recent proliferation of innovative and competitive approaches, often marketed prior to conclusive demonstration of their efficacy, has also brought confusion about which therapeutic modalities to select for a particular case [1]. Today, the success of treating a patient with hepatic malignancy is often linked to the appropriate use of various treatments, combining neoadjuvant and adjuvant modalities with surgery. Thus, the best approach for a patient with an hepatic tumor is achieved by a multidisciplinary team comprising a medical oncologist, hepatologist, hepatic surgeon, radiotherapist, and interventional radiologist. The availability of such specialists in a center per se is not enough for success. Of vital importance is the daily interaction of those specialists, which is mandatory in order to provide optimal treatment for each patient presenting with a complex liver malignancy [2]. Since most innovative approaches are still experimental and often technically demanding, patients presenting with hepatic tumors should optimally be managed in centers with a strong commitment to research. Patients often need to travel long distances to reach such centers. Therefore, for adequate long-term management of these patients, it is imperative to establish a close collaboration between specialized centers and local oncologists, as well as other physicians. To this end, the third edition of Malignant Liver Tumors has been extensively revised compared to the two previous editions, including a new format, new associate editors, and 16 new chapters containing guidelines for the treatment of each specific type of malignancy. However, the goal remains similar in providing a comprehensive and critical approach to current and established therapeutic modalities, while critically evaluating promising new avenues. The book was written by a multidisciplinary panel of international

experts, each with extensive experience in this population of patients. Each chapter was reviewed by the Editor, Deputy Editor, two Associate Editors, and at least one external reviewer to achieve comprehensive and balanced coverage of each topic, to minimize redundancy among chapters, and to provide appropriate cross-references. While each chapter can be read separately, the book was written with the intention that the chapters be read sequentially. The first and second editions received many positive comments published in several surgical, oncologic, and gastrointestinal journals, testifying to the interdisciplinary interest in the field. Besides many eulogistic comments, such as “best book in the area” [3], the most relevant criticism of the second edition appeared in the New England Journal of Medicine: “If I were a physician who was consulting this book for advice on how to treat my patient, I would be impressed by how many treatment options my patient had, but I would have no idea how to pick up the best one” [4]. To address this pertinent comment we added an entire new section (Section 5) on “Guidelines for liver tumor treatment,” covering the most common liver malignancies: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), gallbladder cancer, and colorectal liver metastases. These guidelines were prepared by the Associate Editors, taking into account other guidelines prepared by international or national societies, which should now offer a specific strategy to treat a patient with a specific condition through algorithms. Each chapter has been updated, often by the original authors. Sixteen new chapters have been added. The book starts with a new chapter (Chapter 1) on the history of liver tumors and their therapies. The next chapter (Chapter 2) is also new, covering the liver anatomy and the consensus terminology for the various types of liver resection. A new emphasis is also given to histologic changes in the liver related to underlying conditions such as steatosis and cirrhosis, as well as neoadjuvant chemotherapies, which are increasingly used in clinical practice (Chapter 4). Three new chapters (Chapters 5–7) cover the epidemiology and the natural history of HCC, CC, and colorectal liver metastases, respectively. Novel developments have occurred in the field of internal radiation therapy of liver tumors, which is

xi

Preface covered in Chapter 12. Strategies for liver resection are newly covered in two separate chapters (Chapters 16 and 17), one for HCC and gallbladder cancer, and another for colorectal metastases. Among the emerging therapies, novel therapies, targeted at specific signaling pathways, appear to be the most promising, and a new chapter has been included which covers relevant signaling pathways in liver tumors (Chapter 31). Finally, a new chapter has been included to cover the economic aspects of the treatment of liver tumors (Chapter 44). This book also has an important educational purpose, and therefore we include 5–10 questions after each chapter. This will enable the reader to test his or her understanding of the main information in each chapter. I hope that this third edition of Malignant Liver Tumors: Current and Emerging Therapies will prove useful, and will

xii

provide timely information and guidelines for the management of this difficult population of patients. P.-A.C.

References 1 Clavien PA, Petrowsky H, deOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 2007;356:1545–59. 2 Clavien PA, Mullhaupt B, Pestalozzi B. Do we need a center approach to treat patients with liver diseases? Forum on Liver Transplantation. J Hepatol 2006;44:639–42. 3 Morris DL. Book review. Br J Surg 2000;87:1117. 4 Di Bisceglie AM. Book review. N Engl J Med 2004;350:203.

Acknowledgments

Madeleine Meyer, assistant to the Editor, deserves special thanks for her enthusiasm and tireless work to get each initial and revised chapter in on time. A hearty thanks goes to all authors who often served as reviewers of other chapters, and in particular to the Associate Editors, Jacques

Belghiti, Ravi Chari, Chung-Mau Lo, Josep Llovet, Michael Morse, Tadatoshi Takayama, and Jean-Nicolas Vauthey, as well as the Deputy Editor, Stefan Breitenstein, who despite their busy schedules have dedicated a large amount of their time to the success of this book.

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Abbreviations

5-FU AFLD AFP AFU AIDS Akt APAF-1 ASH ATP BMI BSC CAG CASH CBA CC CEA CEUS CGH CK CLM CRC CSI CT CTAP

5-fluorouracil alcoholic fatty liver disease alpha-fetoprotein alpha-L-fucosidase acquired immunodeficiency syndrome protein kinase B apoptosis protease activating factor alcoholic steatohepatitis adenosine triphosphate body mass index best supportive care chronic atropic gastritis chemotherapy-associated steatohepatitis cost-benefit analysis cholangiocarcinoma cost-effective analysis contrast-enhanced ultrasound comparative genomic hybridization cytokeratin colorectal liver metastasis colorectal cancer chemical shift imaging computed tomography computed tomography during arterial portography CTHA computed tomography during hepatic arteriography CTNNB1 catenin (cadherin-associated protein), beta CTV clinical target volume CUA cost-utility analysis CEA, carcinoembryonic antigen CUSA cavitron ultrasonic surgical aspiration CyA cyclosporin A DFS disease-free survival DRG diagnosis-related group ECC extrahepatic cholangiocarcinoma ECM extracellular matrix EGF epidermal growth factor EGFR epidermal growth factor receptor ERC endoscopic retrograde cholangiography

xiv

ERCP ERK FDG FLR FNH FSE FUDR GRE GSK-3β GTV H&E HAC HAI HBV HCC HCG HCV HEHE HNPCC HIV HPB HSC IAP ICC ICER ICG IGF IHP IL IMTP IOUS ITV IVC LDLT LMET LOH LSF MAPK MDCT

endoscopic retrograde cholangiopancreatography extracellular signal-regulated kinase fluoro-2-deoxy-D-glucose future liver remnant focal nodular hyperplasia fast spin echo floxuridine gradient recalled echo glycogen synthase kinase 3 beta gross tumor volume hematoxylin and eosin hepatic artery chemotherapy hepatic arterial infusion hepatitis B virus hepatocellular carcinoma human chorionic gonadotropin hepatitis C virus hepatic epithelioid hemangioendothelioma hereditary nonpolyposis colorectal cancer human immunodeficiency virus hepato-pancreatico-biliary hepatic stellate cell inhibitor of apoptosis protein intrahepatic cholangiocarcinoma incremental cost-effectiveness ratio indocyanine green insulin-like growth factor isolated hepatic perfusion interleukin intensity modulated radiation therapy intraoperative ultrasound internal target volume inferior vena cava living donor liver transplantation liver metastases from endocrine tumor loss of heterozygosity lung shunt function mitogen-activated protein kinase multidetector-row computed tomography

Abbreviations MEK MELD MEN MIP MMAC MMF MNET MRC MRCP MRI mTOR MWA NAFLD NASH NCNEM NET NIH NO NSF OLT PAAI PAS PEI PET PFS PHoT PHP PI3K PKC PSC PTC

mitogen-activated protein kinase model for end-stage liver disease multiple endocrine neoplasia maximum intensity projections mutated in multiple advanced cancer mycophenolate mofetil metastatic neuroendocrine tumor magnetic resonance cholangiography magnetic resonance cholangiopancreatography magnetic resonance imaging mammalian target of rapamycin microwave ablation nonalcoholic fatty liver disease nonalcoholic steatohepatitis noncolorectal nonendocrine metastases neuroendocrine tumor National Institutes of Health nitric oxide nephrogenic systemic sclerosis orthotopic liver transplantation percutaneous acetic acid injection periodic acid–Schiff percutaneous ethanol injection positron emission tomography progression free survival percutaneous hot saline therapy percutaneous hepatic perfusion phosphoinositid-3-kinase protein kinase C primary sclerosing cholangitis percutaneous transhepatic cholangiogram

PTEN PTV PVE PVT QALY RAD RECIST RFA RILD RLN RTK SBRT SEER SIRT SMA SNP STAT TACE TAE TART TGF TKR TLV TNF TNM TPP UPA VEGF VOD ZES

phosphatase and tensin homolog planning target volume portal vein embolization portal vein thrombosis quality adjusted life year radiation absorbed dose response evaluation criteria in solid tumor radiofrequency ablation radiation-induced liver disease regional lymph node receptor tyrosine kinase stereotactic body radiotherapy surveillance epidemiology and end results selective internal radiation therapy superior mesenteric artery single nucleotide polymorphism signal transducers and activators of transcription transarterial chemoembolization transarterial embolization transarterial radionuclide therapy transforming growth factor tyrosine kinase receptor total liver volume tumor necrosis factor tumor/node/metastasis time to progression urokinase-type plasminogen activator vascular endothelial growth factor veno-occlusive disease Zollinger−Ellison syndrome

xv

1

Introduction

1

From Promethean to Modern Times Kuno Lehmann, Stefan Breitenstein, and Pierre-Alain Clavien Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland

From myths to mysteries In the dark ages of our ancestors, liver surgery was inexistent and the organ was a source for myths, legends, and spirituality. During the Babylonian era (∼3000–1500 BC), the liver was thought to bear the soul. Priests used hepatoscopy in animal livers as a tool for divine connection, predicting the future. Clay models of sheep livers, probably used for teaching or divination, still exist from this period. The famous legend of Prometheus was written by Hesiod (750–700 BC), recounting very ancient times (Figure 1.1). Prometheus stole fire from Zeus, the godfather of ancient Greece, and gave it to mankind. For this infringement, the angry Zeus chained him to a rock and sent an eagle to devour his liver. Prometheus was captured in eternal pain. The liver regenerated and gained its normal size overnight, and the hungry eagle returned daily to its victim. Over 2000 years later, the amazing regenerative capacity of the liver is no longer a mystical tale, but the basis for current hepatobiliary surgery and a promising topic of surgical research [1]. Probably the first anatomist to describe the liver was the Alexandrian Herophilus (330–280 BC). Although his written work has not survived, another famous scientist cited him. This was the Greek Galen (130–200 AD), who dominated medical literature for the following centuries. He made accurate descriptions of the lobar anatomy and the vasculature, interpreting the liver as the source of blood. In contrast to his empirical anatomic insights, he propagated a humoral basis of medicine. Originating from the theories of Hippocrates (460–380 BC), diseases were based on an imbalance of the four humors: black and yellow bile, blood and phlegm. However, in the following years and centuries of the Middle Ages, theories became traditions and knowledge moved forward very little. Brilliant exceptions were Leonardo da Vinci’s drawings of the extra- and intra-hepatic portal and venous vessels.

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

In 1640, Johannis Walaeus, from Leiden, Netherlands, reported a common tunic, surrounding the branches of the choledochal duct, the celiac artery, and the portal vein. In 1654, Francis Glisson, from Cambridge, England removed the liver parenchyma by cooking the organ in hot water and explored the hepatic blood flow with colored milk [2]. He discussed the intrahepatic anatomy and topography of the vasculature (Figure 1.2). The growing knowledge of liver anatomy was one of the substantial preconditions for the development of liver surgery. However, this was still far from realization, and the liver remained a fragile bleeding mystery. We would like to refer to the comprehensive overview by McClusky et al for the fruitful interaction between anatomists and pioneers of liver surgery [3].

Of inquisitive anatomists and courageous surgeons In 1842, Crawford W. Long used ether as a surgical anesthetic for the first time in the United States. This was a fundamental step in the development of abdominal surgery. In 1867, Joseph Lister from Glasgow, Scotland, introduced antiseptic techniques against bacterial infections after Louis Pasteur, from Paris, France, had discovered the dangers of bacteria. Before this period, only anecdotal records exist of descriptions about the removal of protruding liver tissue after trauma. Among these surgeons were Ambroise Paré from Paris, France, J.C. Massie from the United States, Victor von Bruns from Germany, and many others. However, liver trauma at this time was generally managed without operation. It took many years before any courageous surgeon was successful in the first attempt of a planned liver resection. Carl Langenbuch from Berlin, Germany (Figure 1.3), who was among those to perform the first cholecystectomy, reported the first elective and successful hepatic resection in 1888 [4]. William W. Keen from Philadelphia performed the first liver resection in the United States in 1891. He used the “finger-fracture” technique to divide the liver parenchyma. By 1899, the first case series were being reported in the

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Introduction

Figure 1.1 Prometheus bound to a rock, with an eagle eating out his liver. 550 BC. Figure 1.3 Carl Langenbuch (1846–81).

Figure 1.2 Intrahepatic vasculature as illustrated in Francis Glisson’s Anatomia Hepatis (1654). (Reproduced from Glisson [2], with permission.)

United States [5]. The most striking challenge at this time was the control of intraoperative bleeding. In 1896, Michel Kousnetzoff and Jules Pensky introduced a continuous mattress suture above the resection line for bleeding control [6]. In 1908, J. Hogarth Pringle from Glasgow, Scotland described a method of temporary compression of the portal ligament in a small series of patients [7]. However, it took 70 years before tolerance of this maneuver – exceeding 20 min – was shown [8].

4

Bleeding control remained a major limiting factor in the development of hepatic surgery for many years. The fine work of anatomists provided the key insights to overcome major bleeding. In 1888, Hugo Rex from Germany [9], and in 1897 James Cantlie from Liverpool, England [10], revisited the accepted anatomic division of the liver by the falciform ligament. Using corrosion studies, they separated the liver by the branches of the portal vein and defined an avascular plane through the gallbladder bed. Today, the plane passing through the gallbladder bed towards the vena cava and through the right axis of the caudate lobe along the middle hepatic vein is known as the Rex–Cantlie line. Walter Wendell from Magdeburg, Germany [11] and Hans von Haberer from Graz, Austria [12] were the first surgeons at the beginning of the 20th century to apply resections along this anatomic plane. Following World War II, Carl-Herman Hjortsjo from Lund, Sweden [13] and John E. Healey from Huston, United States [14] further refined hepatic anatomy by their description of the intrahepatic biliary duct system and the vascular tree. In 1954, Claude Couinaud from Paris, France (Figure 1.4) published his seminal work on the segmental architecture of the liver [15, 16]. Based on the branches of the portal vein, he separated the liver into eight well-described segments. Before this time, liver resections were mostly performed in a “blindly manner.” The findings of Carl-Herman Hjortsjo, John Healey, and Claude Couinaud had a major impact on surgical technique and related mortality. The rapidly evolving era of liver surgery had begun.

CHAPTER 1

In 1950, Ichio Honjo from Kyoto, Japan reported the first “anatomic” liver resection [17]. Jean-Louis LortatJacob from Paris, France in 1952 [18], followed by Julian. K. Quattlebaum, from Georgia, United States in 1953 [19], reported the first resections in Europe and the United States. Subsequent, descriptions of the procedure were provided by Alexander Brunschwig [20] and George T. Pack [21] in New York, United States, and later by William P. Longmire and Samuel A. Marable [22] in Los Angeles, United States. At this time, George T. Pack documented the regenerative potential of the human liver after a major hepatectomy [23]. A few years later, Tien-Yu Lin and Chiu-Chiang Chen from Taipei, Taiwan described the decrease of regenerative capacity of the cirrhotic liver [24]. The knowledge about liver regeneration in humans was preceded by animal experiments years before. In 1879, Hermann Tillmanns from Leipzig, Germany [25] demonstrated regeneration in rabbit livers. In 1883, Themisocles Gluck from Berlin [26], and later Emil Ponfick from Breslau, Germany, demonstrated liver regeneration after major resections in animals. In the 1960s, perioperative mortality rates up to 50% were common after right hemihepatectomy. Furthermore, serious concern was growing over hepatic nomenclature, and notably, liver surgeons throughout the world used different, sometimes confusing, terms [27]. In 2000, a group of international liver surgeons proposed a standardized nomenclature, which was introduced at the bi-annual

Figure 1.4 Claude Couinaud working with his collection of liver casts at the School of Medicine in Paris, 1988.

From Promethean to Modern Times

meeting of the International Hepato-Pancreato-Biliary Association (IHPBA) in Brisbane, Australia. The terminology for hepatic anatomy was subsequently called the Brisbane nomenclature [28]. Nomenclature in hepatic surgery is discussed in detail in Chapter 2. Over the years, growing anatomic and physiologic knowledge, and ongoing specialization in experienced centers, have significantly lowered mortality from liver resections to below 5% [29]. We would like to refer to the comprehensive overviews by Joseph G. Fortner and Leslie H. Blumgart [30], and James H. Foster [31], for an in-depth coverage of liver surgery in the 20th century.

The era of liver transplantation A giant leap forward and a driving force in the rapid development of hepatobiliary surgery was the onset of the transplantation era. In 1955, Cristopher S. Welch from Albany, United States, published the first heterotopic liver transplantation in a dog [32]. Others, such as J. A. Cannon, Thomas E. Starzl, and Francis D. Moore, followed with orthotopic liver transplantations (OLT), also in dogs, and established the basis for transplantation in humans [33]. In 1963, Thomas E. Starzl (Figure 1.5) made the first attempt to transplant a human liver in Denver, United States [34]. However, the patient died during the operation. Another attempt by Francis D. Moore in Boston also did not succeed

Figure 1.5 Thomas E. Starzl has the honor of the first pitch at the Three Rivers Stadium in 1983, Pittsburgh. (Reproduced from the Pittsburgh Post-Gazette.)

5

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Introduction

[35]. The first series of successful OLTs was reported in 1968 by Thomas E. Starzl [36]. A year later, Sir Roy Calne performed the first OLT in Europe in Cambridge, England [37]. However, although many patients initially tolerated the transplantation well, most did not survive OLT longer than a few weeks or months. Another quantum leap was the discovery of cyclosporine A (CyA) by Hartmann F. Stähelin and Jean-Francois Borel from Basel, Switzerland, in 1972. Seven years later, Sir Roy Calne reported the first use of CyA in OLT patients with a dramatic improvement in long-term survival [38]. Before the introduction of CyA, 5-year survival after OLT was less than 20% and improved to 60% or more with the introduction of CyA [39]. In the late 1980s, Thomas E. Starzl introduced FK-506 (tacrolimus) as a new and promising immunosuppressant at the University of Pittsburgh. The introduction of effective immunosuppressants such as polyclonal antilymphocyte antibodies, anti-CD3 antibodies in the 1980s, or mycophenolate mofetil (MMF) in the early 1990s, and rapamycin in the late 1990s offered further alternatives in the management of patients after OLT. Already in the early stage of solid organ transplantation, it was recognized, that success could only be achieved with adequate preservation of the organs. Cold preservation was described as early as 1912 by the French surgeon Alexis Carell, who preserved and transplanted vessels, skin, and connective tissues in dogs [40]. Together with the famous aviator and engineer Charles A. Lindberg, he constructed a perfusion pump and successfully preserved thyroid glands [41]. Years later, in the era of liver transplantation, the relevance of cooling the donor organ was recovered during animal experiments by Francis D. Moore [33]. Lawrence Brettschneider from Denver, United States used cooling of the animal donor organ and intraportal infusion with a balanced, cooled electrolyte solution, buffered to pH. The organ was additionally perfused after harvesting, but this technique was much too complex for clinical application [42]. For many years, storage in cold Collins solution was the standard for organ procurement [43]. A landmark advance was the development of the University of Wisconsin (UW) solution by Folkert O. Belzer and James H. Southard in 1988 [44], representing an important growth of knowledge in the pathophysiology of ischemia/reperfusion injury. This solution contains colloids to prevent cell swelling, the oxygen scavengers allopurinol and glutathione, and adenosine to facilitate adenosine triphosphate (ATP) production. In 1983, a National Institutes of Health (NIH) Consensus Conference considered liver transplantation as an accepted therapy for patients with end-stage liver disease. The consequence of this statement was a rapid increase in the numbers of patients on waiting lists in the following years, resulting in a dramatic shortage of available donor organs for trans-

6

Figure 1.6 Henri Bismuth.

plantation. The development of new concepts was therefore crucial. The shortage of size-matched liver donors for pediatric patients was responsible for a high death rate on the cadaveric pediatric waiting list. This stimulated the development of technical innovations based on the segmental anatomy of the liver. Reduced liver graft, split graft, and living donor liver transplantation were such innovative techniques. In 1984, Henri Bismuth (Figure 1.6) from Paris, France, performed the first OLT using a left hemiliver [45]. In 1988, Rudolf Pichlmayr from Hannover, Germany extended the concept of partial liver graft transplantation and published in 1988 a report of a split graft, where the right hemiliver was transplanted to an adult, and the left to a child [46]. Two years later, Christoph E. Broelsch published the first patient series of split liver transplantation in Chicago, United States [47]. The introduction of living donors was a critical step in the further evolution of liver transplantation [48]. In 1989, Silvano Raia from Sao Paulo, Brazil [49], and one year later Russell W. Strong from Brisbane, Australia [50], reported the first living donor liver transplantations using the left hemiliver. In 1994, Yoshio Yamaoka from Kyoto, Japan used the right hemiliver for transplantation, expanding this procedure also for adults [51]. The first series of patients was published by Christoph E. Broelsch in Chicago [52], later by Chung-Mau Lo in Hong Kong [53]. Nowadays, patient survival after one year has reached 80–90% in many contemporary series of OLT [54]. Conse-

CHAPTER 1

quently, donor criteria are still expanding under the pressure of an insufficient donor pool. Beside end-stage liver disease and acute liver failure, selected patients with primary liver cancer [55] and early stage hilar cholangiocarcinoma [56] have become accepted indications for OLT (see also Chapter 26 for indications of OLT in treatment of liver tumors). A potential approach to solve the shortage of donor organs was the use of steatotic donor organs and this was shown to have a favorable outcome by McCormack et al [57]. Donor risk scores and appropriate matching to selected recipients may further improve the outcome [58]. Thus, extending donor criteria, improvement of allocation procedures, and finally, translation of knowledge from basic research about donor organ protection into clinical application, may help to overcome the problem of donor organ shortage in the near future.

Surgical oncology: breaking down the limits Parallel to the progress in the field of liver transplantation, liver surgery, mostly for oncologic diseases, became more sophisticated. In 1983, William P. Longmire from Los Angeles, California, published the results of 138 patients after major resections with a 30-day mortality of 10% [59]. In the 1990s, Jacques Belghiti from Paris, France reported – in a large series of 747 patients – a mortality of 1% in patients with normal liver parenchyma [60]. Leslie H. Blumgart from New York, United States [61] and Sheung Tat Fan from Hong Kong [62] published similar results. However, the presence of cirrhosis [63], portal hypertension [64], and liver steatosis [65] were identified as important risk factors for perioperative morbidity and mortality. An important step for the improved outcomes was the understanding that these complex diseases must be treated in specialized, interdisciplinary centers [66]. A higher caseload in such hepato-pancreatico-biliary (HPB) centers translates into more experience, an important factor for favorable outcomes [67, 68]. In the last decades, basic research provided new insights into liver physiology and pathophysiology [69–71]. Interleukin-6 [72], tumor necrosis factor α [73], platelet-derived serotonin [74], and bile salts [75] were identified as central mediators of liver regeneration. Explorations of mechanisms of ischemic damage and cell death provided novel perceptions of liver injury [76–79]. However, only few new strategies, such as ischemic preconditioning, made the transition into clinical practice [80]. Diagnostic accuracy improved due to the availability of computed tomography (CT) scans and magnetic resonance (MR) tomography. Masatoshi Makuuchi, from Tokyo, Japan, introduced the concept of routine intraoperative

From Promethean to Modern Times

ultrasonography for liver surgery [81]. He was also among the first to use portal vein embolization to increase the future liver remnant prior to major resection [82], although the mechanism of selective portal occlusion and subsequent contralateral hypertrophy was already known since 1920 [83]. For the treatment of unresectable tumors, radiofrequency was introduced as an alternative treatment [84–86]. The complex treatment strategies for metastatic liver disease are illustrative examples of the progress of HPB surgery [1]. In 1940, Richard B. Cattell, in Boston, United States, performed the first resection of a metastatic tumor [87], although resection of colorectal liver metastases remained controversial until the early 1980s. The survival of patients after resection was 21%, but the operative mortality still reached 17% [88]. Today, resection for liver metastasis, especially of colorectal origin, provides favorable outcomes compared to the natural history [89]. In a series of 1001 consecutive patients, the 5-year survival rate was 37% [1, 90]. In selected patients with unresectable and multifocal metastases, a two-stage hepatectomy combined with chemotherapy was recognized as an effective and safe treatment strategy [91]. In 2004, promising survival rates for patients treated with two-stage procedures, combined with portal vein ligation, were published [92]. Down-staging of previously unresectable colorectal liver metastases could also be achieved by portal vein ligation combined with intraarterial chemotherapy [93]. Multistage procedures are currently recognized as effective strategies for patients with otherwise unresectable tumors [1]. In conclusion, liver surgery has enjoyed a dramatic development during the last three decades. Surgical experience and outcomes after major surgery improved as a result of progress in many fields. Furthermore, multidisciplinary patient management became a mainstay of care in recognized HPB centers. Today, liver surgery no longer carries the high risk that it did in its infancy. In experienced hands, liver surgery became reliable and effective, and consequently saved the lives of many patients.

Self-assessment questions 1 Name the surgeon who performed the first successful liver resection. 2 Name the surgeons who performed the first major liver resections. 3 What was a prerequisite for safe major liver surgery? 4 What was the major innovation making OLT a successful treatment? 5 A great problem was the availability of size-matched donor organs for children. Who found the solution, which had also a major impact on later developments?

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Introduction

References 1

2 3

4 5

6 7 8

9 10 11 12 13 14

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16 17 18 19 20 21

22 23

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Clavien PA, Petrowsky H, DeOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 2007;356:1545–59. Glisson F. Anatomia Hepatis. London, 1654. McClusky DA, 3rd, Skandalakis LJ, Colborn GL, Skandalakis JE. Hepatic surgery and hepatic surgical anatomy: historical partners in progress. World J Surg 1997;21:330–42. Langenbuch C. Ein Fall von Resection eines linksseitigen Schnurlappens der Leber. Heilung Klin Wochenschr 1888;25:37. Keen WW. IV. Report of a case of resection of the liver for the removal of a neoplasm, with a table of seventy-six cases of resection of the liver for hepatic tumors. Ann Surg 1899;30:267–83. Kousnetzoff M, Pensky J. Sur la resection partielle du foie. Rev Chir 1896;16:501–21. Pringle JH. V. Notes on the arrest of hepatic hemorrhage due to trauma. Ann Surg 1908;48:541–9. Huguet C, Nordlinger B, Galopin JJ, Bloch P, Gallot D. Normothermic hepatic vascular exclusion for extensive hepatectomy. Surg Gynecol Obstet 1978;147:689–93. Rex H. Beiträge zur Morphologie der Säugerleber. Morphol Jahrb 1888;14:517. Cantile J. On a new arrangement of the right and left lobes of the liver. J Anat Physiol 1897;32:4–9. Wendell W. Beiträge zur Chirurgie der Leber. Arch Klin Chir 1911;95:887. vonHaberer H. Zur Frage der nicht parasitären Leberzysten. Wien Klin Wochenschr 1909;22:1788. Hjortsjo CH. The topography of the intrahepatic duct systems. Acta Anat (Basel) 1951;11:599–615. Healey JE, Jr., Schroy PC, Sorensen RJ. The intrahepatic distribution of the hepatic artery in man. J Int Coll Surg 1953;20:133–48. Couinaud C. Lobes des ségments hépatiques: notes sur architecture anatomique et chirurgicale du foie. Presse Med 1954; 62:709–12. Sutherland F, Harris J. Claude Couinaud: a passion for the liver. Arch Surg 2002;137:1305–10. Honjo I, Araki C. [Total resection of the right lobe of the liver: report of a successful case]. Shujutsu 1950;4:345–9. Lortat-Jacob J, Robert H. Hepatectomie droite reglée. Presse Med 1952;60:549. Quattlebaum JK. Massive resection of the liver. Ann Surg 1953;137:787–96. Brunschwig A. The surgical treatment of primary and secondary hepatic malignant tumors. Am Surg 1954;20:1077–85. Pack GT, Miller TR, Brasfield RD. Total right hepatic lobectomy for cancer of the gallbladder; report of three cases. Ann Surg 1955;142:6–16. Longmire WP, Jr, Marable SA. Clinical experiences with major hepatic resections. Ann Surg 1961;154:460–74. Pack GT, Islami AH, Hubbard JC, Brasfield RD. Regeneration of human liver after major hepatectomy. Surgery 1962;52: 617–23. Lin TY, Chen CC. Metabolic function and regeneration of cirrhotic and non-cirrhotic livers after hepatic lobectomy in man. Ann Surg 1965;162:959–72.

25 Tillmans H. Experimentelle und anatomische Untersuchungen ueber Wunden der Leber und der Niere. Virchows Arch 1879;78:437–65. 26 Gluck T. Ueber die Bedeutung physiologisch-chirurgischer Experimente an der Leber. Arch Klin Chir (Berl) 1883; 29:139–43. 27 Strasberg SM. Terminology of liver anatomy and liver resections: coming to grips with hepatic Babel. J Am Coll Surg 1997;184:413–34. 28 IHPBA. Terminology of liver anatomy and resections. HPB Surg 2000;2:333–9. 29 Cunningham JD, Fong Y, Shriver C, Melendez J, Marx WL, Blumgart LH. One hundred consecutive hepatic resections. Blood loss, transfusion, and operative technique. Arch Surg 1994;129:1050–6. 30 Fortner JG, Blumgart LH. A historic perspective of liver surgery for tumors at the end of the millennium. J Am Coll Surg 2001;193:210–22. 31 Foster JH. History of liver surgery. Arch Surg 1991;126:381–7. 32 Welch C. A note on transplantation of the whole liver in dogs. Transplant Bull 1955;2:54. 33 Moore FD, Wheele HB, Demissianos HV, et al. Experimental whole-organ transplantation of the liver and of the spleen. Ann Surg 1960;152:374–87. 34 Starzl TE, Marchioro TL, Vonkaulla KN, Hermann G, Brittain RS, Waddell WR. Homotransplantation of the liver in humans. Surg Gynecol Obstet 1963;117:659–76. 35 Moore FD. A Miracle and a Privilege: Recounting a Half-Century of Surgical Advance. Washington, DC: Joseph Henry Press, 1995. 36 Starzl TE, Groth CG, Brettschneider L, et al. Orthotopic homotransplantation of the human liver. Ann Surg 1968; 168:392–415. 37 Calne RY, Williams R, Dawson JL, et al. Liver transplantation in man. II. A report of two orthotopic liver transplants in adult recipients. Br Med J 1968;4:541–6. 38 Calne RY, Rolles K, White DJ, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet 1979; 2:1033–6. 39 Iwatsuki S, Starzl TE, Todo S, et al. Experience in 1,000 liver transplants under cyclosporine-steroid therapy: a survival report. Transplant Proc 1988;20(1 Suppl 1):498–504. 40 Dutkowski P, de Rougemont O, Clavien PA. Alexis Carrel: genius, innovator and ideologist. Am J Transplant 2008;8: 1998–2003. 41 Carrel A, Lindbergh CA. The culture of whole organs. Science 1935;81:621–3. 42 Brettschneider L, Kolff J, Smith GV, Martin AJ, Taylor P, Starzl TE. An evaluation of perfusion constituents in liver preservation. Surg Forum 1968;19:354–6. 43 Benichou J, Halgrimson CG, Weil R, 3rd, Koep LJ, Starzl TE. Canine and human liver preservation for 6 to 18 hr by cold infusion. Transplantation 1977;24:407–11. 44 Kalayoglu M, Sollinger HW, Stratta RJ, et al. Extended preservation of the liver for clinical transplantation. Lancet 1988;1:617–9. 45 Bismuth H, Houssin D. Reduced-sized orthotopic liver graft in hepatic transplantation in children. Surgery 1984;95:367–70.

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46 Pichlmayr R, Ringe B, Gubernatis G, Hauss J, Bunzendahl H. [Transplantation of a donor liver to 2 recipients (splitting transplantation) – a new method in the further development of segmental liver transplantation]. Langenbecks Arch Chir 1988;373: 127–30. 47 Broelsch CE, Emond JC, Whitington PF, Thistlethwaite JR, Baker AL, Lichtor JL. Application of reduced-size liver transplants as split grafts, auxiliary orthotopic grafts, and living related segmental transplants. Ann Surg 1990;212:368–75; discussion 375–7. 48 Chan SC, Fan ST. Historical perspective of living donor liver transplantation. World J Gastroenterol 2008;14:15–21. 49 Raia S, Nery JR, Mies S. Liver transplantation from live donors. Lancet 1989;2:497. 50 Strong RW, Lynch SV, Ong TH, Matsunami H, Koido Y, Balderson GA. Successful liver transplantation from a living donor to her son. N Engl J Med 1990;322:1505–7. 51 Yamaoka Y, Washida M, Honda K, et al. Liver transplantation using a right lobe graft from a living related donor. Transplantation 1994;57:1127–30. 52 Broelsch CE, Whitington PF, Emond JC, et al. Liver transplantation in children from living related donors. Surgical techniques and results. Ann Surg 1991;214:428–37; discussion 37–9. 53 Lo CM, Fan ST, Liu CL, et al. Adult-to-adult living donor liver transplantation using extended right lobe grafts. Ann Surg 1997;226:261–9; discussion 269–70. 54 Busuttil RW, Farmer DG, Yersiz H, et al. Analysis of long-term outcomes of 3200 liver transplantations over two decades: a single-center experience. Ann Surg 2005;241:905–16; discussion 16–18. 55 Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693–9. 56 Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 2005;242:451–8; discussion 458–61. 57 McCormack L, Petrowsky H, Jochum W, Mullhaupt B, Weber M, Clavien PA. Use of severely steatotic grafts in liver transplantation: a matched case-control study. Ann Surg 2007;246:940–6; discussion 6–8. 58 Cameron AM, Ghobrial RM, Yersiz H, et al. Optimal utilization of donor grafts with extended criteria: a single-center experience in over 1000 liver transplants. Ann Surg 2006;243:748–53; discussion 53–5. 59 Thompson HH, Tompkins RK, Longmire WP, Jr. Major hepatic resection. A 25-year experience. Ann Surg 1983;197:375–88. 60 Belghiti J, Hiramatsu K, Benoist S, Massault P, Sauvanet A, Farges O. Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J Am Coll Surg 2000;191:38–46. 61 Jarnagin WR, Gonen M, Fong Y, et al. Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade. Ann Surg 2002;236:397–406; discussion 406–7. 62 Poon RT, Fan ST, Lo CM, et al. Improving perioperative outcome expands the role of hepatectomy in management of benign and malignant hepatobiliary diseases: analysis of 1222 consecutive

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patients from a prospective database. Ann Surg 2004;240:698– 708; discussion 708–10. Nagasue N, Yukaya H, Ogawa Y, Kohno H, Nakamura T. Human liver regeneration after major hepatic resection. A study of normal liver and livers with chronic hepatitis and cirrhosis. Ann Surg 1987;206:30–9. Bruix J, Castells A, Bosch J, et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 1996;111:1018–22. McCormack L, Petrowsky H, Jochum W, Furrer K, Clavien PA. Hepatic steatosis is a risk factor for postoperative complications after major hepatectomy: a matched case-control study. Ann Surg 2007;245:923–30. Clavien PA, Mullhaupt B, Pestalozzi BC. Do we need a center approach to treat patients with liver diseases? J Hepatol 2006;44:639–42. Dimick JB, Wainess RM, Cowan JA, Upchurch GR, Jr, Knol JA, Colletti LM. National trends in the use and outcomes of hepatic resection. J Am Coll Surg 2004;199:31–8. Glasgow RE, Showstack JA, Katz PP, Corvera CU, Warren RS, Mulvihill SJ. The relationship between hospital volume and outcomes of hepatic resection for hepatocellular carcinoma. Arch Surg 1999;134:30–5. Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology 2006;43(Suppl 1):S45–53. Michalopoulos GK, DeFrances MC. Liver regeneration. Science 1997;276:60–6. Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol 2004;5:836–47. Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 1996;274:1379–83. Yamada Y, Kirillova I, Peschon JJ, Fausto N. Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc Natl Acad Sci U S A 1997;94:1441–6. Lesurtel M, Graf R, Aleil B, et al. Platelet-derived serotonin mediates liver regeneration. Science 2006;312:104–7. Huang W, Ma K, Zhang J, et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 2006;312:233–6. Clavien PA, Harvey PR, Sanabria JR, Cywes R, Levy GA, Strasberg SM. Lymphocyte adherence in the reperfused rat liver: mechanisms and effects. Hepatology 1993;17:131–42. McKeown CM, Edwards V, Phillips MJ, Harvey PR, Petrunka CN, Strasberg SM. Sinusoidal lining cell damage: the critical injury in cold preservation of liver allografts in the rat. Transplantation 1988;46:178–91. Otto G, Wolff H, David H. Preservation damage in liver transplantation: electron-microscopic findings. Transplant Proc 1984;16:1247–8. Caldwell-Kenkel JC, Thurman RG, Lemasters JJ. Selective loss of nonparenchymal cell viability after cold ischemic storage of rat livers. Transplantation 1988;45:834–7. Clavien PA, Selzner M, Rudiger HA, et al. A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning. Ann Surg 2003;238:843–50; discussion 851–2.

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81 Makuuchi M, Hasegawa H, Yamazaki S. Intraoperative ultrasonic examination for hepatectomy. Ultrasound Med Biol 1983;(Suppl 2):493–7. 82 Makuuchi M, Thai BL, Takayasu K, et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 1990;107:521–7. 83 Rous P, Larimore L. Relation of the portal blood to liver maintenance. J Exp Med 1920;31:609–70. 84 Curley SA, Izzo F, Delrio P, et al. Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: results in 123 patients. Ann Surg 1999;230:1–8. 85 Elias D, Debaere T, Muttillo I, Cavalcanti A, Coyle C, Roche A. Intraoperative use of radiofrequency treatment allows an increase in the rate of curative liver resection. J Surg Oncol 1998;67:190–1. 86 Siperstein AE, Rogers SJ, Hansen PD, Gitomirsky A. Laparoscopic thermal ablation of hepatic neuroendocrine tumor metastases. Surgery 1997;122:1147–54; discussion 1154–5. 87 Cattell R. Successful removal of a liver metastasis from carcinoma of the rectum. Lahey Clin Bull 1940;2:7–11. 88 Foster JH. Survival after liver resection for secondary tumors. Am J Surg 1978;135:389–94. 89 Wagner JS, Adson MA, Van Heerden JA, Adson MH, Ilstrup DM. The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann Surg 1984;199:502–8. 90 Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230:309–18; discussion 318–21. 91 Adam R, Laurent A, Azoulay D, Castaing D, Bismuth H. Two-stage hepatectomy: A planned strategy to treat irresectable liver tumors. Ann Surg 2000;232:777–85. 92 Jaeck D, Oussoultzoglou E, Rosso E, Greget M, Weber JC, Bachellier P. A two-stage hepatectomy procedure combined with portal vein embolization to achieve curative resection for

10

initially unresectable multiple and bilobar colorectal liver metastases. Ann Surg 2004;240:1037–49; discussion 1049–51. 93 Selzner N, Pestalozzi BC, Kadry Z, Selzner M, Wildermuth S, Clavien PA. Downstaging colorectal liver metastases by concomitant unilateral portal vein ligation and selective intraarterial chemotherapy. Br J Surg 2006;93:587–92.

Self-assessment answers 1 Carl Langenbuch, a German surgeon, performed the first successful liver resection in 1888 in Berlin. 2 Ichio Honjo reported the first “anatomic” liver resection in 1950 in Kyoto, Japan. In 1952, Jean-Louis LortatJacob from Paris, France reported the first resection in Europe, followed by Julian K. Quattlebaum from Georgia, who reported the first resections in the United States in 1953. 3 The fine work of Carl-Herman Hjortsjo from Lund, Sweden, John E. Healey from Huston, United States and Claude Couinaud from Paris, France revealed the complex anatomy of intrahepatic structures, a fundamental basis for safe liver surgery. 4 Before the advent of cyclosporine A, discovered in 1972 by Hartmann F. Stähelin and Jean-Francois Borel from Basel, Switzerland, the prognosis after OLT was poor. Cyclosporine A improved the outcome of these patients significantly. 5 The segmental anatomy of the liver was the key to the problem. Henri Bismuth from Paris, France performed the first OLT using a left hemiliver in 1984. Later, Rudolf Pichlmayr from Hannover, Germany performed a split graft, where the right hemiliver was transplanted to an adult, and the left to a child. This principle was also the basis for living related liver transplantation.

2

Hepatic Anatomy and Terminology Steven M. Strasberg Section of Hepatobiliary-Pancreatic Surgery, Washington University in Saint Louis, Saint Louis, MO, USA

Overview A clear understanding of hepatic anatomy is critical to the planning and conduct of liver surgery. The branching pattern of the hepatic artery and bile ducts within the liver is regular and virtually identical to each other, unlike for the portal vein. Consequently the Brisbane 2000 Terminology of Hepatic Anatomy and Resections of the International Hepatobiliary Pancreatic Association (IHBPA) [1] (Members of the Committee of the Brisbane Classification: Strasberg SM, Belghiti J, Clavien PA, Gadzijev E, Garden JO, Lau W, Makuuchi M, Strong RW) is based on the anatomy of the hepatic artery and bile duct. The IHBPA terminology has now been adopted by most major textbooks of hepatic anatomy and surgery. In this chapter the most common anatomic pattern is referred to as the “prevailing pattern.” All other patterns are “anomalies” and they need not be rare.

Anatomic basis of the Brisbane 2000 Terminology: Division of the liver based on the hepatic artery and bile ducts The primary (first-order) division of the proper hepatic artery is into the right and left hepatic arteries (Figure 2.1). These branches supply arterial blood to the right and left hemilivers or livers (Figure 2.2). The plane between two distinct zones of vascular supply is called a watershed. The watershed of the first-order division intersects the gallbladder fossa and the fossa for the inferior vena cava (Figure 2.2). It is called the mid-plane of the liver. The second-order division (Figures 2.1 and 2.3) of the hepatic artery is into four sectional arteries, two on the right and two on the left (Figure 2.1). On the right side, the right anterior sectional artery and the right posterior sectional hepatic artery supply arterial blood to the right anterior section and the right posterior section (Figure 2.3). The plane between these sections is the right intersectional plane, which does not have

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

any markings on the surface of the liver to indicate its position. On the left, the left medial sectional hepatic artery and a left lateral sectional hepatic artery (Figure 2.1) supply arterial blood to the left medial section and the left lateral section (Figure 2.3). The plane between these sections is the left intersectional plane, which does have surface markings indicating its position. These are the umbilical fissure and the line of attachment of the falciform ligament to the anterior surface of the liver. The third-order division of the hepatic artery is into segmental arteries (Figure 2.1) and divides the liver into seven segments (segments (Sg) 2–8) (Figures 2.1 and 2.4). Each of the segments has its own feeding segmental artery. The left lateral section is divided into Sg 2 and Sg 3. The pattern of ramification of vessels within the left medial section does not permit subdivision of this section into segments, each with its own arterial blood supply. Therefore, the right medial section and Sg 4 are synonymous. However, Sg 4 is arbitrarily divided into superior (4a) and inferior (4b) parts without an exact anatomic plane of separation based on internal ramification of vessels. Note then that Sg 4 and the right medial section are identical. The right anterior section is divided into two segments, Sg 5 and Sg 8. The right posterior section is divided into Sg 6 and Sg 7. The planes between segments are referred to as intersegmental planes. The ramification of the bile ducts is identical to that described for the arteries and the zones of the liver drained by the ducts are identical to the zones supplied by the respective arteries. Sg 1 (caudate lobe) is a distinct portion of the liver, separate from the right and left hemilivers (Figure 2.5). It consists of three parts, the bulbous left part (Spiegelian lobe), hugging the left side of the vena cava and readily visible through the lesser omentum; the paracaval portion, anterior to the vena cava; and the caudate process, on the right, merging indistinctly with the right hemiliver. It lies posterior to the hilum and the portal veins and its upper extent is limited by the hepatic veins, which lie anterior and superior to the paracaval portion of the caudate lobe [2, 3] (Figure 2.5). It receives vascular supply from both right and left hepatic arteries (and portal veins). Caudate bile ducts drain

11

SECTION 1

Introduction into both right and left hepatic ducts [2, 3]. The caudate lobe is drained by several short caudate veins that enter the inferior vena cava (IVC) directly from the caudate lobe. Their number and size is variable. On occasion caudate veins are quite short and wide, and therefore must be isolated and divided cautiously. Commonly, these veins enter the IVC on either side of the midplane of the vessel, an anatomic feature which normally allows passage of a clamp behind the liver on the surface of the IVC without encountering the caudate veins.

8 7

3

4 e c d

2 f

B A

Terminology of liver resections Terminology of resections is based upon anatomic terminology. Resection of one side of the liver is called a hepatectomy or hemihepatectomy (Figure 2.2). Resection of the right side of the liver is a right hepatectomy or hemihepatectomy, and resection of the left side of the liver is a left hemihepatectomy or hepatectomy. Resection of a liver section is referred to as a sectionectomy (Figure 2.3). Resection of the liver to the left side of the umbilical fissure is referred to as a left lateral sectionectomy. The other sectionectomies are named accordingly: left medial sectionectomy, right anterior sectionectomy, and right posterior sectionectomy. Resection of three contiguous sections is referred to as a trisectionectomy. When the sections are right posterior section, right anterior section, and right medial section (right liver plus Sg 4), this is referred to as a right trisectionectomy (Figure 2.3). Similarly, resection of the two sections of the left hemiliver plus the right anterior section is referred to as a left trisectionectomy (Figure 2.3). Resection of one of the numbered segments is referred to as a segmentectomy (Figure 2.4). Resection of the caudate lobe can be referred to as a caudate lobectomy or resection of Sg 1. It is always appropriate to refer to a resection by the numbered segments. For instance, it would be appropriate to call a left lateral sectionectomy a resection of Sg 2 and Sg 3.

5 6

Figure 2.1 Prevailing pattern of branching of the hepatic artery. The proper hepatic divides into the right (A) and left (B) hepatic arteries, which supply the right and left hemilivers (see Figure 2.2) respectively. The right hepatic artery divides into anterior (c) and posterior (d) sectional arteries, which supply the right anterior and right posterior sections (see Figure 2.3). The right anterior sectional artery divides into two segmental arteries, which supply Sg 5 and Sg 8 (see Figure 2.4) and the right posterior sectional artery divides into arteries that supply Sg 6 and Sg 7. The left hepatic artery (B) also divides into two sectional arteries, the left medial (e) and left lateral (f). The former supplies the left medial section (see Figure 2.3) also called Sg 4, while the latter supplies the left lateral section. The left lateral sectional artery divides into segmental arteries to Sg 2 and Sg 3 (see Figure 2.4). The caudate lobe (Sg 1 and Sg 9) are supplied by branches from A and B. Bile duct anatomy and nomenclature are similar to those of the hepatic artery. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

Anatomic term

Couinaud segments referred to

Term for surgical resection

Diagram (pertinent area is shaded) 2

Right hemiliver or right liver

Sg 5–8 (±Sg 1)

Right hepatectomy or right hemihepatectomy (stipulate ±Sg 1)

8

4

7 6

3

5

2 Left hemiliver or left liver

12

Sg 2–4 (±Sg 1)

Left hepatectomy or left hemihepatectomy (stipulate ±Sg 1)

8 7 6

5

4

3

Figure 2.2 Nomenclature for first-order division anatomy (hemilivers) and resections. The border or watershed of the first-order division which separates the two hemilivers is a plane which intersects the gallbladder fossa and the fossa for the inferior vena cava (IVC) and is called the midplane of the liver. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

CHAPTER 2

Anatomic term

Couinaud segments referred to

Hepatic Anatomy and Terminology

Term for surgical resection

Diagram (pertinent area is shaded) 2

Right anterior section

Sg 5,8

Add (-ectomy) to any of the anatomic terms as in right anterior sectionectomy

8 7 6

Right posterior section

Sg 6,7

Right posterior sectionectomy

Sg 4

Left lateral section

Sg 2,3

(a)

Figure 2.3 Nomenclature for (a) secondorder division anatomy (sections, based on bile ducts and hepatic artery) and (b) other “sectional” liver resections, including extended resections. The borders or watersheds of the sections are planes referred to as the right and left intersectional planes. The left intersectional plane passes through the umbilical fissure and the attachment of the falciform ligament. There is no surface marking on the right intersectional plane. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

Sg 4–8 (±Sg 1)

Sg 2,3,4,5,8 (±Sg 1)

(b)

Surgical anatomy for liver resections Hepatic arteries In the prevailing anatomic pattern, the celiac artery terminates by dividing into common hepatic and splenic arteries. Rarely the hepatic artery arises directly from the aorta (Figure 2.6). The common hepatic artery runs for 2–3 cm anteriorly and to the right to ramify into gastroduodenal and proper hepatic arteries. The proper hepatic artery enters the hepatoduodenal ligament, normally runs for 2–3 cm along the left side of the common bile duct, and terminates by

Left medial sectionectomy or Resection segment 4 (also see third order) or Segmentectomy 4 (also see third order)

Left lateral sectionectomy or Bisegmentectomy 2,3 (also see third order)

2 3

4

2 3

4

2 3

4

2 3

4

2 3

5

8 7 5

8 7 6

Right trisectionectomy (preferred term) or Extended right hepatectomy 7 or Extended right hemihepatectomy 6 (stipulate ±Sg 1) Left trisectionectomy (preferred term) or Extended left hepatectomy or Extended left hemihepatectomy (stipulate ±Sg 1)

4

7

6

5

8 5

8 7 6

3

5

8

6 Left medial section

4

5

dividing into the right and left hepatic arteries, the right artery immediately passing behind the common hepatic duct. The four sectional arteries arise from the right and left arteries 1–2 cm from the liver. The preceding description is the prevailing pattern but variations are very common (Figure 2.7). The surgeon is wise not to make assumptions regarding hepatic arteries based on size or position, but to rely instead on exposure, trial occlusions, and radiologic support. “Replaced” arteries are surgically important anomalies. “Replaced” means that the artery supplying a particular part of the liver is in an unusual location and also that it provides

13

SECTION 1

Introduction

Anatomic term

Couinaud segments referred to

Term for surgical resection

Sg 1–8

Any one of Sg 1–8

Segmentectomy (e.g. segmentectomy 6)

Diagram (pertinent area is shaded) 2 8

4

7 6

3

5

2 Two contiguous segments

Any two of Sg 1–8 in continuity

Bisegmentectomy (e.g. bisegmentectomy 5,6)

8 7 6

5

4

3

Figure 2.4 Nomenclature for third-order division anatomy (segments) and resections. The borders or watersheds of the segments are planes referred to as intersegmental planes. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

MHV

IVC

LHV

RHV

SL PC CP LPV

RPV

PV

IVC

Figure 2.5 Schematic representation of the anatomy of the caudate lobe. The caudate lobe consists of three parts, the caudate process (CP) on the right, the paracaval portion anterior to the vena cava (PC), and the bulbous left part (Spiegelian lobe, SL). IVC, inferior vena cava; PV, portal vein; RHV, MHV, LHV, right hepatic, middle hepatic and left hepatic veins, respectively; RPV, LPV, left and right portal vein, respectively (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

the sole blood supply to that part of the liver. “Aberrant” means the structure is in an unusual location. While the definition of “aberrant” does not state whether the structure provides sole supply, it is usually considered to be synonymous with “replaced” in respect to these arteries. “Accessory” refers to an artery which is additional, i.e. is present in addition to the normal structure and as a result is not the

14

Figure 2.6 CT scan of patient with absent celiac artery. Hepatic artery (HA), splenic artery (SA) (labeled “b” in sagittal view, inset) and left gastric artery (labeled “a” in sagittal view, inset) arise independently from the aorta. Superior mesenteric artery is labeled “c” in inset. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

sole supply to a volume. Consequently, ligation of an accessory artery does not cause ischemia. Approximately 25% of patients have a replaced hepatic artery. A replaced right hepatic artery arises from the superior mesenteric artery and runs from left-to-right behind the lower end of the common bile duct to emerge and course on its right posterior border. It may supply a segment, section, or the entire right hemiliver. Rarely its supplies the whole liver and then it is called a replaced hepatic artery. A replaced left hepatic artery arises from the left gastric artery and courses in the lesser omentum with vagal branches to the liver. It may also supply a segment, section, hemiliver, or very rarely the whole liver. Sometimes left hepatic arteries arising from the left gastric artery are actually accessory, and exist in conjunction with normally situated left hepatic

CHAPTER 2

arteries. Replaced arteries may confer an advantage during surgery. For instance, when a replaced left artery supplies the left lateral section, it is possible to resect the entire proper hepatic artery when performing a right trisectionectomy for hilar cholangiocarcinoma. In performing hepatectomies by the standard technique of isolating individual structures instead of pedicles, it is necessary to correctly identify the particular artery(ies) supplying the volume of liver to be resected. A helpful rule is

Figure 2.7 A dangerous anomaly. In this patient the right hepatic artery (RHA) came off the gastroduodenal artery (GDA). The common hepatic artery (CHA) divided into the left hepatic artery (LHA) and the GDA. There was no proper hepatic artery. The LHA could easily be mistaken for the proper hepatic artery. Ligation of the GDA could lead to arterial devascularization of the right liver. Note early branching of the RHA into anterior and posterior sectional branches. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

B8 B7

Right posterior sectional bile duct Right anterior sectional bile duct Right bile duct

B8

B7

Correct

Hepatic Anatomy and Terminology

that an artery located to the right side of the bile duct always supplies the right side of the liver, but arteries found on the left side of the bile duct may supply either side of the liver. Therefore, when using the individual vessel ligation method, it is important to determine the position of the common hepatic duct.

Bile ducts Prevailing pattern and variations of bile ducts draining the right hemiliver Normally the right hepatic duct is a short structure with only about 1 cm in an extrahepatic position. The prevailing pattern of bile duct drainage is shown in Figure 2.8a. The segmental ducts from Sg 6 and Sg 7 (called B6 and B7) unite to form the right posterior sectional bile duct and the segmental ducts from Sg 5 and Sg 8 (B5 and B8) unite to form the right anterior sectional bile duct (Figure 2.8a). The sectional ducts unite to form the right hepatic duct, which unites with the left hepatic duct at the confluence to form the common hepatic duct. There are two important sets of biliary anomalies on the right side of the liver. In the first, a right sectional bile duct joins the left hepatic duct. This is a common anomaly. The right posterior sectional duct inserts into the left hepatic duct in 20% of individuals (Figure 2.8b) and the right anterior bile duct does so in 6% (Figure 2.8c). A right sectional bile duct inserting into the left hepatic duct may be injured during left hepatectomy if the left duct is divided close to the midplane of the liver (Figure 2.8b, “incorrect”). The left hepatic duct should be divided close to the umbilical fissure to avoid this injury (Figure 2.8b, “correct”). The second important anomaly is insertion of a right bile duct into the biliary tree at a lower level than the prevailing site of confluence. Low union may affect the right hepatic duct, a sectional right duct (usually the anterior one), a segmental duct, or a subsegmental duct. The duct will unite with the common hepatic duct well below the prevailing site of confluence in about 2% of individuals. In some it first

B8 B7

Incorrect

B6 B5

B6

(a)

(b)

B5

B6

(c)

B5

(d)

Figure 2.8 Variations in formation of the right hepatic ducts. (a) Prevailing pattern and (b–d) some variations of bile ducts draining the right hemiliver (see text). (b,c) Separate entry of right anterior and right posterior sectional ducts (no right duct). (d) Shifting of entry of a right bile duct inferiorly. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

15

SECTION 1

Introduction

unites with the cystic duct and then with the common hepatic duct. The right posterior sectional duct normally hooks over the origin of the right anterior sectional portal vein (“Hjortsjo’s crook”) [4], where it is in danger of being injured if the right anterior sectional pedicle is clamped too close to its origin (Figure 2.9).

Prevailing pattern and important variations of bile ducts draining the left hemiliver The prevailing pattern of bile duct drainage from the left liver is shown in Figure 2.10a, and is present in only 30% of individuals, i.e. anomalous patterns are present in the majority of individuals. In the prevailing pattern the segmental ducts from Sg 2 and Sg 3 (B2 and B3) unite to form the left lateral sectional bile duct. This duct passes behind the umbilical portion of the portal vein and unites with the duct from Sg 4 (B4) (also called the left medial sectional duct RASBD

Hjortsjo’s crook

RPSBD

Figure 2.9 Hjortsjo’s crook. Note that the right posterior sectional bile duct (RPSBD) crosses the origin of the right anterior sectional portal vein. RASBD, right anterior sectional bile duct. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

B4

B4

B3

Prevailing pattern of bile ducts draining the caudate lobe (Sg 1) Two to three caudate ducts normally enter the biliary tree. Their orifices are usually located posteriorly on the left duct, right duct, or right posterior sectional duct [2, 3].

B3 B4

B2 Left lateral sectional bile duct

B4

B3

Combined B3, B4 duct

B4

B3 B2

B2

B2 Left lateral sectional bile duct

Left lateral sectional duct

Left bile duct

(a)

since section and segment are synonymous for this volume of liver). The union of these ducts to form the left hepatic duct occurs about one-third of the distance between the umbilical fissure and the confluence of left and right bile ducts at the midplane of the liver. The left hepatic duct continues from this point for 2–3 cm along the base of Sg 4 to its termination. Note that it is in an extrahepatic position and that it has a much longer extrahepatic course than the right bile duct. The extrahepatic position of the left hepatic duct is a key anatomic feature, which makes this section of duct the prime site for high biliary–enteric anastomosis. The left hepatic duct runs at a variable angle. In some individuals it is almost horizontal but in others it runs sharply upward. It is much easier to expose a long length of duct in the former type. The major anomalies of the left ductal system involve variations in site of insertion of B4 (Figure 2.10b), multiple ducts coming from B4 (Figure 2.10c), and primary union of B3 and B4 with subsequent union of B2 (Figure 2.10d). B4 may join the left lateral sectional duct to the left or right of its point of union in the prevailing pattern (Figure 2.10b); in the former case the insertion of B4 is at the umbilical fissure, and in the latter it may occur at any place to the right of the usual point of insertion up to the site where the left lateral sectional duct unites with the right hepatic duct. Rarely the left lateral sectional duct and the duct to B4 do not unite before a confluence with the right hepatic duct. In these cases the confluence of the three ducts forms the common hepatic duct and there is no left hepatic duct. The bile duct to Sg 3 has been used to perform biliary bypass and can be isolated by following the superior surface of the ligamentum teres to the portal pedicle for Sg 3. The technique is less commonly used now that internal endoscopic bypass has been developed.

Left hepatic duct

(b)

(c)

(d)

Figure 2.10 Variations in formation of the left hepatic ducts. (a) Prevailing pattern and (b–d) some variations of bile ducts draining the left hemiliver. (b) Insertion of B4 shifted to right or left. (c) Multiple ducts draining B4. (d) B3, B4 form a common channel before insertion of B2. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

16

CHAPTER 2

Portal veins The portal vein divisions on the right side of the liver correspond exactly to those of the hepatic artery and bile duct, and they supply the same hepatic volumes. There is a right portal vein which supplies the entire right hemiliver and it divides into two sectional portal veins and four segmental portal veins (Figure 2.11) supplying the same sections and segments as the respective right hepatic arteries. On the left side of the liver, however, the left portal vein is quite unusual because of the fact that its structure was adapted to function in utero as a conduit between the umbilical vein and the ductus venosus, whereas postnatally the direction of flow is reversed. The left portal vein consists of a horizontal or transverse portion, which is located under Sg 4, and a vertical part or umbilical portion, located in the umbilical fissure (Figure 2.11). Unlike the right portal vein, neither portion of the left portal vein actually enters the liver substance, but rather lies directly on the surface. The umbilical portion is usually hidden by a bridge of tissue passing between left medial and lateral sections. This bridge of liver tissue may be as thick as 2 cm or only be a fibrous band. The junction of the transverse and umbilical portions of the left portal vein is marked by the attachment of a stout cord – the ligamentum venosum. This structure, the remnant of the fetal ductus venosus, runs in the groove between the left lateral section and the caudate lobe, and attaches to the left hepatic vein–IVC junction.

8

Hepatic Anatomy and Terminology

The transverse portion of the left portal vein sends no or only a few small branches to Sg 4. Large branches from the portal vein to the left liver arise exclusively beyond the attachment of the ligamentum venosum, i.e. from the umbilical part of the vein [5]. These branches come off both sides of the vein; those arising from the right side pass into Sg 4 and those from the left supply into Sg 2 and Sg 3. There is usually only one branch to Sg 2 and one to Sg 3, but often there is more than one branch to Sg 4. The left portal vein terminates in the ligamentum teres at the free edge of the left liver. Note that the umbilical portion of the left portal vein has a unique pattern of ramification with multiple branches emanating from its sides as it narrows to terminate blindly in the ligamentum teres (Figures 2.11 and 2.12). This unusual branching pattern of the umbilical portion of the left portal vein represents both an opportunity and a danger for the hepatic surgeon. The portal vein branches to Sg 4 may be isolated in the umbilical fissure on the right side of the umbilical portion of the left portal vein. The veins here become associated with the bile ducts and the arteries and enter Sg 4 within a segmental fibrous sheath. Isolation of these structures in this location may provide an extra tissue margin when resecting a tumor in Sg 4 that impinges upon the umbilical fissure. Also, by dividing these branches, the portal vein may be rolled to the left to allow exposure of an extra length of left lateral sectional bile ducts in operations for hilar cholangiocarcinoma. The danger of dissection

LT

7

3 4 2

U c d

T A LV

5 6

Figure 2.11 Ramification of the portal vein in the liver. The portal vein divides into right (A) and left (T) branches. The right portal vein divides into anterior (c) and posterior (d) sectional arteries. The branches in the right liver correspond to those of the hepatic artery and bile duct (see Figure 2.1). The branching pattern on the left is unique. The left portal vein has transverse (T) and umbilical portions (U). The transition point between the two parts is marked by the attachment of the ligamentum venosum (LV). All major branches come off the umbilical portion (see text). The vein ends blindly in the ligamentum teres (LT). (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

Figure 2.12 Ramification of the left portal vein as seen on computed tomography. Note the branches to Sg 2–4 and the ligamentum teres (LT). The arrowhead points to the groove between the left lateral section and the caudate lobe. This is also the site of origin of the ligamentum venosum, where the transverse portion of the portal vein becomes the umbilical portion of the vein, proving conclusively that the branch to Sg 2 is not part of a terminal division of the transverse portion of the vein as might be concluded from cast studies. (See also ref. [5]). (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

17

SECTION 1

Introduction

in the umbilical fissure is that injury to the portal vein in this position could deprive Sg 2 and Sg 3 of portal vein supply, as well as Sg 4. It is also is possible to isolate the portal vein branches going into Sg 2 and Sg 3 in the umbilical fissure in order to extend a margin when resecting a tumor in the left lateral section. In order to access the portal vein in the umbilical fissure it is usually necessary to divide the bridge of liver tissue, between the left medial and lateral sections. This is done by passing a blunt instrument behind the bridge before dividing it, usually with cautery. Note that arteries and bile ducts passing to the left lateral section are in danger of being injured as the most posterior–superior portion of the bridge is isolated. Although the anatomy of the portal vein is unusual, it is uncommon to have variations. The most common variation is absence of the right portal vein. In these cases the right posterior and right anterior sectional veins originate independently from the main portal vein; the anterior sectional vein is not readily visible because of it high position in the porta hepatis. An unsuspecting surgeon may divide the posterior sectional vein thinking that it is the right portal vein and become confused when the anterior sectional vein is come upon during hepatic transection. Rarely there is no extrahepatic left portal vein. Failure to recognize this anomaly may lead to a catastrophic complication. The apparent right vein is really the main portal vein, a structure which enters the liver, gives off branches to the right liver, and then loops back within the liver substance

to supply the left side (Figure 2.13). The vein looks like a right vein in terms of position but it is larger. Transection results in total portal vein disconnection from the liver. This anomaly should always be searched for on computed tomography (CT) scans as right hepatectomy is not usually possible when it is present. The presence of the umbilical portion of the left vein in the umbilical fissure on CT scan precludes the presence of this problem.

Hepatic veins and liver resection (Figure 2.14) Normally there are three large hepatic veins. Respectively, these run in the midplane of the liver (middle hepatic vein), the right intersectional plane (right hepatic vein), and the left intersectional plane (left hepatic vein). The left hepatic vein actually begins in the intersegmental plane between Sg 2 and Sg 3, and travels in that plane for most of its length. It becomes quite a large vein even in that location. About 1 cm from its termination in the IVC, it enters the left intersectional plane, where it receives the “umbilical vein” from Sg 4 (Figures 2.14–2.16). The latter tributary of the left hepatic vein normally drains the most leftward part of Sg 4 [6, 7]. (It is important not to confuse the “umbilical vein” with the “umbilical portion of the left portal vein.”) The length of the left hepatic vein in the left intersectional plane is short. It lies between the point where it receives the umbilical vein and the IVC, a distance of only about 1–2 cm (see both the 3D radiograph in Figure 2.15 and the operative picture in Figure 2.16). The left and middle hepatic veins

IVC R

L UV

7 8

M

2

4

5 3 6

Figure 2.13 Absent extrahepatic left portal vein, a rare and very dangerous anomaly. Three-dimensional reconstruction of CT scan. Note that main portal vein (MPV) enters the right liver, gives off the right posterior sectional portal vein (RPSPV) and some branches to the right anterior section, and then proceeds to the left as an internal left portal vein (LPV). (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

18

Figure 2.14 Hepatic veins. There are normally three hepatic veins: right (R), middle (M), and left (L). Note the segments drained. The umbilical vein (UV) normally drains part of Sg 4 into the left hepatic vein. The latter is proof that the terminal portion of the left vein lies in the intersectional plane of the left liver. IVC, inferior vena cava. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

CHAPTER 2

Figure 2.15 Three-dimensional reconstruction of CT scan showing prevailing pattern of the umbilical vein (UV). The UV receives tributaries form Sg 4 and Sg 3 and travels in the plane of the umbilical fissure (left intersectional plane) to join the left hepatic vein (LPV). The LPV continues in the same plane for 1–2 cm before joining the middle hepatic vein and entering the IVC. This shows that a major hepatic vein can lie in the same plane as a major portal vein (left portal vein which also lies in this plane; see also Figure 2.16). The pattern shown in this figure is the prevailing pattern, but the UV is not usually this prominent. RHV, MHV, LHV, right hepatic, middle hepatic and left hepatic veins, respectively; IVC, inferior vena cava. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

Figure 2.16 Operative photograph at completion of left lateral sectionectomy in which the side of left hepatic vein (LHV) was cleared. Note that the terminal 2 cm of the LHV lie in the same plane as the umbilical portion of the left portal vein (UPLPV). The umbilical vein (UV) from Sg 4 can be seen entering the side of the LHV. HPL, hepatoduodenal ligament; ALHA, aberrant left hepatic artery off the left gastric artery; RL, round ligament; IVC, inferior vena cava. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

Hepatic Anatomy and Terminology

usually fuse at a distance of about 1 cm from the IVC, so that when viewed from within the IVC there are only two hepatic vein openings, the right and the combined left/middle vein openings. Rarely hepatic veins join the IVC above the diaphragm. Note that the termination of the left hepatic vein lies in the plane of the umbilical fissure (left intersectional plane) at the point it receives tributaries from Sg 4. This is an apparent contradiction of the contention of Couinaud regarding separation of planes of portal and hepatic veins and another example of the unusual venous anatomy on the left side of the liver. In about 10% of individuals there is more than one large right hepatic vein. In addition to the right superior hepatic vein (normally called the right hepatic vein), which enters the IVC just below the level of the diaphragm, there is a right inferior hepatic vein which enters the IVC 5–6 cm below this level. In the presence of this vein resections of Sg 7 and Sg 8 may be performed, including resection of the right superior vein without compromising the venous drainage of Sg 5 and Sg 6. As noted above, the caudate lobe is drained by its own veins – several short veins that enter the IVC directly from the caudate lobe. When performing a classical right hepatectomy, caudate veins are divided in the preliminary portion of the dissection. As dissection moves up the anterior surface of the vena cava to isolate the right hepatic vein, a bridge of tissue lateral to the IVC is encountered, referred to as the “inferior vena caval ligament” [7]. It connects the posterior portion of the right liver to the caudate lobe behind the IVC. This bridge of tissue usually consists of fibrous tissue, but occasionally is a bridge of liver. It limits exposure of the right side of the IVC at a point just below the right hepatic vein and must be divided in order to isolate the right hepatic vein. This must be done with care as the ligament may contain a large vein and forceful dissection of the ligament may also result in injury to the right lateral side of the IVC. Isolation of the right hepatic vein is also aided by clearing the areolar tissue between the right and middle hepatic veins down to the level of the IVC when exposing these veins from above. Another approach to right hepatectomy is to leave division of the caudate and right hepatic veins until after the liver is transected. In this case a clamp may be passed up along the anterior surface of the vena from below to emerge between the right and middle hepatic veins. By passing an umbilical tape the liver may be hung to facilitate transection (“hanging maneuver”) [8]. This is possible since caudate veins usually lie lateral to the midplane of the vena cava, as noted above. The left and middle veins can also be isolated prior to division of the liver. There are several ways to achieve this anatomically. One method is to divide all the caudate veins as well as the right hepatic vein. This exposes the entire anterior surface of the retrohepatic vena cava and leaves the liver attached to the vena cava only by the middle and left

19

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Introduction

hepatic veins, which are then easily isolated. This is suitable when performing a right hepatectomy or extended right hepatectomy, especially when the caudate lobe is also to be resected. The advantage of having control of these veins during operations on the right liver is that total vascular occlusion is possible without occlusion of the IVC, and hemodynamically the effect is not much different from occlusion of the main portal pedicle alone (Pringle maneuver). A different anatomic approach to isolation of the left and middle hepatic veins is required when performing a left hepatectomy since the right hepatic vein is conserved (Figure 2.17). The veins may be isolated from the left side by dividing the ligamentum venosum where it attaches to the left hepatic vein, then dividing the peritoneum at the superior tip of the caudate lobe and gently passing an instrument on the anterior surface of the vena cava to emerge between the middle and right veins (Figure 2.17) and/or between the left and middle veins. Again care needs to be applied when performing this maneuver in order to avoid injury to the structures. Isolation of the vena cava above and below the hepatic veins is also a technique that should be in the armamentarium of surgeons performing major hepatic resections, although it is not required routinely. Isolation of the vena

Sg 8 Sg 4

cava superior to the hepatic veins is done by dividing the left triangular ligament and the lesser omentum, being careful to first look for a replaced left hepatic artery. Next the peritoneum on the bulbous superior border of the caudate lobe is divided and a finger is passed behind the vena cava to come out just inferior to the crus of the diaphragm. Isolation of the vena cava below the liver is more straightforward but awareness of the position of the adrenal vein is needed. Finally, the surgeon should be aware that during transection of the liver large veins will be encountered in certain planes of transection. For instance, in its passage along the midplane, the middle hepatic vein usually receives two large tributaries, one from Sg 5 inferiorly and the other from Sg 8 superiorly (Figure 2.14). Both are routinely encountered in performing right hepatectomy. The venous drainage of the right side of the liver is variable and additional large veins, including one from Sg 6, may also enter the middle hepatic vein.

Plate/sheath system of the liver The plate/sheath system was originally described by Waleaus and Glisson in the 17th century and was clarified in modern times by Couinaud [3]. Understanding this complicated anatomy is essential to performing pedicle isolation. The analogy of a shirt with the front cut away to leave only the back and the sleeves is helpful (Figure 2.18 inset) [9]. If the shirt were made of fibrous tissue, its back would be a plate and the sleeves would be sheaths. The true plate/sheath

LHV MHV

Sheath

RHV

LV

Sheath Plate 4

Sg 1

IVC

Cystic

Umbilical 3

4 Hilar 8 Figure 2.17 Isolation of left and middle hepatic veins (LHV/MHV). Isolation of these veins may be accomplished from the left side of the liver by opening the triangular space between the left hepatic vein, the inferior vena cava (IVC) and the underside of Sg 4. This is facilitated by dividing the ligamentum venosum and dividing the peritoneum at the superior border of the caudate. Gentle dissection in this space on the IVC with a blunt clamp is aimed at the space between the right hepatic vein (RHV) and MHV to isolate the MHV and LHV. LV, ligamentum venosum. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

20

2

7 5

6 Arantian 1

1

Figure 2.18 Plate/sheath system of the liver with inset showing a schematic of a plate with two sheaths. (Redrawn with permission from the Journal of the American College of Surgeons.)

CHAPTER 2

Hepatic Anatomy and Terminology

Right anterior sectional pedicle Figure 2.19 Isolation of right portal pedicle and sectional pedicles using the technique of dissection on the surface of pedicles. No inflow occlusion or separate hepatotomies are used (see ref. [10]). The umbilical tape in the upper right of the photograph is around the bridge of liver tissue over the umbilical fissure. (Reproduced with permission from the Journal of the American College of Surgeons.)

Right posterior sectional pedicle

system is more complex. There are four plates (hilar, cystic, umbilical, and arantian) and several sheaths [3] (Figure 2.18). The hilar plate is the most important plate in liver surgery. It is a mostly flat structure, which lies principally in the coronal plane, posterior to the main bilo-vascular structures in the porta hepatis. However, its upper border is curved, so that it has the shape of a toboggan when viewed in the sagittal plane (Figure 2.18). This upper curved edge lies superior to the right and left bile ducts, the most superior structures in the porta hepatis. It is this taut, firm, upper curved edge of the hilar plate which is dissected free from the underside of the liver when “lowering the hilar plate.” The sheath of the right portal pedicle extends off the hilar plate like a sleeve in the “shirt” analogy. It carries into the liver surrounding the portal structures, i.e. portal vein hepatic artery and bile duct. The combined structure consisting of a hepatic artery, bile duct, and portal vein surrounded by its fibrous sheath is referred to as a “portal pedicle.” As the right portal pedicle enters the liver, it divides into a right anterior and right posterior portal pedicle supplying the respective sections and then into segmental pedicles supplying the four segments. On the left side, only the segmental structures are sheathed. There is no sheathed main portal pedicle because the main portal vein, proper hepatic artery, and common hepatic duct are not close enough to the liver to be enclosed in a sheath. The cystic plate is the ovoid fibrous sheet on which the gallbladder lies (Figure 2.18). In its posterior extent the cystic plate narrows to become a stout cord which attaches to the anterior surface of the sheath of the right portal pedicle. The latter is a point of anatomic importance for the surgeon wishing to expose the anterior surface of the right portal pedicle, because this cord must be divided to do so, as we have described [10]. The other plates are the umbilical and arantian, which underlie the umbilical portion of the left portal vein and the ligamentum venosum, respectively (Figure 2.18). The other sheaths carry segmental bilo-vascular pedicles of the left liver and caudate lobe.

In performing a right hepatectomy, isolation of the right portal pedicle can be performed by making hepatotomies above the right portal pedicle in Sg 4 and in the gallbladder fossa after removing the gallbladder. A finger is passed through the hepatotomy to isolate the right portal pedicle. This technique usually requires inflow occlusion. It can also be done without inflow occlusion by lowering the hilar plate and coming around the right portal pedicle directly on its surface, as we have recently described (Figure 2.19) [9]. It is advisable to divide caudate veins in the area below the vena caval ligament before performing pedicle isolation, since hemorrhage from these veins can be considerable if they are injured during isolation of the right portal pedicle. The advantage of pedicle isolation over isolation of individual vessels and the bile duct is that true anatomic sectional and segmental resections require isolation of pedicles (Figure 2.18) [9]. Furthermore, pedicle isolation is much easier to do laparoscopically than by individual structure isolation.

Liver capsule and attachments The liver is encased in a thin fibrous capsule which covers the entire organ except for a large bare area posteriorly where the organ is in contact with the IVC and with the diaphragm to the right of the IVC. The bare area stretches anterosuperiorly to include the termination of the three hepatic veins and ends in a point anterior to the veins. This point corresponds to the highest point of attachment of the falciform ligament. The limit of the bare area, where the peritoneum passes from the body wall to the liver surface, is called the coronary ligament. It is one of three structures that connect the liver to the abdominal wall “dorsally,” the other two being the right and left triangular ligaments. The liver also has another bare area, best thought of as a bare crease, where the hepatoduodenal ligament and the lesser omentum attach on the “ventral” surface. It is through this crease that the portal structures enter the liver at the hilum (hilum means “a crease on a seed”).

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Introduction

The other ligamentous structures of interest to surgeons are the ligamentum teres, falciform ligament, and ligamentum venosum. The ligamentum teres (teres means “round”) is the obliterated left umbilical vein and it runs in the free edge of the falciform ligament from the umbilicus to the termination of the umbilical portion of the left portal vein. The falciform (falciform means “scythe shaped”) is the filmy fold that runs between the anterior abdominal wall above the umbilicus and attaches to the anterior surface of the liver between the left medial and left lateral sections. The ligamentum venosum marks the transition from the transverse portion of the left portal vein to the umbilical portion of the vein. It runs from that point to insert at the junction of the left hepatic vein and IVC. Note that its origin on the left portal vein is 1–2 cm proximal to the takeoff of the vein to Sg 2, which proves that the vein to Sg 2 is a branch of the umbilical portion of the portal vein [5] and not a terminal branch of the horizontal portion of the vein as claimed by Couinaud. Its surgical importance lies in the isolation of the left and middle hepatic veins as described above.

Surface anatomy Numerous terms for surface anatomy exist. They are of minimal surgical importance. Since the term “lobe” has been used in different ways by various anatomists and surgeons, it is best avoided except in reference to the caudate lobe. Fissure and scissure or scissura are similarly confusing terms since they apply only to clefts in casts of the liver. The shape of the liver is variable, especially the right liver, which may have a long inferior extension (Riedel’s lobe). Consideration of liver shape is important in determining whether all hepatic ducts are seen on a cholangiogram. Using CT images as a guide, and thereby reconciling the cholangiogram to the shape of the liver, is helpful [10].

Pathologic conditions Pathologic conditions may distort or alter the position of normal hepatic structures. Tumors may push vessels so that they are stretched and curved over the surface of the tumor, narrowing or occluding them by direct pressure. Tumors may partially or completely occlude vessels by mural invasion, inducing bland thrombi, or entering the lumen and producing tumor thrombi. They may cause bile ducts to dilate to a size many times normal. Atrophy of a liver volume will be induced by processes that occlude either the portal vein or bile duct. Since the liver will undergo hyperplasia to maintain a constant volume of liver cells, atrophy of one part of the liver is usually accompanied by growth of another. If the right portal vein is occluded by a tumor, the right liver will atrophy and the left liver will grow. When seen from below, this process will exert a counter-clockwise rotational effect on the porta hepatis, rotating the bile duct posteriorly, the hepatic artery to the right, and the portal vein to the left and anteriorly.

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Gallbladder and extrahepatic bile ducts and arteries Gallbladder The gallbladder lies on the cystic plate (see above). The edge of the gallbladder forms one side of the hepatocystic triangle. The other two sides are the right side of the common hepatic duct and the liver. Eponyms covering this anatomy (e.g. Calot and Moosman) are confusing and should be abandoned. The hepatocystic triangle contains the cystic artery, cystic node, and a portion of the right hepatic artery, as well as fat and fibrous tissue. Clearance of this triangle along with isolation of the cystic duct and elevation of the base of the gallbladder off the lower portion of the cystic plate gives the “critical view of safety” that we have described for identification of the cystic structures during laparoscopic cholecystectomy [11]. The following are anomalies of importance to the surgeon: • Agenesis of the gallbladder. Agenesis is rare (1 in 8000 births) and can be difficult to recognize. An ultrasonographer may describe a “shrunken” gallbladder. When agenesis is suspected it may be confirmed by axial imaging. If doubt remains, laparoscopy is definitive. • Double gallbladder. This is also a very rare anomaly but can be the cause of persistent symptoms after resection of one gallbladder. A gallbladder may also be bifid, which usually does not cause symptoms, or have an hourglass constriction, which may cause symptoms due to obstruction of the upper segment.

Cystic duct This structure is normally 1–2 cm in length and 2–3 mm in diameter. It joins the common hepatic duct at an acute angle to form the common bile duct. The cystic duct normally joins the common hepatic duct approximately 4 cm above the duodenum. However, the cystic duct may enter at any level from the right hepatic duct to the ampulla. In fact the cystic duct may also join the right hepatic duct either when the right duct is in its normal position or in an aberrant location. There are three patterns of confluence of the cystic duct and common hepatic duct (Figure 2.20). In the 20% of patients in which there is a parallel union, the surgeon approaching the common hepatic duct by dissecting the cystic duct is prone to injure the side of the former structure (Figure 2.20). Although a gallbladder with two cystic ducts has been described, the author has not seen convincing proof that this anomaly actually occurs. If it does, it must be an anomaly of extreme rarity. When two “cystic ducts” are identified, it is likely that the cystic duct is congenitally short or has been effaced by a stone and that the two structures thought to be dual cystic ducts are, in fact, the common bile duct and the common hepatic duct.

CHAPTER 2

(a)

(b)

(c)

Figure 2.20 The three types of cystic duct/common hepatic duct confluence: (a) angular (75%), (b) parallel (20%), and (c) spiral (5%). Dissection of the parallel union confluence (b, arrow) may lead to injury of the side of the common hepatic duct. During laparoscopic cholecystectomy this is often a cautery injury. (Adapted from Warrren et al. In: Irvine WT, ed. Modern Trends in Surgery. London: Butterworth, 1966, with permission from Washington University, Saint Louis, MO, USA.)

Cystic artery The cystic artery is about 1 mm in diameter and normally arises from the right hepatic artery in the hepatocystic triangle in the prevailing pattern (85%). The cystic artery may also arise from a right hepatic artery that runs anterior to the common hepatic duct, or from the right hepatic artery on the left side of the common hepatic duct and run anterior to this duct, while the right hepatic artery runs behind it. Such cystic arteries tend to tether the gallbladder and make dissection of the hepatocystic triangle more difficult. The cystic artery may arise from an aberrant right hepatic artery coming off the superior mesenteric artery (SMA). In this case the cystic artery and not the cystic duct tends to be in the free edge of the fold leading from the hepatoduodenal ligament to the gallbladder. This should be suspected whenever the “cystic duct” looks smaller than the “cystic artery.” Normally the cystic artery runs for 1–2 cm to meet the gallbladder superior to the insertion of the cystic duct. The artery ramifies into an anterior and posterior branch at the point of contact with the gallbladder and these branches continue to divide on their respective surfaces. Sometimes the cystic artery divides into branches before the gallbladder edge is reached. In that case the anterior branch may be mistaken to be the cystic artery proper and the posterior branch will not be discovered until later in the dissection when it may be inadvertently divided. The artery may ramify into several branches before arriving at the gallbladder giving the impression that there is no cystic artery. The anterior and posterior branches may arise independently from the right hepatic artery, giving rise to two distinct cystic arteries.

Hepatic Anatomy and Terminology

Multiple small cystic veins drain into intrahepatic portal vein branches by passing into the liver around or through the cystic plate. Sometimes there are cystic veins in the hepatocystic triangle that run parallel to the cystic artery to enter the main portal vein. The cystic plate has been described above. Small bile ducts may penetrate the cystic plate to enter the gallbladder. These “ducts of Luschka” are very small, usually submillimeter accessory ducts. However, if divided during a cholecystectomy postoperative biloma may result. Bilomas and hemorrhage may also be caused by penetration of the cystic plate during dissection. In about 10% of patients there is a large peripheral bile duct immediately deep to the plate, disruption of which will cause copious bile drainage. The origin of the middle hepatic vein is also in this location, and if it is injured massive hemorrhage may ensue.

Extrahepatic bile ducts The common hepatic duct is a structure formed by the confluence of left and right ducts (see above). The union normally occurs at the right extremity of the base of Sg 4, anterior and superior to the bifurcation of the portal vein. The common hepatic duct travels in the right edge of the hepatoduodenal ligament for 2–3 cm, and then it joins the cystic duct to form the common bile duct. The latter has a supraduodenal course of 3–4 cm and then passes behind the duodenum to run in or occasionally behind the pancreas to enter the second portion of the duodenum. The external diameter of the common bile duct varies from 5 to 13 mm when distended to physiologic pressures. However, the duct diameter at surgery, i.e. in fasting patients with low duct pressures, may be as small as 3 mm. Radiologically, the internal duct diameter is measured on fasting patients. Under these conditions the upper limit of normal is about 8 mm. Size should never be used as a sole criterion for identifying a bile duct. Although the cystic duct may be enlarged due to passage of stones, the surgeon should take extra precautions before dividing a “cystic duct” that is greater than 2 mm in diameter because the common bile duct can be 3 mm in diameter and aberrant ducts may be smaller.

Anomalies of extrahepatic bile ducts As already noted there are biliary anomalies of the right and left ductal systems that can affect outcome of hepatic surgery. The same is true for biliary surgery. The most important clinical anomaly is low insertion of right hepatic ducts. In approximately 2% of patients, one of the right hepatic sectional ducts, usually the posterior, joins the common hepatic duct at a level close to the point where the cystic duct normally enters the common hepatic duct. Sometimes the aberrant duct is a segmental duct and rarely it is the main right hepatic duct itself. Its low location means it may be mistaken for the cystic duct and be injured. This is even more likely

23

SECTION 1

Introduction

to occur when the cystic duct unites with an aberrant duct as opposed to joining the common hepatic duct. An extremely rare (if it exists at all) and even more hazardous anomaly occurs when an aberrant right hepatic duct joins the infundibulum of the gallbladder. This anomaly will in most instance not be recognized and lead to an injury of the duct. In most cases this appearance is probably due to a Mirizzi syndrome of the type in which the anterior wall of the common hepatic duct has been destroyed, giving the appearance that the right hepatic duct enters the gallbladder. Left hepatic ducts can also join the common hepatic duct at a low level. They are less prone to be injured since the dissection during cholecystectomy is on the right side of the biliary tree.

Extrahepatic arteries The course of these arteries has been described above. Anomalies of the hepatic artery may be important in gallbladder surgery. Normally the right hepatic artery passes posterior to the bile duct (80%) and gives off the cystic artery in the hepatocystic triangle. However, in 20% of cases the right hepatic artery runs anterior to the bile duct. The right hepatic artery may lie very close to the gallbladder and chronic inflammation can draw the right hepatic artery directly onto the gallbladder where it lies in an inverse Uloop and is prone to injury. Sometimes the right hepatic artery makes a “hairpin” turn in the triangle of Calot. This variation results in the appearance the right hepatic artery is the cystic artery, especially if the latter is narrow in caliber (Figure 2.21). In the “classical injury” in laparoscopic cholecystectomy in which the common bile duct is mistaken for the cystic duct, an associated right hepatic artery injury is very common, since the right hepatic artery is considered to be the cystic artery.

Blood supply of bile ducts Bile ducts receive supply only from the hepatic artery and this is axial [12]. Inferiorly the common bile duct receives supply from the retroduodenal arteries, branches of the gastroduodenal arcade. These arteries pass onto the bile duct at the 3 o’clock and 9 o’clock positions and run upward along the common bile duct. Superiorly, branches pass from the proper, right, and left hepatic arteries onto the common hepatic duct at the level of the confluence of the right and left bile ducts (Figure 2.22). Arteries pass onto the bile duct at the 3 o’clock and 9 o’clock positions, run downward along the common bile duct, and anastomose with the longitudinal arteries coming up from below. The arteries which pass onto the bile duct form a plexus – the epicholedochal plexus, which covers the entire surface of the common bile duct, common hepatic duct, and the right and left bile ducts. The uppermost part of the plexus has been referred to as the hilar plexus. The hilar communicating artery is a marginal artery like the 3 o’clock and 9 o’clock arteries, but lies on

24

Figure 2.21 A dangerous anatomic variant – the “hairpin” right hepatic artery (RHA). Note that the RHA (enlarged in inset) enters the triangle of Calot and gives off two cystic arteries then takes a U-turn towards the liver. The artery is parallel to and about the same size as the cystic duct (CD). This artery is in danger of being mistaken for a cystic artery if dissection of the triangle of Calot is incomplete. CHD, common hepatic duct. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

top of the confluence of the right and left ducts, and forms part of the hilar plexus. There is a watershed of arterial blood supply on the bile duct. If the common hepatic bile duct is transected at a high level, i.e. close to the confluence, the arterial blood supply to the inferior cut edge of the common hepatic duct will come from the retroduodenal arteries through the longitudinal vessels running along the supraduodenal bile duct to the level of transection – a distance of several centimeters. Consequently, ischemia of the inferior cut edge of the bile duct is possible (Figure 2.22a). Similarly, if the bile duct is transected at the level of the duodenum, the upper cut edge of the common bile duct may be ischemic (Figure 2.22b). The clinical implication is that whenever hepatico-jejunostomy is performed, the bile duct should be divided close to its upper end to assure good blood supply, e.g. 1–2 cm below the normal site of confluence of left and right ducts. A corollary is that choledocho-choledochototomy is inherently risky because of the potential for one or other of the cut ends to be ischemic depending on the level of transection. When either the right or left hepatic arteries are occluded, there is usually little clinical effect because of rapid reflow

CHAPTER 2

Figure 2.22 Blood supply to the bile ducts. Longitudinal 3 o’clock and 9 o’clock arteries are enlarged. 1. Transection 1 cm below confluence. Blood supply at the lower cut margin is tenuous. 2. Transection 1 cm below confluence. Blood supply at the upper cut margin is tenuous. (Reproduced with permission from Washington University, Saint Louis, MO, USA.)

from the artery of the nonoccluded side through the hilar plexus.

Self-assessment questions 1 The anatomic basis of The Brisbane 2000 Terminology of Hepatic Anatomy and Resections is based on divisions of which of the following? (more than one answer is possible) A Hepatic vein B Hepatic artery C Bile ducts D Plate/sheath system E Portal vein

Hepatic Anatomy and Terminology

1

2

4 Which of the following statements are true? (more than one answer is possible) A The transverse portion of the left portal vein provides a large branch to segment 4 B Segmental branches of the left portal vein may be isolated in the umbilical fissure C The right portal vein has a long extrahepatic course D The left portal vein enters the liver substance at the base of the umbilical fissure E The branches of the left portal vein combine with hepatic arteries and bile duct to enter segmental sheaths

2 Which of the following are correct terms for hepatic resections? (more than one answer is possible) A Right hepatic lobectomy B Right trisectionectomy C Left lateral segmentectomy D Left lateral sectionectomy E Resection segments 5 and 6

5 Which of the following statements are true? (more than one answer is possible) A The termination of the left hepatic vein lies in the plane of the umbilical fissure B The middle hepatic vein drains segments 4, 5, and 8 C The right hepatic vein drains segments 5–8 D The umbilical vein drains blood from the umbilicus through the round ligament E The inferior right hepatic vein drains the caudate lobe.

3 After division of the apparent right hepatic artery and the right portal vein, failure of the entire right liver to demarcate might be due to which of the following? (more than one answer is possible) A Failure to occlude the caudate veins B Presence of a replaced artery supplying part of the right liver C Presence of steatosis D Absence of the right portal vein with failure to appreciate a separate right anterior sectional portal vein E Hypoxia

6 When transecting the liver during a right hepatectomy the surgeon encounters a large venous structure. Which of the following structures might this be? (more than one answer is possible) A Umbilical vein B Right anterior sectional vein in a case of absent right portal vein C Left hepatic vein coursing through the interior of the liver in a case of absent extrahepatic left portal vein D Hepatic vein from segment 5 E Hepatic vein from segment 8

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SECTION 1

Introduction

7 Which of the following statements are true? (more than one answer is possible) A All arteries to the left of the common hepatic duct supply the left liver B All arteries to the right of the common hepatic duct supply the right liver C The cystic artery may arise from an artery on the left side of the bile duct D The right hepatic artery lies superior to the right hepatic duct in the porta hepatic E Rarely, an artery arising from the left gastric artery may supply the right liver 8 Which of the following statements are false? (more than one answer is possible) A The cystic duct is uniformly smaller than the common hepatic duct B The cystic duct may enter the left side of the bile duct C The cystic duct may enter the right hepatic duct. D Double cystic ducts are common but double gallbladders never occur E The cystic plate connects to the sheath of the right portal pedicle 9 A 59-year-old male with a large central tumor has had resection of segments 2–5 and 8. What is this operation called? A Left trisegmentectomy B Right trisegmentectomy C Central hepatectomy plus left lateral sectionectomy D Left trisectionectomy E Right trisectionectomy 10 The right lobe of the liver consists of which of the following? A Segments 5-8 B Segments 4-8 C Segments 4-8 and the caudate process D The right hemiliver plus segment 4 E “Lobe” is a confusing term and should be abandoned except for caudate lobe

References 1 Terminology Committee of the IHPBA. The Brisbane 2000 Terminology of Liver Anatomy and Resections. HPB Surg 2000;2:333–9.

26

2 Healey JE, Schroy PC. Anatomy of the biliary ducts within the human liver; Analysis of the prevailing pattern of branchings and the major variations of the biliary ducts. Arch Surg 1953; 66:599–616. 3 Couinaud C. Le Foie. Etudes Anatomiques et Chirugicales. Paris: Masson & Cie, 1957. 4 Hjortsjo C-H. The topography of the intrahepatic duct systems. Acta Anat 1951;11:599–615. 5 Botero AC, Strasberg SM. Division of the left hemiliver in man – segments, sectors, or sections. Liver Transplant Surg 1998; 4:226–31. 6 Masselot R, Leborgne J. Anatomical study of hepatic veins. Anat Clin 1978;1:109–125. 7 Makuuchi M, Yamamoto J, Takayama T, et al. Extrahepatic division of the right hepatic vein in hepatectomy. Hepatogastroenterology 1991;38:176–9. 8 Belghiti J, Guevara OA, Noun R, Saldinger PF, Kianmanesh R. Liver hanging maneuver: a safe approach to right hepatectomy without liver mobilization. J Am Coll Surg 2001;193:109–11. 9 Strasberg SM, Linehan DC, Hawkins WG. Isolation of right main and right sectional portal pedicles for liver resection without hepatotomy or inflow occlusion. J Am Coll Surg 2008;206: 390–6. 10 Strasberg SM, Picus DD, Drebin JA. Results of a new strategy for reconstruction of biliary injuries having an isolated rightsided component. J Gastrointest Surg 2001;5:266–74. 11 Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary injury during laparoscopic cholecystectomy. J Am Coll Surg 1995;180:101–25. 12 Northover JM, Terblanche J. A new look at the arterial supply of the bile duct in man and its surgical implications. Br J Surg 1979;66:379–84.

Self-assessment answers 1 2 3 4 5 6 7 8 9 10

B, C B, D, E B, D B, E A, B, C B, C, D, E B, C, E A, D D E

2

Epidemiology and Diagnosis

Introduction Chung-Mau Lo Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Malignant liver tumors are among the most dismal of all cancers. While primary liver cancer is the sixth most common cancer worldwide, it is the third most common cause of cancer death with a mortality-to-incidence ratio exceeding 0.9. The liver is also a common site of metastases, notably from primaries arising from the gastrointestinal tract. Colorectal cancer in particular is one of the most common malignancies and over 50% of cases will eventually develop liver metastases. Although liver metastases are usually regarded as part of systemic metastasis and the prognosis is poor, isolated colorectal liver metastases are currently managed as locoregional disease with surgical resection for cure similar in many ways to that for primary liver cancer. This section focuses on the pathology, epidemiology, natural history, and diagnosis of various liver cancers. It starts with a comprehensive review of the pathology of benign and malignant liver disease, followed by the epide-

miology, etiology, and natural history of different liver cancers. There is a striking variation in the risk of different kinds of liver cancer in different geographic areas, suggesting that various lifestyle and environment factors have a role in the etiology, and that a better understanding of the epidemiology provides excellent opportunity for prevention. For example, chronic hepatitis B is a major risk factor for hepatocellular carcinoma and prevention of hepatitis B infection by vaccination of newborns has resulted in a dramatic decrease in the incidence of liver cancer. Knowledge of the epidemiology also allows identification of the high-risk population for screening. Together with the chapters on advances in molecular diagnosis using tumor markers and imaging techniques, this section provides the framework for the recent advances in prevention, early diagnosis, and effective treatment of malignant liver tumors.

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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3

Histology and Pathology of Normal and Diseased Liver Valérie Paradis1 and Achim Weber2 1 Department of Pathology, Beaujon Hospital, Clichy, and INSERM U773, Centre de Recherche Bichat Beaujon, Paris, France 2 Swiss HPB (Hepato-Pancreato-Biliary) Center, Department of Pathology, Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland

Introduction The pathologic analysis of liver background parenchyma is crucial for a better understanding of the development of liver tumors, as well as improvements in the management of patients who are potential candidates for liver surgery. This chapter will describe the normal histology of the liver and review the main pathologic changes observed in the context of malignant tumors. Primary malignant tumors, and especially hepatocellular carcinomas (HCCs), usually develop on already diseased liver parenchyma, since HCC progression follows a multistep process of carcinogenesis. Due to the increase in metabolic syndrome and viral chronic hepatitis worldwide, which represent significant risk factors for HCC, specific interest will be focused on steatosis and liver fibrosis. More recently, specific liver changes, including vascular damage, have been described in the context of liver metastases.

called Kupffer cells. The space between the endothelium and hepatocytes is known as the space of Disse, which contains hepatic stellate cells (HSCs, previously named Ito cells, lipocytes, or fat-storing cells) [1] (Figure 3.2). Such cells account for less than 10% of a normal liver, where they store vitamin A, and may acquire an activated myofibroblast-like phenotype during the fibrogenic process [2]. In normal liver, extracellular matrix (ECM) is restricted to the portal tracts, sinusoid walls, and central veins. Quantitatively, ECM is very limited, accounting for less than 3% of the total area of liver tissue [3]. The most common proteins found in the liver are collagens, with types I, III, IV, and V the most abundant, and display a specific localization and function in the liver [4]. Noncollagenous glycoproteins, such as laminin, fibronectin, tenascin, glycosaminoglycans, and proteoglycans are also constitutive ECM components of the liver [5]. ECM is organized into a complex network that fulfils major functions, such as maintaining mechanical coherence and resistance of the liver, as well as biologic functions, including cell proliferation, migration, differentiation, and gene expression [6].

Histology of normal liver The structural unit of the liver is represented by the hepatic lobule, which is composed of plates of hepatocytes radiating from the periphery to the center of the lobule. A lobule is roughly hexagonal in shape with portal tracts, and contains a bile duct and a terminal branch of the hepatic artery and portal vein at the vertices, and a central vein in the middle (Figure 3.1). The concept of acinus is rather functional, describing three main zones, based on the afferent vascular system. Liver cells are composed of different phenotypic cell populations; among them, the hepatocytes represent the majority, accounting for almost 80% of total resident cells. These hepatocytes make contact with blood in sinusoids, which are vascular channels lined by highly fenestrated endothelial cells and containing liver resident macrophages,

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

30

Steatosis The adult human liver normally contains up to 5% of its mass as lipid. Steatosis, i.e. an abnormal accumulation of lipids in hepatocytes, results from a variety of different underlying conditions. It is not a mere histologic finding, but rather can point to a potentially progressive liver disease. The clinical impact of the diagnosis of steatosis ranges from a harmless condition to an acutely threatening situation, depending on the amount and kind of fatty change and the clinical context. Steatosis is the basis for fatty liver diseases, which now are a common cause of liver function test elevation, paralleling the worldwide increase in obesity not only in adults but also in children. A major complication of steatosis is the development of steatohepatitis, a chronic inflammatory condition associated with fibrosis and potentially leading to cirrhosis. Alcoholic steatohepatitis (ASH) develops in the context of alcoholic

CHAPTER 3

Histology and Pathology of Normal and Diseased Liver

fatty liver disease (AFLD), which is delineated from nonalcoholic steatohepatitis (NASH) developing in the context of nonalcoholic fatty liver disease (NAFLD) in which patients lack a history of significant alcohol consumption. The latter conditions are considered to be mostly hepatic manifestations of insulin resistance in metabolic syndrome, which has become a major health problem in Western societies, paralleling the increased prevalence of obesity [7, 8]. NAFLD and NASH are associated with central obesity, type 2 diabetes mellitus, and the metabolic syndrome, but also with disorders of lipid metabolism, like hyperlipidemia. Liver biopsy is the current gold standard for diagnosis (or exclusion) of fatty liver disease. It can reveal clinically unsuspected fatty liver, and provide a grading and staging

of the fatty liver disease, evaluating the degree of steatosis, inflammation, liver cell injury, fibrosis, and architectural changes. Histologically, steatosis is described according to the amount of fatty change, the distribution with respect to zones involved, and the dominant kind of lipid drops, discriminating macrovesicular steatosis from microvesicular steatosis. Macrovesicular steatosis, the more common pattern, is characterized by lipid drops which predominantly fill most of the cell and push the nucleus to the periphery (Figure 3.3), whereas in microvesicular steatosis, the fat is finely dispersed in uniform droplets throughout the cytoplasm, and the nucleus remains centrally located. Frequently, steatosis shows a combination of both patterns.

Figure 3.1 Organization of a liver lobule. PT, portal tract; CV, central vein.

Figure 3.2 Hepatic stellate cell. A quiescent stellate cell is present in the space of Disse (arrow, Trichrome staining).

(a)

(b)

Figure 3.3 Features of alcoholic steatohepatitis. (a) Mostly macrovesicular steatosis, extensive hepatocyte ballooning, numerous Mallory bodies, and lobular inflammation including neutrophils. (b) Sirius stain highlights fibrosis with primarily pericellular distribution, extending to portal and perivenular areas.

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SECTION 2

Epidemiology and Diagnosis

(a)

(b)

Figure 3.4 Adenoma and steatosis in the liver from a 19-year-old male with glycogenosis type I. (a) Yellow cut surface of adenoma and nontumorous tissue indicating increased fat content. (b) Histology reveals a mostly macrovesicular steatosis and several neutrophils reflecting “surgical” hepatitis.

Numerous conditions lead to macrovesicular steatosis, including obesity and diabetes mellitus in the context of metabolic syndrome; drugs and toxins, including alcohol, corticosteroids, methotrexate; infections (e.g. particular types of hepatitis C virus); total parenteral and protein– calorie nutrition; as well as (inherited) metabolic disorders, e.g. particular types of glycogen storage diseases (Figure 3.4) or Wilson disease. Among these causes, histology is not uniform, but can point to the underlying condition. For example, whereas steatosis is mostly perivenular, periportal steatosis is observed in parenteral nutrition or acquired immunodeficiency syndrome (AIDS), and glycogenated nuclei can point to diabetes mellitus. The histology of microvesicular steatosis reveals mostly unspectacular changes with swollen hepatocytes containing numerous small vacuoles and centrally located nuclei, and therefore is difficult to diagnose based on hematoxylin and eosin (H&E) staining of paraffin sections alone. In contrast to the generally mild morphologic changes, microvesicular steatosis is usually a clinically more serious condition. It results from mitochondrial damage and impaired βoxidation. Causes are acute fatty liver of pregnancy, Reye syndrome, acute alcohol intoxication, and several hepatotoxic drugs, e.g. valproate and nucleoside analogs given for human immunodeficiency virus (HIV) infection. Liver biopsy remains the gold standard for the diagnosis of steatohepatitis as a complication of AFLD or NAFLD [9, 10]. Histopathologic changes of ASH (Figure 3.3) and NASH are similar, and the two conditions cannot readily be distinguished based on histology alone. Diagnosis of NASH (and also ASH) relies not on a single feature, but rather on a combination of lesions [11]. Morphologic hallmarks of steatohepatitis are – besides steatosis – hepatocellular damage in

32

the form hepatocyte ballooning, formation of Mallory bodies and megamitochondria, liver cell apoptosis, predominantly lobular inflammation, and infiltration by neutrophils, sometimes including satellitosis, as well as fibrosis with primarily pericellular distribution (so-called chicken-wire fibrosis; Figure 3.3b), potentially extending to a portal and perivenular distribution [12, 13]. Based on the criteria of steatosis, lobular inflammation, and hepatocellular ballooning, a semiquantitative scoring system has been developed to score the spectrum of NAFLD, which has mostly been applied to treatment trials [14]. Both ASH and NASH can progress to cirrhosis, and NASH frequently is the reason for “cryptogenic cirrhosis” [15]. Patients are also at risk for liver failure and the development of HCC. Several observations provide evidence that NAFLD also can predispose to the development of HCC, even in the absence of cirrhosis [16]. Finally, histologic evaluation of hepatic steatosis is a wellestablished procedure in the setting of liver transplantation, since significant (macrovesicular) steatosis can cause initial poor liver graft function and therefore result in rejection of a potential donor organ [17, 18].

Fibrosis and cirrhosis Liver fibrosis is the main hallmark of almost all chronic liver diseases, whatever their origin. It is defined by the accumulation of various ECM components in different parts of the liver, mainly sinusoids and portal tracts. Due to its localization, excessive deposits of ECM will have deleterious consequences for liver functions, and may be taken into consideration in the surgical management of patients: the presence of fibrosis may result in significant decrease in liver

CHAPTER 3

function reserve, impairing potential regeneration. However, it is now clear that ECM metabolism is a very dynamic process and deposition of ECM in tissue is much more reversible than was previously thought [19].

Extracellular matrix in fibrotic liver In fibrotic liver, the ECM components are similar to those present in normal liver but are quantitatively increased (three- to five-fold increase) [20]. Importantly, redistribution of the relative amounts of ECM components is also observed. In the setting of chronic liver diseases, liver fibrosis is associated with additional mechanisms, including architectural distortion, liver cell regeneration, and vascular redistribution, that also contribute to the impairment of liver functions. ECM accumulation in sinusoid walls is one of the early changes, leading to sinusoid capillarization and thus strong impairment of exchange between hepatocytes and blood flow [21]. During this process of fibrogenesis, several types of cells are able to produce and secrete ECM components [22]. Besides hepatocytes, HSCs and portal fibroblasts are the major contributors of ECM [23]. A specific interest was shown in HSC activation in this process as HSCs show significant morphologic changes (elongated shape, loss of lipid droplets), phenotypic modifications (de novo expression of intermediate filaments characteristic of a smooth muscular phenotype), and function gains (proliferation, migration, contractility, and protein synthesis) [24]. Via the production of various mediators, including growth factors, HSCs participate in an autocrine and paracrine pathway of regulation. Since these cells are also able to produce specialized enzymes, such as matrix metalloproteases, involved in the remodeling of ECM, HSCs play a key role in the control of both synthesis and destruction of fibrosis [25].

Morphologic patterns of fibrosis For pathologists, the most obvious change in fibrosis is the expansion of ECM from the portal space or central vein. The preferential site for fibrosis to start is related to the mechanism responsible for fibrosis induction and is closely linked to etiology, mainly as follows: central fibrosis for vascular or alcohol/metabolic fibrosis; and portal fibrosis for viral, autoimmune, or biliary diseases. The stellate expansion of fibrous tissue around the portal tract or central vein leads to the development of fibrous connections from one vascular structure to another. At a more advanced stage, when most vascular spaces are interconnected, cirrhosis is constituted. In this new organization, redistribution of incoming liver blood flow is observed, with the blood supply derived mainly from branches of the hepatic artery (arterialization) in association with phenotypic modifications of sinusoid endothelial cells associated with capillarization. In chronic viral and autoimmune hepatitis, the portal area enlarges and extends through zone 1 of the acinus as a broad-based area of fibrosis to create portal–portal bridges. Chronic biliary diseases also

Histology and Pathology of Normal and Diseased Liver

produce periportal injury that leads to fibrosis of acinar zone 1, and further extends along acinar zone 1, usually associated with ductular proliferation. The resulting septa that link adjacent portal tracts produce fairly regular nodules of parenchyma, often with a terminal hepatic venule in the center.

Evaluation and staging of fibrosis As mentioned above, malignant tumors, and especially HCC, arise in the course of chronic liver diseases characterized by the development of liver fibrosis. Therefore, pathologic analysis of nontumoral liver tissue, in that context, aims to assess with accuracy the necroinflammatory grade and stage of fibrosis. This is currently achieved by the development of different scales such as Ishak, Scheuer scores, or the METAVIR system [26–28]. Figure 3.5 is a schematic representation of the METAVIR scoring system. These scores have been fully validated in viral chronic hepatitis. More recently, an additional scoring system has been proposed by Brunt and Kleiner dedicated to AFLD and NAFLD [14]. In scoring systems, fibrosis is categorized into five to six progressive stages, from normal liver to cirrhosis with intermediate stages according to the number and extent of fibrous septa (Table 3.1). Since alcoholic- and nonalcoholic-related fibrosis is characterized by early and prominent sinusoidal fibrosis, fibrosis stage according to Brunt and Kleiner takes into account the degree of sinusoidal fibrosis in the evaluation of liver fibrosis [14]. Although a good to excellent reproducibility was reported in independent studies, especially for the staging of fibrosis, it should be pointed out that assessment of liver fibrosis, which is the main endpoint of chronic liver disease, may be affected by tissue sampling in as much as the tissue sample is provided by needle liver biopsy [29–31]. Further approaches, including immunohistochemistry, may be of significant value in measuring the activity of the profibrogenic state. Such studies allow the demonstration and quantification of activated HSCs by evaluating the expression of various protein markers, including α-smooth muscle actin [32] (Figure 3.6).

Table 3.1 Semiquantitative fibrosis staging systems. Fibrosis

METAVIR

Scheuer

Ishak

Normal Few portal tracts Most portal tracts Rare portal septa Few septa Numerous septa Incomplete cirrhosis Cirrhosis

0 1 1 2 2 3 4 4

0 1 1 2 3 3 4 4

0 1 2 2 3 4 5 6

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SECTION 2

Epidemiology and Diagnosis

Figure 3.5 Schematic representation of the METAVIR system. F1, portal enlargement without septa; F2, few portal septa; F3, numerous fibrous septa; F4, cirrhosis; PT, portal tract; CV, central vein.

Figure 3.7 Hepatocellular carcinoma in a patient with hepatitis C virus infection. A 2-cm encapsulated tumor (early hepatocellular carcinoma) has developed in a cirrhotic liver (macroscopic view).

Figure 3.6 Activated hepatic stellate cell immunostained with α-smooth muscle actin (immunohistochemistry).

“Typical features” of nontumoral liver according to the type of malignant tumor Malignant liver tumors are divided into primary and metastatic tumors. In the group of primary tumors, HCCs and cholangiocarcinomas (CCs) are generally the most frequent.

34

Although cirrhosis is one of the major risk factors for HCC, some variation in incidence of HCC may be observed according to the etiologic cause of chronic liver injury [33]. Hepatitis C virus (HCV) infection is the leading cause of HCC (Figure 3.7) associated with cirrhosis in Western countries and Japan, followed by alcoholic cirrhosis and hereditary hemochromatosis in Europe [34, 35]. In Asia and Africa, the major cause of HCC is related to hepatitis B virus (HBV) infection. It should be pointed out that HCC developing in the context of HBV infection is more often diagnosed at an

CHAPTER 3

(a)

Histology and Pathology of Normal and Diseased Liver

(b)

(c) Figure 3.8 Hepatocellular carcinoma arising in a patient with metabolic syndrome. (a) An encapsulated large heterogeneous tumor with cholestatic areas (macroscopic view). (b) Well-differentiated hepatocellular carcinoma formed of widened cell trabeculae (H&E staining). (c) Nontumoral liver shows marked steatosis (>66%) without any significant fibrosis (H&E staining).

earlier stage than cirrhosis [36]. In addition, several preneoplastic changes may be observed, including cirrhotic macronodules, also called dysplastic nodules, and dysplastic foci, including large and small liver cell changes. Due to the rising incidence of obesity and metabolic syndrome worldwide, NAFLD is now recognized as one of the leading causes of chronic liver disease and then HCC [37, 38]. In that context, histologic analysis of nontumoral liver may reveal a wide spectrum of metabolic fatty liver disorders, including simple steatosis, NASH, fibrosis, and cirrhosis (Figure 3.8). Finally, a distinct subtype of HCC – fibrolamellar HCC, which occurs in a young population without any evidence of chronic liver injury, arises on a quite normal liver parenchyma [39] (Figure 3.9). CCs, the second most common primary malignant tumors of the liver, arising from epithelial biliary cells, occur on

Figure 3.9 Fibrolamellar hepatocellular carcinoma (macroscopic view). A large unencapsulated polychrome tumor with fibrous septa inside.

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SECTION 2

Epidemiology and Diagnosis

(a)

(b)

Figure 3.10 Cholangiocarcinoma. (a) A white, well-limited tumor surrounded by cholestatic and fibrous liver parenchyma (macroscopic view). (b) Nontumoral liver tissue shows extensive fibrosis with a pattern of biliary fibrosis (Trichrome staining).

(a)

(b)

Figure 3.11 Liver metastasis. (a) One tumoral white unencapsulated nodule developed on a nodular parenchyma without fibrosis (regenerative nodular hyperplasia, macroscopic view). (b) Nontumoral liver tissue and peritumoral liver tissue.

nondiseased liver in most cases. However, cirrhosis carries a 10-fold risk for developing such a tumor [40, 41]. Primary sclerosing cholangitis, HCV infection, and genetic hemochromatosis are the most frequent risk factors encountered in the development of CC in Western countries, whereas parasitic infection and hepatolithiasis are common in Asia [41–43]. A specific pattern of liver damage, including a significant degree of secondary biliary fibrosis and cholestasis, may be observed in cases of hilar CC where the tumor results in the chronic obstruction of the large bile ducts (Figure 3.10).

36

Finally, in cases of liver metastasis, various features of liver damage may be seen, mainly depending on the “liver history” of the patient, such as alcohol consumption, presence of chronic liver disease or metabolic syndrome. Also, it has been recently pointed out that systemic chemotherapy may induce morphologic changes in the nontumoral tissue. Major disorders include vascular lesions, such as sinusoidal obstruction syndrome, steatosis, and even steatohepatitis in some studies [44–46]. Several cases of regenerative nodular hyperplasia also have been reported (Figure 3.11).

CHAPTER 3

Impact of diseased liver on surgical management of patients with malignant liver tumors To be able to determine the pathologic aspect of nontumoral liver tissue is a key point for surgeons who have to manage patients with malignant tumors. Indeed, in order to improve peri- and post-operative care, especially in candidates for extended liver resection, specific procedures may be performed in patients with potentially insufficient hepatic functional reserve. In that setting, a preoperative liver biopsy may be proposed since imaging modalities are insufficiently accurate to date. Noninvasive serum markers, developed for the diagnosis of cirrhosis mainly in chronic viral diseases, have not been validated in the context of malignant liver tumors. For that purpose, the objectives of the liver biopsy are to evaluate the architecture of the liver parenchyma, and to establish the staging of fibrosis, histologic grading of inflammation, and severity of steatosis.

Self-assessment questions 1 Which one of the following statements concerning steatosis is true? A Liver biopsy for the evaluation of steatosis is nowadays replaced by ultrasonography and blood tests B Macrovesicular steatosis is usually a clinically more severe condition than microvesicular steatosis C Mallory bodies are a characteristic histologic finding of alcoholic steatohepatitis (ASH), but not of nonalcoholic steatohepatitis (NASH) D Pericellular fibrosis and ballooned hepatocytes are a characteristic histologic finding of both ASH and NASH E Macrovesicular and microvesicular steatosis are mutually exclusive, and usually do not coexist in the same liver 2 Which one of the following statements regarding evaluation and staging of fibrosis is false? A Scoring systems are based on a semiquantitative assessment of fibrosis B Scoring systems have been mainly validated in viral chronic hepatitis C Different patterns of fibrosis are observed according to the etiology of the liver disease D Sinusoidal fibrosis is a typical feature observed in biliary fibrosis E Specific stains are useful in fibrosis staging

Histology and Pathology of Normal and Diseased Liver

3 Which one of the following statements concerning fibrosis is false? A Fibrosis is defined by production and accumulation of extracellular matrix (ECM) B Definition of cirrhosis is restricted only to fibrosis C Hepatic stellate cells are the main producers of ECM during fibrogenesis D Hepatic stellate cells are able to proliferate during fibrogenesis E In normal liver, hepatic stellate cells contain lipid droplets 4 Which one of the following statements concerning fibrosis is false? A In chronic liver disease, patterns of fibrosis depend on etiology B In biliary fibrosis, ductular proliferation is prominent C Semiquantitative scoring of fibrosis is based on morphometry analysis D Immunohistochemistry may help to identify activated hepatic stellate cells E In alcoholic fatty liver disease and nonalcoholic fatty liver disease the pattern of fibrosis is similar 5 Which one of the following statements concerning hepatocellular carcinomas is false? A Hepatocellular carcinomas (HCCs) are the most frequent tumors to develop in cirrhotic patients B Incidence of HCC varies according to the etiologic cause of chronic liver disease C In alcoholic patients, HCCs are usually diagnosed early in the course of chronic liver disease D HCCs may occur via the development of premalignant changes, including dysplastic cirrhotic nodules E Nonalcoholic steatohepatitis is a clinical condition associated with the development of HCCs 6 Which of the following are true concerning cholangiocarcinomas? (more than one answer is possible) A Cholangiocarcinomas are tumors derived from biliary epithelial cells B Cirrhotic patients do not display an increased risk for developing cholangiocarcinomas C Parasitic infections and hepatolithiasis are risk factors for cholangiocarcinomas D Features of primary sclerosing cholangitis are never observed in the nontumoral liver adjacent to a cholangiocarcinoma E Dilatation of large bile ducts may be related to the presence of hilar cholangiocarcinomas

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Epidemiology and Diagnosis

7 Which of the following statements concerning metastatic tumors of the liver is false? A Metastatic tumors are the most frequent liver malignancies B Nontumoral liver may be abnormal C Histologic changes of the nontumoral liver tissue may be related to systemic chemotherapy D Fibrosis is the most common pathologic change observed following systemic chemotherapy E Steatosis and vascular lesions are common features on surgical specimens

16

17

18

19

References

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and risk factors for underlying disease. Hepatology 1999;29: 664–9. Guzman G, Brunt EM, Petrovic LM, Chejfec G, Layden TJ, Colter SJ. Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis? Arch Pathol Lab Med 2008;132:1761–6. McCormack L, Petrowsky H, Jochum W, Furrer K, Clavien PA. Hepatic steatosis is a risk factor for postoperative complications after major hepatectomy: a matched case-control study. Ann Surg 2007;245:923–30. Clavien PA, Petrowsky H, DeOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 2007;356:1545–59. Friedman SL, Arthur MJ. Reversing hepatic fibrosis. Sci Med 2002;8:194–205. Rojkind M, Giambrone MA, Biempica L. Collagen types in normal and cirrhotic liver. Gastroenterology 1985;76:710–19. Schaffner F, Popper H. Capillarization of the sinusoids in man. Gastroenterology 1963;44:239–42. Cassiman D, Libbrecht L, Desmet V, et al. Hepatic stellate cell/ myofibroblast subpopulations in fibrotic human and rat livers. J Hepatol 2002;36:200–9. Knittel T, Kobold D, Saile B, et al. Rat liver myofibroblasts and hepatic stellate cells: different cell populations of the fibroblast lineage with fibrogenic potential. Gastroenterology 1999;117: 1205–21. Friedman SL, Arthur MJ. Activation of cultured rat hepatic lipocytes by Kupffer cell conditioned medium: direct enhancement of matrix synthesis and stimulation of cell proliferation via induction of platelet-derived growth factor receptors. J Clin Invest 1989;84:1780–5. Milani S, Herbst H, Schuppan D, et al. Differential expression of matrix-metalloproteinase-1 and -2 genes in normal and fibrotic human liver. Am J Pathol 1994;144:528–37. Desmet VJ, Gerber M, Hoofnagle JH, et al. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994;19:1513–20. Ishak K, Baptista A, Bianchiu L, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22:696–9. Bedossa P, Poynard T. The French METAVIR Cooperative Study Group. An algorithm for grading activity in chronic hepatitis C. Hepatology 1996;24:298–3. Abdi W, Millan JC, Mezey E. Sampling variability on percutaneous liver biopsy. Arch Intern Med 1979;139:667–9. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003;38:1449–57. Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002;97:2614–18. Iredale JP, Benyon RC, Pickering J, et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 1998;102:538–49. Gines P, Gardenas A, Arroyo V, et al. Management of cirrhosis and ascites. N Engl J Med 2004;350:1646–54. El-Serag HB. Hepatocellular carcinoma and hepatitis C in the United States. Hepatology 2002;36:S74–83. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907–17.

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36 Lam CM, Chan AO, Ho P, et al. Different presentation of hepatitis B-related hepatocellular carcinoma in a cohort of 1863 young and old patients: implications for screening. Aliment Pharmacol Ther 2004;19:771–7. 37 Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001; 50:1844–50. 38 Diehl AM. Nonalcoholic steatohepatitis. Semin Liver Dis 1999;19:221–9. 39 Soreide O, Czeiniak A, Bradpiece H, et al. Characteristics of fibrolamellar carcinoma. Am J Surg Pathol 1986;151:518–23. 40 Sorensen HT, Friis S, Olsen JH, et al. Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark. Hepatology 1998;28:921–925 41 Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004;24:115–25. 42 Watanapa P, Watanapa WB. Liver fluke-associated cholangiocarcinoma. Br J Surg 2002;89:962–70. 43 Donato F, Gelatti U, Tagger A, et al. Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy. Cancer Causes Control 2001;12:959–64. 44 Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemo-

Histology and Pathology of Normal and Diseased Liver

therapy in patients with metastatic colorectal cancer. Ann Oncol 2004;15:460–6. 45 Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 2006;24:4983–90. 46 Zorzi D, Laurent A, Pawlik TM, et al. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg 2007;94:274–86.

Self-assessment answers 1 2 3 4 5 6 7

B D B C C A, C, D, E D

39

4

Pathology of Primary and Secondary Malignant Liver Tumors Kay Washington Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA

Primary Epithelial Tumors of the Liver Hepatocellular carcinoma Gross morphology Hepatocellular carcinomas (HCCs) may be divided into nodular, massive, and diffuse types. The nodular type, the most common, is the type usually seen in cirrhosis, with tumor nodules scattered among regenerating cirrhotic nodules. A dominant tumor nodule may be present. The massive type consists of a large single mass with or without satellite nodules and is usually seen in a noncirrhotic liver. The diffuse type is relatively uncommon and consists of innumerable indistinct small tumor nodules scattered throughout the liver. HCCs are generally soft and variegated in appearance, with color ranging from pale tan or gray to green, reflecting the presence of bile. Invasion and growth into large vessels such as hepatic vein branches and the portal vein is common; invasion of intra- or extra-hepatic bile ducts is seen less often, but occasionally a patient presents with symptoms of large bile duct obstruction from intrabiliary growth of HCC.

the neoplastic cells closely resemble normal hepatocytes, with minimal alterations in nuclear-to-cytoplasmic ratio and chromatin content and distribution. In most tumors, however, the nuclear-to-cytoplasmic ratio is increased and there is some degree of nuclear atypia. Cytoplasm is eosinophilic and slightly granular, and may contain inclusions such as Mallory’s hyaline, α-fetoprotein (AFP), α-1antitrypsin, or bile. The cytoplasm may appear clear due to accumulation of glycogen, and the tumor cells may contain fat. Poorly differentiated tumor cells may be spindle-shaped and have a sarcomatoid appearance. The World Health Organization grading scheme for HCC [1] separates HCCs into four grades, based on resemblance of the tumor cells to normal hepatocytes. Well-differentiated HCCs are usually small early stage lesions; the cells show minimal nuclear atypia. In moderately-differentiated tumors, tumor cells are typically arranged in trabeculae three or more cell layers thick; the nuclear-to-cytoplasmic ratio is higher, and nuclei are more pleomorphic and hyperchromatic than in well-differentiated tumors. Poorly differentiated tumors grow in a solid pattern and are composed of highly pleomorphic cells; multinucleated tumor giant cells are not uncommon. Undifferentiated HCCs are anaplastic and difficult to recognize as hepatocellular.

Histologic types In the most common growth pattern of HCC, tumor cells form trabeculae that vary in width from two to over 20 cells and are separated by sinusoidal-like spaces lined by endothelial cells. Little or no intervening connective tissue stroma is present (Figure 4.1). Other patterns include an acinar or pseudoglandular pattern, in which tumor cells are arranged around a large central bile canalicular structure, and a solid pattern in which the trabeculae are broad and compact, obscuring intervening sinusoidal spaces. Cytologically the cells of HCC display varying degrees of hepatocellular differentiation. In well-differentiated tumors,

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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Precursor lesions The precursor lesion for HCC arising in the cirrhotic liver is considered to be the dysplastic nodule. Nodular lesions arising in the setting of cirrhosis show a wide spectrum of histologic changes, from large macroregenerative nodules without atypical features, to nodules falling just short of the morphologic criteria considered diagnostic of HCC. Although terminology applied to these nodular lesions has been quite varied, the most widely accepted classification scheme is that proposed by the International Working Party [2]. Multiacinar regenerative nodules distinctly larger than the surrounding cirrhotic nodules but lacking cytologic and architectural atypia are termed macrogenerative nodules or large regenerative nodules. A minimum size criterion has not been established but is based upon the size suitable to distinguish the large nodules from background cirrhotic

CHAPTER 4

Pathology of Primary and Secondary Malignant Liver Tumors

Figure 4.1 The tumor cells in hepatocellular carcinoma are arranged in trabeculae of variable thickness separated by sinusoidal spaces. A few pseudoacinar structures are present.

Figure 4.2 The fibrous stroma in fibrolamellar carcinoma has a characteristic dense lamellar appearance.

nodules. These large regenerative nodules are usually multiple and measure 0.5–1.5 cm, but can be 5 cm or more in diameter. They are found in 15% to nearly 50% of cirrhotic livers and are three to four times more common than dysplastic nodules.

pared to the surrounding liver, and is considered a precursor lesion for HCC [3]. Whether large cell change, characterized by cellular enlargement, nuclear pleomorphism, and hyperchromasia, is a precursor lesion for HCC remains more controversial. While large cell change has been associated with HCC development, it may also be seen in the setting of chronic cholestasis [4] and may not be directly related to hepatocarcinogenesis.

Dysplastic nodules Dysplastic nodules are nodular lesions generally occurring in the setting of cirrhosis and displaying some degree of cytologic or architectural atypia, but lacking definitive histologic features of malignancy. The International Working Party has defined a dysplastic nodule as being 1 mm or more in diameter and having either histologic features indicative of presumed genetic alteration (characterized by “the presence of nuclear or cytoplasmic alterations and the topographic clustering of such variations to form recognizable subpopulations of cells”) or proof of genetic alteration (e.g. clonality) without definitive histologic features of malignancy [2]. Dysplastic nodules are further subdivided into low and high grades, depending on the degree of histologic abnormality, for purposes of risk stratification and clinical utility. Dysplastic changes include architectural aberrations such as focal areas of pseudogland formation and solid areas [2]. If uniformly thick cells plates (three or more cells thick) or large areas of pseudoglandular architecture are encountered, the diagnosis of small HCC should be considered. Two categories of atypical cytologic features are recognized: small cell change and large cell change. Dysplastic foci or nodules often consist of hepatocytes with small cell change, characterized by smaller cell size, a greater nuclearto-cytoplasmic ratio, cytoplasmic basophilia, and denser cellularity in comparison with the surrounding extranodular hepatocytes. Small cell change has been shown to have a higher proliferative rate and a lower apoptotic rate com-

Special variants of hepatocellular carcinoma Fibrolamellar carcinoma The fibrolamellar variant of HCC accounts for less than 5% of HCCs. In contrast to the usual HCC, it occurs in young patients (primarily 5–35 years old). On gross examination, fibrolamellar carcinomas are circumscribed gray or green masses ranging in size from 9 to 14 cm, and are usually single [5]. The tumors are solid, and frequently contain a central fibrous scar reminiscent of focal nodular hyperplasia. The interface of tumor with surrounding liver is scalloped and pushing, rather than infiltrative on gross examination, and the tumor is well circumscribed. The surrounding liver is as a rule not cirrhotic. The microscopic appearance is distinctive, with lamellar bands of collagen separating large polygonal tumor cells with abundant eosinophilic cytoplasm (Figure 4.2). The tumor cells contain single round to oval central nuclei, and the nuclear-tocytoplasmic ratio is relatively low due to the abundant granular cytoplasm, which on ultrastructural examination contains numerous swollen mitochondria. Accumulation of bile within the tumor is common, and cells may contain α-1-antitrypsin, seen as proteinaceous cytoplasmic inclusions, and fibrinogen, seen as pale areas within the cytoplasm known as “pale bodies.” α-Fetoprotein accumulation is not seen.

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Epidemiology and Diagnosis

(a)

(b)

Figure 4.3 Polyclonal antibodies to carcinoembryonic antigen cross-react with biliary glycoprotein to give a distinctive canalicular staining pattern in normal liver (a) and hepatocellular carcinoma (b).

Table 4.1 Immunohistochemical stains in the diagnosis of malignant tumors in the liver.

Cytokeratins AE1/AE3 CAM 5.2 CK 7/CK 20 HepPar1* MOC-31* α-Fetoprotein Polyclonal CEA* Monoclonal CEA

Hepatocellular carcinoma

Cholangiocarcinoma

Metastatic adenocarcinoma

Negative Positive Negative/negative Positive Negative Positive in 10–50% Canalicular Negative

Positive Positive Positive/negative Negative Positive Negative Cytoplasmic Cytoplasmic

Positive Positive Variable Negative (rare exceptions) Positive Rare Cytoplasmic Cytoplasmic

*Most useful

Sclerosing hepatocellular carcinoma The sclerosing subtype of HCC is a rare variant characterized by the presence of abundant fibrous stroma that lacks the distinctive lamellar quality seen in fibrolamellar carcinoma. The tumor cells are arranged in cords and acinar structures within this diffuse fibrous stroma. While previous reports indicate that sclerosing HCC occurs in older patients and may be associated with hypercalcemia, a more recent study reports a younger mean age (42 years) and normal serum calcium levels in the seven patients studied [6].

Special studies Although most HCCs are readily distinguished from metastatic tumors and other primary malignancies of the liver, their wide range of appearance occasionally overlaps with

42

other tumors. A limited panel of immunohistochemical stains has proven useful in some cases, and ultrastructural analysis may also provide evidence for hepatocellular differentiation. The most useful immunoperoxidase studies for diagnosis of HCC include antibodies to HepPar-1, carcinoembryonic antigen (CEA), and MOC-31 (Table 4.1). The antibody Hep Par 1 is a sensitive and relatively specific marker of hepatocyte differentiation, but may not be detectable in poorly differentiated tumors. Polyclonal antibodies to CEA, but not most monoclonal antibodies, cross-react with a biliary glycoprotein to produce a canalicular staining pattern in 60–90% of HCCs (Figure 4.3). While many adenocarcinomas will display cytoplasmic staining with antibodies to CEA, the canalicular pattern is considered specific for HCC. MOC-31,

CHAPTER 4

Pathology of Primary and Secondary Malignant Liver Tumors

Table 4.2 Staging of hepatocellular carcinoma and intrahepatic cholangiocarcinoma [9] (see Chapter 16). TNM definitions Primary tumor T1 Solitary tumor, without vascular invasion T2 Solitary tumor with vascular invasion or multiple tumors, none >5 cm T3 Multiple tumors >5 cm or tumor involving a major branch of the portal or hepatic vein(s) T4 Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum Regional lymph nodes N0 No regional lymph node metastases N1 Regional lymph node metastases

Figure 4.4 The low pattern appearance of the fetal pattern of hepatoblastoma has a distinctive alternating light and dark appearance, due to accumulation of glycogen in light-staining tumor cells.

Distant metastases M0 No distant metastases M1 Distant metastases

pediatric liver tumors and 25% of all liver tumors in children.

Stage grouping

Gross morphology

Stage Stage Stage Stage Stage Stage

I II IIIA IIIB IIIC IV

T1, N0, M0 T2, N0, M0 T3, N0, M0 T4, N0, M0 Any T, N1, M0 Any T, any N, M1

a cell surface glycoprotein, is generally absent in HCC, but present in almost all cholangiocarcinomas and adenocarcinomas metastatic to the liver [7]. Tumor staining for AFP is relatively specific for HCC; other tumors that may express AFP include germ cell tumors, gastric carcinomas and occasionally other gastrointestinal tract malignancies, and the occasional pancreatic and lung adenocarcinoma. However, AFP is relatively insensitive and positive staining is seen in 50% or less of tumors [8].

Tumor staging The most widely used staging system for HCC, developed by the International Union Against Cancer and the American Joint Committee on Cancer, incorporates tumor size, number of tumor deposits, and vascular invasion [9] (Table 4.2). Several criticisms have been levied against this system, including lack of ability to predict survival. Other schemes have been proposed, such as the Liver Cancer Staging Group of Japan system, but have not been widely adopted [10].

Hepatoblastoma Hepatoblastoma is the most common primary tumor of liver in young children, accounting for over 50% of malignant

Hepatoblastoma is typically a single mass, located in the right lobe in about 60% of cases. The tumors range in size from 6 to over 20 cm, are generally well circumscribed, and may be encapsulated. The cut surface is fleshy, faintly lobulated, pale tan to gray–white, and often variegated because of hemorrhage and necrosis, which may be prominent and more extensive if preoperative chemotherapy has been given [11]. The background liver is generally normal.

Histologic classification Hepatoblastomas are broadly subdivided into epithelial, and mixed epithelial/mesenchymal types. Epithelial hepatoblastomas, the most common type, are further subdivided into fetal, embryonal, macrotrabecular, and small cell undifferentiated patterns. The fetal pattern of hepatoblastoma most closely resembles developing liver. The cells are easily recognized as showing hepatocellular differentiation and are arranged in plates two cell layers thick separated by sinusoids. On low power, zones of pale-staining tumor cells with relatively clear cytoplasm alternate with areas of more deeply eosinophilic cells, imparting a distinctive striped appearance (Figure 4.4). The fetal type is generally divided into mitotically inactive (two or fewer mitotic figures per 10 high power fields) and mitotically active subtypes (more than two mitoses per 10 high power fields) [12]. In the embryonal pattern, the tumor cells are smaller and more primitive in appearance compared to the fetal type cells. These cells are irregular and angulated, with hyperchromatic nuclei and less cytoplasm, and are arranged in sheets, pseudoacini, and ribbons rather than cell plates. The macrotrabecular pattern is distinguished by the presence of large broad trabeculae more than 10 cells thick. The cells may be fetal-

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Epidemiology and Diagnosis

Table 4.3 Staging of hepatoblastoma. Stage I Stage II Stage III

Stage IV

Complete resection Microscopic residual tumor Gross residual tumor: Primary completely resected, positive lymph nodes Primary incompletely resected Distant metastases

or embryonal-type, or may resemble cells of HCC. The small cell undifferentiated pattern is relatively rare; it is characterized by small primitive cells with scant cytoplasm and hyperchromatic nuclei, growing in loosely cohesive sheets and clusters. Mixed epithelial/mesenchymal hepatoblastomas contain areas of fetal epithelial and embryonal cells admixed with primitive mesenchyme. The mesenchymal cells are elongated, spindle cells resembling fibroblasts; some areas may have a myxoid appearance. Deposition of osteoid-like material is seen in the mixed hepatoblastomas, and cartilage is often present.

Staging and pattern of spread Hepatoblastoma is staged by a scheme used by the Children’s Cancer Study Group Hepatoma Study [13] (Table 4.3). Hepatoblastoma spreads to regional lymph nodes and can disseminate through hematogenous routes as well. Common sites of metastases include adrenal, lung, bone, and brain.

Cholangiocarcinoma Cholangiocarcinomas are the second most frequent primary hepatic malignancy, and make up from 5 to 30% of malignant hepatic tumors. Although several classification schemes for these malignant bile duct tumors have been proposed, the most widely accepted divides these lesions into two broad categories: intrahepatic (peripheral) and extrahepatic, which includes hilar (Klatskin) tumors.

Peripheral or intrahepatic cholangiocarcinomas The Liver Cancer Study Group of Japan has defined peripheral cholangiocarcinoma as cholangiocarcinoma arising in a segmental duct or a more peripheral duct [14]. Intrahepatic cholangiocarcinoma is currently staged using the same tumor/node/metastasis (TNM) classification and stage grouping as HCC [9] (see Table 4.2).

Gross and microscopic features On gross examination, intrahepatic cholangiocarcinomas are generally gray–white to tan masses; larger lesions may contain areas of central necrosis or, less commonly, hemorrhage. Most tumors are firm because of the prominent desmoplastic stroma, which may be gritty because of dystrophic calcifications. In general, the intrahepatic cholangi-

44

Figure 4.5 The neoplastic cells of cholangiocarcinoma form tubules and glands within a prominent fibrous stroma.

ocarcinoma consists of a single nonencapsulated mass in a noncirrhotic liver, although satellite lesions may be present. The margins may be deceptively well circumscribed on gross examination, but microscopic examination shows infiltrative borders. Rarely, involvement of portal or hepatic veins may be seen, and occasionally intraductal growth occurs. Some investigators have subdivided intrahepatic cholangiocarcinomas based on the pattern of growth, and report that tumors without biliary strictures behave more like HCC, in that they are more likely to occur in a diseased liver and have frequent intrahepatic spread without lymph node metastases [14]. Most cholangiocarcinomas are adenocarcinomas; rarely, areas of squamous differentiation may be seen, and sarcomatoid variants have been reported [15]. Other variants include papillary adenocarcinoma, found generally within larger ducts, and signet ring cell carcinoma. The most common microscopic pattern is a well to moderately differentiated adenocarcinoma forming small tubular glands and duct-like structures (Figure 4.5). The tumor cells are low cuboidal to columnar, with clear to eosinophilic cytoplasm and round to oval nuclei. Intracellular mucin production may be scant, but is usually demonstrable with special stains for mucin; typically a mixture of neutral and acidic mucins is found. A desmoplastic stroma is generally prominent, but is not always present. Perineural and lymphovascular invasion is common, and cholangiocarcinomas often involve portal tracts, by spread either within portal vein radicals or within the intrahepatic biliary tree. Bile ducts in adjacent portal tracts may demonstrate varying degrees of epithelial dysplasia; however, it is usually not possible to identify a specific bile duct of origin.

Differential diagnosis The primary challenge for the pathologist in diagnosing most intrahepatic cholangiocarcinomas is distinction from metastatic adenocarcinoma. Primary sites producing tumors with

CHAPTER 4

similar histology include pancreas, extrahepatic biliary tree, breast, and occasionally lung. Immunohistochemical stains are of limited use in distinguishing cholangiocarcinoma from other adenocarcinomas, and mucin stains are helpful only in distinguishing cholangiocarcinoma from HCC. The distinction between cholangiocarcinoma and metastatic adenocarcinoma therefore depends heavily on the exclusion of a primary site elsewhere. Comparative immunohistochemical studies suggest that cytokeratins (CKs) 7 and 20 may be useful in some cases in distinguishing peripheral cholangiocarcinomas, which are generally CK 7+/CK 20–, from colorectal metastases, which are usually CK 7–/CK 20+ [7, 16]. The distinction between HCC and cholangiocarcinoma is usually more straightforward. In problematic cases, a panel of immunohistochemical stains can be employed to distinguish between the two (see Table 4.1).

Extrahepatic cholangiocarcinoma Gross and microscopic features The typical gross appearance of perihilar cholangiocarcinomas is dense white scar infiltrating the hepatic hilum and extending into the adjacent parenchyma. In cases of sclerosing cholangitis, the presence of tumor on gross examination may be obscured by dense fibrosis. The bile duct may be encircled and thickened by dense desmoplastic tumor. In some cases, the tumor is papillary and protrudes into the lumen of the bile duct. In general, the microscopic appearance is similar to that of intrahepatic cholangiocarcinoma, with most of the tumors composed of small well-formed ducts. Desmoplasia is a prominent feature in many perihilar cholangiocarcinomas, and perineural invasion is commonly found. The differential diagnosis includes benign reactive changes and bile ductular proliferation; in patients with biliary stents, diagnosis may be particularly difficult because of the significant degree of cellular atypia associated with reactive change in bile duct epithelium.

Staging Perihilar cholangiocarcinoma can be staged using a TNM classification scheme devised by the American Joint Committee on Cancer (Table 4.4) for staging extrahepatic bile duct carcinomas [9]. For more clinically oriented staging systems see Chapter 16.

Mixed hepatocellular/cholangiocarcinoma Occasional primary epithelial malignancies in the liver will show divergent differentiation, with features of both cholangiocarcinoma and HCC. These tumors assume one of two patterns, termed “collision tumors” and “transition tumors” [15]. In the “collision tumor,” different areas of the neoplasm or separate tumor masses in the liver show different patterns of differentiation, with separate areas of HCC and cholangiocarcinoma. The “transition tumors” show more intermixed patterns. Most cases show the same multiple

Pathology of Primary and Secondary Malignant Liver Tumors

Table 4.4 Staging of perihilar cholangiocarcinoma [9]. TNM definitions Primary tumor Tis Carcinoma in situ T1 Tumor confined to the bile duct histologically T2 Tumor invades beyond the wall of the bile duct T3 Tumor invades the liver, gallbladder, pancreas, and/or ipsilateral branches of the portal vein or hepatic artery T4 Tumor invades any of the following: main portal vein or its branches bilaterally, common hepatic artery, or other adjacent structures, such as the colon, stomach, duodenum, or abdominal wall Regional lymph nodes N0 No regional lymph node metastasis N1 Regional lymph node metastases Metastasis M0 M1

No distant metastasis Distant metastasis

Stage grouping Stage Stage Stage Stage Stage

0 IA IB IIA IIB

Stage III Stage IV

Tis, N0, M0 T1, N0, M0 T2, N0, M0 T3, N0, M0 T1, N1, M0 T2, N1, M0 T3, N1, M0 T4, any N, M0 Any T, any N, M1

allelic losses in both tumor components, suggestive of divergent differentiation from a single clone [17]. Metastases maintain the mixed pattern or exhibit hepatocellular differentiation [18].

Biliary cystadenocarcinoma Biliary cystadenocarcinoma is a rare tumor, generally arising in a pre-existing biliary cystadenoma. These tumors arise in adults, and although benign biliary cystadenomas are more common in women, for cystadenocarcinomas the sex ratio is approximately 1 : 1 [15].

Gross morphology Most biliary cystadenocarcinomas are multilocular, although rare unilocular cases have been reported. Cystadenocarcinomas in one series ranged in size from 3 cm to 30 cm, essentially no different in size from benign biliary cystadenomas [15]. The cyst fluid may be clear mucinous, bile-stained, or blood tinged. The cyst lining may contain papillary projec-

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Epidemiology and Diagnosis

tions into the cyst lumen. Areas of solid thickening and large papillary projections are clues to malignancy.

Microscopic features The epithelial lining of the cysts generally consists of tall columnar cells and should display cytologic features of malignancy. The tumor infiltrates the underlying cyst wall. Most biliary cystadenocarcinomas are well differentiated; the most common patterns are a tubulopapillary or tubular adenocarcinoma. Rarely, the tumor shows adenosquamous differentiation. The stroma is variable in biliary cystadenocarcinomas; mesenchymal ovarian-type stroma is often present in tumors in women; in men, the stroma consists of dense fibrosis.

Determination of malignancy The prediction of behavior from morphologic features is difficult in cystic mucinous neoplasms. Many otherwise benign biliary cystadenomas have areas of nuclear enlargement, crowding, and stratification, considered areas of dysplastic change. Many pathologists reserve the term “cystadenocarcinoma” for cases with frankly invasive adenocarcinoma involving the stroma or adjacent parenchyma. Surgical resection offers the greatest opportunity for cure; long-term survival is relatively high for women with biliary cystadenocarcinomas arising in pre-existing cystadenomas with ovarian-type stroma. Cystadenocarcinomas in men may have a more aggressive course [15].

Primary hepatic sarcomas Angiosarcoma The most common primary sarcoma of the liver is angiosarcoma, occurring in older men (only 25% of patients are women), with a peak incidence in the sixth and seventh decades. It is a rare tumor, accounting for only 25–30 cases per year in the United States. On gross examination, the entire liver is usually involved by angiosarcoma, which appears as gray–white hemorrhagic masses measuring up to 5 cm. The liver is not cirrhotic in most cases. The tumor cells of angiosarcoma are spindle-shaped, with pale cytoplasm with indistinct cell borders. Nuclei are irregular, angulated, enlarged, and hyperchromatic. Angiosarcoma grows in a characteristic pattern by extending along preexisting vascular channels in the liver. With tumor progression the hepatocytes atrophy and disruption of the local architecture by the growing tumor produces larger and larger vascular channels (Figure 4.6). Eventually blood-filled cavitary spaces lined by tumor cells are formed. Thorotrast deposits, if present, appear as coarse brown refractile material in Kupffer cells and the fibrous tissue of portal tracts or Glisson’s capsule.

46

Figure 4.6 Angiosarcoma forms blood-filled channels of varying sizes; tumor cells are plump spindle cells with irregular pleomorphic nuclei.

A variety of immunohistochemical stains may be used to confirm vascular differentiation in hepatic angiosarcomas. The cells are usually positive for Factor VIII-related antigen and Ulex europeus, although staining may be focal and weak in poorly differentiated tumors. Staining for CD34 antigen may be more sensitive than staining for Factor VIIIrelated antigen and is considered more specific than Ulex europeus. Ultrastructural examination shows Weibel-Palade bodies, the characteristic feature establishing endothelial differentiation. Differentiation from other vascular neoplasms may be a problem, but the distinction rests on the presence of malignant cytologic features in angiosarcoma. Overlap with epithelioid hemangioendothelioma may occur. Primary angiosarcoma in the liver must be distinguished from metastatic angiosarcoma on clinical grounds, as the pathologic features are identical.

Epithelioid hemangioendothelioma This tumor occurs in slightly younger patients than angiosarcoma and has a slight female preponderance [19]. Epithelioid hemangioendothelioma is usually multifocal, with firm white–tan sometimes gritty tumor nodules involving both hepatic lobes. Histologically, at the growing edge of tumor nodules, the tumor cells grow along pre-existing sinusoids, and the preservation of the lobular architecture with identifiable residual portal triads may be a clue to diagnosis. Intravascular growth of tumor cells also occurs [15]. Within the tumor nodules the tumor cells grow in small nests surrounded by a distinctive sclerotic or sometimes myxoid stroma (Figure 4.7). Two types of tumor cells are identified: a dendritic type, with irregular cell processes, and an epithelioid type, more rounded, with abundant cytoplasm. The cells of epithelioid hemangioendothelioma contain cytoplasmic vacuoles, which represent intracyto-

CHAPTER 4

Figure 4.7 In epithelioid hemangioendothelioma, the tumor cells are embedded in a sclerotic or myxoid stroma; cytoplasmic vacuoles (arrow) represent intracytoplasmic vascular lumina.

Pathology of Primary and Secondary Malignant Liver Tumors and diastase-resistant. These globules mark variably with immunohistochemical studies for α-1-antitrypsin, α-1chymotrypsin, and albumin but are negative for AFP [15]. Immunohistochemical studies on undifferentiated (embryonal) sarcoma show that the tumor cells stain with a variety of mesenchymal markers; in some cases cytokeratin positivity is reported [20]. These findings are interpreted as evidence of the capability of multipotential differentiation of the primitive tumor cells. The differential diagnosis for undifferentiated (embryonal) sarcoma includes embryonal rhabdomyosarcoma and mesenchymal hamartoma. Embryonal rhabdomyosarcoma occurs as a polypoid mass involving the large bile ducts at the hepatic hilum, and usually is seen in younger children. The cells should demonstrate rhabdomyoblastic differentiation [21]. Mesenchymal hamartoma is regarded by some as the benign counterpart of undifferentiated sarcoma [12]. It is less cellular than undifferentiated sarcoma and the cells do not display cytologic features of malignancy.

Other primary hepatic sarcomas

Figure 4.8 In undifferentiated (embryonal) sarcoma, stellate tumor cells are dispersed in a myxoid background. Large bizarre tumor cells containing eosinophilic proteinaceous droplets (arrow) are common in undifferentiated sarcoma.

This group of tumors is rare as a whole, and includes leiomyosarcoma, malignant fibrous histiocytoma, synovial sarcoma, solitary fibrous tumor, and liposarcoma [15]. Most occur in adults and prognosis is generally poor, except for solitary fibrous tumor, which generally behaves in a benign fashion. Histologically these tumors resemble their soft tissue counterparts in more common locations. Care must be taken to exclude primary sites elsewhere, especially the retroperitoneum, and to exclude metastatic gastrointestinal stromal tumor. Sarcomatoid HCC is also in the differential diagnosis, but can usually be excluded by thorough sampling of the tumor and immunohistochemical studies.

Primary hepatic lymphoma plasmic vascular lumina. High tumor cellularity may indicate a poor prognosis [15].

Undifferentiated sarcoma Although rare, undifferentiated or embryonal sarcoma is the most common hepatic sarcoma in children, and is the third most common malignant liver tumor of childhood, after hepatoblastoma and HCC. On gross examination, these tumors form large, circumscribed, gray–white soft gelatinous masses. Areas of necrosis, hemorrhage, and cystic degeneration are common. Microscopic examination shows pleomorphic stellate tumor cells within a myxoid stroma (Figure 4.8). The tumor cells vary greatly in size, but generally have hyperchromatic irregular nuclei; bizarre multinucleated tumor giant cells are frequently seen. Eosinophilic proteinaceous cytoplasmic globules are present in some tumor cells; these globules are periodic acid-Schiff (PAS)-positive

Although the liver is frequently involved by malignant lymphoma, primary hepatic lymphomas are rare. On gross examination, a single large tumor mass or multiple small masses are seen; diffuse hepatic involvement is present in 5–16% of cases [22]. Most primary hepatic lymphomas are classified as diffuse large cell lymphomas of B-cell lineage, although occasional T-cell malignancies such as gamma delta T-cell lymphoma are seen [23]. The neoplastic cells in most cases involve portal triads and may extend into the parenchyma as destructive tumor nodules. Sinusoidal infiltration is reported with T-cell malignancies. An association of primary hepatic lymphoma with acquired immunodeficiency syndrome (AIDS) has been noted [24], and primary lymphoma of the liver in association with chronic liver disease, including chronic hepatitis B and hepatitis C infection, has been described [25].

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Epidemiology and Diagnosis

Secondary tumors Metastatic tumors account for 95% of all malignancies involving the liver and for 50% of malignancies in the cirrhotic liver [26]. While the primary tumor site is often known at the time of liver biopsy, carcinomas of the lung and pancreas, and stomach and neuroendocrine tumors not infrequently present with hepatic metastases from previously undetected primaries.

Gross morphology Most metastases to the liver are multiple, but solitary nodules, with or without satellite lesions, do occur. Metastatic tumor can infiltrate the liver as small ill-defined nodules, simulating cirrhosis on gross examination. Size is variable. Most hepatic metastases are gray–white to yellow. Areas of necrosis and hemorrhage are frequently found, and umbilication due to central necrosis is common in colorectal carcinoma metastases. In most cases, the gross morphology is not distinctive, although metastases from malignant melanoma may have a tell-tale dark brown or black hue. Although most hepatic metastases are parenchymal or capsule-based lesions, colorectal carcinoma may rarely metastasize to bile ducts and grow as an intrabiliary tumor [27].

Microscopic features Most metastatic tumors to the liver retain the histologic features of the primary tumor. Sinusoidal growth pattern is often seen at the edge of the tumor mass, particularly in poorly differentiated carcinomas.

Distinction from primary tumors On occasion, distinction of a metastasis from a primary neoplasm of the liver may be difficult. One of the more common problems is distinguishing intrahepatic cholangiocarcinoma from metastatic adenocarcinoma. Histologic features of cholangiocarcinoma and other adenocarcinomas, particularly those from the pancreas and other gastrointestinal sites, may be very similar. Differentiation of metastatic clear cell carcinomas growing in a trabecular pattern, such as renal cell carcinoma, from HCC may be difficult. A limited number of immunohistochemical stains are useful in these situations (see Table 4.1). Expression of prostatic specific antigen and prostatic acid phosphatase is relatively specific; however, since prostatic adenocarcinoma rarely presents as liver metastases, this situation rarely arises in the evaluation of a liver tumor. Thyroglobulin stain may help identify metastatic thyroid carcinoma. Breast carcinoma metastases may theoretically be diagnosed by positive immunohistochemistry for gross cystic disease fluid protein. Caution should be used in interpreting positivity for estrogen and progesterone receptors as indication of origin from breast, as primary liver tumors and other metastatic carcinomas can also express

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Figure 4.9 Metastatic neuroendocrine or carcinoid tumor forms tubular, trabecular, or cribriform structures in the liver, usually associated with desmoplasia. The tumor cells have uniform round to oval nuclei with evenly dispersed chromatin and without prominent nucleoli.

these receptors [28]. The diagnosis of malignant melanoma is usually easily confirmed by using immunohistochemistry for S-100 protein and HMB-45.

The problem of neuroendocrine tumors in the liver Because liver metastases from neuroendocrine tumors may be more indolent than other secondary tumors (Chapter 36), it is important for the pathologist to identify these lesions, although distinction from HCC may be difficult in a small biopsy. Metastatic neuroendocrine tumor should be suspected when the tumor has a nesting, organoid, or trabecular pattern (Figure 4.9), with tumor trabeculae separated by thin connective tissue stroma rather that floating free as in HCC. The chromatin pattern is usually finely granular and nucleoli are inconspicuous, in contrast to the large nucleoli seen in HCC. Immunohistochemistry for chromogranin and other neuroendocrine markers are useful in identifying neuroendocrine tumors. Caution must be used in interpreting the results of immunohistochemical studies, however. While tumors with typical neuroendocrine morphology and prominent positivity for chromogranin are almost always metastatic to the liver, HCC and cholangiocarcinoma may display focal positivity for neuroendocrine markers. Careful correlation of biopsy findings with clinical impression is helpful in problematic cases.

Carcinoma of the gallbladder Gross morphology Carcinoma of the gallbladder may be visible as a solid mass, polypoid mucosal growth, a mucosal plaque, or may cause

CHAPTER 4

Pathology of Primary and Secondary Malignant Liver Tumors

Table 4.5 Staging of gallbladder cancer [9]. TNM definitions

Figure 4.10 The histologic appearance of adenocarcinoma of the gallbladder is varied; in this example the tumor is moderately differentiated and associated with calcifications (arrow).

diffuse thickening of the gallbladder wall. Extension into the liver is a common pattern of spread, and these cases may show a concentric ring of tumor growth encasing the gallbladder.

Microscopic appearance Most gallbladder cancers are readily recognizable as adenocarcinomas (Figure 4.10). Many are well differentiated, with variable sized glands lined by columnar or cuboidal cells. The tumor cells have clear to eosinophilic cytoplasm and occasional tumor cells show goblet cell differentiation. Gallbladder carcinomas are associated with a desmoplastic response in most cases. Extension into Rokitansky–Aschoff sinuses should not be confused with tumor invasion. Other histologic patterns include papillary adenocarcinoma, adenosquamous or squamous differentiation, poorly differentiated signet ring cell carcinoma, primary carcinoid tumors, and giant cell carcinoma with osteoclast-like giant cells [29]. Clear cell adenocarcinomas with abundant glycogen accumulation may be confused with metastatic renal cell carcinoma. Small cell undifferentiated carcinoma is usually associated with recognizable adenocarcinoma. Malignant mesenchymal tumors of the gallbladder are quite rare; rhabdomyosarcoma, angiosarcoma, and malignant histiocytoma are among those reported [29].

Staging In the United States, gallbladder cancer is staged using a TNM system (Table 4.5) [9]. The predominant pattern of tumor spread is by direct extension, primarily involving the gallbladder fossa and the liver, followed by involvement of the extrahepatic bile ducts. Duodenum, pancreas, transverse colon, and hepatic artery and portal vein may also be involved by direct extension. Regional lymph nodes are

Primary tumor Tis Carcinoma in situ T1 Tumor invades lamina propria or muscle layer T1a Tumor invades lamina propria T1b Tumor invades muscle layer T2 Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver T3 Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts T4 Tumor invades main portal vein or hepatic artery or invades two or more extrahepatic organs or structures Regional lymph nodes N0 No regional lymph node metastasis N1 Regional lymph node metastasis Metastasis M0 M1

No distant metastasis Distant metastasis

Stage grouping Stage Stage Stage Stage Stage

0 IA IB IIA IIB

Stage III Stage IV

Tis, N0, M0 T1, N0, M0 T2, N0, M0 T3, N0, M0 T1, N1, M0 T2, N1, M0 T3, N1, M0 T4, Any N, M0 Any T, any N, M1

positive in up to 70% of cases. Frequent sites of hematogenous spread include liver, lungs, and bone.

Self-assessment questions 1 Which of the following are considered precursor lesions for hepatocellular carcinoma? (more than one answer is possible) A High grade dysplastic nodule B Focal nodular hyperplasia C Small cell change D Mesenchymal hamartoma E Von Meyenburg complex 2 Which one of the following statements concerning fibrolamellar carcinoma is true?

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A Is associated with hepatitis B infection B Is strongly associated with the use of oral contraceptives C Occurs in the cirrhotic liver D Occurs primarily in young adults E Is associated with a poorer outcome compared to typical hepatocellular carcinoma 3 Immunohistochemistry for α-fetoprotein is the best marker for hepatocellular differentiation in hepatic tumors, because it is the most sensitive and specific test available. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 4 Which of the following are important prognostic indicators for hepatocellular carcinoma? (more than one answer is possible) A Production of bile by tumor cells B Overall TNM stage C Microvascular invasion D Cirrhosis in the background liver 5 Which one of the following statements concerning hepatoblastoma is true? A Is the most common hepatic tumor occurring in teenagers B Is staged using an AJCC/UICC TNM staging system C Is broadly divided into epithelial and mixed epithelial/mesenchymal subtypes on the basis of histologic appearance D The small cell subtype is associated with a better prognosis 6 Intrahepatic cholangiocarcinomas are associated with which of the following conditions? (more than one answer is possible) A Primary sclerosing cholangitis B Liver flukes C Recurrent bacterial cholangitis D Thorotrast 7 The histologic differential diagnosis for intrahepatic cholangiocarcinomas includes metastatic adenocarcinoma, because the typical microscopic appearance for both tumors is that of glandular structures embedded in a desmoplastic stroma. A First part wrong, second part wrong B First part correct, second part wrong

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C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 8 Which of the following statements regarding hepatic sarcomas are true? (more than one answer is possible) A Leiomyosarcoma is the most common primary hepatic sarcoma B Epithelioid hemangioendotheliomas are common neoplasms in elderly men C The most common hepatic sarcoma in children is embryonal or undifferentiated sarcoma D The tumor cells in embryonal sarcoma are small, uniform in cell size, and show little pleomorphism E The differential diagnosis for hepatic sarcomas includes sarcomatoid (spindle cell) hepatocellular carcinoma 9 Metastatic neuroendocrine tumors in the liver may mimic hepatocellular carcinoma in microscopic appearance on small biopsies, because both tumors may exhibit trabecular architecture. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 10 Which one of the following statements regarding gallbladder cancer is true? A Gallbladder carcinoma is commonly associated with diffuse calcification of the gallbladder wall (porcelain gallbladder) B Most gallbladder tumors are sarcomas C DNA content as measured by flow cytometry is an important prognostic indicator D Epithelial dysplasia is considered a precursor lesion for gallbladder carcinoma E Most gallbladder cancers are suspected clinically prior to cholecystectomy

References 1 Hirohashi S, Ishak KG, Kojiro M, et al. Hepatocellular carcinoma. In: Hamilton SR, Aaltonen LA, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System. Lyon: IARC Press, 2000. 2 International Working Party. Terminology of nodular hepatocellular lesions. Hepatology 1995;22:983–93.

CHAPTER 4

3 Hytiroglou P. Morphological changes of early human hepatocarcinogenesis. Semin Liver Dis 2004;24:65–75. 4 Natarajan S, Theise ND, Thung SN, Antonio L, Paronetto F, Hytiroglou P. Large-cell change of hepatocytes in cirrhosis may represent a reaction to prolonged cholestasis. Am J Surgl Pathol 1997;21:312–8. 5 Torbenson M. Review of the clinicopathologic features of fibrolamellar carcinoma. Adv Anat Pathol 2007;14:217–23. 6 Yeh C-N, Hung C-F, Lee K-F, Chen M-F. Sclerosing hepatocellular carcinoma: clinicopathologic features in seven patients from Taiwan and review of the literature. Hepato-Gastroenterology 2005;52:1201–5. 7 Kakar S, Gown AM, Goodman ZD, Ferrell LD. Best practices in diagnostic immunohistochemistry: hepatocellular carcinoma vesus metastatic neoplasms. Arch Pathol Lab Med 2007;131:1648– 54. 8 Varma V, Cohen C. Immunohistochemical and molecular markers in the diagnosis of hepatocellular carcinoma. Adv Anat Pathol 2004;11:239–49. 9 Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual. New York: Springer-Verlag, 2002. 10 Minagawa M, Ikai I, Matsuyama Y, Yamaoka Y, Makuuchi M. Staging of hepatocellular carcinoma: assessment of the Japanese TNM and AJCC/UICC TNM systems in a cohort of 13,772 patients in Japan. Ann Surg 2007;245:909–22. 11 Saxena R, Leake JL, Shafford EA, et al. Chemotherapy effects on hepatoblastoma. A histological study. Am J Surg Pathol 1993;17:1266–71. 12 Finegold MJ. Hepatic tumors in childhood. In: Russo P, Ruchelli eD, Piccoli D, eds. Pathology of Pediatric Gastrointestinal and Liver Disease. New York: Springer-Verlag, 2004, 300–46. 13 Reynolds M. Pediatric liver tumors. Semin Surg Oncol 1999; 16:159–72. 14 Yamanaka N, Okamoto E, Ando T, et al. Clinicopathologic spectrum of resected extraductal mass-forming intrahepatic cholangiocarcinoma. Cancer 1995;76:2449–56. 15 Ishak KG, Goodman ZD, Stocker JT. Tumors of the Liver and Intrahepatic Bile Ducts, 3rd series, fascicle 31 vol. Washington, DC: Armed Forces Institute of Pathology, 2001. 16 Rullier A, Le Bail B, Fawaz R, Blanc JF, Saric J, Bioulac-Sage P. Cytokeratin 7 and 20 expression in cholangiocarcinomas varies along the biliary tract but still differs from that in colorectal carcinoma metastasis. Am J Surg Pathol 2000;24:870–6. 17 Fujii H, Zhu XG, Matsumoto T, et al. Genetic classification of combined hepatocellular-cholangiocarcinoma. Hum Pathol 2000;31:1011–7. 18 Maeda T, Adachi E, Kajiyama K, Sugimachi K, Tsuneyoshi M. Combined hepatocellular and cholangiocarcinoma: proposed criteria according to cytokeratin expression and analysis of clinicopathologic features. Hum Pathol 1995;26:956–64. 19 Mehrabi A, Kashfi A, Fonouni H, et al. Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive

Pathology of Primary and Secondary Malignant Liver Tumors

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review of the literature with emphasis on the surgical therapy. Cancer 2006;107:2108–21. Kiani B, Ferrell LD, Qualman S, Frankel WL. Immunohistochemical analysis of embryonal sarcoma of the liver. Appl Immunohistochem Mol Morphol 2006;14:193–7. Nicol K, Savell V, Moore J, et al. Distinguishing undifferentiated embryonal sarcoma of the liver from biliary tract rhabdomyosarcoma: a Children’s Oncology Group study. Pediatr Dev Pathol 2007;10:89–97. Aozasa K, Mishima K, Ohsawa M. Primary malignant lymphoma of the liver. Leuk Lymphoma 1993;10:353–7. Tamaska J, Adam E, Kozma A, et al. Hepatosplenic gammadelta T-cell lymphoma with ring chromosome 7, an isochromosome 7q equivalent clonal chromosomal aberration. Virchows Archiv 2006;449:479–83. Jacobs SL, Rozenblit A. HIV-associated hypervascular primary Burkitt’s lymphoma of the liver. Clin Radiol 2006;61:453–5. Salmon JS, Thompson MA, Arildsen RC, Greer JP. NonHodgkin’s lymphoma involving the liver: clinical and therapeutic considerations. Clin Lymphoma Myeloma 2006;6:273–80. Melato M, Laurino L, Mucli E, Valente M, Okuda K. Relationship between cirrhosis, liver cancer, and hepatic metastases. An autopsy study. Cancer 1989;64:455–9. Riopel MA, Klimstra DS, Godellas CV, Blumgart LH, Westra WH. Intrabiliary growth of metastatic colonic adenocarcinoma: a pattern of intrahepatic spread easily confused with primary neoplasia of the biliary tract. Am J Surg Pathol 1997;21:1030–6. Nash JW, Morrison C, Frankel WL. The utility of estrogen receptor and progesterone receptor immunohistochemistry in the distinction of metastatic breast carcinoma from other tumors in the liver. Arch Pathol Lab Med 2003;127:1591–5. Albores-Saavedra J, Henson DE, Klimstra DS. Tumors of the Gallbladder, Extrahepatic Bile Ducts, and Ampulla of Vater, 3rd series, fascicle 27 vol. Washington, DC: Armed Forces Institute of Pathology, 2000.

Self-assessment answers 1 2 3 4 5 6 7 8 9 10

A, C D A B, C, D C A, B, C, D E C, E E D

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5

Epidemiology, Etiology, and Natural History of Hepatocellular Carcinoma Wei-Chen Lee and Miin-Fu Chen Department of General Surgery, Chang-Gung Memorial Hospital, Chang-Gung University Medical School, Taoyuan, Taiwan

Malignant liver tumor ranks the fifth most common cancer in the world and the third most common cause of cancer mortality [1]. This indicates that they are not only common but also very deadly. Among various primary malignant liver tumors, hepatocellular carcinoma (HCC) is the most common and accounts for 80–90% of all malignant liver tumors. This chapter describes the epidemiology, etiology, and natural history of HCC (regarding treatment of HCC please see Chapters 16 and 26).

Epidemiology Geographic area/ethnic group The incidence of HCC is unevenly distributed in the world. Eastern Asia has the highest incidence, followed by middle Africa, South-East Asia, the Pacific Islands, East Africa, West Africa, Southern Europe, Southern Africa, Eastern and Western Europe, South and North Americas, Australia and New Zealand, Northern Europe, and Central America [2]. The three highest incidence rates of HCC are 35.2–48.8 per 100 000 in Eastern Asia, 24.2 per 100 000 in middle Africa, and 18.3 per 100 000 in South-East Asia and the Pacific Islands. The incidence rates in Europe, the Americas, Australia, and New Zealand are all below 10 per 100,000. The two lowest incidence rates are in Northern Europe and Central America, with only 2.6 and 2.1 per 100 000, respectively [2, 3]. The incidence rates among ethnic groups are also varied. In the United States, the incidence rate is twice that in Asians compared to African Americans, and the rate in African Americans is higher than that in the whites [3].

Gender Primary malignant liver tumor ranks the fifth most common cancer for males and the eighth for females, and males also have a higher incidence of HCC than females [1]. The ratio of

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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incidence rates between males and females ranges from 1.3 : 1 to 4 : 1 [3, 4]. The reason why males are more susceptible to this disease than females is not really known. Sex hormones may be an important factor. In a community-based cohort study carried out in Taiwan, serum samples collected from 9691 males showed that 35 newly developed HCC cases were associated with elevated testosterone levels [5].

Age The age distribution of HCC varies around the world and depends on region, sex and etiology. In high-risk areas, the incidence of HCC, increasing with age, reaches its peak at the age of 50 years and plateaus afterwards. In low-risk areas, the incidence of HCC steadily increases with age until 75 years or even older [3]. In regard to the influence of sex on age distribution, males have their peak incidence rate 5 years earlier than females. In regard to the influence of etiology on age distribution, the mean age for hepatitis B-related HCC is 10 years earlier than that for hepatitis C-related HCC. In Japan, for example, most HCC cases are related to hepatitis C and the incidence of HCC reaches a plateau at the age of 65 years, whereas in Korea, where most of the HCC cases are related to hepatitis B, the mean age for HCC onset is 55 years [2]. In a study from Taiwan, clinical diagnosis was made at a mean age of 49 years for hepatitis B-related HCC and 61 years for hepatitis C-related HCC [6].

Etiology Eighty to ninety per cent of all HCC cases develop from underlying chronic liver diseases. Multiple risk factors associated with chronic liver diseases have been identified. These include cirrhosis, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, alcohol consumption, tobacco consumption, iron overload and hereditary hemochromatosis, obesity, and ingestion of aflatoxin-contaminated food. However, genetic events and cell transformation involved in hepatocarcinogenesis are still poorly understood. There have been recent reports about HCC displaying genomic alterations, which include chromosomal instability, CpG

CHAPTER 5

Epidemiology, Etiology, and Natural History of Hepatocellular Carcinoma

island methylation, DNA rearrangements, and DNA hypomethylation [7]. Nevertheless, the exact mechanism of hepatocarcinogenesis remains an enigma.

Cirrhosis Cirrhosis is a common late-stage development of many liver diseases including chronic viral hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis, hemochromatosis, primary biliary cirrhosis, autoimmune liver diseases, and metabolic disorder diseases. HCC is strongly associated with cirrhosis. Most HCC develops from cirrhosis induced by chronic viral hepatitis, alcoholic liver disease, hemochromatosis, or metabolic disorder diseases. On the other hand, primary biliary cirrhosis and autoimmune liver diseases rarely give rise to HCC [8]. HCC usually develops after many years of chronic hepatitis. Hepatocarcinogenesis is a complex procedure which remains to be unraveled. The procedure involves gene alterations and eventually malignant transformation of hepatocytes. Cirrhosis is the end stage of chronic inflammation, which involves cell damage, cell regeneration, and cell proliferation. During cell damage and cell regeneration, the chronic inflammatory liver may provide an environment for gene mutation or instability, which leads to HCC development [9]. However, as HCC rarely develops in autoimmunity-induced cirrhotic livers, factors other than chronic liver inflammation must contribute to the development of HCC.

Hepatitis B virus Hepatitis B virus infection is a major cause of HCC, especially in Eastern and South-East Asia. Chronic active inflammation of HBV may lead to fibrosis and cirrhosis, which contribute to the development of HCC. Most HBV-related HCC is associated with cirrhosis. However, sometimes HBVrelated HCC also develops in liver without cirrhotic change. In fact, HBV itself is an important factor for HCC. In a study from Taiwan, the risk of HCC development increased 10-fold in males who were positive for HBsAg, and 60-fold for males who were positive for both HBsAg and HBeAg, compared with males who were negative for HBsAg [10]. By measuring the level of HBV DNA, the replication level of HBV can be evaluated. However, using the replication level of HBV to predict HCC development is still controversial. Currently, it is known that HBV DNA sequence can integrate into cellular DNA in HCC tissue or even in the nontumor portion of liver tissue with chronic inflammation. HBV insertion may cause chromosomal deletion at HBV DNA insertion sites and thus increase chromosomal instability. HBV DNA integration may also occur in genes which encode proteins for cell signaling, proliferation, and viability [11]. Cell proliferation brought about by chronic inflammation may cause rearrangement of the sequence of the inserted HBV and induce cell transformation, and hence increase the possibility of HCC development.

That HBV is an important cause of HCC can be further proven by the results of vaccination against HBV. In Taiwan, HBV infection is highly prevalent and most HCC is associated with it. A mass vaccination program against HBV was launched in 1984. Since then, all neonates born to HBVcarrier mothers have been vaccinated against HBV, and the incidence of HCC has declined from 0.52 to 0.13 per 100 000 children aged 6–9 years [12].

Hepatitis C virus Hepatitis C virus infection is another major cause of chronic liver diseases. The clinical course of HCV infection progresses from acute inflammation to fibrosis, and eventually cirrhosis. Although it varies in rate, in most cases the progression from infection to cirrhosis takes more than 20 years. HCC is a complication of HCV-related cirrhosis, particularly in the United States, Europe, Australia, and Japan. The relative risk of HCC among hepatitis C patients ranges from 11.5 to 20 [3, 4, 13]. The annual incidence rate of HCC developing from HCV-related cirrhosis is around 1–4%, but is up to 7% in Japan [3]. Currently, pegylated interferon plus ribavirin is used to treat HCV infection and can achieve a sustained viral response rate of 50–60%. However, whether treatment for HCV infection can reduce HCC development is still controversial. The mechanism of HCV-inducing HCC may be a result of viral cytopathic effects. Chronic liver injury by HCV induces regeneration and proliferation of hepatocytes. Frequent hepatocyte proliferation increases the chance of genetic mutation or instability and accumulation of genetic mutation or instability enhances the possibility of malignant transformation of hepatocytes. A recent study showed that chronic inflammation in hepatitis C-directed hepatic transforming growth factor (TGF)-β signaling to fibrogenesis, accelerating liver fibrosis and so increasing the risk of HCC [14].

Alcohol Most alcohol-related HCC develops in cirrhotic livers resulting from long-term alcohol consumption. The risk of HCC development markedly increases if alcohol consumption exceeds 80 g daily for more than 10 years [15]. In fact, the risk of HCC is proportionate to alcohol consumption. The relative risk of HCC is 1.17 for alcohol consumption at 25 g per day, 1.36 at 50 g per day, and 1.86 at 100 g per day [16]. For patients with hepatitis B or C, alcohol is particularly conducive to HCC. A study from Taiwan showed that the risk of HCC increased three-fold to four-fold in hepatitis B patients who consumed alcohol compared with patients who did not, and two studies from Japan and Taiwan showed that the risk increased two-fold in hepatitis C patients who consumed alcohol compared with patients who did not [15]. The mechanism by which alcohol causes HCC is unknown, yet it has been found in studies on animals that alcohol alone cannot induce HCC. It is postulated

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Epidemiology and Diagnosis

that the mechanism may involve oxidative stress, DNA methylation, decreased immune surveillance, and genetic susceptibility.

Hemochromatosis Hemochromatosis, whether hereditary hemochromatosis or an iron overload disorder, is a well-known risk factor for HCC. Patients with hereditary hemochromatosis have a relative risk of HCC ranging between 93 and 200 [17, 18]. Iron overload disorders, whether dietary iron overload in Africa or homozygous β-thalassemia, also increase the incidence of HCC. The possible mechanisms of iron-inducing HCC include direct and indirect effects. Cell proliferation and direct damage to DNA resulting in inactivation of tumor suppressor genes, such as p53, have a direct effect in engendering of HCC, while formation of reactive oxygen species in the liver, lipid peroxidation, and acceleration of fibrogenesis lead to HCC indirectly [19, 20].

Obesity Epidemiologic studies have shown that obesity is a significant risk factor for the development of HCC. In a study enrolling 43 965 obese patients from Denmark, the relative risk of HCC development in these patients was 1.9-fold that of the general population [21]. In another study from the United States on the relationship between mortality from cancer and body mass index (BMI), the relative risk of mortality from liver cancer was 4.52-fold for males and 1.68-fold for females having a BMI equal to or greater than 35 kg/m2 compared to the reference groups with a BMI between 18.5 and 24.9 kg/m2 [22]. It is believed that there is a correlation between the development of HCC and the pathophysiologic aspects of nonalcoholic steatohepatitis, including lipid peroxidation, free radical oxidative stress, and oval cell proliferation [23].

398 days with a mean of 136 days [27]. In the study from Italy, 39 patients with asymptomatic small HCC (≤5 cm in diameter) were observed for 92–962 days. The doubling time of the tumors ranged from 27 to 605 days with a mean of 204 days. No correlation between the doubling time and the initial diameter of the tumors was found. The survival rates were 81% at 1 year, 55.7% at 2 years, and 21% at 3 years [28]. In the study from Japan, 30 patients with small HCC (<3 cm in diameter) were observed for 6–48 months. The doubling time of the tumors ranged from 1.0 to 35.7 months with a mean of 6.5 months, and was found to correlate with the histologic differentiation of the tumors. Well-differentiated tumors grow slowly whilst those differentiated moderately or poorly grow rapidly. Rapid-growing tumors are likely to become multiple nodules or massive type of HCC. The survival rates in this Japanese study were 90.71% at 1 year, 55.0% at 2 years, and 12.8% at 3 years [29]. Most HCC develops in cirrhotic livers or livers with underlying diseases, and regular abdominal ultrasonographic check-ups on the liver are helpful in discovering HCC which is still small in size. However, HCC may also be found in noncirrhotic livers, and in such cases, the HCC discovered is usually large already. Generally, when symptomatic HCC is found, the patient only has a remaining lifespan of 4–6 months.

Self-assessment questions 1 Where is the highest incidence area of HCC? A Northern Europe B Southern Europe C Central America D Eastern Asia E Eastern Africa

Aflatoxin Aflatoxin is a potent hepatocarcinogen. Human exposure to aflatoxin is mostly by ingestion of moldy foods which are a consequence of poor storage of grains. The most exposed populations are in sub-Saharan Africa as well as East and South-East Asia [24–26]. Aflatoxin contributes synergistically with HBV to the development of HCC in HBV-infected patients.

Natural history of HCC The natural history of HCC is delineated in the following studies from Taiwan, Italy and Japan, in which patients were observed for a certain period of time without any treatment. In the study from Taiwan, 31 asymptomatic liver tumors (≤5 cm in diameter) in 28 HCC patients were observed for 36–860 days. The doubling time of HCC ranged from 29 to

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2 Which cause of cirrhosis is less likely to develop HCC? A HBV B HCV C Hemochromatosis D Autoimmune diseases E Obesity 3 Which description of HBV is false? A HBV DNA can integrate into cellular DNA B HBV DNA level can be applied to predict HCC development C HBV vaccine can decrease the incidence of HCC development D HBV is a major cause of HCC in South-East Asia E HCC can develop in HBV-infected non-cirrhotic liver

CHAPTER 5

Epidemiology, Etiology, and Natural History of Hepatocellular Carcinoma

4 Which description of HCV is false? A It takes 20 years for the liver to become cirrhotic from HCV infection B HCV is a major cause of HCC in Western countries C HCV is a major cause of HCC in Japan D Alcohol consumption does not enhance HCC development in HCV-infected liver E The mean age for HCV-related HCC is 10 years behind that for HBV-related HCC 5 Which description is false? A Homozygous β-thalassemia increases the incidence of HCC B Body mass index >35 kg/m2 markedly increases the risk of HCC development C Obese females and obese males share equal risk of HCC D The mean doubling time of HCC is about 4–7 months E The survival rate at 3 years is 12–21% for small asymptomatic HCC

References 1 Parkin DM, Bray F, Ferlay J, et al. Estimating the world cancer burden: globocan 2000. Int J Cancer 2001;94:153–6. 2 Bosch FX, Ribes J, Diaz M, et al. Primary liver cancer: Worldwide incidence and trends. Gastroenterology 2004;127:S5–S16. 3 El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132:2557–76. 4 Sherman M. Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis 2005;25:143–54. 5 Yu MW, Chen CJ. Elevated serum testosterone levels and risk of hepatocellular carcinoma. Cancer Res 1993;53:790–4. 6 Lee WC, Jeng LB, Chen MF. Hepatectomy for hepatitis B, hepatitis C, and dual hepatitis B- and C-related hepatocellular carcinoma in Taiwan. J Hepatobiliary Pancreat Surg 2000;7: 265–9. 7 Herath NI, Leggett BA, Macdonald GA. Review of genetic and epigenetic alterations in hepatocarcinogenesis. J Gastroenterol Hepatol 2006;21:15–21. 8 Fattovich G, Stroffolini T, Zagni I, et al. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127:S35–S50. 9 Elsharkawy AM, Mann DA. Nuclear factor-kB and the hepatic inflammation-fibrosis-cancer axis. Hepatology 2007;46:590–7. 10 Yang HI, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002;347:168–74. 11 Brechot C. Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: Old and new paradigms. Gastroenterology 2004;127:S56–S61. 12 Chang MH, Chen CJ, Lai MS, et al. Universal Hepatitis B Vaccination in Taiwan and the Incidence of Hepatocellular Carcinoma in Children. N Engl J Med 1997;336:1855–9. 13 Donato F, Boffetta P, Pouti M. A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C

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infections in causing hepatocellular carcinoma. Int J Cancer 1998;75:347–354. Matsuzaki K, Murata, M, Yoshida K, et al. Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor β signaling, promoting cirrhosis and hepatocellular carcinoma. Hepatology 2007;46:48–57. Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology 2004;127:S87–S96. Pelucchi C, Gallus S, Garavello W, et al. Cancer risk associated with alcohol and tobacco use: Focus on upper aero-digestive tract and liver. Alcohol Res Health 2006;29:I93–8. Bradbear RA, Bain C, Siskind V, et al. Cohort study of internal malignancy in genetic hemochromatosis and other chronic nonalcoholic liver diseases. J Natl Cancer Inst 1985;75:81–4. Hsing AW, McLaughlin JK, Olsen JH, et al. Cancer risk following primary hemochromatosis: a population-based cohort study in Denmark. Int J Cancer 1995;60:160–2. Kowdley KV. Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 2004;127:S79–S86. Kew MC, Asare GA. Dietary iron overload in the African and hepatocellular carcinoma. Liver Int 2007;27:735–41. Moller H, Mellemgaard A, Lindvig K, et al. Obesity and cancer risk: a Danish record-linkage study. Eur J Cancer 1994; 30A:344–50. Calle EE, Rodriguez C, Walker-Thurmond K, et al. Overweight, obesity and mortality from cancer in a prospectively studied cohort of U. S. adults. N Engl J Med 2003;348:1625–38. Caldwell SH, Crespo DM, Kang HS, et al. Obesity and hepatocellular carcinoma. Gastroenterology 2004;127:S97–S103. Ross RK, Yuan JM, Yu MC, et al. Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma. Lancet 1992;339: 943–946. Kensler TW, Egner PA, Wang JB, et al. (2004) Chemoprevention of hepatocellular carcinoma in aflatoxin endemic areas. Gastroenterology 2004;127:S310–S318. Yu MC, Yuan JM. Environmental factors and risk for hepatocellular carcinoma. Gastroenterology 2004;127:S72–S78. Sheu JC, Sung JL, Chen DS, et al. Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications. Gastroenterology 1985;89:259–66. Barbara L, Benzi G, Gaiani S, et al. Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumor growth rate and patient survival. Hepatology 1992;16:132–7. Ebara M, Hatano R, Fukuda H, et al. Natural course of small hepatocellular carcinoma with underlying cirrhosis. A study of 30 patients. Hepato-Gastroenterology 1998;45:1214–20.

Self-assessment answers 1 2 3 4 5

D D B D C

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6

Epidemiology, Etiology, and Natural History of Cholangiocarcinoma Peter Neuhaus, Ulf P. Neumann, and Daniel Seehofer Department of General, Visceral and Transplantation Surgery, Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany

Cholangiocarcinomas arise from the extra- or intra-hepatic biliary epithelium. Histologically, adenocarcinomas are seen in more than 90% of cases. The majority of cases (50–60%) are hilar cholangiocarcinomas originating from the bifurcation of the hepatic ducts (Klatskin tumors). About 20–30% of cholangiocarcinomas are situated in the distal common bile duct and only 10–15% arise in peripheral intrahepatic bile ducts. Both forms of cholangiocarcinomas, the extrahepatic cholangiocarcinoma (ECC) and the intrahepatic cholangiocarcinoma (ICC), are distinct clinical entities with significant therapeutic and epidemiologic differences. However, their differentiation is often difficult in clinical and epidemiologic studies. For example, owing to the proximity of hilar tumors to the liver, 92% of hilar cholangiocarcinomas, which are traditionally classified as ECCs, were classified as ICCs in the US National Cancer Institute SEER registry (surveillance epidemiology and end results), which represents more than 10% of the total United States population. In addition, gallbladder carcinoma, which is a clinically and epidemiologically distinct entity, has eventually been included in the ECC subgroup. Therefore, epidemiologic studies have to be compared cautiously. Wherever possible this chapter describes the two forms of cholangiocarcinomas separately, with hilar tumors assigned to the ECCs. Carcinomas of the distal bile duct, which are managed in the same way as pancreatic tumors, are not considered specifically.

Epidemiology Worldwide, cholangiocarcinoma accounts for 3% of all gastrointestinal cancers and for approximately 15% of primary liver cancers. It represents the second most common primary liver malignoma. However, the incidence of primary liver cancers varies enormously in different geographic regions. This reflects the variable distribution of local risk factors and

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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genetic differences among populations. In some regions of Thailand, cholangiocarcinomas are more frequently observed than hepatocellular carcinomas (HCCs). Conversely, in countries with a high incidence of HCC, the proportion of cholangiocarcinomas is much lower, and they account for a mere 2% of liver cancers in parts of Africa and Java. This relation is mainly based on risk factors for the development of HCC, but to a lesser extent also on risk factors for cholangiocarcinoma, as discussed below. In the United States about 5000 cases of cholangiocarcinomas are diagnosed annually, and cases of ICC and ECC are almost equally distributed [1]. However, the overall incidence of cholangiocarcinoma has increased within the last decades in most European countries, the United States, and parts of Asia. Interestingly, the incidence of ICC is considered to be rising, whereas that of ECC is decreasing [2–4]. It has been debated whether the former is a true increase or a statistical phenomenon, caused by changing classifications of the subtypes or increasing diagnosis of earlier stages by means of improved diagnostic methods. Against this theory are the facts that the increased incidence of ICC in several national databases is not associated with an increased number of small and early stage tumors, and that the increase has been delineated in various age groups. As a result, the age-standardized mortality rates for ICC are increasing. Since the overall prognosis for cholangiocarcinomas is relatively poor, mortality data can be considered a good surrogate parameter for tumor incidence. In addition (e.g. in the SEER registry), the rise of ICC is greater than the relative decline of ECC, arguing against a simple phenomenon of altered classification. Therefore, the data may reflect a true increase in the incidence of ICC, although the underlying causes are still unclear.

Intrahepatic cholangiocarcinoma The highest incidence of ICC globally is observed in NorthEast Thailand with 96 and 38 cases per 100 000 men and women, respectively. One of the lowest recorded incidences per 100 000 people is found in Australia; 0.2 in men and 0.1 in women [5]. In most Western countries, incidences range between 0.4 and 1.0 cases per 100 000.

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In general, males prevail, but this is less pronounced than in HCC epidemiology. The male-to-female ratio ranges from 1.3 in white Americans to 3.3 in France [5]. No clear racial predisposition has been identified. ICC rarely occurs before the age of 40 years. The average age worldwide is 50 years [6], but in Western countries the maximum incidence is found in people older than 65 years [5]. In the United States, the SEER registry revealed that ageadjusted incidence rates for ICC have increased by 165% from 0.32 per 100 000 in the 1970s to 0.85 per 100 000 in the 1990s [5]. This has been confirmed across all gender, racial, and age groups. Not unexpectedly, the highest increase was observed in those older than 65 years of age. Whereas the incidence in the group aged from 45 to 64 years doubled from the late 1970s to the late 1990s, it increased three-fold in the group over 65 within the same period. In parallel, World Health Organization (WHO) data show a worldwide increase in the age-standardized mortality rate of ICC in both men and women [7]. This is underlined by several national databases in the United States, France, Italy, Australia, the UK, and Japan. For example, the agestandardized mortality rate increased in Japan by 130% and in Australia by 600% [8]. In the United States, mortality from ICC increased 10-fold from 0.07 per 100 000 in 1973 to 0.69 per 100 000 in 1997 [2], reflecting the increasing incidence and overall poor prognosis. This increase in mortality rate was higher in most countries than that for HCC in the same period, leading to more ICC- than HCC-related deaths in countries with a low incidence of HCC, like England and Wales since the mid-1990s [3]. The underlying causes are still unclear. Primary sclerosing cholangitis, as the commonest known predisposing factor in the UK, although associated with only a minority of cases, has not increased in incidence at the same rate as cholangiocarcinoma mortality.

from 0.6 per 100 000 in 1979 to 0.3 per 100 000 in 1998 [2]. Comparable trends have been reported worldwide [10]. However, the decrease in mortality was, for example in England and Wales, more distinctive, with a decline in mortality from 0.80 per 100 000 in 1979 to 0.23 per 100 000 in men [3]. In total, these data have to be interpreted with some caution, since in several databases gallbladder cancer is included in the ECC entity [8]. This might impact the data considerably, because gallbladder cancer has a different clinical course and its incidence is known to be declining, probably as a result of increasing cholecystectomy rates over the past decades.

Etiology In most countries, the known risk factors for cholangiocarcinomas (Table 6.1) account for only a small proportion of the emerging cases, and the etiology in the majority of cases is still unknown. An established risk factor is chronic inflammation of the biliary tract, leading to epithelial damage, cellular proliferation, and increased rate of cellular DNA synthesis. The presence of other cofactors (e.g. chemical carcinogens) eventually induces DNA damage and subsequently malignant

Table 6.1 Factors associated or possibly associated with the development of cholangiocarcinoma and respective incidence in the affected subpopulation.

Strong association

Extrahepatic cholangiocarcinoma Relatively few data exist on the incidence and mortality of ECC. Its incidence in different countries does not show as marked variation as is the case for ICC. The reported incidence varies between 0.53 per 100 000 in the UK to 1.14 per 100 in Manitoba, Canada [9]. In a large analysis from the SEER registry between 1973 and 1987, the age-adjusted incidence was 1.2 per 100 for men and 0.8 per 100 000 for women [9]. In the same registry, ECC was slightly more common in whites than in blacks, and in men than in women. Like for ICC, most ECC patients are older than 65, and the maximum incidence is observed between 70 to 74 years of age. In contrast to ICC, incidence and mortality rates for ECC are declining in many countries. The age-adjusted incidence decreased in the United States from 1.08 per 100 000 in 1979 to 0.82 per 100 000 in 1998 [6]. Accordingly, the age-standardized mortality rate for ECC in the United States halved

Weak association

Possible association

Factor

Incidence (%)

Primary sclerosing cholangitis Thorotrast Choledochal cysts Type I, IV Choledochal cysts Type II, III Caroli syndrome (Todani Type V) Hepatolithiasis Biliary papillomatosis Liver fluke infestation Chronic HCV infection Lynch syndrome (HNPCC) Chronic HBV infection HIV infection Liver cirrhosis of any cause Diabetes mellitus Alcohol abuse Smoking Nitrosamines Organochlorines Dioxins

7–15 10–20 20–30 10–15 7–14 5–10 25–50 ∼1 ∼1 <1 <1 <1 <1

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transformation. Cancer development is in most other cases not related to chronic inflammatory conditions and cholangiocarcinoma mostly evolves, apart from primary sclerosing cholangitis, in an otherwise normal liver.

Primary sclerosing cholangitis Primary sclerosing cholangitis (PSC) is an idiopathic inflammatory disorder of the intrahepatic and/or extrahepatic bile ducts, which results in inflammatory and fibrotic stricturing of the biliary tree. It is a well-established risk factor for cholangiocarcinoma and the lifetime risk in PSC patients is estimated to be between 7% and 15% [11, 12]. However, single studies have shown a cholangiocarcinoma risk of up to 30%. The detected incidence of cholangiocarcinoma in PSC patients depends very much on the sensitivity of the diagnostic method, and, for example, estimates of cholangiocarcinoma rates in PSC patients are consistently higher in autopsy series or in livers explanted during transplantation. The clinical incidence in most large series is below 15%. Overall, only the minority of cholangiocarcinomas are based on PSC. The duration of PSC is not related to the development of cholangiocarcinoma and about 30% of tumors manifest within 2 years after primary diagnosis of PSC [12]. Additionally, no significant association between presence, type, and duration of inflammatory bowel disease and cholangiocarcinoma has been detected [12]. Cholangiocarcinoma in PSC patients presents typically at a younger age than in sporadic cases, with the maximum age in most studies between 40 and 50 years. Since early diagnosis is difficult and many tumors present in advanced stages, a number of prognostic models have been proposed for clinical use in PSC patients, but none has proven helpful in predicting which patients might develop cholangiocarcinoma. Likewise, additional cofactors have been analyzed in PSC patients, but the results have been conflicting. A Swedish study found a correlation between smoking and cholangiocarcinoma, but not alcohol [13], whereas a US study found a correlation with alcohol but not with smoking. Both studies included a relatively small number of patients; hence these cofactors need to be further evaluated.

Choledochal cysts Choledochal cysts are rare congenital cystic dilatations of the bile ducts. Although the majority of patients are diagnosed during the first decade of life, about 20–30% remain undiagnosed until adulthood. Possibly due to improved hepatobiliary imaging, choledochal cysts have recently been considered to be increasingly diagnosed in adults. The estimated incidence in Western countries lies between 1 in 15 000 and 1 in 200 000 [14]. The incidence is markedly higher in the Far East, and especially in Japan, with a

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reported maximum prevalence of 1 in 1000. Choledochal cysts are predominantly seen in females with a male-tofemale ratio of about 1 : 4. Cholangiocarcinomas have been reported in all types of choledochal cysts (Todani classification). Todani types I–III are extrahepatic and therefore risk factors for ECC, type IV is extra- and intra-hepatic, and type V is situated intrahepatically (Caroli disease). The mechanisms of carcinogenesis are unclear, but biliary stasis and reflux of pancreatic juice, which cause chronic inflammation, activation of bile acids, and deconjugation of carcinogens, are supposed to play a role. However, other factors might be involved, as carcinomas can occur decades after surgical resection of the cysts. In types I–IV cysts, the risk increases with age and is about 15% after the second decade in untreated cases [14]. The highest cancer risk of 20–30% in the fourth decade is present in types I and IV cysts, even after surgical removal of the cysts. Caroli disease (type V) is a form of autosomal recessive inherited cystic liver disease characterized by multiple cystic dilatations of the intrahepatic biliary tree, manifesting in one or both lobes. Some cases are additionally associated with liver fibrosis and portal hypertension. Intrahepatic cholestasis leads to recurrent bacterial cholangitis and alterations of the biliary epithelium. The estimated incidence of ICC is between 7% and 14% [15].

Liver flukes Two different liver fluke infestations, Opisthorchis viverrini and Clonorchis sinensis, are supposed to be associated with the development of hepatic cholangiocarcinoma. The causative role of O. viverrini is supported by a substantial amount of clinical and experimental data; the role of C. sinensis is less clearly defined but also very likely [16]. These infections are very common in East and South-East Asia, and in parts of Eastern Europe. Endemic areas of O. viverrini are found in North-East Thailand, Laos, and Malaysia, and of C. sinensis in parts of China and Korea. In most other regions, C. sinensis infestation is becoming rare, including Hong Kong and Japan. Worldwide more than 20 million people are estimated to be infected with liver flukes. Humans are infected by eating undercooked fish containing adult worms, which inhabit and lay their eggs in the bile ducts, and occasionally the gallbladder and the pancreatic duct. The eggs are excreted via feces and later ingested by snails (intermediate host). The parasites leave the snail as cercariae and subsequently penetrate fish (second intermediate host). Most data on O. viverrini are derived from Thailand, where the worldwide highest incidence of cholangiocarcinoma is found. A case-control study demonstrated a strong association between O. viverrini and cholangiocarcinoma with an odds ratio of 4.8, thus attributing two-thirds

CHAPTER 6

Epidemiology, Etiology, and Natural History of Cholangiocarcinoma

of the cholangiocarcinoma cases in this series to the parasite [17]. However, most patients with liver fluke infection will never develop cholangiocarcinoma. For example, in the Thai North-Eastern province of Khon-Kaen, O. viverrini infection affects 90–94% of the population, but the incidence of cholangiocarcinoma is below 1% (0.79%). This highlights the relevance of other cofactors for liver fluke-induced carcinogenesis. Alimentary carcinogens especially, like nitrosoamines, are supposed to initiate cholangiocarcinogenesis. Experimentally, nitrosoamines have been shown to be an essential cofactor for developing cholangiocarcinoma after O. viverrini infection in Syrian hamsters [18]. The role of C. sinensis in carcinogenesis is less clear, but also very likely. Initial reports of a positive correlation [16] have been confirmed by a study from Korea, where C. sinensis is still endemic. This case-control study revealed a strong association between C. sinensis infection and cholangiocarcinoma with an adjusted odds ratio of 2.2 [19]. In summary, considering the relatively low incidence of cholangiocarcinoma in countries that have a high prevalence of liver fluke infestations, flukes appear to be promoters rather than initiators of cholangiocarcinomas.

Hepatolithiasis Hepatolithiasis is a rare disease in Western countries, but endemic in some parts of Asia, especially in Taiwan, China, and Korea, and to a lesser extent in Japan. Bacterial infection is present in more than 90% of patients with hepatolithiasis [20] and leads, in combination with biliary stasis, to a chronic proliferative cholangitis. This promotes carcinogenesis via atypical hyperplasia of the biliary epithelium. Several studies have demonstrated an association of hepatolithiasis with ICC and ECC; the association with ICC is the stronger. Hepatolithiasis has been observed in 6–16% of Japanese patients with cholangiocarcinoma [21], and in Taiwan – where the incidence of hepatolithiasis is even higher – more than 50% of patients with ICC had concomitant hepatolithiasis. Overall about 5–10% of patients with of hepatolithiasis eventually develop ICC.

Viral hepatitis Additional risk factors such as cirrhosis and chronic infection with hepatitis B (HBV) or hepatitis C viruses (HCV) are becoming increasingly recognized in the pathogenesis of ICC. There is good evidence that viral hepatitis induces not only HCC but also cholangiocarcinomas. A hint to its possible involvement in cholangiocarcinogenesis is the detection of HCV antigens in proliferating but not normal biliary epithelial cells [23]. This might be explained by the fact that HCV can infect oval cells, a progenitor common to hepatocytes and cholangiocytes, as well as proliferating bile duct cells. Accordingly, Asian patients with ICC show a significantly increased rate of viral hepatitis. In a survey of the Liver Cancer Study Group of Japan, 24–32% of male patients and 16–29% of female patients with cholangiocarcinoma were HCV positive compared to an average HCV incidence of 1% in the general population. Further evidence comes from a prospective study of 600 individuals with HCV-related cirrhosis in Japan between 1980 and 1997, in whom a 2.3% incidence of cholangiocarcinoma was seen, an incidence 1000-fold higher than in the general population [24]. The cholangiocarcinoma risk for HCV infection seems to be markedly higher than for HBV infection. In an Italian study, the odds ratio for ICC was 9.7 for anti-HCV-positive patients and 2.7 for HBsAg-positive patients [25]. In the survey of the Liver Cancer Study Group of Japan referred to above, HBsAg positivity was less frequent than HCV positivity, but 4–15% of the cholangiocarcinoma patients were positive for HBV, which is still far above the overall incidence of hepatitis B in Japan. Only one study from Thailand found no correlation between ICC and chronic viral hepatitis. However, the incidence of cholangiocarcinoma was very high in this study and the patient numbers relatively low. These results do not argue against a causative role for HCV, because other risk factors like fluke infection might obscure the effect of viral hepatitis in this specific study. In summary, it seems very likely that chronic HCV infection and also chronic HBV infection, albeit less clearly, are risk factors or at least cofactors for the development of ICC.

Liver cirrhosis of other causes Thorotrast Thorotrast was used as contrast agent from 1920 to 1955, before it was banned. After intravenous application, 70% of the dose is taken up in the liver and stored in the reticuloendothelial system. Many years after application, a high incidence of liver tumors is seen. In a German series, 20% of patients developed primary liver tumors, including cholangiocarcinoma, HCC, and hemangiosarcomas, 16–50 years after being given the contrast agent. Likewise, in a Japanese follow-up study, the risk of a cohort exposed to thorotrast was more than 300-fold higher than for the general population [22].

Not only viral cirrhosis, but also liver cirrhosis of other origin might be complicated by cholangiocarcinoma. A Danish study of more than 11 000 patients with cirrhosis of any cause revealed a 10-fold higher risk for cholangiocarcinoma compared to the general population [26]. However, the cholangiocarcinoma risk was most pronounced in patients with alcoholic cirrhosis (standardized incidence ratio 15.3), and not seen, for example, in patients with PBC. Since a strong association between alcohol intake and, for example, smoking is well recognized, and since tobacco-related cancers were increased in the group with alcoholic cirrhosis, it is not clear if cirrhosis alone is a risk factor for

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cholangiocarcinoma or if this might be the effect of a combination of two or more associated risk factors. However, since also the SEER registry showed any liver cirrhosis to be a risk factor for ICC [27], an association seems to be present, although additional risk factors might be involved.

Biliary papillomatosis Biliary papillomatosis is a very rare disease characterized by multiple papillary adenomas in the biliary tree. It typically presents with relapsing episodes of cholangitis and obstructive jaundice. It is also considered a premalignant condition, because transformation to papillary adenocarcinoma is reported to occur in 25–50% of cases. Biliary papillomatosis seems to be more common in Asian countries and to be associated with liver fluke infection and hepatolithiasis [28].

Hereditary nonpolyposis colorectal cancer The hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, also known as Lynch syndrome, is caused by inherited defects of the DNA mismatch repair system. This carries the risk of development of various cancers, mainly colorectal and endometrial cancer. Among others, however, the risk for cancer of the biliary tract is significantly elevated in comparison with the general population. In a Finnish analysis, the incidence of biliary tract cancer in HNPCC carriers was about 0.5%, corresponding to a standardized incidence ratio of 9.7 [29].

Further possible risk factors Various other risk factors have been investigated, but the reported data reveal conflicting results or only small numbers of patients have been included, so further evaluation of these potential risk factors is needed. For example, several case-control analyses have reported an association between cholangiocarcinoma and alcohol abuse [27], whereas others have found no association [22]. A recent case-control analysis based on the SEER registry identified diabetes mellitus (adjusted odds ratio 2·0), human immunodeficiency virus infection (adjusted odds ratio 5·9), and inflammatory bowel disease as risk factors for development of cholangiocarcinoma [27]. In a smaller study, α-1-antitrypsin deficiency, a known risk factor for HCC, was associated with the development of cholangiocarcinoma, even in heterozygous individuals [30]. In addition, it has been shown that high exposition to certain industrial chemicals is associated with an increased risk of liver cancers, mainly hepatomas and angiosarcomas, but also cholangiocarcinomas. Associations have been suspected with exposure to by-products from the rubber and chemical industries, such as organochlorines, nitrosamines, dioxins, polychlorinated biphenyls, and cadmium. These substances are supposed to be implicated in the pathogenesis of pancreatic cancer and cholangiocarcinoma [31], but the reported results for some of these substances are contradic-

60

tory and no definite conclusions can be drawn so far. However, as for most other tumors, a patient’s genetic and epigenetic constitution may predispose to the development of the disease. There is increasing evidence that individual genetic variants in hepatic enzymes induce an attenuated detoxification of chemical substances and environmental toxins. Especially in conditions with delayed emptying of the bile ducts, as seen in stone or chronic inflammatory disease of the biliary tree, a prolonged exposure of biliary epithelia to carcinogens is the consequence.

Natural history Carcinogenesis As for other tumors, cholangiocarcinogenesis is a multistep process, dependent on interactions between environmental factors and host genetic factors. Most known risk factors for cholangiocarcinoma cause chronic biliary irritation and inflammation, and thereby contribute to a promotional stage of carcinogenesis. There is evidence that the neoplastic transformation of biliary epithelial cells and the malignant progression of cholangiocarcinoma is accompanied by various genetic and epigenetic alterations. An enormous diversity of altered gene functions, including activation of growth-promoting genes as well as silencing of genes with tumor suppressing functions, have been detected also in cholangiocarcinomas, together leading to an uncontrolled cellular proliferation. In contrast to HCC, preneoplastic lesions and the progression of cholangiocarcinoma have been less well investigated and most data are derived from populations at risk for cholangiocarcinoma, mainly patients with PSC, choledochal cysts, fluke infections, or hepatolithiasis. It remains unclear if sporadic cases, which represent the majority, share common mechanisms. Conversely, the pattern of gene expression in cholangiocarcinomas associated with chronic inflammation and liver fluke infection is proven to be different from that for sporadic cholangiocarcinomas [32]. However, there is growing evidence that conversion from normal to malignant biliary epithelium requires several consecutive genomic mutations similar to those observed in other gastrointestinal cancers. A detailed description of genetic and epigenetic alterations in cholangiocarcinomas at the molecular level is beyond the scope of this chapter, therefore only some relevant findings are introduced below. In chronically inflamed biliary epithelium, several changes culminate in the upregulation of growth and prevention of cell death. Several factors which activate cellular proliferation are supposed to link chronic biliary inflammation to pathogenesis of cholangiocarcinoma. In this regard, interleukin-6 (IL-6) appears to be a pivotal cytokine, and cholangiocarcinoma cells have been shown to constitutively secrete

CHAPTER 6

Epidemiology, Etiology, and Natural History of Cholangiocarcinoma

IL-6. Via autocrine pathways, IL-6 stimulates proliferative mechanisms, like p38 mitogen-activated protein kinase, and antiapoptotic pathways, like upregulation of Mcl-1. Other mechanisms which might be involved in the carcinogenesis of chronically inflamed biliary epithelium include inducible nitric oxide, cyclooxygenase-2, and amplification of the epidermal growth factor receptor. For example, nitric oxide (NO) can directly or via formation of reactive peroxynitrite species promote DNA mutations, inactivate DNA repair proteins, and, via nitrosylation of caspase 9, inhibit apoptosis. Additionally, cyclooxygenase-2-derived prostanoids activate the transcription factor β-catenin, which is highly oncogenic. β-Catenin has been recognized as a critical member of the Wnt signaling pathway and plays an important role in the generation/differentiation of many tissues. Inappropriate activation of this pathway has been implicated in carcinogenesis and it plays a key role in hepatocellular and colorectal carcinoma. At later stages, as in other cancer types, matrix metalloproteinases have been shown to play a pivotal role in the malignant behavior of cholangiocarcinoma cells, such as rapid tumor growth, invasion, and formation of metastasis by degradation of extracellular matrix (ECM) [33]. In cases of sporadic cholangiocarcinomas, a variety of mutations in oncogenes (k-Ras, c-Myc, c-Erb-b2, c-MET, and others) and tumor suppressor genes (among others p53 and Bcl-2) have been described. These mutations eventually lead to detectable phenotypic changes. Some of the genetic alterations (e.g. k-Ras and p53 mutations) are associated with a more aggressive phenotype in this cancer [34]. In addition, epigenetic alterations in the form of promoter region hypermethylation and histone deacetylation are becoming increasingly recognized also for cholangiocarcinomas [35]. This is particularly true for tumor suppressor genes, which can be silenced by promoter hypermethylation. Although single tumor suppressor gene methylation can be seen in nonmalignant conditions of the biliary epithelium, methylation of multiple tumor suppressor genes is only seen in cholangiocarcinomas. Another factor which might be of relevance is genetic polymorphisms of the cytochrome P450 enzymes or in the bile salt transporter proteins. These might induce alterations in hepatic detoxification of environmental toxins (xenobiotics). In combination with a biliary stasis (e.g. in stone disease), this can lead to a prolonged and increased exposure of biliary epithelia to carcinogens. The final development of cholangiocarcinoma probably needs a “second hit,” like chronic inflammation, viral hepatitis, worm infection, or recurrent cholangitis. Morphologically, two distinct neoplastic lesions preceding invasive ICC have been described in intrahepatic large bile ducts. The first is a flat or micropapillary lesion, termed biliary intraepithelial neoplasia (BilIN); the second is a lesion with prominent papillary growth, termed intraductal papil-

lary neoplasia of the bile duct (IPNB). Histopathological similarities between these lesions and their pancreatic counterparts, intraductal papillary mucinous neoplasm (IPMN) and pancreatic intraepithelial neoplasia (PanIN), have been reported. However, unlike the pancreatic analogs, little is known about the molecular pathogenesis and progression of BilIN and IPNB within the biliary tree.

Natural course According to the mechanisms of carcinogenesis described above in chronically inflamed bile ducts, it is generally assumed that a dysplasia–carcinoma sequence exists for cholangiocarcinomas, especially in ECC (Figure 6.1). The duration from manifestation of biliary dysplasia to carcinoma is estimated to be as long as 10–15 years. When clinically diagnosed, the natural history of cholangiocarcinoma is normally short, and median survival ranges in months. Survival data from the SEER registry in patients with ICC aged 65 years or older, which is the main population at risk in Western countries, revealed that the median survival in all patients was 124 days (95% confidence interval 110–151 days) [36]. However, less than 10% of all ICC patients received surgical resection with curative intention. In the same study, median survival for patients receiving endoscopic palliation was only 123 days (108–148 days) and for those receiving no treatment it was 57 days (41–152 days). All palliative groups had a significantly worse survival rate than the small group of patients who underwent liver resection (median survival after resection 708 days). Survival data for ECC are within a similar range. Patients with unresectable ECC and palliative drainage of the bile ducts have a median survival of 3–6 months [37]. Without any treatment, the median survival of ECC is below 3 months. Thus, the prognosis is considered worse for lesions affecting the biliary confluence and better for lesions in the distal bile duct or affecting only one hepatic duct. Septic complications secondary to biliary obstruction and liver failure mainly contribute to death in patients with unresectable cholangiocarcinoma.

Self-assessment questions 1 An increased risk for cholangiocarcinoma is associated with which of the following? (more than one answer is possible) A Echinococcus granulosus infection B Hepatolithiasis C Cholecystolithiasis D Chronic hepatitis C infection E Gilbert syndrome 2 The mortality of intrahepatic cholangiocarcinoma is decreasing in Western countries because the incidence

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a

b

DNA mutation in key genes

Cell division Persistence of mutation

Initiation

Environmental factors

Host factors

• Genotoxic chemicals (e.g. thorotrast, dioxins, nitrosamines)

• DNA-repair enzymes • Toxin metabolizing enzymes • Bile salt transporter polymorphism • Defects in oncogenes/ tumor suppressor genes

c

Preneoplastic lesion

Further DNA mutations and epigenetic alterations

Promotion

Progression

Escape from senescense p16ink4a, p53, p21, Mdm-2 Autonomous proliferation IL-6, k-ras, iNOS, c-erb-2, EGF-R, COX-2 Evasion from apoptosis Mcl-2, Bcl-2, NO, cFLIP

Metastasis

Tissue invasion/metastasis E-cadherin, β-catenin, MMP, VEGF

Chronic inflammation • Primary sclerosing cholangitis • Liver flukes • Hepatolithiasis • Choledochal cysts

Figure 6.1 Schematic model of cholangiocarcinogenesis via dysplasia carcinoma sequence. Examples of bile cytology at the top show (a) normal biliary epithelia, (b) moderate dysplasia, and (c) cholangiocarcinoma cells.

of intrahepatic cholangiocarcinoma is stable and therapeutic options have improved. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 3 Which one of the following is false with regards to how cholangiocarcinomas manifest? A In 30% of cases within 2 years after Opisthorchis viverrini infection B At lower ages in Asian countries than in Western countries C With an age maximum between 40 and 50 years in Western countries D Mostly later than 10 years after diagnosis of primary sclerosing cholangitis E Often in childhood in patients with Caroli disease

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4 The worldwide highest incidence of intrahepatic cholangiocarcinoma is reported in some regions of Thailand because about 20% of patients with liver fluke infestation develop cholangiocarcinomas. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 5 Which of the following are true with regards to major causes of death in patients with untreated cholangiocarcinoma? (more than one answer is possible) A Brain metastases B Septic complications C Variceal hemorrhage D Liver failure E Pulmonary embolism

CHAPTER 6

Epidemiology, Etiology, and Natural History of Cholangiocarcinoma

References 1 Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5–26. 2 Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 2001;33:1353–7. 3 Taylor-Robinson SD, Toledano MB, Arora S, et al. Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968–1998. Gut 2001;48:816–20. 4 Shaib YH, Davila JA, McGlynn K, El-Serag HB. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol 2004;40:472–7. 5 Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004;24:115–25. 6 de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. N Engl J Med 1999;341:1368–78. 7 Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2002;2:10. 8 Khan SA, Taylor-Robinson SD, Toledano MB, et al. Changing international trends in mortality rates for liver, biliary and pancreatic tumours. J Hepatol 2002;37:806–13. 9 Strom BL, Hibberd PL, Soper KA, Stolley PD, Nelson WL. International variations in epidemiology of cancers of the extrahepatic biliary tract. Cancer Res 1985;45:5165–8. 10 Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD. Cholangiocarcinoma. Lancet 2005;366:1303–14. 11 Kornfeld D, Ekbom A, Ihre T. Survival and risk of cholangiocarcinoma in patients with primary sclerosing cholangitis. A population-based study. Scand J Gastroenterol 1997;32:1042–5. 12 Broome U, Olsson R, Loof L, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 1996;38:610–15. 13 Bergquist A, Glaumann H, Persson B, Broome U. Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study. Hepatology 1998;27:311–16. 14 Soreide K, Korner H, Havnen J, Soreide JA. Bile duct cysts in adults. Br J Surg 2004;91:1538–48. 15 Chapman RW. Risk factors for biliary tract carcinogenesis. Ann Oncol 1999;10 (Suppl 4):S308–S311. 16 Watanapa P, Watanapa WB. Liver fluke-associated cholangiocarcinoma. Br J Surg 2002;89:962–70. 17 Parkin DM, Srivatanakul P, Khlat M, et al. Liver cancer in Thailand. I. A case-control study of cholangiocarcinoma. Int J Cancer 1991;48:323–8. 18 Thamavit W, Bhamarapravati N, Sahaophong S, Vajrasthia S, Angsuhakorn S. Effects of dimethylnitrosamine on induction of cholangiocarcinoma in Opisthorchis viverrini infected Syrian golden hamsters. Cancer Res 1978;38:4634–9. 19 Shin HR, Lee CU, Park HJ, et al. Hepatitis B and C virus, Clonorchis sinensis for the risk of liver cancer: a casecontrol study in Pusan, Korea. Int J Epidemiol 1996;25:933–40. 20 Tabata M, Nakayama F. Bacteria and gallstones. Etiological significance. Dig Dis Sci 1981;26:218–24. 21 Sugihara S, Kojiro M. Pathology of cholangiocarcinoma. In: Okuda K, Ishak KG, eds. Neoplasms of the Liver. Tokyo: Springer Verlag, 1987.

22 Hardell L, Bengtsson NO, Jonsson U, Eriksson S, Larsson LG. Aetiological aspects on primary liver cancer with special regard to alcohol, organic solvents and acute intermittent porphyria – an epidemiological investigation. Br J Cancer 1984;50:389–97. 23 Uchida T, Shikata T, Tanaka E, Kiyosawa K. Immunoperoxidase staining of hepatitic C virus in formalin-fixed, paraffinembedded needle liver biopses. Virchow Arch 1994;424:465–9. 24 Kobayashi M, Ikeda K, Saitoh S, et al. Incidence of primary cholangiocellular carcinoma of the liver in japanese patients with hepatitis C virus-related cirrhosis. Cancer 2000;88:2471–7. 25 Donato F, Gelatti U, Tagger A, et al. Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy. Cancer Causes Control 2001;12:959–64. 26 Sorensen HT, Friis S, Olsen JH, et al. Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark. Hepatology 1998;28:921–5. 27 Shaib YH, El-Serag HB, Davila JA, et al. Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology 2005;128:620–6. 28 Lee SS, Kim MH, Lee SK, et al. Clinicopathologic review of 58 patients with biliary papillomatosis. Cancer 2004;100:783–93. 29 Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 1999; 81:214–18. 30 Zhou H, Fischer HP. Liver carcinoma in PiZ alpha-1-antitrypsin deficiency. Am J Surg Pathol 1998;22:742–8. 31 Bond GG, McLaren EA, Sabel FL, et al. Liver and biliary tract cancer among chemical workers. Am J Ind Med 1990;18:19–24. 32 Jinawath N, Chamgramol Y, Furukawa Y, et al. Comparison of gene expression profiles between Opisthorchis viverrini and nonOpisthorchis viverrini associated human intrahepatic cholangiocarcinoma. Hepatology 2006;44:1025–38. 33 Westermarck J, Kahari VM. Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J 1999;13:781–2. 34 Isa T, Tomita S, Nakachi A, et al. Analysis of microsatellite instability, K-ras gene mutation and p53 protein overexpression in intrahepatic cholangiocarcinoma. Hepatogastroenterology 2002; 49:604–8. 35 Sandhu DS, Shire AM, Roberts LR. Epigenetic DNA hypermethylation in cholangiocarcinoma: potential roles in pathogenesis, diagnosis and identification of treatment targets. Liver Int 2008;28:12–27. 36 Shaib YH, Davila JA, Henderson L, McGlynn KA, El-Serag HB. Endoscopic and surgical therapy for intrahepatic cholangiocarcinoma in the United States: a population-based study. J Clin Gastroenterol 2007;41:911–17. 37 Ortner ME, Caca K, Berr F, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology 2003;125:1355–63.

Self-assessment answers 1 2 3 4 5

B, D A B B B, D

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7

Epidemiology, Etiology, and Natural History of Colorectal Liver Metastases Robert J. Porte Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Colorectal cancer is one of the most common malignancies in Western countries, ranking fourth behind lung, breast, and prostate cancers. Regarding mortality, colorectal cancer is the second most lethal malignancy after lung cancer. Worldwide, around 850 000 people annually develop a colorectal malignancy and about 500 000 die from the disease [1, 2]. In the United States, about 140 000 new cases are diagnosed annually and around 56 000 patients die of the disease per year [2, 3]. In Europe, there are about 380 000 new cases per year and more than 200 000 deaths per year due to colorectal cancer [3]. While the incidence is slowly decreasing in the United States and Europe, a steady increase has been noted in Asia [4, 5]. For both men and women, the incidence of colorectal cancer begins to rise around the age of 40 years. The incidence sharply increases at the age of 50 years and 82% of all colorectal cancers are diagnosed in persons aged 50 years or older [2]. The disease affects all ethnic groups and epidemiologic studies indicate that environmental factors, especially dietary and lifestylerelated factors, are leading risk factors. High-fat diets with few fruits and vegetables, inactivity, obesity, smoking, and alcohol use are associated with an increased risk [2]. Changes in lifestyle and eating habits have been blamed for the increasing rate of colorectal tumors in Asia [4]. Approximately 80% of all colorectal cancers are nonhereditary, or sporadic, and about 20% are familial. The two main hereditary syndromes are familial adenomatous polyposis and hereditary nonpolyposis colon cancer [2]. Of all patients with colorectal cancer, more than 50% will eventually develop liver metastases. Each year about 30 000 patients in the United States develop hepatic metastases from colorectal cancer and the majority of patients who die of colorectal cancer have hepatic metastases. Almost onethird of the patients dying from colorectal cancer have tumor limited to the liver [6]. Various other malignancies can result in metastasis to the liver as part of systemic dis-

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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semination, and liver metastases are usually a sign of endstage disease. Colorectal carcinoma is an exception to this general rule, as in this type of malignancy metastases are confined to the liver in 30–40% of patients. In these cases, resection of the hepatic metastases may be curative (Chapters 17 and 29).

Epidemiology and etiology The observation that the liver is the most common organ of distant metastases from colorectal cancer has been explained by the fact that the liver is the first major organ reached by venous blood draining form the gastrointestinal tract [7]. The exact routes of dissemination and the pathogenesis of liver metastasis in patients with colorectal cancer are unknown. There is a large amount of literature about the treatment and prognosis of patients with liver metastases from colorectal cancer, but only a limited number of studies have focused on the epidemiologic characteristics and etiology of these metastases [8–10]. Accurate epidemiologic data of colorectal liver metastases can only be derived from figures relating to the overall population with colonic or rectal cancer within a particular population and area. Such studies are rare because they require accurate and detailed data collection, as well as active participation of all medical professions involved within a certain area. Most reports on management and prognosis of colorectal liver metastases have been generated in specialized, tertiary centers. This information is unavoidably influenced by selection bias and, therefore, may not be extrapolated to the general population. Only a few studies have been based on a populationbased series [8–10].

Synchronous metastasis Around 15–25% of patients with colorectal cancer will have metastases in their liver at the time of initial diagnosis of the colorectal cancer (synchronous liver metastases) [8, 9]. Among them, about three-quarters have metastases confined to the liver and about one-quarter have other visceral metastases as well [8]. Analysis of a population-based cancer registry in Burgundy, France, including 13 463 patients with

CHAPTER 7

Epidemiology, Etiology, and Natural History of Colorectal Liver Metastases

colorectal cancer, showed a significant reduction in the proportion of patients with synchronous liver metastases with increasing age [8]. In this study, synchronous liver metastases were present in 19.8% of the patients below the age of 55 years and in 11.7% of the patients over 75 years. Similar proportions of synchronous liver metastasis have been reported in other large European and Australian population-based studies [9, 10].

Metachronous metastasis Metachronous liver metastases, or metastases that become apparent in time, after resection of the primary tumor, are found in up to 40% of all patients with this malignancy. However, a much lower rate of 14.5% was recently reported in a large community-based study in France [8]. The risk of developing metachronous liver metastases decreases over time. Most metachronous metastases are detected within 2 years after diagnosis of the primary disease, but liver metastases may be detected up to 5 years after resection of the primary colon tumor [3]. Independent risk factors for the development of metachronous liver metastases are the original tumor stage at the time of diagnosis, male sex, and gross features (ulcerofungating or ulceroinfiltrating tumors having a higher risk than fungating tumors). Patients with an initial colorectal stage III have a more than eight-fold higher risk of developing liver metastasis than patients with stage I. Localization of the primary tumor, however, is not significantly related to the development of metachronous liver metastases [8]. It is increasingly recognized that many of these so-called metachronous liver metastases were actually present at the time of initial presentation of the colon tumor. Significant improvements in the quality of imaging techniques in recent years have enabled the detection of smaller liver tumors. This has resulted in a decline in the proportion of patients with unrecognized occult liver metastases, who would have been classified previously as having no hepatic involvement. As a result, survival for patients with truly nonmetastasized disease will subsequently improve. Moreover, those patients with previously undetected small liver metastases have a relatively good survival, and therefore, overall survival in patients with liver metastases will improve [11]. It remains unknown what percentage of metachronous liver metastases are actually present at the time of detection of the colon tumor and what percentage develop during or after resection of the primary tumor. It is well known that tumor cells can be detected in the circulation during surgical resection of colorectal tumors, and it can be imagined that this may contribute to the development of metachronous liver metastases [12]. Formal proof of this concept, however, is difficult to obtain. Reported percentages of patients with colorectal liver metastases that are surgically resectable vary between 20% and 32% [8, 13]. However, these numbers have increased

in recent years due to increasing surgical experience and the development of safer techniques, allowing more extensive and complex resections [14]. Indications and guidelines for surgical and medical treatment of colorectal liver metastases are provided in Chapter 29.

Detection of liver metastasis Liver metastases generally remain asymptomatic until late in the course of the disease. Pain is much less common than in primary hepatic cancer, and most patients who cannot be cured die from cachexia and tumor load [15, 16]. Currently, many liver metastases are detected by ultrasound screening or a rising serum carcinoembryonic antigen (CEA) long before they become symptomatic.

Natural history When discussing the natural history of liver metastases from colorectal cancer, it should be kept in mind that metastases reflect systemic disease and that the prognosis may be influenced by multiple factors, including percent of liver involvement, concomitant lymph node metastases, localization and malignancy grade of the primary tumor, and the general condition of the patient [17]. Knowledge about the natural history of colorectal liver metastases is essential for the development and evaluation of curative or palliative treatments, preferably in prospective, randomized studies. Because it has become increasingly difficult to assign patients to a nontreatment group, it is usual to compare the effects of two treatment modalities or to make comparison with often outdated historic controls. This shortcoming has hampered our understanding of the natural history of liver tumors, and this is illustrated by the paucity of papers discussing the natural history of colorectal liver metastases during the last decades [15]. When studying the natural history of colorectal liver metastases, it should be kept in mind that reported data are influenced by selection bias when patients with limited metastases who are in relatively good condition undergo surgical resection, whereas the natural history is studied in the remaining unresected patients. More recent series also have been influenced by a lead-time bias as more sensitive diagnostic methods, allowing earlier diagnosis, have become available. These considerations should be kept in mind during interpretation of data on patient survival in different series. Data on growth rates of hepatic metastases from colorectal tumors are very limited. Finlay et al have attempted to evaluate growth rates of untreated lesions using serial computed tomography (CT) scans [18]. Tumor doubling times were found to differ between clinically overt lesions and “occult” metastases. For clinically overt metastases, doubling time varied from 48 to 321 days (mean, 155 days), whereas doubling times in the smaller “occult” metastases ranged from

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30 to 192 days (mean, 86 days). Purkiss and Williams have documented tumor doubling times varying between 52 and 199 days, also with the fastest growth rate in the smallest tumors [19]. Although there is clearly a large variation in growth pattern, the doubling times seem to be shorter than those found in primary hepatic tumors such as hepatocellular carcinoma [20]. Variations in tumor stage have hampered the comparison of outcomes in different series of untreated patients. Nevertheless, several prognostic factors that affect the natural course of the disease can be identified, of which the extent of extrahepatic disease, as well as the number of hepatic metastases and proportion of the liver involved, seem to be the most important. The median survival time for patients with untreated synchronous liver metastases ranges from 6.6 to 11 months after diagnosis (Table 7.1). Median survival time for patients with unresected solitary lesions is 15–20 months in different series, compared with 10–15 months for patients with multiple unilobular lesions and about 3 months for patients with widespread metastases involving both lobes of the liver (Table 7.2). In a large series of 484 untreated patients, Stangl et al found survival rates of 31.3% at 1 year, 7.9% at 2 years, and 2.6% at 3 years [21]. Using multivariate analysis, these authors found survival to be significantly related to four independent risk factors, the most important of which were percent of liver volume replaced by tumor, followed by grade of primary tumor, presence of extrahepatic disease, and mesenteric lymph node involvement. In another series of 252 patients with unresected hepatic metastases, which were the only evidence of metastatic disease, Wagner et al found higher 3-year survival rates of

21% in patients with solitary lesions, 6% in those with multiple unilateral lesions, and 4% in those with widespread disease [22]. Survival beyond 5 years without treatment is very unusual, although a few such cases have been described in the literature. Similar survival data were found in an earlier retrospective analysis of 113 patients by Wood et al [15] (see Table 7.2). These authors also examined survival in a subgroup of patients with no evidence of local tumor invasion, lymph node spread, or more distant metastatic spread other than the presence of liver metastases [15]. These patients would now have been considered potential candidates for liver resection. In six patients who fulfilled those criteria and who had multiple metastases localized to one segment or lobe of the liver, these authors found a mean survival time of 17 months and a 1-year survival of 50%. A

Table 7.1 Natural history of untreated patients with synchronous liver metastasis from colorectal cancer. Study

No of patients (months)

Mean or median (range) survival

Finan et al (1985) [17] Hafström et al (1994) [27]

90 synchronous 14 synchronous 12 metachronous 232 synchronous 252 metachronous 47 synchronous 13 solitary 34 multiple

10.3 (0–48) 10 (1–31) 9 (5–25) 6.6 8.0 8.5 (1–27) 11 7.5

Stangl et al (1994) [21] Gorog et al (1997) [28]

Table 7.2 Natural history of liver metastasis from colorectal cancer in series with specification of amount of liver involvement. Study

No of patients

Mean or median survival (months)

Survival rate (%) 1 year

2 year

5 year

Wood et al (1976) [15] Widespread Localized Solitary

113 87 11 15

6.6 3.1 10.6 16.7

5.7 27 60

0 9.9 13.3

Wagner et al (1984) [22] Widespread Localized Solitary

252 182 31 39

– 15 21

41* 63* 70*

4 6 21

2 0 3

Stangl et al (1994) [21] ≥8 metastases 2–7 metastases Solitary

484 320 90 74

7.5 5.9 12.5 10.8

31.3 21 52 29

2.5 1 7 6

0.9 0 4 0

*Data deduced from graph in original publication.

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similar subgroup of patients with solitary liver metastases (n = 7) had a mean survival of 25 months and a 1-year survival of 100%. Unfortunately, there are no randomized studies making a direct comparison between nonsurgical and surgical treatment of colorectal metastasis, and such studies would be considered unethical today. The only data on natural history are available from the above mentioned historical series of rather heterogeneous groups of patients, which have several limitations. Nevertheless, the 2- and 3-year survival data from surgical (or other interventional) series should always be critically analyzed in light of these data of natural history and survival. The natural course of the disease in potentially resectable patients is such that the operative mortality rate must be low, probably less than 4–5%, and the expected survival rates should be significantly higher than those determined by the natural history of the disease [16].

Determination of prognosis In several studies, investigators have tried to identify adverse prognostic factors that might preclude surgical resection. Although the results of these studies can vary in detail, they consistently point towards the importance of the following variables: the original tumor stage, number of liver metastases, size of the liver metastases, CEA level, metastases occurring within 12–20 months after resection of the primary colon tumor, and presence of metastasis outside the liver and primary colon site [2, 7, 23]. Apart from these biologic and anatomic characteristics, there is increasing evidence that the host systemic inflammatory response is an important prognostic factor in patients with colorectal cancer [3]. It should be noted, however, that the relative importance of individual prognostic factors may be evolving with the introduction of newer and more effective chemotherapeutic or biologically active antitumor regimens. Important new information may emerge from studies focusing on the genetic expression profile of patients with colorectal liver metastases [24–26]. This area is developing rapidly and preliminary evidence suggests that the metastatic potential is already encoded in the primary tumor and is detectable by a gene expression profile, which allows the prediction of liver metastasis in patients diagnosed with localized tumors and also the design of new strategies for the treatment and diagnosis of colorectal cancer.

Self-assessment questions 1 The expected median survival time in patients with untreated synchronous colorectal liver metastases is: A <3 months B 3–10 months

C 10–20 months D 20–30 months E >30 months 2 The expected median survival time in patients with an untreated solitary liver metastases from a colorectal malignancy is: A <3 months B 3–10 months C 10–20 months D 20–30 months E >30 months 3 More than 50% of patients with a colorectal malignancy will develop liver metastases, but, fortunately, around 80% of them can be resected. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct 4 At the time of diagnosis of a colon malignancy, liver metastases can be detected in: A 0–5% B 5–15% C 15–25% D 25–50% E >50% 5 Variables that are significantly associated with the prognosis in patients with colorectal liver metastases include (more than one answer is possible): A Localization of the original tumor B Size of the original tumor C Time interval between detection of the original tumor and detection of the liver metastases D Level of serum CEA E Level of serum CA19-9 F Number of liver metastases G Side of the liver where the metastases are located

References 1 Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Canacer statistics, 2007. CA Cancer J Clin 2007;57:43–66. 2 Benson AP. Epidemiology, disease progression and economic burden of colorectal cancer. J Manag Care Pharm 2007;13(Suppl S-c):S5–S18. 3 McMillan DC, McArdle CS. Epidemiology of colorectal liver metastases. Surg Oncol 2007;16:3–5. 4 Goh KL. Changing trends in gastrointestinal disease in the AsiaPacific region. J Gig Dis 2007;8:179–85.

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5 Shaheen NJ, Hansen RA, Morgan DR, et al. The burden of gastrointestinal and liver diseases, 2006. Am J Gastroenterol 2006;101:2128–38. 6 Fong Y, Kemeny N, Paty P, Blumgart LH, Cohen AM. Treatment of colorectal cancer: hepatic metastasis. Semin Surg Oncol 1996;12:219–52. 7 Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer. Ann Surg 1999;230:309–21. 8 Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 2006;244:254–9. 9 Gatta G, Capocaccia R, Sant M, et al. Understanding variations in survival for colorectal cancer in Europe: a EUROCARE high resolution study. Gut 2000;47:533–8. 10 Kune GA, Kune S, Field B, White R, Brough W, Schellenberger R, Watson LF. Survival in patients with large-bowel cancer: a population-based investigation from the Melbourne Colorectal Cancer Study. Dis Colon Rectum 1990;33:938–46. 11 Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med 1985;312:1604–8. 12 Uen YH, Lin SR, Wu DC, et al. Prognostic significance of multiple molecular markers for patients with stage II colorectal cancer undergoing curative resection. Ann Surg 2007;246:1040–6. 13 Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004;240: 644–57. 14 Clavien PA, Petrowsky H, DeOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 2007;356:1545–59. 15 Wood CB, Gillis CR, Blumgart LH. A retrospective study of the natural history of patients with liver metastases from colorectal cancer. Clin Oncol 1976;2:285–8. 16 Nortstein J, Silen W. Natural history of liver metastases from colorectal carcinoma. J Gastrointest Surg 1997;1:398–407. 17 Finan PJ, Marshall RJ, Cooper EH, Giles GR. Factors affecting survival in patients presenting with synchronous hepatic metastasis from colorectal cancer: a clinical and computer analysis. Br J Surg 1985;72:373–7. 18 Finlay IG, Meek D, Brunton F, McArdle CS. Growth rate of hepatic metastases in colorectal carcinoma. Br J Surg 1988;75: 641–4.

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19 Purkiss SF, Williams NS. Growth rate and percentage hepatic replacement of colorectal liver metastases. Br J Surg 1993;80: 1036–8. 20 Barbara L, Benzi G, Gaiani S, et al. Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumor growth rate and patient survival. Hepatology 1992;16:132–7. 21 Stangl R, Altendorf-Hofmann A, Charnley RM, Scheele J. Factors influencing the natural history of colorectal liver metastases. Lancet 1994;343:1405–10. 22 Wagner JS, Adson MA, Van Heerden JA, et al. The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann Surg 1984;199:502–8. 23 Minagawa M, Yamamoto J, Kosuge T, Matsuyama Y, Miyagawa S, Makuuchi M. Simplified staging system for predicting the prognosis of patients with resectable liver metastasis. Arch Surg 2007;142:269–76. 24 Diep CB, Teixeira MR, Thorstensen L, et al. Genome characteristics of primary carcinomas, local recurrences, carcinomatoses, and liver metastases from colorectal cancer patients. Mol Cancer 2004;3:6. 25 Yamasaki M, Takemasa I, Komori T, et al. The gene expression profile represents the molecular nature of liver metastasis in colorectal cancer. Int J Oncol 2007;30:129–38. 26 Ki DH, Jeung HC, Park CH, et al. Whole genome analysis for liver metastasis gene signatures in colorectal cancer. Int J Cancer 2007;121:2005–12. 27 Hafstrom L, Engaras B, Holmberg SB, et al. Treatment of liver metastases from colorectal cancer with hepatic artery occlusion, intraportal 5-fluorouracil infusion, and oral allopurinol. A randomized clinical trial. Cancer 1994;74:2749–56. 28 Gorog D, Toth A, Weltner J. Prognosis of untreated liver metastasis from colorectal cancer. Acta Chir Hung 1997;36:106–7.

Self-assessment answers 1 2 3 4 5

B C B C A, C, D, F

8

Tumor Markers in Primary and Secondary Liver Tumors Ketsia B. Pierre and Ravi S. Chari Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN, USA

The goal of tumor marker research is to identify markers with the potential to enhance clinical decision-making with regards to diagnosis, treatment, and patient outcome. Tumor markers are molecular or biologic substances whose expression implies the presence of a particular cancer. In general, tumor markers are produced by the tumor, or by the body in response to a tumor. Carcinogenesis not only changes the characteristics of the cells involved (histopathologic markers), but the process may also induce the altered production of molecules (serologic markers). Due to the overabundance of tumor marker reports, the American Society for Clinical Oncology (ASCO) has established a Tumor Marker Utility Grading System (TMUGS) [1, 2]. The scoring system was designed to determine whether the weight of available evidence supporting the marker in question is sufficient for the marker to be reliably used in clinical decision-making. The TMUG worksheet (Figure 8.1) was created to organize the characteristics of the tumor marker in question. The qualities of an ideal tumor marker are outlined in Table 8.1. Broadly, an ideal tumor marker is statistically proven to include people who have the tumor (highly sensitive) and exclude those without (highly specific). The levels of expression of such a marker would correlate with disease burden and fall in the face of successful treatment. More importantly, the ideal tumor marker would allow for detection of the tumor marker in the preclinical stages of the disease where therapeutic options are more viable. Although not an absolute requirement, it also should not require tissue, thus allowing noninvasive measurement. Preferably the assay would also be comparatively cheap. In general, the term tumor marker implies that a compound/product is measured in soluble form in bodily fluids – most commonly blood or urine. Tumor markers also have been studied on tumor cells. Among the earliest tumor markers were the histologic and cytologic markers used by surgical pathologists; these techniques defined aberrant features that aided the diagnosis of the malignancy. Through

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

improvements in molecular biologic techniques, reports of new tumor markers often center on those found in the tumors themselves. These latter tumor markers help define the tumor and may aid prognosis; however, they require tissue and thus cannot be easily measured for diagnosis or treatment response. Discussion of these tumor markers is beyond the scope of this chapter and as such they will not be discussed in detail here. We will limit our discussion to serologic tumor markers used in the diagnosis and treatment of liver tumors in which resection is indicated as these are felt to be the more clinically useful.

Tumor-specific versus tumor-associated markers Tumor markers are classified in the oncologic literature as tumor-specific markers or tumor-associated markers. When a marker is exclusively expressed by tumor cells of one or more histologic types, but not by normal cells, it is considered tumor specific. In contrast, when it is “shared” by several tumors and selected normal tissues, it is considered tumor associated.

Tumor markers in primary liver cancer Hepatocellular carcinoma The development of hepatocellular carcinoma (HCC) is a multistep process associated with changes in host gene expression, some of which correlate with the appearance, progression, and even recurrence of the tumor. Many markers have been described in HCC; the most common are outlined in Table 8.2.

Tumor-associated markers This group comprises the majority of clinically useful tumor markers. Because many of these are serologic tests, they have utility not only in diagnosis but therapeutic monitoring as well.

Alpha-fetoprotein Alpha-fetoprotein (AFP) has a molecular weight of 64 000– 74 000 Da. The gene coding for AFP has been localized to

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DEFINITIONS AND SPECIFICATIONS OF MARKER MARKER DESIGNATION/ NOMENCLATURE

MOLECULE/SUBSTANCE ASSAYED & ALTERATION DETECTED

(e.g. ER, P53, CEA, etc.)

(e.g. DNA/mutation, RNA/overexpression, Protein/increased levels, etc.)

ASSAY FORMAT TO DETECT MARKER (e.g. EIA, ICA, SSCP, etc.)

REAGENTS USED

SPECIMEN SOURCE

(e.g. specific MAb or probe, or commercial assay)

(e.g. frozen or fixed tissue, plasma, urine, circulating cells, etc.)

DISEASE (e.g. breast cancer, colon cancer, etc.)

UTILITY

Marker association with biologic: Process

Uses

Use leads to decision in practice that results in a more favorable clinical outcome:

Endpoint

Utility Level of Utility Score Evidence Score

Level of Evidence

Survival Utility Score

Level of Evidence

Disease Free Survival

Quality of Life

Utility Score

Utility Score

Level of Evidence

Level of Evidence

Cost of Care Utility Score

Level of Evidence

Determine risk Screening Differential diagnosis Prognosis: Predict relapse/progression Primary Metastatic Prognosis: Predict response to therapy Primary Metastatic Monitor course Detect relapse in patient with no evidence of disease after therapy for primary or recurrent disease Follow detectable disease

Figure 8.1 Tumor marker utility grading worksheet (redrawn with permission from Hayes [1]).

Table 8.1 Qualities of ideal tumor markers. High sensitivity to detect all patients with the specified tumor High specificity to detect only a particular tumor and exclude those without Marker level that correlates with the tumor burden Marker level that falls after adequate treatment Ability to detect tumor in preclinical stage

chromosome 4q, close to the gene encoding albumin. It is present in large quantities during fetal development but falls rapidly after birth, and thereafter remains normal at the adult level of 10 ng/mL or less. In adult females, AFP levels are elevated during the second and third trimester of pregnancy, reflecting production from the fetal liver and yolk sac. Following delivery, the level falls rapidly due to its short half-life of 5 days. AFP is produced in small amounts (<10 μg/L) in certain healthy individuals.

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Alpha-fetoprotein in the diagnosis of hepatocellular carcinoma In the United States, 75% of patients with HCC arising in association with hepatitis B virus (HBV) cirrhosis had AFP levels above 400 ng/mL. Sixty-five percent of patients with HCC secondary to alcoholic cirrhosis had positive results, whereas only 33% of patients with carcinoma arising in a noncirrhotic liver had positive assays. Overall AFP has a low specificity, and many cirrhotic patients without HCC have “positive” values. Thus, levels above 500 ng/mL in areas of high incidence, and appropriate radiologic and clinical findings are considered diagnostic of HCC [3]. In this setting, where cirrhosis is the clinical parameter, biopsy is unnecessary. Alpha-fetoprotein in the monitoring of hepatocellular carcinoma treatment AFP can be used to monitor response to therapy. Following curative surgery, AFP has been shown to normalize [4]. In

CHAPTER 8

Table 8.2 Tumor markers in hepatocellular carcinoma (HCC). Serologic Tumor specific • RASSF1A Tumor associated • Alpha-fetoprotein (AFP) and AFP isoforms • Des-γ-carboxyprothrombin (DCP) or prothrombin induced by vitamin K absence or antagonist-11 (PIVKA-11) • Urokinase-type plasminogen activator (UPA) • C-reactive protein • Carcinoembryonic antigen (CEA) • Cytokeratin-19 (CK-19) • Transforming growth factor β (elevated in urine also) • B2-macroglobin • 90K/MAC-2BP glycoprotein • Serum telomerase activity • Serum AFP mRNA • Serum alpha-L-fucosidase (ALF) • Plasma thrombomodulin • Serum angiotensin converting enzyme • β-catenin • Unsaturated vitamin B12-binding capacity (in fibrolamellar variant of HCC) • Serum neurotensin (in fibrolamellar variant of HCC) Tissue/histopathologic Tumor specific • Mutation p53 codon 249 • Circulating HCC cells • Loss of heterozygosity (LOH): chromosome 13q (Rb and BRCA-2 loci) and chromosome 6q26-q27 (M6P/IGF2R locus) Tumor associated • MAGE, GAGE, and BAGE gene expression • AFP • CA 19-9 • Glypican-3 mRNA • UPA • cMet • CEA • Androgen receptorCD-34 • Anti-MOC31 • Flow cytometry

the initial stages of chemotherapy, AFP can actually rise due to tumor shrinkage and release of AFP from dying tumor cells; however, in patients with a positive response, the level will eventually fall. Persistent elevation indicates chemoresistance and nonresponse. Alpha-fetoprotein in screening for hepatocellular carcinoma Because most tumors are unresectable at the time of diagnosis due to advanced stage, screening programs have been developed in an effort to identify patients with early stage disease who have the best chance of response to surgical

Tumor Markers in Primary and Secondary Liver Tumors

intervention. Unfortunately, AFP has low specificity and moderate sensitivity.

Prothrombin induced by vitamin K absence or antagonist-11 or des-γ-carboxy prothrombin (DCP) Prothrombin induced by vitamin K absence or antagonist-11 (PIVKA-11) is made by the liver in the presence of substances such as warfarin or in patients with nutritional deficiency of vitamin K. In 1984, Liebman et al [5] found raised des-γ-carboxy prothrombin (DCP) levels in 76% of patients with HCC. As with AFP, small HCC tends to be associated with low DCP levels, although Wang et al have suggested that DCP is more effective than AFP in detecting small HCC [6]. Koike has also suggested through multivariate Cox regression analysis that elevated DCP is the most useful predisposing clinical parameter for the development of portal vein invasion [7]. Kasahara [8] found that 48.2% of patients with HCC had PIVKA-11 levels above 0.1 AU/mL, compared with 7.1% of those with cirrhosis and 3.1% with chronic hepatitis. These authors also showed that in subjects with low or negative AFP, 32.8% had elevated PIVKA-11 levels. The results suggested the use of a combination of these two assays because almost 60% of patients with HCC will test positive for elevated levels of one or both of these. Urokinase-type plasminogen activator Urokinase-type plasminogen activator (UPA) is a serine protease whose levels can be monitored by radioimmunoassay. It is cleared by the liver, so like other markers in HCC, chronic liver disease can alter serum levels. It has been linked to invasion and metastasis in HCC. Transforming growth factor β1 Transforming growth factor β1 (TGFB1β1) is a multifunctional polypeptide involved in the growth and development of both normal and malignant cells [9]. In various cancers, TGFβ1 is overexpressed; in HCC, the quantity of mRNA encoding TGFβ1 is elevated but falls following treatment. Serum alpha-L-fucosidase Serum alpha-L-fucosidase (AFU) has been examined clinically in Italy [10]. Giardina et al examined the serum AFU levels of 120 cirrhotic individuals. In seven of 16 who developed carcinoma, AFU levels increased 6–9 months before ultrasonographic evidence of HCC was present; in only three of these seven was there an elevation in AFP. However, in three of the cases, only the AFP was elevated. Thus, there is an association with increasing AFU and development of HCC. Other markers described in hepatocellular carcinoma Other candidate markers have been investigated for clinical utility in HCC. Many of these have shown some promise, but have not gained widespread use due to

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Epidemiology and Diagnosis

complexity and cost of assay, or because of the unclear role of these markers.

Fibrolamellar variant of hepatocellular carcinoma Fibrolamellar variant of HCC characteristically develops in females younger than the age of 35; it is possible that some of these tumors are linked etiologically to oral contraceptives. These tumors are often found to be AFP negative. Serum neurotensin levels have been found to be elevated in the majority of cases reported in a small series by Collier [11]. The neurotensin level fell soon after treatment (suggesting a short half-life.) Another marker reported in the fibrolamellar variant of HCC is unsaturated vitamin B12 binding capacity. Seven of 10 patients with fibrolamellar HCC had elevated levels of unsaturated vitamin B12-binding capacity and normal AFP. Vitamin B12-binding capacity is currently used as a marker of this variant of HCC [12]. Unfortunately, with the fibrolamellar variant of HCC, no new candidate tumor markers have been introduced since the last edition of this book.

Cholangiocarcinoma The greatest risk factor for cholangiocarcinoma is primary sclerosing cholangitis (PSC), with a lifetime risk of 10% [13, 14]. In one study of PSC comparing 26 patients with cholangiocarcinoma with 87 patients without tumors, only alcohol consumption was significantly associated with cancer development (odds ratio, 2.95; 95% CI, 1.04–8.3); however, this study could not test for dose response due to inadequate data [15]. In addition, these authors did not confirm a previous link [16] made between smoking and cholangiocarcinoma in PSC. Finally, in a 3-year prospective study of 75 patients with PSC without clinical signs of cholangiocarcinoma, the authors determined that carcinoembryonic antigen (CEA), CA 19-9, CA 50, and CA 242 were not useful in diagnosing bile duct cancer because of limited specificity [17].

Tumor markers in metastatic liver cancer

trauma, as well as in smokers and some healthy individuals. Immunohistochemical methods have located CEA in normal colonic epithelium, where it functions as a cell adhesion molecule. Unfortunately, CEA lacks sensitivity, and is therefore not useful as a screening tool, even in a high-risk population for colorectal carcinoma, such as those with familial adenomatous polyposis. The current guidelines from the American Society of Clinical Oncology (ASCO) expert panel on tumor markers state that CEA should be measured every 3 months after surgery for colorectal cancer for at least 3 years to detect recurrent disease. It is the marker of choice for monitoring metastatic colorectal cancer during systemic treatment and is the most sensitive marker for liver metastasis [18]. From 25% to 50% of those with local regional recurrence and 95% of those with liver metastases have been shown to have an elevated CEA [2]. Preoperative CEA elevations have prognostic implications; levels above 5 ng/mL have demonstrated a higher relapse rate that is unrelated to tumor stage or histopathologic grade. Also, the time to development of recurrent disease is shorter in those with elevated preoperative levels [19]. CEA should return to normal by 6 weeks after surgical resection, and a persistently elevated CEA following colorectal surgery suggests occult liver metastases that may be amenable to liver resection. There is no evidence to date that treating for metastatic disease on the basis of an elevated CEA level alone is of any benefit. The major aim of using CEA in the follow-up period is to detect patients with isolated, potentially resectable liver metastases. Those patients undergoing surgical resection for hepatic metastases have longer survival rates that those treated with chemotherapy alone. Although CEA has a high sensitivity rate for liver metastases (97%) [20], it should be noted that up to 30% of patients with relapsed colorectal carcinomas do not have an elevated CEA level [21]. CEA elevations can occur during the first few cycles of treatment due to the slight hepatotoxicity of drugs such as 5-fluorouracil (5-FU). When CEA levels respond during chemotherapy for advanced disease, those patients survive longer as compared to cases where CEA levels fail to decrease.

Metastatic colorectal cancer Carcinoembryonic antigen

CA 19-9

CEA is a 200 000 Da glycoprotein that was initially detected by using antibodies derived from rabbits that had been injected with cells from human colon cancer. With refinement of assay techniques, CEA was found to be elevated in cancer of the gastrointestinal tract and in other carcinomas (lung, breast, stomach, pancreas, kidney, and bladder), especially those with widespread metastatic disease. In fact, CEA elevation is observed in a wide range of conditions, such as benign liver disease, inflammatory conditions such as pancreatitis, gastritis, collagen disorders, infections, and

CA 19-9 is a marker that is generally more commonly used in pancreatic and biliary cancer than in colorectal carcinoma metastatic to the liver. CEA and CA 19-9 have been compared and combined as markers of recurrent disease, and found to have an abnormality in 48% and 84%, respectively, of those with recurrence of colorectal carcinoma [22].

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Other markers Sialic acid and related glycoproteins are found on the surface of malignant cells at increased levels compared to normal

CHAPTER 8

cells, and their presence relates to the metastatic capacity in colorectal cell lines [23].

Microsatellite instability in colorectal carcinoma Microsatellite instability is a measure of the inability of the DNA mismatch repair system to correct errors that occur during DNA replication. It is the alternative pathway to chromosomal instability with loss of heterozygosity in colorectal carcinogenesis. Microsatellite instability has been suggested to be prognostic for survival and predictive for response to therapy in patients with colorectal cancer; however, the current recommendation by the ASCO expert panel on tumor markers does not advocate its use for prognosis or prediction of response to therapy (specifically, 5-FU) in colorectal cancer [24]. Gryfe et al [25] tested the hypothesis that colorectal cancers arising from the microsatellite instability pathway would have distinctive clinical attributes that affect clinical outcome. Specimens of 607 patients with colorectal cancer from population-based series (50 years of age or younger at diagnosis) were tested for microsatellite instability. The authors compared the clinical features and survival of patients who had colorectal cancer characterized by highfrequency microsatellite instability with the same characteristics in patients who had colorectal cancers with microsatellite stability. Microsatellite instability was identified in 17% of the colorectal cancers in 607 patients, and in a multivariate analysis, microsatellite instability was associated with a significant survival advantage independently of all standard prognostic factors, including tumor stage (hazard ratio, 0.42; 95% CI, 0.21–0.53) or distant organs (odds ratio, 0.49; 95% CI, 0.27–0.89; p = 0.02). These authors concluded that high frequency microsatellite instability in colorectal cancer is independently predictive of a relatively favorable outcome and, in addition, reduces the likelihood of metastasis. More recently, Watanabe et al [26] examined colorectal carcinoma for loss of heterozygosity at 18q, and found that it was present in 155 of 319 cancers (49%). They found high levels of microsatellite instability in 62 of 298 tumors (21%), and 38 of these 62 tumors (61%) had a mutation of the gene for the type II receptor for TGFβ1. Among patients with microsatellite-stable stage III cancer, 5-year overall survival after 5-FU–based chemotherapy was 74% in those with loss of 18q alleles (relative risk of death with loss at 18q, 2.75; 95% CI, 1.34–5.65; p = 0.006). The 5-year survival rate among patients whose cancer had high levels of microsatellite instability was 74% in the presence of a mutated gene for the type II receptor for TGFβ1, and 46% if the tumor did not have this mutation (relative risk of death, 2.90; 95% CI, 1.14–7.35; p = 0.03). This study shows that retention of 18q alleles in microsatellite-stable cancers and mutation of the gene for the type II receptor for TGFβ1 in cancers with high levels of microsatellite instability point to a favorable outcome after adjuvant chemotherapy with 5-FU-based regimens for stage III colon cancer.

Tumor Markers in Primary and Secondary Liver Tumors

Metastatic breast cancer CA 15-3 CA 15-3 is a product of the MUC-1 gene along with CA 549 and its close relative, CA 27-29 [27]. These markers belong to a group of high molecular weight glycoproteins that are similar to mucin. CA 15-3 is defined by its reaction with monoclonal antibodies 115D8 and DF3 raised against milk fat globulin membrane and liver secondaries from breast cancer, respectively, and is measured by bi-determinate immunoradioassay. CA 15-3 is the most widely used marker in breast cancer. Levels correlate with extent of disease [28]. In a series by Martin et al [29], preoperative CA 15-3 levels were significantly higher in patients with large tumors and node-positive disease (both p = 0.0001) In univariate analyses, elevated CA 15-3 was associated with lower probabilities of relapse-free and overall survival (p = 0.0001 and p = 0.004, respectively). The authors concluded that CA 15-3 could be used as a prognostic marker. Due to poor sensitivity in detecting early stage disease, CA 15-3 is not useful in the early diagnosis of breast cancer. The 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer does not support the use of CA 15-3 and CA 27-29 for screening, diagnosis, staging, or early detection of recurrence after primary breast cancer treatment. Treating tumor marker-positive asymptomatic recurrent breast cancer has not been shown to improve survival and runs the risk of treatment-related side effects. Therefore, the role of tumor markers in early detection of relapsed breast cancer is only investigational. For patients with metastatic disease undergoing active therapy, however, CA-15-3 and CA 27-29 can be used in conjunction with clinical history, examination, and diagnostic imaging to monitor treatment response [30].

Metastatic carcinoid Carcinoid tumor is one of the most common types of neuroendocrine tumors to affect the liver. Presence of hepatic metastases of carcinoid tumor can result in carcinoid syndrome. Several hormones are produced, including serotonin (5-hydroxytryptamine,[5-HT]), neuropeptide K, substance P, chromogranin, 5-hydroxyindoleacetic acid (5-HIAA) and human chorionic gonadotropin (HCG). Some of these can be used as tumor markers.

Conclusions There has only been incremental change with regards to tumor markers for primary and secondary liver cancer since the last edition of this book was published. New candidate markers have yet to be validated through rigorous clinical trials. It remains true that in the setting of both primary and secondary liver tumors, very few treatment strategies are curative, primarily because of late diagnosis. The solution to

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Table 8.3 Clinically established markers in liver tumors. Hepatocellular carcinoma

Metastatic colorectal carcinoma Cholangiocarcinoma Breast cancer Metastatic carcinoid

Alpha-fetoprotein (AFP) AFP-L3 Prothrombin induced by vitamin K absence or antagonist-11 (PIVKA-11) Carcinoembryonic antigen (CEA) CA 19-9 CA 19-9 CA 15-3 5-hydroxyindoleacetic acid (5-HIAA)

this problem, in simplistic terms, is diagnosis of liver tumors in the preclinical stages of disease. Tumor markers are expected to herald the onset of cancer yet there are few tumor-specific markers for primary HCC, and very few ideal markers for either primary or secondary tumors of the liver. Table 8.3 outlines markers used clinically for the various tumors of the liver. Very few of the markers discussed actually impact clinical diagnosis, monitoring, and most importantly survival. Serologic tumor markers, in theory, provide the best opportunity for clinicians to diagnose and monitor therapy. Developments in molecular biology and immunohistochemistry continue to identify new substances associated with malignancy that may have a role as markers of disease activity. As new tumor markers become available, either alone or in concert with already known traditional markers, clinical detection and therapeutic efficacy may be better monitored with the ultimate goal of improved survival and quality of life for cancer patients.

Self-assessment questions 1 What is the half-life of alpha-fetoprotein? A 1 day B 2 days C 3 days D 4 days E 5 days 2 In patients with cirrhotic liver disease, above what level is the alpha-fetoprotein considered indicative of malignancy? A 10 ng/mL B 50 ng/mL C 100 ng/mL D 400 ng/mL E 1000 ng/mL 3 Fibrolamellar variant of HCC is often found to have an associated elevated level of AFP. True or false?

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4 The high specificity of CA 19-9 makes it a useful marker in the diagnosis of cholangiocarcinoma. True or false? 5 Carcinoembryonic antigen (CEA) is a useful screening tool in the diagnosis of metastatic colorectal carcinoma to the liver. True or false?

References 1 Hayes DF. Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. J Natl Cancer Inst 1996;88:1456–66. 2 Bast RC. 2000 Update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001;19:1865–78. 3 Chari RS, Foley DP, Meyer WC. Primary hepatic neoplasms. In: Bland, Daly and Karakousis, eds. Surgical Oncology: Contemporary Principles and Practice. McGraw Hill, New York, 2001: 659–71. 4 Tang Z. Three decades’ experience in surgery of hepatocellular carcinoma. Yu Y, Zhou X, editors. Chin Med J 2004;110: 245–249. 5 Liebman HA. Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N Engl J Med 1984;310:1427–31. 6 Wang CS, Lin CL, Lee HC, et al. Usefulness of serum des-gammacarboxy-prothrombin in detection of hepatocellular carcinoma. World J Gastroenterol 2005;11:6115–19. 7 Koike Y. Des-gamma-carboxy prothrombin as a useful predisposing factor for the development of portal venous invasion in patients with hepatocellular carcinoma: a prospective analysis of 227 patients. Cancer 2001;91:561–9. 8 Kasahara A. Clinical evaluation of des-gamma-carboxy prothrombin as a marker protein of hepatocellular carcinoma in patients with tumors of various sizes. Dig Dis Sci 1993; 38:2170–6. 9 Chari RS. Downregulation of transforming growth factor beta receptors type I, II and III during liver regeneration. Am J Surg 1994;195:126–32. 10 Giardina MG. Serum alpha-L-fucosidase activity and early detection of hepatocellular carcinoma: a prospective study of patients with cirrhosis. Cancer 1998;83:2468–74. 11 Collier NA. Neurotensin secretion by fibrolamellar carcinoma of the liver. Weinbren K, Bloom SR et al, editors. Lancet 1984;1:538–40. 12 Pardinas FJ. High serum vitamin B12 binding capacity as a marker of the fibrolamellar variant of hepatocellular carcinoma. Br Med J Clin Res Ed 1982;285:840–2. 13 Chalasani N. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study. Hepatology 2000;1:7–11. 14 de Groen PC. Cholangiocarcinoma in primary sclerosing cholangitis: who is at risk and how do we screen? [editorial; comment]. Hepatology 2000;8:247–8. 15 Chalasani N. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study. Hepatology 2000;1:7–11.

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16 Bergquist A. Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study. Hepatology 1998;27:311–16. 17 Hulcrantz R. A 3-year prospective study on serum tumor markers used for detecting cholangiocarcinoma in patients with primary sclerosing cholangitis. J Hepatol 1999;30:669–73. 18 Locker G, Hamilton S, Harris J, et al. ASCO 2006 Update of Recommendation for the Use of Tumor Markers in Gastrointestinal Cancer. J Clin Oncol 2006;24:5313–27. 19 Wanebo HJ. Preoperative carcinoembryonic antigen level as a prognostic indicator in colorectal cancer. N Engl J Med 1978;299:448–51. 20 Arnaud JP, Cervi C, Bergamaschi R, Tuech JJ. Value of oncologic follow-up of patients operated for colorectal cancer. A prospective study of 1000 patients. J Chir 1997;134:45–50. 21 Fletcher RH. Carcinoembryonic antigen. Ann Intern Med 1986;104:66–73. 22 Filella X, Molina R, Pique JM, et al. Use of CA 19-9 in the early detection of recurrences in colorectal cancer: comparison with CEA. Tumour Biol 1994;15:1–6. 23 Yogeeswaran G, Salk PL. Metastatic potential is positively correlated with cell surface sialylation of cultured muring tumor cell lines. Science 1981:212:1514–16. 24 Locker G, Hamilton S, Harris J, et al. ASCO 2006 Update of Recommendation for the Use of Tumor Markers in Gastrointestinal Cancer. J Clin Oncol 2006;24:5313–27. 25 Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 2000;342:69–77.

Tumor Markers in Primary and Secondary Liver Tumors

26 Watanabe T, Wu TT, Catalano PJ, et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 2001;344:1196–206. 27 Chan DW, Beveridge RA, Muss H, et al. Use of Truquant BR radioimmunoassay for early detection of breast cancer recurrence in patients with stage II and stage III disease. J Clin Oncol 1997;15:2322–8. 28 Tampellini M, Berruti A, Gerbino A, et al. Relationship between CA 15-3 serum levels and disease extent in predicting overall survival of breast cancer patients with newly diagnosed metastatic disease. Br J Cancer 1997;75:697–702. 29 Martin A, Corte MD, Alvarez AM, et al. Prognostic value of pre-operative CA 15-3 levels in breast cancer. Anticancer Res 2006;26:3965–71. 30 Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. 33. J Clin Oncol 2007;25:5287–312.

Self-assessment answers 1 2 3 4 5

E D False False False

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9

Modalities for Imaging Liver Tumors Dominik Weishaupt1 and Thomas F. Hany2 1 2

Division of Radiology, Triemli Hospital, Zurich, Switzerland Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland

Introduction

Ultrasound

The main goals of liver tumor imaging are to assess: (1) the number and size of the liver lesions; (2) the location of the lesions relative to the liver vessels; (3) the nature of the lesions (benign versus malignant); (4) the origin of the lesions (primary versus secondary); (5) the liver parenchyma surrounding the lesions; and (6) the presence or absence of extrahepatic disease. In addition, with the increasing use of innovative strategies in liver resection and partial liver transplantation, the accurate assessment of the surgically created liver remnant volume or the partial graft volume is becoming another goal for imaging. Currently, there is no consensus concerning the optimal strategy for the imaging of liver tumors. The choice of which modality to use is determined based on the request of the referring clinician, the availability of the equipment, the condition of the patient, and the experience of the imager. For imaging of the liver and the bile ducts, most centers use ultrasound (US), computed tomography (CT), or magnetic resonance imaging (MRI). In addition, other imaging modalities such as positron emission tomography (PET), CT during arterial portography (CTAP) or CT during hepatic arteriography (CTHA), and laparoscopy with intraoperative ultrasound are also used, depending on the availability of the equipment and the experience of the clinicians. Finally, in some patients, catheter-assisted techniques can provide important information, and in patients with cholangiocarcinoma, direct or indirect cholangiography may be useful to determine the longitudinal extension of the tumor along the bile ducts. This chapter describes a number of aspects of liver tumor imaging, including the technical principal of each modality, and the current status and role of the imaging modalities in assessing these liver abnormalities.

Transabdominal ultrasound

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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Ultrasound (US) is the initial examination performed in most patients clinically suspected of having a liver mass, because it enables a rapid, accurate, and noninvasive assessment of the liver parenchyma. US relies on reflected sound waves to generate an image. The standard (gray scale) US image represents a spatial map of the boundaries of objects with different acoustic properties that act to reflect the sound waves generated by the transducer. US provides for good soft tissue contrast, is easily applied, is relatively inexpensive, and does not use ionizing radiation. In addition, US provides real-time images and enables the real-time guidance of biopsies. The main disadvantage is its operator dependency and limited reproducibility. In addition, its applicability can depend on the patient’s body habitus, so that obese patients can be difficult to scan. Several properties can be exploited to modulate contrast in a US image. The Doppler shift refers to a frequency shift in sound associated with its reflection from a moving object. The Doppler shift can be used to calculate the velocity of flowing blood by estimating the frequency shift of the US waves reflected from the blood cells. In practice, a Doppler US can be used to estimate the velocity of the blood flowing towards and away from the transducer. With respect to liver tumors, it can be used to estimate the vascularity of a tumor or to determine vascular patency. Power Doppler US is a technique which was developed to overcome some of the drawbacks of Doppler US. One of the major limitations of Doppler US is its dependency on angle. This means that Doppler US loses sensitivity for flows that are perpendicular to the sound field. Power Doppler US is independent of the angle, but has no directional flow information. The major disadvantage of power Doppler is its sensitivity to motion artifacts. Another property that can be exploited with US is the distortion of the US wave caused by the local deformity of the tissues, as the US wave is passing through. The wave distortion is manifested by the development of harmonic (at

CHAPTER 9

frequencies corresponding to a multiplier of the base frequency) waves. In addition to a primary mechanism of generating contrast, harmonic imaging is particularly effective in detecting sonographic contrast agents. Sonographic contrast agents are composed of microbubbles of gas encapsulated in lipid or lipoprotein shells. The bubbles represent strong reflectors of sound and thus generate brightness on the ultrasound image. The use of microbubble contrast agents combined with harmonic US waves has significantly expanded the role of US. With the use of contrast-enhanced US (CEUS), focal liver lesions can be diagnosed based on their vascularity and specific enhancement features. With microbubble contrast agents (a second-generation contrast media), real-time imaging is performed through all vascular phases, including the arterial phase (15–35 s after injection); the portal venous phase (35–90 s after injection), and the sinusoidal (parenchymal or late vascular) phase (90–120 s after injection). The information accumulated about the hemodynamic behavior of liver lesions allows for the formulation of a differential

(a)

Modalities for Imaging Liver Tumors

diagnosis. Several enhancement patterns have been described for the different liver lesions [1]. For example, advanced hepatocellular carcinoma (HCC) demonstrates a strong arterial enhancement during the hepatic arterial phase with one or more hypertropic feeding arteries reaching lesion poles and branching intralesionally (Figure 9.1). Liver metastasis may show different enhancement patterns during the arterial phase of the contrast agent. Since washout is rapid in metastases, these are seen as filling defects that progressively increase in conspicuity relative to the normal parenchymal enhancement (black holes on a bright background) [1]. CEUS has 89% sensitivity and 100% specificity in the diagnosis of hemangiomas [2]. In a study by von Herbay et al [3], the use of CEUS improved the sensitivity and specificity of the US in the differentiation of malignant versus benign from 78% to 100% and from 23% to 92%, respectively. CEUS has 94% sensitivity and 93% specificity for the diagnosis of HCC and has proven to be sensitive in demonstrating HCC vascularity [2].

(b)

(c) Figure 9.1 Hepatocellular carcinoma in a patient with chronic liver disease and an elevated alpha-fetoprotein level. (a) Baseline ultrasound (US) shows a nearly isoechoic lesion (arrow). (b) Very early arterial phase US image obtained 20 second after contrast material injection shows an enhancing mass (arrow). (c) Portal venous phase US image obtained 120 s after injection shows a hypoechoic lesion (arrow). (Courtesy of Beat Muellhaupt MD, University Hospital Zurich, Zurich, Switzerland).

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Epidemiology and Diagnosis

Clinical role of transabdominal ultrasound In most institutions, conventional gray-scale US eventually supplemented by Doppler US is the first step for liver evaluation with respect to a suspected liver mass. When the US findings are typical for a cyst, a hyperechoic hemangioma, a focal steatosis, or a skip area in fatty liver, further study may be obviated. However, when the US findings are atypical or the patient has an extrahepatic malignancy, a focal lesion other than a cyst or clear hemangioma, CEUS may be performed for further assessment. If the diagnosis remains unclear, the patient may undergo CT or MR imaging for a definitive diagnosis. In patients with chronic liver disease, US is increasingly used for early detection of HCC. When a clear nodule or an ill-defined, nodule-like area of heterogeneity is found with conventional US, CEUS is performed. In cases of arterialphase hypervascularity, a diagnosis of HCC is made and the patient should be scheduled for a staging CT or MR imaging examination. US in combination with CEUS may be used as an alternative to CT or MR imaging for the follow-up of cancer patients. Finally, Doppler US is a tool for monitoring the therapeutic response of the tumor to interventional treatments.

Intraoperative ultrasonography Intraoperative US of the liver provides the operating surgeon with useful real-time diagnostic and staging information during laparotomy, and may result in an alteration in the planned surgical approach. Current applications for intraoperative US of the liver include tumor staging, metastatic survey, guidance for resection of focal liver lesions and various tumor ablation procedures, documentation of vessel patency, evaluation of intrahepatic biliary disease, and guidance for whole organ or split-liver transplantation. Dedicated intraoperative transducers should be used for intraoperative US of the liver. Typically, 5-MHz side-fire or T-shaped linear- or curvilinear-array transducers are used. Transducers should have color Doppler flow and pulsed Doppler imaging capabilities and should provide good nearfield resolution. Preoperative coordination between the surgeon and the physician performing the intraoperative US ensures that the sonographer is available at the time of the operation. The results of many studies have shown that intraoperative US can change the clinical management in up to 50% of patients undergoing hepatic resection for malignancy [4, 5]. However, even when intraoperative US has not modified the surgical management, it has resulted in a correction of the disease staging and, consequently, in an alteration of the postoperative treatment in 11% of patients [6]. In a substantial proportion of patients undergoing hepatic resection, intraoperative US provides additional specificity in the evaluation of liver lesions. In a prospective study, Clarke et al [7] have shown that intraoperative US depicted 25–35%

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more lesions than the preoperative US, CT, or angiography. Surprisingly, 40% of the lesions demonstrated with intraoperative US were neither visible nor palpable at surgery [7]. The impact of intraoperative US on treatment selection may be lowered because of the advent of F-18-fluoro-2-deoxyD-glucose (FDG)-PET. A recent study has shown that although intraoperative US helps to determine the anatomic location of metastases, thus facilitating surgical resection, its adjunctive use in patients screened preoperatively by FDG-PET has a limited impact on treatment selection [8].

Computed tomography The production of an image by CT is based on the differential absorption of an X-ray beam by tissues within the body in the same way as in conventional radiography. In CT, the X-ray beam is collimated into a narrow beam, which passes through a thin slice of the patient. The attenuated X-ray beam is absorbed by detectors that are capable of differentiating subtle differences in the tissue density. Since its initial development, there has been a continuous evolution of the CT scanner from devices that acquire a single slice at a time, through single- and multidetector-row spiral scanning (MDCT). MDCT means that multiple slices can be acquired per each gantry rotation. Image acquisition is accomplished using a spiral acquisition where the patient continuously moves through the scan plane during the acquisition. With current MDCT technology, fast data acquisition over a large anatomic area (entire body with isotropic voxels) can be obtained. The data acquisition is performed in the transaxial plane. The isotropic nature of the data facilitates the generation of three- dimensional (3D) images, and allows the images to be reformatted in any desired plane. The rapid 3D scanning provides opportunities to freeze the respiratory and bowel motion during the acquisition, resulting in great clarity of the abdominal contents. In addition, the rapidity of scanning allows the entire image to be acquired during the peak of the bolus of intravenous contrast, which optimizes the effect of contrast agents and the supporting 3D angiography. Using current MDCT scanner technology, the liver can be scanned with submillimeter collimation within one breathhold of not more than 2–3 s. These short scanning times allow for imaging of the distinct phases after intravenous administration of iodinated contrast agents, including the unenhanced phase, the arterial phase, the portovenous phase, and the extracellular phase (triple phase contrastenhanced CT) (Figure 9.2). The contrast phases provide important information concerning the enhancement patterns and hence the possibility of characterization of liver lesions. Several studies have assessed the value of thin slices to improve detection of small liver lesions. Weg et al have

CHAPTER 9

(a)

(b)

(c)

(d)

Modalities for Imaging Liver Tumors

Figure 9.2 Triple-phase contrast-enhanced multidetector CT (MDCT) of the liver in a middle-aged male patient. (a) Transaxial image obtained prior to intravenous contrast administration demonstrates a subtle low-attenuation mass in the central part of the liver. No calcification is noted. (b) Transaxial image obtained during the hepatic arterial phase (HAP) following intravenous administration of iodinated contrast agent reveals a mass with strong peripheral enhancement in the central part of the liver. (c) Transaxial image from the same patient obtained during the portal venous phase (PVP) of contrast enhancement. The lesion shows peripheral enhancement and the center is hypodense. (d) Transaxial image obtained in the delayed phase of contrast administration (extracellular phase). Subtle peripheral enhancement of the mass is demonstrated, whereas the central part remains hypodense. Biopsy revealed an hepatocellular carcinoma with central necrosis.

demonstrated that 2.5-mm thick slices were significantly superior to 5-, 7.5-, and 10-mm thick slices with regard to detection of metastases [9]. However, there is a trade-off between slice thickness and image quality. When slice thickness is decreased to 1 mm, there is a considerable increase in image noise with a subsequent degradation of the image quality [10]. Therefore, a slice thickness of 2–4 mm is generally recommended for transaxial viewing.

The main advantage of obtaining submillimeter slices when using MDCT is that these datasets allow high-quality 3D reconstructions. This is particularly beneficial for the attainment of high quality CT angiography (CTA) images in order to depict the vascular anatomy of the arteries and veins. Maximum intensity projections (MIP), surface-shaded display, and volume-rendered techniques have been applied to the production of CTA (Figure 9.3). CTA enables surgeons

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Figure 9.3 (a) Volume-rendered multidetector CT (MDCT) arteriogram and (b) maximum intensity projection (MIP) obtained from the hepatic arterial phase of a contrast-enhanced MDCT data set. Both reconstructions show the coronal projection variant of the left hepatic artery originating from the left gastric artery, as well as an accessory right hepatic artery originating from the superior mesenteric artery. The isotropic nature of the voxels facilitates high-quality MDCT angiograms of the abdominal arteries. CHA, common hepatic artery; LHA, left hepatic artery; RHA, right hepatic artery; ARHA, accessory right hepatic artery; SMA, superior mesenteric artery; GDA, gastroduodenal artery; T, tumor (metastasis in this case).

to understand the anatomy of the celiac trunk, hepatic arteries, and hepatic and portal venous systems before a liver resection or transplantation. This helps in the planning of chemoembolization and surgical implantation of chemotherapy catheters by depicting the anatomy of the gastroduodenal artery and the origins of the proper hepatic and right and left hepatic arteries. MDCT portal venography can display the entire portal venous system and help to determine the extent and location of portosystemic collateral vessels in patients with portal hypertension. In addition, MDCT venography can detect and identify all major variations of the hepatic venous confluence and portal venous trifurcation. A virtual hepatectomy with volume-rendered images and a liver volume estimation before surgery is useful in planning the extent and nature of the hepatic resection. Estimation of the liver volume before surgery can facilitate the prediction of postoperative liver failure in patients undergoing resection, and assist in embolization procedures. Volumetric analyses in phantoms as well as in humans have shown a strong congruity between the intraoperatively measured hepatic volume and the hepatic weight, when CT data are used [11]. Currently, dedicated software is available which enables the accurate estimation of the liver volume and the weight based on CT datasets using semiautomated algorithms.

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To summarize, the major achievement of MDCT is the large anatomic coverage and the superb imaging of the vascular anatomy and vascular abnormalities. However, one fundamental limitation of CT remains the lack of the ability to alter the intrinsic soft tissue contrast. The other main limitation of CT is the radiation issue. Scanning with thinner slice collimation and multiphase scanning with increased number of phases can cause an increase in the radiation dose. Recently developed prepatient filtration and collimation of the X-ray beam, automatic modulation of the tube current in all three dimensions, and various dose-reduction filters help to reduce the radiation exposure.

Clinical role of computed tomography Currently, CT of the liver is still the mainstay of hepatic imaging. In most centers CT is performed as the next step after a liver tumor has been detected using US. CT of the liver can be performed with or without intravenous contrast material (contrast enhanced versus unenhanced). The indications for unenhanced CT are few, but include patients with known malignancies who are being studied for the first time (as screening for calcifications), patients with cirrhosis in whom regenerating nodules may be hyperattenuating on unenhanced images (owing to their high iron content), and patients with diffuse liver disease. In particular, if echinococcosis is in the differential diagnosis

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of a liver tumor, unenhanced CT is sometimes of particular value in order to detect subtle calcification which may be missed on other imaging modalities such as MRI. Dynamic contrast-enhanced CT is a more sensitive examination for the detection of focal liver lesions. CT is accurate in diagnosing simple hepatic cysts which may be present in up to 18% of patients undergoing routine CT of the upper abdomen [12]. Cysts, typically measured by water density (<20 Houndsfield Units [HU]), have well-defined borders without perceptible walls and which do not enhance. CT is also useful for diagnosing hemangiomas, which typically show early peripheral nodular enhancement with gradual filling over time, from the periphery to the central portion of the tumor. The identification of globular enhancement that is isodense to the aorta allows for the discrimination of hemangiomas from metastasis [13]. However, small lesions often enhance uniformly even on early phases of imaging, and large hemangiomas, such as giant hemangiomas, may show as persistent regions that do not enhance. Therefore, in cases where findings are equivocal, further assessment, preferentially with MRI, may be necessary. Correct diagnosis of focal nodular hyperplasia (FNH) and hepatic adenoma is notoriously difficult using CT. The enhancement pattern of a hypervascular lesion on multiphase CT may be suggestive of the diagnosis; however, differential diagnosis from a malignant lesion may be difficult. Imaging of HCC, particularly in patients with chronic liver disease, remains a challenge (Figures 9.4 and 9.5). HCC is currently diagnosed on the basis of the results of serologic

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Modalities for Imaging Liver Tumors

determination of alpha-fetoprotein (AFP) levels, liver US, CT, and MRI [14]. In a recent meta-analysis, the accuracy of US, CT, and MRI in diagnosing HCC was investigated [15]. Studies were only included when the standard of reference was the pathology of the explanted or resected liver, or the histology of the focal lesions. According to Colli et al [15], for CT, the pooled sensitivity for HCC was 68%, specificity 93%, and likelihood ratio 0.4. Ronzoni et al investigated the role of MDCT in the diagnosis of HCC in patients with cirrhosis undergoing liver transplantation [16]. In that study MDCT had a sensitivity of 64% and a specificity of 73% for detection of HCC. However, there were a large number of false-positive findings, most of them smaller than 1 cm in diameter. Cholangiocarcinoma is the second most common primary hepatobiliary malignancy after HCC. These tumors can be divided into intrahepatic and extrahepatic, with extrahepatic cholangiocarcinoma occurring more frequently. The resectability of hilar cholangiocarcinoma depends on various factors, including the level of the bile duct obstruction, the presence of vascular involvement, the extent of parenchymal invasion, and the presence of metastatic disease. Therefore, imaging plays an important role in the preoperative assessment of these tumors. CT is part of the diagnostic work-up in many institutions. Several studies have shown that the accuracy of standard contrast-enhanced CT for the determination of the longitudinal extent of the tumor involvement along bile duct, according to the Bismuth– Corlette classification, is relatively low, with reported accu-

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Figure 9.4 A 74-year-old patient with bleeding hepatocellular carcinoma. (a) Contrast-enhanced transaxial multidetector CT (MDCT) obtained during early hepatic arterial phase (HAP) demonstrates a noncirrhotic liver with an enhancing exophytic mass located in the liver lobe (arrow). (b) The mass (arrow) is hypodense compared to the liver parenchyma in the portal venous phase. Perisplenic free fluid with density values consistent with fresh blood (arrow) is also visible.

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Figure 9.5 A young female patient with hepatitis B-associated liver cirrhosis and a highly-differentiated neuroendocrine cancer of the liver. (a) Transaxial late HAP MDCT image, (b) coronal and (c) sagittal multiplanar reformations demonstrate the tumor located in segment II and III (arrow in a). The enhancement of this hypervascular neoplasm is maximized during this phase. (d) Transaxial CT image obtained during the portal venous phase demonstrates nicely the relationship of the tumor to the left portal vein (arrow).

racy values between 45% and 74% [17–20]. When CT is combined with direct cholangiography (i.e. direct filling of the biliary tree through a percutaneous transhepatic biliary drainage or endoscopic nasobiliary drainage using either fluoroscopy or CT imaging as imaging modality), the accuracy of CT for assessment of bile duct involvement can be increased to 84–100% [19, 21, 22]. As discussed above, MDCT technology is particularly useful in providing excel-

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lent imaging of the vascular anatomy and abnormalities. Therefore, it is understandable that CT has a high diagnostic accuracy in prediction of the vascular involvement in patients with hilar cholangiocarcinoma [19, 21]. Traditionally CT has been used for the assessment of the metastatic spread to the liver. With the exception of infiltrative tumors, such as lymphoma, most metastatic diseases of the liver manifest on CT as multiple masses, usually with

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ill-defined margins and an irregular rim. Those lesions that enhance rapidly, such as metastatic disease from breast cancer, thyroid cancer, renal cell carcinoma, and neuroendocrine and carcinoid tumors, appear hyperdense when compared with the normal liver parenchyma. The arterial phase of imaging, in particular, may appear isodense or hypodense to the normal liver parenchyma on the portal venous phase of imaging. In contrast, most metastatic liver disease arising from the gastrointestinal tract tumors, such as colon cancer, is typically best identified as hypodense lesions on the portal venous phase of imaging. Many reports on the accuracy of CT for detecting liver metastasis are based on the experience with single-detector spiral CT. A recent study of dual-phase spiral CT for the detection and characterization of liver lesions (primary and metastatic) showed a sensitivity of 69–71% for malignant disease [23]. The sensitivity for detecting colon cancer metastases in the liver has been reported to be 85% [24].

Modalities for Imaging Liver Tumors

makes this PET tracer also attractive for PET imaging at imaging centers without a cyclotron. FDG is used as a metabolic marker in oncology, cardiology, neurology, and inflammation imaging. All of the data currently available point in the direction that PET/CT is more sensitive and specific than either of its constituent imaging methods. Many groups have demonstrated PET to be more sensitive than CT over the last 10 years [25]. With PET/CT, the most relevant additional effect is that the CT data frequently add specificity to the FDG-PET data [26]. However, FDG-PET data also help to specify findings on CT, such as lymph nodes with equivocal appearances. According to industry, PET/CT has developed into the fastest growing imaging modality worldwide, with between 500 and 1000 new systems being installed in 2004, but all major manufacturers appear to be offering similar systems [27].

Malignant primary liver tumors

Positron emission tomography/computed tomography imaging The basic principle of PET is the use of positron-emitting isotope-labeled pharmaceuticals, which bind to a specific receptor or are integrated into a metabolic pathway. Positron-emitting isotopes are characterized by a beta plus decay, in which a positron is emitted. This positron collides with any of the many shell electrons in the neighboring atoms, with which it annihilates and produces two 511 keV gamma rays. The two photons are detected in coincidence by the PET scanner. Since the annihilation reaction occurs within the body, photons traveling through the body tissues are attenuated. To obtain quantitative results, an attenuation correction is necessary and performed by using data from a transmission scan. This scan must be acquired in addition to the emission scan and takes around 30–50% of the total imaging time. The shortest duration transmission scans are obtained using CT-like X-rays combined with PET/CT scanners. On a dedicated PET/CT scanner, CT data are acquired in less than 30 s. This is much less time than the 12–15 min required for a transmission scan on a PET machine. The great additional advantage of using CT data for this purpose is that the CT images, which are “hardware” coregistered with PET images, can also be used for anatomic referencing for the PET lesions, thereby enhancing the diagnostic accuracy of integrated PET/CT imaging. The clinically and most widely evaluated positron-emitting isotope-labeled pharmaceutical is F-18-FDG. This glucose analog is transported into the cell by specific transporters and phosphorylated by hexokinase to F-18-FDG-6 phosphate, which is inert to further metabolic processing or to transmembrane back transport outside the cell, and is therefore accumulated within the cells. The physical half-life of FDG is around 110 min, which

Hepatocellular carcinoma HCCs are frequently multifocal and have been shown to involve multiple sites in both liver lobes at the time of exploration. Preoperative assessment should also include the search for extrahepatic metastases, because this condition will preclude a curative approach. Interestingly, extrahepatic metastasis of HCC occurs relatively late in the clinical course and therefore does not significantly shorten the survival time. Whenever the stage of disease allows, surgical treatment should be pursued. Torizuka et al evaluated patients with known HCC by using dynamic and static FDG-PET data acquisition [28]. High grades of correlation were found between the histologic grade and the kinetic rate constants, as well as the hexokinase activity. Delbeke et al reported a rather good agreement in the differentiation of malignant and benign solid liver lesions by FDG-PET in a study of 110 consecutively referred patients [29]. Interestingly, false-negative results in the detection of HCC occurred in seven of 23 patients. In two other studies using static FDG-PET imaging, only low sensitivity ratios in the detection of HCC were calculated, since well-differentiated HCC was not diagnosed due to undetectable changes in FDG uptake [30]. This could be explained by the rather high number of welldifferentiated HCC in the study population and the low metabolic activity of low grade HCC. On the other hand, FDG-PET was useful in the detection of extrahepatic disease not seen on US or CT. In conclusion, FDG-PET seems not to be suited to the evaluation of patients with unclear solid liver tumors. Only in selected cases with known, moderately to poorly differentiated HCC may FDG-PET be useful in a pretherapy setting to detect additional intra- or extra-hepatic lesions, and in the evaluation of recurrent disease after therapy (Figure

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Figure 9.6 A 63-year-old male patient with a history of hepatitis B-related chronic liver cirrhosis Child A with histologically proven hepatocellular carcinoma referred for staging by FDG-PET/CT imaging. (a) Maximum intensity projection (MIP) PET image of the FDG-PET/CT demonstrates a large FDG-avid liver lesion (arrow). In addition a focal uptake in the small pelvis is visible (arrowhead). (b) The axial PET image, (c) non-enhanced CT image, and (d) fused PET/CT image clearly identify the osteolytic and FDG-avid lesion as an osseous metastasis (arrows).

9.6). However, larger studies, probably using combined dynamic and static FDG-PET data acquisition, have to be performed to prove the efficacy of this method.

Cholangiocarcinoma Only a few studies using FDG-PET alone or by PET/CT have been performed in the evaluation of intrahepatic cholangiocarcinoma. This type of hepatic cancer is associated with primary sclerosing cholangitis. In the study by Kluge et al, sensitivity and specificity ratios in the detection of primary

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lesions of over 90% have been reported [31]. On the other hand, FDG-PET showed a poor performance in the detection of locoregional metastases. The detection of distant metastases was somewhat better. In the study by Fritscher-Ravens et al, several false-negative cases were found, especially in patients with mucinous adenocarcinoma; otherwise the same results regarding locoregional and distant metastases were achieved [32]. Reinhardt et al [33] used FDG-PET/CT in the evaluation of extrahepatic strictures in 20 patients. In seven patients with stage II (n = 5) and stage III (n = 2)

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disease (according to the American Joint Committee on Cancer), FDG-PET/CT showed pathologic FDG uptake. In the study by Petrowsky et al [34], 61 patients with malignancies of the biliary tract proven by histology or cytology were evaluated by FDG-PET/CT and contrast-enhanced CT. PET/ CT detected all the gallbladder cancers (n = 14). Overall, 45 of 61 tumors were correctly identified with PET/CT (sensitivity 74%) and 40 by contrast-enhanced CT scan (sensitivity 66%). All distant metastases (12 of 12) were detected by PET/CT, but only three of 12 by CT (p < 0.001). Regional lymph node metastases were detected by PET/CT and CT in only 12% and 24%, respectively. PET/CT findings resulted in a change of management in 17% of patients deemed resectable after the standard work-up. Therefore, PET/CT seems particularly valuable in detecting unsuspected distant metastases, which are not diagnosed by standard imaging (Figure 9.7).

Liver metastasis from recurrent colorectal cancer The standard patient work-up for the detection of recurrence and metastases in colorectal cancer include regular clinical examinations, CT scans, colonoscopy, and usually measurement of tumor markers such as carcinoembryonic antigen (CEA). The morphology-based information in CT does not permit for distinction between postsurgical changes and tumor recurrence, nor can it detect tumor involvement of normal sized lymph nodes. In a study by Cohade et al [35], a direct comparison of PET and noncontrast-enhanced PET/CT in 45 patients with known colorectal cancer demonstrated an improvement in diagnostic accuracy from 78% to 89% using PET/CT compared to PET alone. Not only did PET/CT improve the localization of lesions, but also the certainty in interpreting lesions as normal or definitively abnormal. In a study by Seltzner et al [36], the diagnostic value of contrast-enhanced CT and nonenhanced PET/CT were prospectively evaluated against each other in 76 patients referred for preoperative evaluation before a liver resection or for metastatic colorectal cancer. Detection of the intrahepatic tumor load, extra- or intra-hepatic metastases, and local recurrence at the colorectal site were evaluated. Contrast-enhanced CT and PET/CT provided comparable findings for the detection of intrahepatic metastases with a sensitivity of 95% and 91%, respectively. However, PET/CT was superior in establishing the diagnosis of intrahepatic recurrence in patients with prior hepatectomy (specificity 50% versus 100%; p = 0.04). Local recurrences at the primary colorectal resection site were detected by contrast-enhanced CT and PET/CT with a sensitivity of 53% and 93%, respectively (p = 0.03). Extrahepatic disease was missed in the contrast-enhanced CT in one-third of the cases (sensitivity 64%), while PET/CT failed to detect extrahepatic lesions in only 11% of cases (sensitivity 89%) (p = 0.02). New findings on PET/CT resulted in a change in the therapeutic strategy

Modalities for Imaging Liver Tumors

in 21% of patients. This study also demonstrated the wellknown limitation in spatial resolution of around 4–6 mm of PET imaging because small tumors (e.g. < 5 mm) were often not detected.

Magnetic resonance imaging MRI is a modality which is not based on ionizing radiation. MRI uses magnetic fields and radiofrequency waves to induce and detect a signal from different body tissues, which is converted into a gray-scale image. When a patient is placed within a large-bore circular magnet of an MRI scanner, spinning (precessing) hydrogen ions (protons) in water and lipid molecules of the body tissues are aligned, producing a net longitudinal magnetization along the line of the magnetic field. A radiofrequency pulse at a specific frequency is applied, which induces a proportion of precessing protons to change alignment and flip through an angle, the size of which is determined by the strength and duration of the radiofrequency pulse. The net magnetization changes its direction into the transverse plane. This induces a small voltage or signal, which can be detected by the receiver coil placed around the patients. This signal is amplified and processed into the pixel gray-scale level of the MR image. MRI has an inherent high soft tissue contrast. Tissuespecific electromagnetic parameters such as the T1- and T2-relaxation time effect dominate the signal. In an image, either the T1 or the T2 relaxation time effect dominates. In this way an image can be either T1 weighted (fat sensitive) or T2 weighted (water sensitive). MRI uses many types of sequences that investigate a different tissue characteristic of healthy and diseased structures. With different contrast mechanisms, MRI can provide both anatomic and functional information. Chemical shift imaging (CSI) is an example where MRI provides information with regard to the intracellular fat content of the liver parenchyma or a focal liver lesion. CSI relies on obtaining an image in which fat- and water-resonant peaks are obtained first “in phase” and subsequently “out of phase.” A reduction in signal in the outof-phase image implies the presence of lipids, whereas an increased or unchanged in-phase signal implies their absence (Figure 9.8). CSI is useful for confirming the presence of fat as seen in liver adenoma. Recent communications have shown that this technique is also useful for quantification of hepatic macrosteatosis [37]. Over the past few years, several technical advances in MRI have made it an attractive modality for imaging of the liver and the biliary system.

Advances in hardware Recent hardware advances for MRI include increasing numbers of receiving channels and high-density surface elements. These changes result in an improved image signal

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Figure 9.7 A 53-year-old male patient with no history of liver disease or colitis referred for evaluation of a newly found hepatic tumor. A previous colonoscopy was normal. (a) Maximum intensity projection (MIP) PET image of the FDG-PET/CT reveals a highly FDG-avid tumor in the liver (arrow); physiologic uptake in the ascending colon is seen (arrowhead). Otherwise, no further FDG-avid lesions are seen. (b) The axial PET image, (c) intravenous contrast-enhanced CT image, and (d) fused PET/CT image at the level of the liver demonstrates a hypovascular tumor in the left liver lobe in an otherwise normal appearing liver. Since no signs of liver cirrhosis were present, the most likely diagnosis of a cholangiocarcinoma was made and proven at surgery (left hemi-hepatectomy). Histology demonstrated locoregional lymph node involvement not seen on FDG-PET/CT.

that can be translated into increased spatial resolution or faster imaging. A combination of several of these high-density surface coils can image increased anatomic areas quickly, and with high resolution and improved image quality. Most centers undertaking clinical liver MRI currently use MR scanners working at a magnetic field strength of 1.5 T. However, since the MR signal is proportional to the mag-

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netic field strength, there is tendency to image at even higher magnetic field strengths. Compared to the signal obtained at 1.5 T, imaging at 3.0 T theoretically results in a doubling of the signal. This gain in signal might be used for improved image quality, higher resolution imaging, or faster scanning. Clinical MR scanners working at a magnetic field strength of 3.0 T are already available. Hepatobiliary imaging

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Modalities for Imaging Liver Tumors

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(c) Figure 9.8 A 66-year-old female patient with liver cirrhosis Child C and suspicion of a diffusely infiltrating hepatocellular carcinoma based on CT findings. (a) Transaxial contrast-enhanced MDCT image obtained during portal venous phase (PVP) demonstrates signs of liver cirrhosis and multiple ill-defined hypoattenuating areas within the liver parenchyma suggesting diffuse tumor infiltration (arrow), Asterisk, ascites. (b, c) Corresponding T1-weighted gradient recalled echo (GRE) chemical shift MRI obtained in phase (b) and out of phase (c). The signal drop from in phase to out of phase (arrows in b and c) is characteristic for the presence of fat. The MR diagnosis of liver cirrhosis with steatosis without any evidence of a neoplasm was subsequently confirmed by transjugular biopsy.

at 3.0 T provides both opportunities and challenges that are currently being evaluated. The duration of the data acquisition was one of the major limitations of MR, and hampered the use of MRI for imaging of the abdomen. New data acquisition strategies, in particular those that parallel imaging techniques, lead to a reduction of the scan time by a factor of two- to three-fold. For abdominal MRI, the increased speed provided by parallel imaging techniques, aids breath-hold imaging, which eliminates respiratory motion artifact. Nevertheless, an average MR examination of the liver takes significantly longer than a CT scan. This limits the number of patients that can be imaged by MRI and increases costs.

New magnetic resonance sequences and techniques Traditional MRI depicts structures by exciting and acquiring signals from slices of anatomy. Volumetric MRI uses 3Dpulse sequences that excite and image an entire volume of tissue simultaneously. Volumetric imaging allows efficient imaging, acquiring thinner sections covering the anatomy of interest in a reduced time. Currently available 3D gradient recalled echo (GRE) sequences allow for very rapid, thinsection, high-resolution imaging of the liver that can be used to reformat multiplanar images or to generate a 3D MR angiogram or a 3D MR venogram. Gadolinium-enhanced liver MRI is now routinely done with 3D GRE pulse

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(c) Figure 9.9 Hepatocellular carcinoma in a noncirrhotic 67-year-old patient. (a) Transaxial T2-weighted fast spin echo (FSE) image demonstrates nicely the large tumor in the right liver lobe (arrow). (b, c) maximum intensity projection (MIP) of a 3D T1 gradient recalled echo (GRE) MRI obtained during the hepatic arterial phase (HAP) (b) and portal venous phase (PVP) (c) after intravenous gadolinium injection during a 22 s breath-hold. (b) The arterial vascularization of the tumor is nicely demonstrated on targeted MIP. (c) On the corresponding MIP obtained in PVP, the relationship of the tumor to the portal veins is also well delineated.

sequences [38, 39]. Thin sections measuring 2–4 mm thick can now be obtained from the liver while the gadolinium contrast material is being injected intravenously. This enables MR examination of the liver in the different vascular phases of the contrast (i.e. hepatic arterial phase, portal venous phase, and extracellular phase) similar to the approach with dynamic CT of the liver (Figure 9.9). MR cholangiopancreatography (MRCP) is the noninvasive imaging study of choice to investigate the biliary tree. With the intrinsic high signal from bile, an MRCP can produce images of the intrahepatic and extrahepatic bile ducts that rival endoscopic retrograde cholangiopancreatography in image quality. New high-resolution 3D MRCP acquires very thin sections through the biliary tree using fluid-sensitive, heavily T2-weighted MR pulse sequences.

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Biliary strictures are depicted as areas of narrowing of the bile duct. These strictures can be inflammatory or malignant in cause. Biliary investigation with MRI and MRCP is the most comprehensive imaging examination of the biliary system available.

Contrast agents In addition to endogenous sources of contrast, the MR signal can be altered by exogenously delivered contrast agents. Currently, extracellular gadolinium chelates are extensively used for MRI. After injection, gadolinium chelates rapidly distribute from the intravascular space into the extracellular space, similar to iodinated contrast agent material used for CT scanning. In combination with unenhanced sequences, contrast-enhanced MRI shows patterns of enhancement that

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help to detect and characterize benign and malignant liver lesions. Until recently, gadolinium-based contrast was considered to be very safe and well tolerated by patients. However, there is growing evidence that certain extracellular gadolinium-based MRI contrast agents may trigger the development of nephrogenic systemic sclerosis (NSF) in patients with severely reduced renal function (including hepatorenal syndrome) or those on dialysis. This has prompted close attention to the administration of gadolinium chelate-based contrast agents in patients with moderate- to end-stage renal failure or patients with hepatorenal syndrome.

Modalities for Imaging Liver Tumors

Similar to the use of iodinated contrast agents in CT, liver tumors can be assessed by the acquisition of three sets of images through the liver while the gadolinium chelate is being inject, i.e. arterial phase images, portal venous phase images, and delayed equilibrium phase images (Figure 9.10). These three sets of images show different phases of liver and tumor enhancement. The main limitation of extracellular gadolinium-based MR contrast is the fact that they do not provide functional information of the liver tissue. This deficit is overcome by the availability of liver-specific contrast agents. Liver-specific

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Figure 9.10 MRI of a liver hemangioma in a 25-year-old male. (a) On transaxial T2- fast spin echo (FSE) image the lesion is hyperintense (arrow). (b, c) Dynamic gadolinium-enhanced gradient recalled echo (GRE) images obtained in hepatic arterial phase (HAP) (b), portal venous phase (PVP) (c) show progressive filling of the lesion (arrows) from the periphery to the center. (d) On delayed image (10 min after contrast administration) the lesion (arrow) is completely filled with contrast.

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contrast agents are useful in situations in which the findings of either US, CT or unenhanced and gadolinium chelatebased contrast agents are inconclusive. For example, a small hypervascular metastasis seen only on the arterial phase can be difficult to distinguish from a small FNH on gadoliniumenhanced MR or contrast-enhanced CT. These lesions can be readily distinguished by the use of liver-specific MR contrast agents. Liver-specific MR contrast agents are broadly classified into the iron-containing compounds that are taken up by the reticuloendothelial system and those that are taken up by hepatocytes and eliminated in the bile. The ironcontaining contrast agents are called superparamagnetic iron oxide (SPIO) or ferumoxides. SPIO MR contrast agents produce a local susceptibility artifact with shortening of T2 and T2*, resulting in a reduction of signal intensity. Hepatic cysts, most malignant primary liver tumors, and metastases do not take up iron and will become more conspicuous on SPIO-enhanced T2-weigthed images in which the high-signal tumors are surrounded by the very dark liver parenchyma. In contrast, most benign liver lesions, including FNH and adenomas, show variable uptake of iron, depending on the number of functioning Kupffer cells in the tumor. Hepatobiliary contrast agents represent a heterogenous group of paramagnetic contrast agents, of which only a fraction is taken up by hepatocytes and excreted in the bile. Mangafodipir trisodium is taken up by hepatocytes and results in signal intensity increase on T1-weighted images. Focal nonhepatocellular lesions (i.e. metastasis) do not enhance post contrast, therefore resulting in improved lesion conspicuity. Lipophilic variants of gadolinium-chelates (Gd-BOBTA, Gd-EOB-DTPA) show biphasic liver enhancement similar to that seen with nonspecific extracellular contrast agents. Subsequently the hepatic signal intensity continues to rise for up to 2 h because of hepatocytic activity. This results in increasing contrast between liver and hepatocellular tumors (Figure 9.11).

Clinical role of magnetic resonance imaging In our experience, MR of the liver can be used for lesion characterization and as a problem- solving examination in cases where the results for MDCT or US are inconclusive or incomplete. In other clinical situations, MRI can be used as the primary imaging modality, providing a comprehensive examination of the hepatobiliary system. MRI is especially useful for the assessment of patients who are candidates for transplantation, surgical resection, or ablative treatments. Using volumetric MRI techniques, MRI can serve as the sole imaging modality to address all relevant questions with regard to the local staging of liver tumors. In addition, based on MR datasets, exact volumetric assessments can be made with regard to the surgically created liver remnant or partial graft (Figure 9.12).

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The current limitation of MRI is that it is not yet established as a whole body imaging modality for the assessment of extrahepatic disease, the therapy response or the assessment of tumor viability. However, recent studies using diffusion-weighted MRI have shown promise that this technology will play a role in these areas [40, 41]. In addition to these particular limitations there are general contraindications to MRI: cardiac pacemakers, implanted cardiac defibrillators, non-MR compatible aneurysm clips, ferromagnetic or electronically operated stapedial implants, metallic foreign bodies, spine and brain neurostimulators, and some implanted drug infusion devices. Even with faster acquisitions provided by the new generation of MR scanners, abdominal MRI needs longer examination periods and more cooperation from the patient than MDCT. Abdominal MR may be very difficult in patients who are very ill, uncooperative, or claustrophobic, and the image quality in these patients may be degraded by motion artifacts. Orthopedic and spine hardware does not pose a risk to patient safety, but can produce an artifact that degrades image quality. At our centre, we do not undertake MRI on pregnant women during the first trimester, and an intravenous gadoliniumbased contrast agent is usually not used during the first trimester of pregnancy. MRI can classify different lesions more accurately than MDCT [42]. As described above, the fundamental limitation of CT is the lack of soft tissue contrast and its moderate sensitivity for the presence of contrast. For detection and characterization, CT mainly relies on high in-plane resolution and the vascularity of the liver lesions. Small liver lesions (<2 cm) cannot be characterized even with the latest generation of MDCT scanners. With CT the distinction between a benign liver lesion, metastasis, or primary liver tumor may be difficult. In general, MRI provides a more comprehensive work-up of focal and diffuse liver disease than CT. Most liver lesions are correctly identified by a combination of the information obtained from the unenhanced and the contrast-enhanced sequences. Dynamic contrast-enhanced MRI using gadolinium chelates is becoming a protocol standard for MRI of the liver. Gadolinium chelates are useful for detecting hypervascular metastasis and HCC during the arterial phase of liver enhancement [42]. Some centers use specific liver contrast agents, such as SPIO, and hepatobiliary contrast agents to detect and characterize focal liver lesions. The use of liver-specific contrast agents is of particular interest with regard to the depiction of HCC. A study by Krinsky et al has shown that gadolinium-enhanced MRI is too insensitive to diagnose small (<2 cm) HCC and dysplastic nodules [43] (Figure 9.12). There is growing evidence that the combination of gadolinium-enhanced MRI and SPIOenhanced MRI (double-contrast MRI) is a very effective imaging modality for HCC [15, 44, 45]. In the study by Kim et al, double-contrast MRI was found to have similar diag-

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Modalities for Imaging Liver Tumors

(e) Figure 9.11 CT and MR images of a 37-year-old female with a focal nodular hyperplasia (FNH). (a) The lesion (arrow) located in segment V is faintly visible on contrast-enhanced transaxial multidetector CT (MDCT) image. (b) On the corresponding T2-weighted fast spin echo (FSE) image the lesion (arrow) is homogenously isointense with the surrounding liver parenchyma. (c–e) Dynamic T1-weighted 3D gradient recalled echo (GRE) images obtained with a liver-specific hepatobiliary contrast agent (Gd-DTPA-EOB). The lesion (arrow) shows early enhancement in hepatic arterial phase (HAP) (c) with wash-out in portal venous phase (PVP) (d). In the hepatobiliary phase of the contrast agent (e), the lesion is enhancing due to excretion of the contrast agent into the intralesionally biliary ductules (arrow). These features are characteristic for presence of an FNH.

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(a)

(b)

(c) Figure 9.12 A 58-year-old patient with colorectal carcinoma and metastasis to liver who underwent chemotherapy and surgical ligation of the right portal vein. (a) Gadolinium-enhanced transaxial T1-weighted gradient recalled echo (GRE) image obtained in portal venous phase (PVP) demonstrates a large liver metastasis in the right liver lobe. The patient underwent systemic chemotherapy and surgical ligation of the right portal vein. (b) A follow-up MR examination 8 weeks after chemotherapy and portal vein ligation demonstrates shrinking of the liver metastasis. (c) Calculation of the volume of the left liver including segment IV based on a MR dataset for planning of right hepatectomy. Note: The liver volume of left lobe in b and c has increased compared to the volume in a.

nostic accuracy and sensitivity for detecting HCC as CTAP and CTHA [45]. Hepatobiliary contrast agents are particularly useful for an accurate differentiation of FNH from hepatic adenoma [46]. The key histologic feature that enables hepatic adenoma or liver adenomatosis to be differentiated from FNH is that FNH possesses malformed biliary ductules, whereas hepatic adenoma and liver adenomatosis have no biliary ductules (Figure 9.13). Since hepatobiliary contrast agents are excreted through the bile, FNH is characterized by the accumulation of the hepatobiliary contrast agent on delayed T1-weighted MR images (Figure 9.14). Intra- and extra-hepatic cholangiocarcinomas are well depicted on combined MRI and MRCP [18, 22, 47–51]. MRCP in combination with contrast-enhanced MRI localizes a tumor by showing the focal biliary structure and associated

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biliary obstruction. According to our experience, combined volumetric MRI with MRCP allows for the accurate assessment of the local tumor extent, of the possible involvement of either the hepatic arteries or the portal vein, and of lobar atrophy and intrahepatic metastasis in patients with intra- or extra-hepatic cholangiocarcinoma. Staging in these patients is completed by PET/CT for possible extrahepatic disease. Hepatic metastases can occur in virtually any primary abdominal or extra-abdominal malignant disease. Dynamic MRI with nonspecific extracellular gadolinium chelates is considered an effective modality for the detection of liver metastases. By comparison with MDCT, dynamic MRI with gadolinium chelates was found to be superior to dual-phase CT for detection and characterization of liver metastasis [52]. The superiority of MR over MDCT in detection of liver metastasis is substantiated when liver-specific contrast

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(a)

(b)

(c)

(d)

Modalities for Imaging Liver Tumors

Figure 9.13 A 53-year-old female with chronic viral hepatitis type B and a history of right-sided hemihepatectomy due to hepatocellular carcinoma (HCC). Because of an increasing serum alpha-fetoprotein level, there is suspicion of tumor manifestation in residual liver parenchyma. (a) On transaxial T2-weighted fast spin echo (FSE) image, a slightly hypointense lesion is visible (arrow). (b, c) The lesion shows no enhancement following administration of a gadolinium-based MR contrast agent in hepatic arterial phase (HAP) (b), but is visible as a hypointense focus during portal venous phase (PVP) (arrow) (c). (d) Following administration of iron oxide (liver-specific contrast agent), the lesion is not taking up the contrast agent (remains bright, arrow), whereas the surrounding liver parenchyma is becoming dark due to uptake of the contrast agent. This case demonstrates clearly the usefulness of iron oxide nanoparticles for imaging of HCC in chronic hepatitis or liver cirrhosis.

agents are used. Van Etten et al [53] found SPIO-enhanced MRI at least as accurate as CT during CTAP in preoperative assessment of colorectal metastasis in the liver. Other studies have shown the efficacy of hepatobiliary contrast agents in the detection and characterization of liver metastasis [54] (Figure 9.15).

Catheter-assisted angiography, computed tomography during hepatic arteriography and during arterial portography The common feature of catheter-assisted angiography, CTHA and CTAP is that all these techniques are invasive procedures requiring the insertion of an arterial catheter.

Catheter-assisted angiography Catheter-assisted angiography of the liver is performed by means of a catheter that is placed in either a selective or a subselective location. A celiac axis injection is inadequate for the detection of focal liver lesions. A selective or a subselective injection with a slow infusion of iodinated contrast material in combination with a digital subtraction technique is still the most accurate technique for the detection of focal hepatic masses (Figure 9.16). However, since the recent advances of CT and MR imaging have made it possible to detect small liver lesions, the primary role of catheter-assisted angiography lies not in detecting focal hepatic lesions anymore but in: (1) facilitating the administration of chemoembolic therapy to hepatic neoplasms (local chemotherapy for downstaging or as a

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(a)

(b)

(c)

(d)

(e)

(f)

Figure 9.14 A 39-year-old female with a liver adenoma in the right liver. (a–c) The lesion (arrow) is hyperintense on T2-weighted sequences and shows a signal drop from the in-phase (b) compared to the out-of-phase GRE images (c). (d–f) On T1-weighted 3D gradient recalled echo (GRE) images following administration of a hepatobiliary contrast agent (Gd-EOB-DTPA), the lesion (arrow) demonstrates hypervascularity during hepatic arterial phase (HAP) (d) with wash-out during portal venous phase (PVP) (e). The lesion (arrow) is not enhancing in the delayed phase (hepatobiliary phase) of the contrast agent, indicating absence of biliary ductules (f). 94

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(a)

Modalities for Imaging Liver Tumors

(b)

Figure 9.15 A 29-year-old female patient with breast carcinoma and metastasis to the liver. (a) On T2-weighted images, multiple hyperintense lesions are noted within the liver parenchyma (arrow). (b) In the delayed phase following administration of a hepatobiliary contrast agent, the lesions (arrow) are not enhancing in delayed phase (hepatobiliary phase).

bridging procedure in patients with HCC awaiting liver transplantation, in order to minimize the risk for drop-out); (2) positioning and securing one or more arterial catheters before CTHA or CTAP; (3) evaluation of small hepatic arterial branches for evidence of vasculitis; (4) evaluating the hepatic artery for variants, stenosis, or thrombosis in cases where CTA or contrast-enhanced MRI (or MR angiography) is inconclusive, or percutaneous intervention is necessary (Figure 9.17).

Computed tomography during hepatic arteriography and during arterial portography The basis behind catheter-assisted hepatic CT is similar to that of dual-phase CT imaging. Selective enhancement of the liver or tumors relies on the fact that the liver has a dual blood supply, with the normal liver parenchyma receiving most of its blood supply from the portal vein and the liver tumors (whether primary or metastatic) receiving most of their blood supply from the hepatic artery. In catheterassisted CTA, CT images of the liver are obtained while contrast material is administered to the liver by means of an indwelling catheter placed either within the hepatic artery (CTHA) or within the splenic or superior mesenteric artery (CTAP). CT angiograms begin in the vascular radiology suite, where a catheter is inserted through the common femoral artery and left in place after an arteriogram defines the patient’s hepatic arterial anatomy. If a replaced or an accessory right hepatic artery originates off the superior mesenteric artery (SMA), the tip of the catheter must be positioned well distal to the origin of the anomalous vessel in order to use

the SMA for selective portal venous opacification. During CTAP, the enhancement of the normal liver parenchyma is very intense; hepatic tumors are detected as areas of poorly enhancing focal lesions and the contrast difference between the lesion and the normal liver is greater during CTAP than during CT after intravenous contrast material injection. CTHA studies reveal hepatic tumors to be of high attenuation, either uniformly or peripherally, and to be surrounded by normal hepatic parenchyma of a much lower attenuation. The central portion of the tumor typically remains hypoattenuating, particularly when the tumor is large or hypovascular. The selective enhancement of either the hepatic artery or the portal vein results in a very high lesionto-liver contrast and in increased detection rates. In general, CTAP is more frequently used than CTHA because most of the hepatic lesions are hypovascular and because there is a high prevalence of perfusion abnormalities caused by the aberrant origin of the hepatic artery and by the arterial hemodynamic changes due to hepatic tumor and cirrhosis. The sensitivity of CTAP for tumor detection is very high and is reported to be 84–93% [55]. In contrast to its high sensitivity, the specificity of CTAP is low. Many lesions during CTAP appear as an area of hypodensity, including cysts, hemangiomas, or other benign lesions. The frequency of false-positive findings may be lowered if CTAP is combined with CTA. Currently, CTA and CTAP find their main application in the evaluation of patients with malignant hepatic tumors who will undergo a limited surgical resection which requires a precise localization. CTHA is mainly indicated for the preoperative evaluation of patients presenting

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(a)

(b)

(c) Figure 9.16 A 44-year-old patient with liver cirrhosis and multifocal hepatocellular carcinoma (HCC). (a) No definite focal lesion is noted on transaxial T2-weighted FSE or on (b) transaxial 3D gradient recalled echo (GRE) image obtained during hepatic arterial phase (HAP) following intravenous administration of a gadolinium-based contrast agent. (c) Following administration of iron oxide, two small HCC lesions are noted (arrows).

with hypervascular metastasis who are thought to have resectable lesions. In some centers, catheter-based CTA is also used for the diagnostic work-up of HCC. CTAP is one of the most sensitive techniques used for detecting small HCC [56], whereas CTHA is a sensitive technique in cases of hypervascular HCC [57]. However, as discussed above, sometimes it is difficult to evaluate HCC lesions because of false-positive results caused by perfusion abnormalities or hemodynamic changes, especially in patients with cirrhosis [58]. Several studies

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have evaluated whether CTAP and CTHA could be replaced by MR or CT imaging. Whereas some studies have shown that neither MR nor CT imaging can replace CTAP [59, 60], newer studies have shown the opposite [61, 62].

Cholangiography Imaging of the bile ducts is performed for evaluation of intra- and extra-hepatic cholangiocarcinomas as well as for

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Modalities for Imaging Liver Tumors

(a)

(b)

(c)

Figure 9.17 Contrast-enhanced CT of the liver and catheter-assisted angiography in an old male patient with a known bleeding hepatocellular carcinoma (HCC) in a cirrhotic liver and ascites. (a) Transaxial image obtained during the portal venous-dominant phase of hepatic enhancement. An exophytic lesion in segment V with peripheral contrast enhancement is noted. The fluid around the liver and spleen is of high density, indicating hemorrhagic ascites. (b) Catheter angiography of the same patient demonstrates numerous foci of tumor enhancement throughout the right liver. Note the right hepatic artery is originating from the superior mesenteric artery as an anatomic variation. (c) Superselective catheter angiography after embolization of the bleeding (HCC).

the assessment of the other hepatic tumors if they infiltrate or obstruct the bile ducts. The intra- and extra-hepatic bile ducts may be visualized by either direct or indirect methods. Direct cholangiography means evaluation of the bile ducts after direct opacification with contrast material by either a percutaneous transhepatic route (percutaneous transhepatic cholangiogram [PTC]) or a retrograde approach after endo-

scopic cannulation of the common bile duct (endoscopic retrograde cholangiography [ERC]). For direct cholangiography, imaging may be performed by either fluoroscopy or by CT (direct CT cholangiography). Indirect cholangiography means that the bile ducts are imaged without direct opacification. US is well suited for the initial screening of an obstruction of the intra- or extra-hepatic bile ducts, but it

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may fail to detect infiltrative biliary duct cancer, especially when tumors are small [63]. The advent of MR cholangiography (MRC) has provided a very accurate noninvasive method for visualization of the bile ducts. The technique is based on heavily T2-weighted sequences that rely on the long T2-relaxation time of the bile, which maximizes the conspicuity of the bile relative to the hepatic parenchyma. The currently available 3D MRC sequences provide excellent anatomic detail of the intra- and extra-hepatic bile ducts (Figure 9.18).

Due to the lack of soft tissue, contrast CT is less suited for imaging of the bile ducts. The visualization of the bile ducts using CT may be enhanced with intravenous administration of hepatobiliary contrast agents. However, these contrast agents are associated with a relatively high rate of adverse events, thus limiting the use of this technique. Due to the fact that hepatobiliary MR contrast agents are excreted through the biliary system, they can also be used for contrastenhanced MRC. However, the value of contrast-enhanced MRC techniques for imaging of liver tumors is unclear so far.

(a)

(b)

(c)

(d)

Figure 9.18 A 70-year-old male patient with a cholangiocarcinoma Bismuth type IV. (a) Maximum intensity projection (MIP) reformat from respiratorytriggered 3D MR cholangiopancreatography (MRCP) shows central obstruction of the bile duct at the level of the bifurcation (arrow). (b) Selective MIP of the 3D MRCP demonstrates irregular narrowing of the second-order branches of the left (arrow) and right bile ducts, suggesting tumor involvement. The left biliary system is dilated. (c) Direct cholangiography obtained through a percutaneous transhepatic cholangiogram shows similar findings. (d) On axial gadolinium-enhanced T1-weighted 3D gradient recalled echo (GRE) image obtained during portal venous phase (PVP), narrowing of the right portal vein is noted (arrow), consistent with tumor infiltration.

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Self-assessment questions 1 Which of the following statements are true concerning ultrasound (US)? (more than one answer is possible) A US relies on reflected sound waves to generate an image B US uses ionizing radiation C Main disadvantages of US include limited operator dependency and limited reproducibility D US enables real-time guidance for biopsies E US provides good soft-tissue contrast 2 Which of the following statements are true concerning sonographic contrast agents? (more than one answer is possible) A Sonographic contrast agents are composed of microbubbles of gas encapsulated in lipid or lipoprotein shells B Sonographic contrast agents are combined with Doppler US C Sonographic contrast agents are usually combined with power Doppler US D Sonographic contrast agents are usually combined with harmonic US E Sonographic contrast agents allow for imaging of a liver lesion during different vascular phases 3 Which of the following statements regarding computed tomography (CT) are true? (more than one answer is possible) A The production of an image by CT is based on the differential absorption of an X-ray beam by tissues within the body B CT is based on the use of ionizing radiation C A lesion which exhibits a low attenuation is called hyperdense on a CT image D A lesion which exhibits a low attenuation is called hypodense on a CT image E CT provides images with a high soft tissue contrast 4 Which contrast agent is mainly used for intravenous application during CT? A Gadolinium-based contrast agents B Microbubbles C Iodinated contrast agents D Barium E None of the above 5 Which of the following statements regarding PET/CT are true? (more than one answer is possible) A The half-life of FDG is 110 min B FDG never accumulates in inflammation

Modalities for Imaging Liver Tumors

C FDG-PET/CT imaging takes longer than 3 h D FDG-PET/CT imaging is a valuable tool in the evaluation of well-differentiated HCC E The spatial resolution of PET imaging is 4–6 mm 6 FDG-PET/CT imaging is useful in the evaluation of which of the following? (more than one answer is possible) A Liver metastases from colorectal cancer B Detection of distant metastases from poorly differentiated HCC C Detection of locoregional lymph node metastases from cholangiocarcinoma D Inflammatory disease of the gallbladder E Hepatic failure 7 What are the benefits of multidetector-row CT (MDCT)? (more than one answer is possible) A Fast data acquisition over a large anatomic area B Optimizes the effect of iodinated contrast agents C Can provide images with submillimeter voxel size enabling high quality CT angiograms D Multiple slices can be acquired per each gantry rotation E Can provide high quality reconstruction in any desired plane 8 Which imaging characteristic allows differentiation of a hemangioma from a metastasis on a CT scan? A Calcifications on the unenhanced scan B The hemangioma shows a typical contrast enhancement pattern with a progressive filling of the lesion over time from the periphery to the central portion of the tumor C The hemangioma is hyperdense and the metastasis is hypodense on the unenhanced CT scan D The two lesions can usually not be differentiated based on CT scans E The hemangioma shows a rapid enhancement during the arterial phase following contrast administration 9 Which one of the following statements about CT during hepatic arteriography (CTHA) is false? A CTHA is a combination of arteriography and CT B CTHA uses iodinated contrast agent C CTHA is well suited for preoperative evaluation of hypovascular tumors metastasis D CTHA is less frequently used than CTAP E CTHA is a sensitive technique for evaluation of a hypervascular hepatocellular carcinoma

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10 Which of the following statements regarding MRI are true? (more than one answer is possible) A MRI is not based on ionizing irradiation B Fat exhibits a high signal on a T1-weighted MR image C Water exhibits a bright signal on a T2-weighted MR image D Gadolinium chelates are most frequently used as contrast agents E MRI has low soft-tissue contrast 11 Which one of the following statements regarding magnetic resonance cholangiopancreatography is false? A MRCP is useful for delineation of the intrahepatic biliary structures B MRCP is useful for delineation of the extrahepatic biliary structures C Generation of an MRCP image requires administration of an extracellular gadolinium-based contrast agent D MRCP is based on the heavily T2-weighted sequences E MRCP rivals endoscopic retrograde cholangiopancreatography 12 Which of the following devices are absolute contraindications for MRI of the liver? (more than one answer is possible) A Neurostimulator B Orthopedic devices C Cardiac pacemakers D Pregnancy in the first trimester E Foreign metallic body located in proximity of the eye bulb 13 Which of the following statements regarding liverspecific contrast agents are true? (more than one answer is possible) A They provide tissue-specific information B They are useful for the differentiation between an focal nodular hyperplasia and a hepatic adenoma C Some of these contrast agents are excreted through the biliary system D They are useful for assessment of hepatocellular carcinoma in the cirrhotic liver E They do not enhance vessels and therefore do not allow assessment of vascular structures 14 What are the current roles of conventional angiography in liver imaging? (more than one answer is possible) A Facilitating the administration of chemoembolic therapy to hepatic neoplasms

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B Positioning and securing one or more arterial catheters before CTHA or CTAP C Evaluation of small hepatic arterial branches for evidence of vasculitis D Evaluating the hepatic artery for variants, stenosis, or thrombosis in cases where CT angiography or contrast-enhanced MRI (or MR angiography) is inconclusive or percutaneous intervention is necessary E With advent of CT and MRI, conventional angiography no longer has a role in the imaging of liver tumors 15 Which of the following techniques allow indirect visualization of the biliary ducts? (more than one answer is possible) A Ultrasonography B MR cholangiopancreatography C MR with administration of hepatobiliary contrast agents D Endoscopic retrograde cholangiopancreatography E Percutaneous transhepatic cholangiopancreatography

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44 Ward J, Guthrie JA, Scott DJ, et al. Hepatocellular carcinoma in the cirrhotic liver: double-contrast MR imaging for diagnosis. Radiology 2000;216:154–62. 45 Kim YK, Kwak HS, Han YM, Kim CS. Usefulness of combining sequentially acquired gadobenate dimeglumine-enhanced magnetic resonance imaging and resovist-enhanced magnetic resonance imaging for the detection of hepatocellular carcinoma: comparison with computed tomography hepatic arteriography and computed tomography arterioportography using 16-slice multidetector computed tomography. J Comput Assist Tomogr 2007;31:702–11. 46 Grazioli L, Morana G, Kirchin MA, Schneider G. Accurate differentiation of focal nodular hyperplasia from hepatic adenoma at gadobenate dimeglumine-enhanced MR imaging: prospective study. Radiology 2005;236:166–77. 47 Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut 2002;51 (Suppl 6):VI1–9. 48 Kim HJ, Kim AY, Hong SS, et al. Biliary ductal evaluation of hilar cholangiocarcinoma: three-dimensional direct multi-detector row CT cholangiographic findings versus surgical and pathologic results–feasibility study. Radiology 2006;238:300–8. 49 Manfredi R, Masselli G, Maresca G, Brizi MG, Vecchioli A, Marano P. MR imaging and MRCP of hilar cholangiocarcinoma. Abdom Imaging 2003;28:319–25. 50 Manfredi R, Barbaro B, Masselli G, Vecchioli A, Marano P. Magnetic resonance imaging of cholangiocarcinoma. Semin Liver Dis 2004;24:155–64. 51 Masselli G, Gualdi G. Hilar cholangiocarcinoma: MRI/MRCP in staging and treatment planning. Abdom Imaging 8;33:444–51. 52 Semelka RC, Martin DR, Balci C, Lance T. Focal liver lesions: comparison of dual-phase CT and multisequence multiplanar MR imaging including dynamic gadolinium enhancement. J Magn Reson Imaging 2001;13:397–401. 53 van Etten B, van der Sijp J, Kruyt R, Oudkerk M, van der Holt B, Wiggers T. Ferumoxide-enhanced magnetic resonance imaging techniques in pre-operative assessment for colorectal liver metastases. Eur J Surg Oncol 2002;28:645–51. 54 Zech CJ, Herrmann KA, Reiser MF, Schoenberg SO. MR imaging in patients with suspected liver metastases: value of liverspecific contrast agent Gd-EOB-DTPA. Magn Reson Med Sci 2007;6:43–52. 55 Soyer P, Bluemke DA, Fishman EK. CT during arterial portography for the preoperative evaluation of hepatic tumors: how, when, and why? AJR Am J Roentgenol 1994;163:1325–31. 56 Kanematsu M, Oliver JH 3rd, Carr B, Baron RL. Hepatocellular carcinoma: the role of helical biphasic contrast-enhanced CT versus CT during arterial portography. Radiology 1997;205: 75–80.

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57 Kanematsu M, Hoshi H, Imaeda T, et al. Detection and characterization of hepatic tumors: value of combined helical CT hepatic arteriography and CT during arterial portography. AJR Am J Roentgenol 1997;168:1193–8. 58 Yu JS, Kim KW, Sung KB, Lee JT, Yoo HS. Small arterial-portal venous shunts: a cause of pseudolesions at hepatic imaging. Radiology 1997;203:737–42. 59 Furuhata T, Okita K, Tsuruma T, et al. Efficacy of SPIO-MR imaging in the diagnosis of liver metastases from colorectal carcinomas. Dig Surg 2003;20:321–25. 60 Kanematsu M, Hoshi H, Murakami T, et al. Detection of hepatocellular carcinoma in patients with cirrhosis: MR imaging versus angiographically assisted helical CT. AJR Am J Roentgenol 1997;169:1507–15. 61 Choi D, Kim S, Lim J, et al. Preoperative detection of hepatocellular carcinoma: ferumoxides-enhanced MR imaging versus combined helical CT during arterial portography and CT hepatic arteriography. AJR Am J Roentgenol 2001;176:475–82. 62 Vogl TJ, Schwarz W, Blume S, et al. Preoperative evaluation of malignant liver tumors: comparison of unenhanced and SPIO (Resovist)-enhanced MR imaging with biphasic CTAP and intraoperative US. Eur Radiol 2003;13:262–72. 63 Slattery JM, Sahani DV. What is the current state-of-the-art imaging for detection and staging of cholangiocarcinoma? Oncologist 2006;11:913–22.

Self-assessment answers 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

A, A, A, C A, A, A, B C A, C A, A, A, A,

C, D, E D, E B, D E B B, C, D, E

B, C, D B, B, B, B,

C, D, E C, D C, D C

3

Systemic and Regional Therapies

Introduction Ravi S. Chari Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN, USA

This section will address systemic and regional chemotherapy and radiotherapy for hepatic tumors. These therapies remain the mainstay of therapy of unresectable liver tumors, but also have evolved into neoadjuvant and adjuvant therapies in combination with liver resection and in some cases of liver transplantation. As these techniques continue to evolve, combinations of therapies are being used in a coordinated fashion to treat patients with very complex disease. Although most of these therapeutic modalities continue to evolve, they are all important in the treatment of metastatic and primary liver tumors. Use of combinations of these therapies, ablative therapies, resection, and transplantation may further improve survival, but will also increase the number of patients ultimately able to undergo potentially curative operations. These therapies are important components of the arsenal of physicians and surgeons treating tumors of the liver, and their use should be tailored to the individual patient’s needs. Regional hepatic chemotherapy is usually delivered via a hepatic arterial infusion (HAI) pump. This technique has been studied for approximately 20 years in patients with liver metastatic colorectal carcinoma. The early success demonstrated with this technique has been matched by newer systemic chemotherapies. Despite this, HAI continues to play a role in selected patients, such as those who have exhausted systemic chemotherapy options, and those who require staged resection strategies [1]. Minimally invasive and percutaneous techniques have been developed that may decrease the morbidity of HAI, and ongoing studies in noncolorectal metastases may increase its relative utility [2, 3]. Isolated hepatic perfusion consists of complete vascular isolation of the liver and delivery of high-dose chemotherapy. Although some efficacy was demonstrated in early trials, there is no current consensus regarding its role in the

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

therapy of extensive liver tumors, and studies are ongoing in highly selected patients [4]. Transarterial chemoembolization (TACE) has benefited greatly from recent advances in percutaneous catheter technology and available chemoembolic materials. This overall technique differs among centers and should be tailored for each individual patient. In general, there has been little enthusiasm for the treatment of metastatic colorectal carcinoma with TACE, but success has been demonstrated in the palliative treatment of metastatic neuroendocrine tumors [5]. In addition, TACE is used at many centers to treat hepatocellular carcinoma in nontransplantable patients, and its utility has been demonstrated as neoadjuvant therapy for those who are transplant candidates [6]. Radiotherapy for liver tumors has been increasingly utilized for unresectable hepatobiliary tumors. Advances in targeting technologies have minimized normal tissue damage while increasing the therapeutic efficacy. Also advancing this field has been the development of selective internal radiation therapy (SIRT). SIRT, like TACE, is delivered transarterially using substances like lipiodol (131I-lipiodol) or yttrium 90 (90Y) bound to resin microspheres. The expertise in this technique has center-to-center variation, and this potentially useful modality warrants further investigation.

References 1 White RR, Jarnagin WR. The role of aggressive regional therapy for colorectal liver metastases. Cancer Invest 2007;25:458–63. 2 Camacho LH, Kurzrock R, Cheung A, et al. Pilot study of regional, hepatic intra-arterial paclitaxel in patients with breast carcinoma metastatic to the liver. Cancer 2007;109:2190–6. 3 Hildebrandt B, Pech M, Nicolaou A, et al. Interventionally implanted port catheter systems for hepatic arterial infusion of chemotherapy in patients with colorectal liver metastases: a Phase II-study and historical comparison with the surgical approach. BMC Cancer 2007;7:69. 4 Rothbarth J, Tollenaar RA, van de Velde CJ. Recent trends and future perspectives in isolated hepatic perfusion in the

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treatment of liver tumors. Expert Rev Anticancer Ther 2006; 6:553–65. 5 Roche A, Girish BV, de Baere T, et al. Trans-catheter arterial chemoembolization as first-line treatment for hepatic metastases from endocrine tumors. Eur Radiol 2003;13:136–40.

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6 Bharat A, Brown DB, Crippin JS, et al. Pre-liver transplantation locoregional adjuvant therapy for hepatocellular carcinoma as a strategy to improve longterm survival. J Am Coll Surg 2006;203:411–20.

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Systemic Treatment of Hepatobiliary Tumors Panagiotis Samaras1, Michael A. Morse2, and Bernhard C. Pestalozzi3 1 Department of Oncology, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland 2 Division of Medical Oncology, Duke University, Durham, NC, USA 3 Department of Oncology, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland

This chapter describes the systemic treatment of primary and secondary liver cancer, as well as biliary cancer in the adult. The first part focuses on the treatment of liver metastases from colorectal cancer, where therapeutic concepts have shifted from mainly palliative chemotherapy to a multidisciplinary approach with curative intent, combining primary chemotherapy, surgery, and other local treatments. The second and third parts discuss the options for systemic treatment in hepatocellular and cholangiocellular carcinoma. Liver metastases from gastrointestinal neuroendocrine tumors are discussed in the fourth section, followed by a fifth section on chemotherapy of rare liver tumors. Selective regional chemotherapy via the hepatic artery is discussed in Chapter 14. New options with targeted therapy in liver tumors are also discussed in Chapters 30–34.

Liver metatatases from colorectal cancer Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the Western world [1]. At diagnosis, one-third of patients have advanced stage disease without the option of curative resection. Substantial progress in the systemic treatment of CRC has been achieved in the last years with the development of new, more potent combination chemotherapy regimens and targeted agents, including monoclonal antibodies and tyrosine kinase inhibitors against growth factors and their receptors. These systemic therapies permit “downstaging” of advanced stage disease and may enable surgery even in patients initially considered unresectable.

5-Fluorouracil The fluoropyrimidine 5-fluorouracil (5-FU), an inhibitor of thymidylate synthase and an antimetabolite of pyrimidines in DNA and RNA synthesis, remains the backbone of sys-

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

temic chemotherapy regimens including oxaliplatin and/or irinotecan. The response rates to monotherapy with 5-FU (10%) was doubled by biomodulation of 5-FU activity with folinic acid (leucovorin [LV]), a cofactor of the 5-FU thymidylate synthase inhibition [2]. Monotherapy with 5-FU/LV is still an option for some elderly and frail patients.

Irinotecan and oxaliplatin combinations Both irinotecan and oxaliplatin are newer cytotoxic drugs for CRC with modest activity when used alone, but substantial activity when combined with a fluoropyrimidine. The topoisomerase-I-inhibitor irinotecan (CamptoTM, Pfizer) was tested in two pivotal phase III studies in combination with 5-FU/LV versus the latter alone. In a US study, patients received bolus 5-FU (IFL regimen), whereas in a European study continuously infused 5-FU (FOLFIRI) was used [3, 4]. Both studies demonstrated higher response rates and a significantly prolonged overall survival for the irinotecan/5FU/LV regimen compared with 5-FU/LV alone. Accordingly, IFL with bolus irinotecan/5-FU /LV became a new standard in the United States, while FOLFIRI became a standard for first-line chemotherapy in Europe [5]. Similarly, oxaliplatin (EloxatinTM, Sanofi-Aventis) was tested with 5-FU/LV against 5-FU/LV alone as first-line therapy. Higher response rates, better disease-free survival, and a trend to prolonged survival (16.2 versus 14.7 months, p = 0.12) could be seen with the FOLFOX regimen [6]. FOLFOX was accepted as a new standard in the United States when a survival advantage over IFL and IROX (irinotecan combined with oxaliplatin) was demonstrated (19.5 months versus 15 months and 17.4 months, respectively) along with a favorable toxicity profile [7]. Both FOLFOX and FOLFIRI can be considered standard first- and second-line regimens. Tables 10.1 and 10.2 summarize the schedules and efficacy data of the regimens used today. The most common adverse effects of irinotecan are diarrhea, fatigue, mucositis, neutropenia, alopecia, and an acute cholinergic syndrome. The acute cholinergic syndrome manifests with abdominal cramping, salivation, flushing, and visual disturbance. Oxaliplatin is less toxic to bone

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marrow and kidneys than cisplatin, but patients regularly experience a cold-related, reversible, acute neuropathy manifesting as acral and/or pharyngolaryngeal dysesthesia. With increasing number of treatment cycles, the peripheral sensory neuropathy may persist longer and usually becomes dose limiting after 10–15 cycles. Although this peripheral

Table 10.1 Chemotherapy regimens used for colorectal cancer.* Regimen

Doses

Schedule

FOLFIRI [5]

Irinotecan 180 mg/m2 and LV 200 mg/m2 over 2 h; 5-FU 400 mg/ m2 bolus; 5-FU 2400–3000 mg/m2 over 46 h Oxaliplatin 85 mg/m2 and LV 200 mg/m2 over 2 h; 5-FU 400 mg/ m2 bolus (days 1 and 2); 5-FU 600 mg/m2 over 22 h (days 1 and 2) Oxaliplatin 100 mg/m2 and LV 200 mg/m2 over 2 h; 5-FU 400 mg/ m2 bolus; 5-FU 2400–3000 mg/m2 over 46 h Oxaliplatin 130 mg/m2 over 2 h; capecitabine 1000 mg/m2 BID (days 1–14)

Repeated every 14 days

FOLFOX4 [6]

FOLFOX6 [86]

XELOX [8]

Repeated every 14 days

Repeated every 14 days

Repeated every 21 days

sensory neuropathy is (partially) reversible, it may be bothersome and intermittently aggravated by the stress of an operation or acute illness.

Capecitabine The oral fluoropyrimidine capecitabine (XelodaTM, Roche) is a prodrug of 5-FU. After absorption in the intestinal mucosa, it is metabolized in the liver and converted to 5-FU by thymidine phosphorylase in tumor tissue. A few large phase III studies have compared capecitabine to a 5-FU/LV bolus regimen. Capecitabine achieved higher response rates (25% versus 16%) and demonstrated a different toxicity profile with a higher incidence of hand–foot skin reaction and diarrhea. As compared to 5-FU, there was less mucositis, alopecia, and neutropenia. Many studies were performed comparing oxaliplatin–capecitabine combinations (XELOX, CAPOX) with FOLFOX (combining oxaliplatin with 5-FU/ LV), yielding essentially equivalent results [8, 9]. Similarly, irinotecan–capecitabine combinations (XELIRI, CAPIRI) were compared with FOLFIRI (combining irinotecan with 5-FU/LV), yielding slightly inferior results for the former combinations, probably due to overlapping toxicity profiles of the capecitabine–irinotecan combination (diarrhea, neutropenia) [10, 11]. In summary, capecitabine is a valuable oral alternative to 5-FU/LV in monotherapy as well as in combination with oxaliplatin.

Targeted agents

5-FU, 5-fluorouracil; LV, leucovorin. *Dosages are listed for information only. They should not be used for treating patients.

Bevacizumab Vascular endothelial growth factor (VEGF) contributes to the formation of new vessels (angiogenesis) by binding to

Table 10.2 First-line treatment of colorectal cancer with chemotherapy ± immunotherapy. Author

Therapy

No of patients

RR (%)

Overall survival (months)

Saltz et al [3] Douillard et al [4] De Gramont et al [6] Tournigand et al [87]

IFL 5-FU/LV/CPT-11 FOLFOX4 FOLFOX6 → FOLFIRI FOLFIRI → FOLFOX6 FOLFOX4 IFL IROX FOLFOXIRI BEV/IFL BEV/5-FU/LV CET/FOLFIRI FOLFIRI

231 198 210 109 111 267 264 264 122 402 110 172* 176*

39 41 51 56 54 45 31 35 60 45 40 47 39

14.8 17.4 16.2 20.6 21.6 19.5 15 17.4 22.6 20.3 18.3 24.9 21

Goldberg et al [7]

Falcone et al [39] Hurwitz et al [12] van Cutsem et al [17]

5-FU, 5-fluorouracil; LV, leucovorin; CPT-11, irinotecan; BEV, bevacizumab; CET, cetuximab. *Patients with K-ras wild-type only.

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VEGF receptors (VEGFRs) of endothelial cells, thereby promoting tumor growth. Bevacizumab (AvastinTM, Roche) is a humanized monoclonal antibody, which specifically binds VEGF and inhibits its function. In a seminal phase III trial, bevacizumab has been shown to increase overall survival in first-line treatment of CRC when added to chemotherapy. The median overall survival was 20.3 months in the combined treatment arm compared with 15.6 months in the IFL-only arm. Response rates were also higher in the experimental arm (44.8% versus 35%). The side effects observed with bevacizumab were moderate with some arterial hypertension and proteinuria, and very rare gastrointestinal perforation and hemorrhage [12]. On the basis of this trial, bevacizumab was approved for clinical use in CRC in many countries. Another study showed that bevacizumab is effective in combination with FOLFOX and with CAPOX [13]. Secondline bevacizumab was examined with FOLFOX4 (for details see Table 10.1) in patients whose tumor progressed after irinotecan-containing first-line therapy. The median overall survival was significantly prolonged in the combination arm compared with FOLFOX4 alone (12.5 months versus 10.7 months). The reported side effects of bevacizumab treatment were hemorrhage and hypertension [14, 15]. Because of its interference with wound healing, bevacizumab should be stopped 4–8 weeks prior to surgery, especially prior to liver surgery for metastases. Bevacizumab has only limited activity as a single agent in CRC.

Cetuximab The epidermal growth factor receptor (EGFR) is a membrane-bound glycoprotein with intrinsic tyrosine kinase activity. EGFR belongs to the ErbB-receptor family, which comprises HER-1 (EGFR), HER-2, HER-3, and HER-4. The chimeric monoclonal IgG1-antibody cetuximab (ErbituxTM, Merck) leads to inhibition of EGFR. The study leading to approval of cetuximab tested it in patients with progressive metastatic CRC after prior irinotecan-based therapy. Patients were treated with cetuximab alone or with cetuximab and irinotecan. The response rates were 23% in the combination arm compared with 11% in the single agent arm. Progression-free survival was 4.1 months and 1.5 months, respectively. An interesting observation was the association of drug-induced skin reactions with overall survival [16]. In a large phase III study cetuximab–FOLFIRI was compared to FOLFIRI alone. Median progression-free survival was modestly prolonged from 8.0 to 8.9 months, response rate increased from 39% to 47%, and the rate of R0 resections of liver metastases increased from 4.5% to 9.8% [17]. Similarly, first-line treatment of cetuximab in combination with FOLFOX4 achieved higher response rates than FOLFOX4 alone (46% and 36%, respectively) [18]. Several preclinical studies with CRC cell lines revealed an impaired efficacy of anti-EGFR antibodies in the presence of somatic K-ras muta-

Systemic Treatment of Hepatobiliary Tumors

tions. A mutated K-ras allele induces a permanent activation of the mitogen-activated protein kinase (MAPK) cascade, rendering EGFR blockade ineffective. A retrospective analysis of tumor tissue in the two aforementioned trials showed that somatic mutations of the K-ras gene were associated with poor response rates to treatment with cetuximab. In a recently published trial, K-ras mutational status was a strong predictor for response to cetuximab monotherapy. Of note, K-ras was not found to be a relevant prognosticator for overall survival in patients who did not receive cetuximab [19]. K-ras is the first predictive marker established in the treatment of CRC, and, as a consequence, all patients should be analyzed for K-ras mutations of their tumor tissue before EGFR-directed therapy is offered. Combinations of cetuximab with capecitabine and irinotecan (XELIRI) or capecitabine and oxaliplatin (XELOX) also were tested, with promising response rates: 42% for XELIRI and 66% for XELOX [20]. The main toxicity of cetuximab is a skin rash which begins in the first weeks with a papulopustular folliculitis that progresses to a dry atopic dermatitis. Based on the above observation, a randomized dose-escalation study of cetuximab was conducted in patients with no or only slight skin reactions. When doses were escalated up to the point of grade 2 rash, the response rate increased from 16% to 30% [21]. Today bevacizumab represents a good option for first- and second-line therapy. Cetuximab is useful for second-line treatment, but is currently not FDA approved in the firstline setting. However, in an interdisciplinary approach, cetuximab may be combined with irinotecan- or oxaliplatincontaining chemotherapy to achieve higher response rates and permit hepatic metastasectomy in patients with unmutated K-ras status. The results of large phase III trials with immunochemotherapy are listed in Table 10.2.

Panitumumab Panitumumab (VectibixTM, Amgen) is a fully human monoclonal IgG2 antibody that binds to the extracellular domain of EGFR, thus inhibiting the downstream signaling cascade. A phase III trial compared panitumumab to best supportive care (BSC) in patients with EGFR expressing metastatic CRC with disease progression after chemotherapy. Panitumumab significantly prolonged the mean progression-free survival from 8.5 weeks to 13.8 weeks. Response rates after 1 year were 10% with panitumumab and 0% with BSC (p = 0.0001). No significant difference in overall survival was seen, likely due to cross-over (76% of control patients received the treatment after progression). The most common side effects of panitumumab treatment were skin reactions, hypomagnesemia, and diarrhea. Since panitumumab is a fully human antibody, anaphylactic reactions were uncommon [22]. The results of this study led to the approval of panitumumab in the United States for pretreated patients with EGFR-expressing metastatic CRCs.

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As with cetuximab, panitumumab is effective in patients with unmutated K-ras status only, and mutational analysis should be performed before starting therapy with either EGFR-antibody.

New agents AZD2171 (RecentinTM, AstraZeneca) is an oral tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3. In order to block tumor angiogenesis, continuous oral intake of AZD2171 is necessary. Early clinical trials showed promising activity in patients with various solid tumors. Based on results with the anti-VEGF-monoclonal antibody bevacizumab, AZD2171 is being tested in combination with chemotherapy in two large international phase III studies in metastatic CRC. S-1 is a novel oral fluoropyrimidine that contains tegafur, a 5-FU prodrug, and two 5-FU modulators, the active gimeracil and oteracil. These enzyme blockers enhance the concentration of 5-FU in the tumor cells after conversion of tegafur into the active form (gimeracil), and similarly reduce toxicities by blocking enzymatic degradation of damaging metabolites (oteracil). Trials in Japan have shown a favorable side effect profile and promising tumor activity of S-1, either as a single agent or combined with irinotecan [23–26]. S-1 may become an alternative to 5-FU or capecitabine due to the improved toxicity profile, but these preliminary results are yet to be validated in larger randomized controlled trials. Erlotinib (TarcevaTM, Roche) is an oral tyrosine kinase inhibitor of EGFR and its downstream signaling. Erlotinib has been approved in the United States for the treatment of patients with non-small cell lung cancer and pancreatic cancer. In metastatic CRC, erlotinib was tested as a single agent in a phase II study. An 8% response rate and 33% stable disease rate were reported [27]. Recently, a trial testing a four-drug first-line therapy combining FOLFOX, bevacizumab, and erlotinib was closed prematurely due to increased toxicity [28]. This collective experience has shown the limitations of a purely pragmatic approach to clinical research. At the present time, clinical researchers in CRC agree that a structured approach combining clinical studies with translational research (e.g. of predictive factors such as K-ras mutations, or molecular profiling) are preferable to a “blind” testing of possible drug combinations in large randomized trials. At the same time, clinical trial designs should develop innovative endpoints, including quality of life in addition to the traditional outcomes of response rates and progression-free survival, which may not be very reliable. Overall survival may be misleading as an endpoint because it is dependent on second-line (cross-over) and third-line treatments that may underestimate time efficacy. In conclusion, there are many options for the systemic treatment of colorectal liver metastases. The best option is

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to treat the patient on a clinical trial. The selection of the appropriate regimen will depend on the treatment strategy (Figure 10.1). In a young and fit patient with metastases limited to both liver lobes, a downstaging strategy with “aggressive” combination chemotherapy should be chosen, if possible with immunotherapy, while for a patient with unresectable extrahepatic disease, sequential treatment with single agents or doublets is appropriate to minimize exposure and toxicity.

Systemic chemotherapy as part of the multidisciplinary approach to colorectal liver metastases At diagnosis 25% of all CRC patients have detectable (synchronous) metastases and another 30% develop metastatic disease later in their disease course. When a relapse after resection of the primary tumor occurs, the liver is the only affected organ in 50% of patients (metachronous metastases). The lung is the main extra-abdominal organ affected; resectable metastases limited to the lung are found in up to 2% of all patients. Surgical resection of colorectal metastases to the liver remains the gold standard therapy of the disease-free treatment strategy. Five-year survival after resection of colorectal liver metastases reaches 30%, while only few patients are long-term survivors after systemic chemotherapy alone. Surgery represents the only curative treatment option. In addition to liver metastasectomy and resection of isolated lung metastases, the adrenal glands and ovaries may also be involved and resected in select cases, with improvement in disease-free interval. On the other hand, metastases in abdominal lymph nodes or the peritoneum usually are contraindications to further resection. A multidisciplinary team including a liver surgeon, an interventional radiologist, an oncologist, and a hepatologist should decide as early as possible how to proceed. Figure 10.1 proposes an algorithm for the patient with colorectal liver metastases. In the case of clearly resectable liver lesions (e.g. metachronous metastases limited to one liver lobe), immediate resection may be chosen, followed by postoperative “adjuvant” chemotherapy. A 3-month preoperative and 3-month postoperative treatment with FOLFOX is a reasonable first option, based on the randomized EORTC 40983 trial. In this study 182 patients with resectable hepatic metastases (up to four metastases) were treated with six cycles of bi-weekly FOLFOX4 before and six cycles after surgery, and compared with 182 patients who underwent surgery only. In the intention-to-treat analysis, progression-free survival after 3 years was improved by 7.2% when all patients were considered (p = 0.058). When only patients who underwent surgery were considered (n = 151), the progression-free survival was improved by 9.2% with this neoadjuvant regimen (p = 0.025) [29]. A limitation of this study design is the lack of a third arm with postoperative chemotherapy only.

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Systemic Treatment of Hepatobiliary Tumors

Radiological evaluation of CRC-LM (PET-CT)

Resectable

• R0 possible • Unilobar disease • Metachronous LM

Liver resection + perioperative chemo

Potentially resectable • R0 not yet possible • Bilobar disease • Synchronous LM • Involvement of central structures* • < 30% parenchyma remaining

Primary chemo ± liver resection

Unresectable

• R0 not possible • LM in all segments • Extensive extrahepatic disease

Palliative chemo

Figure 10.1 Treatment algorithm for patients with colorectal cancer liver metastases (CRC-LM). LM, liver metastases; PET-CT, positron emission tomography/computed tomography. *Central structures include the inferior vena cava, bile ducts, liver veins, and liver arteries.

Therefore, it is unclear whether 12 cycles of postoperative FOLFOX would yield a result equivalent to the pre- and post-operative chemotherapy strategy shown to be superior to surgery alone.

Determining resectability and downstaging options When a R0 resection of liver metastases is considered impossible in a fit patient, a “downstaging” strategy employing an aggressive preoperative treatment is indicated. The resectability has to be evaluated by an experienced surgeon. Not only number and localization of the metastases have to be considered, but also the proximity to vascular structures like the hepatic veins, the inferior vena cava, and major branches of the portal vein and the hepatic artery. Involvement of bile ducts may cause obstruction, jaundice, and even lobular atresia, but is not a contraindication to resection. Lastly, a remnant liver volume after resection of around 30% with adequate portal vein and hepatic artery inflow, and hepatic venous and biliary drainage is critical to determining resectability [30]. The parenchymal quality of the remnant liver portion (i.e. presence of macrosteatosis, cirrhosis, and hepatotoxicity due to prior chemotherapy) should also be factored into the volume estimation. To assess the extent of disease in potentially resectable patients, a positron emission tomography (PET) with integrated CT scan (PET-CT) is very useful. In retrospective analyses and small prospective trials, a correlation between response rate to chemotherapy and

resection rate of liver metastases has been found. Response rates of 30–80% and R0 resection rates of 3–40% have been reported by using a regimen with 5-FU/LV and oxaliplatin or irinotecan before surgery in patients with unresectable metastases. Overall survival was prolonged to 48 months compared with 15 months in patients not undergoing resection [31–35]. These analyses provide the rationale for intensifying preoperative chemotherapy with the goal to increase response and resection rates. The results of some informative trials are listed in Table 10.3. Two phase II studies achieved response rates of over 70% and resection rates of over 50% by using a triple combination of irinotecan, oxaliplatin, and 5-FU together (FOLFOXIRI) [36, 37]. This approach was also tested in two recently published phase III studies comparing triple combinations with the doublet FOLFIRI. In the first trial, the triple combination was not superior to the doublet regarding overall survival (21.5 months versus 19.5 months) despite slightly higher response and R0 resection rates [38]. In the second trial a modified FOLFOXIRI regimen with higher doses of irinotecan and oxaliplatin was used. The triplet yielded higher response rates (66% versus 41% with FOLFIRI), with 8% complete remissions in a total of 244 patients. The R0 resection rate was 15% in initially unresectable patients (versus 6% with FOLFIRI) for the whole collective and 36% (versus 12%) in patients with hepatic disease only. Progression-free and overall survival were prolonged significantly at the price of considerably higher toxicity (neutropenia and neuropathy) [39]. This triple combination is a valid option in young and

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Table 10.3 Response and resection rates in patients with colorectal cancer liver metastases. Author

Therapy

No of patients

Response rate (%)

Resection R0 and R1 (%)

Alberts et al [32] Pozzo et al [33] Rivoire et al [35] Ho et al [34] Masi et al [ 37] Köhne et al [88]

FOLFOX FOLFIRI FU/LV/OX FOLFIRI FOLFOXIRI FU/LV FU/LV/CPT-11 HAI OX or IROX (+HAI)

43 40 131 28 74 216 214 11 36

51 48 35 54 72 34 64 54 88

40 33 25 11 26 3 7 36 19

Selzner et al [89] Kemeny et al [90]

FU, 5-fluorouracil; LV, leucovorin; OX, oxaliplatin; CPT-11, irinotecan; HAI, hepatic arterial infusion.

fit patients when the treatment goal is downstaging of unresectable liver metastases. Highly active combination chemotherapy with FOLFOXIRI, FOLFOX-bevacizumab, or FOLFIRI-cetuximab may be chosen (for regional chemotherapy see Chapter 14). Response has to be monitored closely, since surgery has to be performed as soon as possible in order to avoid chemotherapy-associated hepatotoxicity or tumor progression. The risk of postoperative liver failure increases with duration of preoperative chemotherapy. Complete remission of hepatic lesions constitutes a new problem; due to chemotherapy, hepatic metastases may disappear and become undetectable radiologically and intraoperatively. Even so, 83% of such “invisible lesions” harbor malignant cells [40]. Therefore, resection of formerly affected liver parenchyma is necessary, and a complete response may render the intervention difficult for the surgeon. When hepatic disease involves all segments and/or infiltrates central structures, or when unresectable extrahepatic disease is present, chemotherapy is given with palliative intent. In this situation it may be preferable to use doublets or single agents sequentially in order to minimize side effects and maintain quality of life.

Unresectable hepatocellular carcinoma Many diagnostic and therapeutic aspects of hepatocellular carcinoma (HCC) are discussed in other chapters of this book. Here we shall discuss exclusively systemic drug treatment used in patients without curative and/or local treatment options. Many trials have studied systemic treatment in HCC with very limited success. The agent most frequently tested was doxorubicin (DOX). One study comparing DOX to BSC found a modest but significant improvement in overall survival from 7.5 to 10.6 weeks [41]. DOX has been

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widely used in HCC, although response rates are low and its impact on overall survival is marginal. In a more recent phase III trial, the PIAF regimen (DOX, cisplatin, interferon, and 5-FU) was tested against DOX alone. A trend for prolonged overall survival was documented with the disadvantage of increased toxicity (8.7 months versus 6.8 months) [42]. Other conventional chemotherapy regimens proved ineffective and cannot be recommended on the basis of the available data (Table 10.4). HCC was found to express somatostatin receptor 2 (SSTR2) and this provided the rationale for using somatostatin or its analog octreotide. The clinical trial data are divergent with only one trial demonstrating significant improvement of survival. In this study 58 patients were treated with octreotide 250 μg BID; 6- and 12-month survival were significantly improved compared with the control group (75% versus 37% and 56% versus 13%, respectively) [43]. This result was not confirmed in a subsequent second randomized placebo controlled study of 120 patients [44]. However, in a few case reports, astonishing results have been reported, suggesting that somatostatin activity may be highly dependent on the expression of somatostatin receptors in carcinoma cells [45]. In summary, treatment with somatostatin or octreotide cannot be generally recommended as standard therapy. Another agent tested in several studies is tamoxifen, an antiestrogen. Preclinical models suggested a correlation between estrogens and liver carcinogenesis, but all larger clinical trials were disappointing, rendering a treatment with tamoxifen obsolete [46]. HCC is a highly vascularized tumor with enhanced microvessel density and high levels of VEGF. As a consequence, different trials have used bevacizumab alone or in combination with other drugs and achieved good preliminary results [47–50]. One study used a combination of gemcitabine plus oxaliplatin – a regimen with activity in pancreaticobiliary

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Systemic Treatment of Hepatobiliary Tumors

Table 10.4 Selected phase II and III trials of systemic treatment in hepatocellular carcinoma. Author

Therapy

Number of patients

DCR (%)

Overall survival (months)

P

Kouroumalis et al [43]

Octreotide Placebo Octreotide Placebo PIAF Doxorubicin Sorafenib Placebo Tamoxifen Placebo BEV/capecitabine BEV/erlotinib BEV/GEMOX BEV/CAPOX Erlotinib Erlotinib

28 30 60 59 94 94 299 303 210 210 45 29 33 30 38 40

32 0 0 0 21 11 43 32 NA NA 60 50 47 77 59 43

13 4 4.7 5.3 8.7 6.8 10.7 7.9 4.8 4.0 10.7 19 9.6 10.6 13 10.8

0.002

Becker et al [44] (HECTOR trial) Yeo et al [42] Llovet et al [52] (SHARP trial) Barbare et al [46] Hsu et al [47] Thomas et al [50] Zhu et al [49] Sun et al [48] Philip et al [54] Thomas et al [55]

NS 0.83 0.0006 0.17 NA NA NA NA NA NA

DCR, disease control rate; BEV, bevacizumab; PIAF, cisplatin, interferon, doxorubicin, 5-fluorouracil; NA, not available; NS, not significant.

tumors – in combination with bevacizumab for advanced HCC. The objective response rate was 20% and 27% of the patients achieved stable disease. The median overall survival was 9.6 months and the median progression-free survival was 5.3 months [49]. Such combinations with encouraging antitumor activity should be tested in larger and comparative trials. The efficacy data of recent trials are listed in Table 10.4. Fibrolamellar carcinoma is a variant of HCC typically affecting young adults. Inoperable and/or metastatic fibrolamellar HCC may be treated with 5-FU and interferon, as described in a phase II study. This regimen may also have a role in the neoadjuvant setting to enhance resection rates [51].

New drugs HCC is associated with the Raf/MAPK-ERK kinase (MEK)/ extracellular signal regulated kinase (ERK) pathway. Overexpression of MEK1 and VEGF enhances growth and spread of the tumor. Sorafenib (NexavarTM, Bayer) is an oral multikinase inhibitor which hampers tumor cell proliferation by blocking the Raf/MEK/ERK pathway as well as tumor angiogenesis by blocking VEGFR-2, VEGFR-3, and plateletderived growth factor receptor beta (PDGFR-β). Sorafenib has been studied in patients and the results of the SHARP trial were first presented in 2007. In this large international placebo-controlled randomized trial, 299 patients with advanced HCC, good performance status, and Child–Pugh status A were treated with sorafenib 400 mg BID and compared to 303 patients who received placebo. Treatment with

sorafenib significantly prolonged overall survival (10.7 versus 7.9 months) and time to progression (5.5 versus 2.8 months). The treatment was well tolerated; the most frequent grade 3/4 toxicities were diarrhea, hand–foot skin reaction, and fatigue [52]. This is the first phase III study to demonstrate a significant benefit from systemic therapy in HCC after decades of frustration in this field, making sorafenib the new standard of care in patients with unresectable tumors (Table 10.4). A recently published phase III study confirmed these results in Asian patients with HCC. Overall survival was significantly prolonged from 4.1 to 6.2 months compared with placebo (p = 0.015) [53]. Encouraged by this success, new agents are being tested in similar trials. The EGFR inhibitor erlotinib was tested and has shown activity in HCC [54, 55]. Sunitinib (SutentTM, Pfizer) is another oral multikinase inhibitor which may prove effective, since both sunitinib and sorafenib are active in the treatment of advanced renal cell carcinoma. A more detailed description of treatment options in HCC with targeted therapy is given in Chapter 34.

Cancer of the biliary tract Cancer of the biliary tract comprises carcinoma of the gallbladder as well as intrahepatic and extrahepatic cholangiocarcinoma. Klatskin tumors arising at the perihilar level are the most frequent form (50%) of cholangiocarcinoma. Multifocal tumors occur rarely (5%). Most biliary tract cancers are adenocarcinomas (95%). Surgery is the only

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potentially curative treatment for these patients, yet only a small minority can be cured. The 5-year survival is 10–20% for intrahepatic cholangiocarcinomas and 20–30% for distal extrahepatic carcinomas. When surgery is not feasible or when relapse after surgery has occurred, systemic therapy may be considered. The literature on the systemic treatment of biliary cancer includes about 100 phase II trials and very few (four) randomized trials. A Scandinavian study performed in the 1990s showed that chemotherapy with 5-FU/LV with or without etoposide (ELF) could prolong overall survival and improve quality of life compared with the best supportive care in pancreatic cancer or in biliary cancer [56]. More recently, three small randomized European studies have compared various regimens, yielding no significant superiority for any regimen. A study from the United Kingdom in 54 patients has compared ECF (epirubicin, cisplatin, 5-FU) to FELV (5-FU, etoposide, leucovorin) and shown a trend in favor of the latter regimen (median survival of 9 months versus 12 months) [57]. A study of the EORTC in 57 patients compared high-dose 5-FU monotherapy to CLF (cisplatin, leucovorin, 5-FU) with a trend in favour of the latter (median survival 5 months versus 8 months) [58]. A study from central Europe in 51 patients compared bi-weekly mitomycin–gemcitabine to mitomycin–capecitabine with a trend favoring the latter regimen (median survival 6.7 months versus 9.3 months) [59]. In addition to these small randomized studies, approximately 100 studies of systemic treatment in biliary tract cancer were performed using one particular regimen. Based on its efficacy in pancreatic cancer and its good tolerability, many of these trials have used gemcitabine, in monotherapy or in combination chemotherapy (Table 10.5). Objective response rates in the range of 10–25% were seen with

monotherapy. Higher response rates (20–50%) with manageable toxicities have been reported using gemcitabine in combination with 5-FU [60], docetaxel [61], cisplatin [62, 63], oxaliplatin [64], and capecitabine [65, 66]. A recent meta-analysis of 104 trials comprising 112 trial arms and 2810 treated patients was performed in an effort to distil clinically meaningful answers from this large and fragmented literature. The trials were analyzed for response rate, tumor control rate, time to progression, overall survival, and toxicity. Pooling these data, an overall response rate of 22.6% and a tumor control rate of 57.3% were found. In monotherapy, 5-FU and gemcitabine were similar. In combination therapy, the addition of a platinum compound added benefit, especially in combination with gemcitabine. The authors therefore suggest gemcitabine with cisplatin or oxaliplatin as “a provisional standard” for the systemic treatment of biliary tract cancer [67]. Similarly, practice guidelines for the treatment of unresectable or metastatic biliary tract cancer recommend 5-FU-based or gemcitabine-based chemotherapy or – preferably – treatment within a clinical trial. The purpose of chemotherapy in the noncurative setting is symptom control and maintaining quality of life. A pragmatic approach will use a well tolerated single-agent therapy for treating an elderly or frail patient. In a young and fit patient with extensive disease, the combination of gemcitabine with a platinum compound can be used with a higher chance to achieve a meaningful response. No sufficient data exist for second-line treatment of biliary tract cancer, but a switch of the regimen or the addition of new drugs is common practice. Adjuvant chemotherapy after surgical resection (R1/R2) of biliary cancer or N1 disease has only been tested in small series, and thus we believe this approach cannot be generally recommended prior to testing in large clinical trials.

Table 10.5 Gemcitabine-based regimens for the treatment of biliary tract cancer. Author

Therapy

No of patients

Response rate (%)

Overall survival (months)

Kubicka et al [91] Park et al [92] Tsavaris et al [93] Kiba et al [94] Knox et al [60] Thongprasert et al [62] Knox et al [65] Adamo et al [63] Riechelmann et al [66] Kuhn et al [61] Giuliani et al [95] Andre et al [64]

GEM GEM GEM GEM GEM GEM GEM GEM GEM GEM GEM GEM

23 23 30 22 27 43 45 27 75 43 38 33

30 26 30 5 33 27.5 31 48 29 11.6 32 36

NA 13.1 14 8.3 5.3 9 14 13.2 12.7 11 8 15.4

+ + + + + + + +

FU/LV CIS CAPE CIS CAPE DOC CIS OX

FU, 5-fluorouracil; LV, leucovorin; OX, oxaliplatin; GEM, gemcitabine; CIS, cisplatin; CAPE, capecitabine; DOC, docetaxel; NA, not available.

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Table 10.6 Chemotherapy regimens for neuroendocrine tumors. Author P-NET regimens Moertel et al [70] Moertel et al [71] McCollum et al [72] Cheng & Saltz [73] Kulke et al [76] CT regimens Engstrom et al [77] Sun et al [78]

Therapy

No of patients

Response rate (%)

Overall survival (months)

p

STZ + 5-FU STZ STZ + DOX STZ + 5-FU STZ + DOX STZ + DOX Temozolomide + thalidomide

42 42 36 33 16 16 11

63 36 69 45 6 6 45

26 16.5 26.4 16.8 20.2 NR NA

NS

STZ + 5-FU DOX STZ + 5-FU DOX + 5-FU

86 86 78 85

22 21 16 16

16 12 24.3 15.7

NS

0.004 NA NA NA

0.027

P-NET, pancreatic neuroendocrine tumor; CT, carcinoid tumor; STZ, streptozocin; 5-FU, fluorouracil; DOX, doxorubicin; NA, not significant; NR, not reached; NA, not assessed.

Newer drugs such as cetuximab and bevacizumab have been tested in combination with GEMOX and have shown modest activity but limited benefit [68, 69]. These and other targeted agents (e.g. Davanat®) are undergoing further clinical testing.

Neuroendocrine tumors Neuroendocrine tumors (NET) can be broadly grouped into pancreatic endocrine tumors (P-NET), carcinoid tumors, and poorly differentiated gastroenteropancreatic NETs. Initial treatment usually includes surgical removal of the primary tumor. The proportion of hormone-secreting malignant cells is highest in carcinoids when compared to the other NET variants. The endocrine symptoms, such as flushing and diarrhea, in the carcinoid syndrome can be effectively treated with octreotide (using long-acting analogs for continued treatment) and, in refractory cases, interferon. However, these agents have no effect on tumor growth. When metastatic disease is unresectable, rapidly progressing and/or causing bulk-related symptoms, chemotherapy is indicated. P-NETs are responsive to chemotherapy and a few trials suggest that combination regimens are more effective than monotherapy. A Mayo Clinic study showed an advantage of streptozocin (STZ) combined with 5-FU over STZ monotherapy in terms of overall survival but without reaching statistical significance (26 versus 16.5 months) [70]. A subsequent Mayo Clinic study showed longer survival for STZ/DOX over STZ/5-FU (26.4 versus 16.8 months, p = 0.004) [71]. However, the high response rate of STZ/DOX (69%) could not be confirmed by other retrospective analyses,

reporting response rates of only 6% [72,73]. STZ in combination with doxorubicin or 5-FU is still considered a standard of care for metastatic P-NET. Activity was also documented for dacarbazine and epirubicin, while taxanes and gemcitabine were ineffective [74, 75]. More recent small studies have focused on temozolomide, an oral prodrug of dacarbazine, and the antiangiogenic drugs thalidomide and bevacizumab, since NETs are highly vascularized tumors [76]. Other new agents with promising activity currently studied in clinical trials include Rad001 and sunitinib. Chemotherapy studies for NETs are summarized in Table 10.6. Carcinoids are the most common NETs, and may be oligosymptomatic. Carcinoids usually exhibit low proliferation rates but are generally unresponsive to chemotherapy. Several drugs have been tested as both single and combined agents, but have proven ineffective. One older phase III study demonstrated efficacy of 5-FU/STZ compared to single-agent doxorubicin [77]. In a recent ECOG study in 249 patients the 5-FU/STZ was compared to 5-FU/DOX. Despite similar response rates (16% versus 15.9%), the 5-FU/STZ regimen was superior regarding median overall survival (24.3 months versus 15.7 months, p = 0.0267). After disease progression, patients received dacarbazine as second-line therapy, with a response rate of 8.2% and a median survival of 11.9 months [78]. In summary, STZ combined with 5-FU may be given to select patients with progressive and symptomatic carcinoid tumor. Dacarbazine may be considered for second-line therapy. Symptoms such as flushing or watery diarrhea are treated with octreotide [79]. Interferon has been shown to have activity against these symptoms [80, 81]. Its contribution when combined with octreotide is

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controversial, and because of its potential for severe side effects (arthralgias, fever, depression), interferon is rarely used. Poorly differentiated gastroenteropancreatic NETs have a biology similar to small cell lung cancer and may run an aggressive course. They are preferably treated with a combination of platinum compounds (cisplatin or carboplatin) and etoposide. Two trials have reported response rates of 67% and 42% , respectively [82, 83].

Rare liver tumors in adults Many solid tumors develop metastases to the liver, and many hematologic neoplasias may involve the liver. Treatments of these entities are based on the primary tumor and are not discussed here. Hepatoblastoma is the most common malignant liver tumor in children, but it may also affect young adults. Treatment of hepatoblastoma in young adults is discussed in detail in Chapter 39. It involves cisplatin and DOX, and possibly carboplatin and etoposide [84]. Hepatic epithelioid hemangioendothelioma is a rare tumor, frequently multifocal, and of unpredictable course. Whenever possible it is treated by resection (or transplantation). In cases of advanced or metastatic disease, systemic therapy may be considered based on a very limited literature. DOX was used in unresectable cases and was active in epithelioid hemangioendothelioma [85]. Due to the origin of this tumor from endothelial cells, treatment with antiangiogenic drugs has been proposed in recent years. Promising anecdotal results have been reported with the use of interferon and thalidomide. Primary hepatic angiosarcoma is a very aggressive and chemoresistant tumor accounting for about 0.1% of primary liver cancers. Vinyl chloride exposure is a risk factor for the development of this malignancy. Regimens using DOX and ifosfamide, and monotherapy with paclitaxel or local treatments (chemoembolization) may be considered.

Self-assessment questions 1 When are colorectal liver metastases an incurable disease? (more than one answer is possible) A When both liver lobes are involved B In the presence of peritoneal disease C When in addition to liver metastases a lung metastasis is present D When all three hepatic veins are infiltrated by tumor E When at surgery a small lymph node at the hepatic hilum is found to be involved with tumor

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2 Rectal cancer is less likely to cause pulmonary metastases than colon cancer, because venous drainage of rectal cancer is different from colon cancer. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 3 When resection of colorectal liver metastases is considered, it is reasonable to perform a PET-CT (FDG-positron emission tomography with integrated CT-scan) because this methodology is very sensitive for detection of extrahepatic disease as well as for localization of hepatic disease A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 4 Which of the following regimens are adequate for first-line treatment of colorectal cancer with metastases in both liver lobes, lungs, peritoneum, and abdominal lymph nodes? (more than one answer is possible) A Capecitabine B 5-FU/leucovorin/oxaliplatin (FOLFOX) C Carboplatin/paclitaxel D 5-FU/leucovorin/irinotecan (FOLFIRI) E Capecitabine/oxaliplatin/bevacizumab 5 In a 40-year old male patient with colorectal liver metastases no extrahepatic disease is found. However, immediate resection is not attempted because of the extension of the disease. Which regimens are adequate to attempt “downstaging” in this case? (more than one answer is possible) A Capecitabine B 5-FU/leucovorin/oxaliplatin/bevacizumab (FOLFOX-Bev) C 5-FU/leucovorin/oxaliplatin/irinotecan (FOLFOXIRI) D 5-FU/leucovorin/irinotecan/cetuximab (FOLFIRICet) for wild type K-ras carcinomas E 5-FU/leucovorin 6 What are known complications of bevacizumab? (more than one answer is possible) A Hemorrhage B Proteinuria

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C Bowel perforation D Hypertension E Reversible posterior leukoencephalopathy syndrome 7 Which one of the following side effects is associated with cetuximab? A Alopecia B Neutropenia C Thrombocytopenia D Proteinuria E Hypomagnesemia 8 Which of the following statements about K-ras are true?(more than one answer is possible) A K-ras is a gene encoding a membrane-bound tyrosine kinase B Activating somatic K-ras mutations may be found in colorectal and pancreatic cancer C Mutations of K-ras are predictive for nonresponse to cetuximab D Mutations of K-ras are predictive for nonresponse to bevacizumab E Patients with K-ras mutated colorectal cancer have a worse prognosis than patients with wild-type K-ras status irrespective of treatment 9 Which one of the following side effects does capecitabine not lead to? A Hand–foot skin reaction B Palmoplantar erythrodysesthesia C Lung injury D Diarrhea E Neutropenia 10 Which of the following statements about fluorouracil are true? (more than one answer is possible) A Fluorouracil is a purine analog B Fluorouracil is a pyrimidine antimetabolite C The activity of fluorouracil on thymidylate synthase can be modulated by leucovorin D Fluorouracil is metabolized by dehydro-pyrimidine dehydrogenase E Fluorouracil usually leads to alopecia 11 Which of the following chemotherapy regimens have been shown to have some activity and may be utilized in advanced cholangiocellular carcinoma? (more than one answer is possible) A Paclitaxel B Gemcitabine monotherapy C Mitoxantrone D Oxaliplatin plus gemcitabine E Capecitabine

Systemic Treatment of Hepatobiliary Tumors

12 Which one of the following drugs has been shown to increase overall survival in the systemic treatment of advanced hepatocellular carcinoma? A Tamoxifen B Sorafenib C Octreotide D Irinotecan E Interferon 13 Which of the following are regular side effects of oxaliplatin? (more than one answer is possible) A Alopecia B Cold-induced pharyngolaryngeal sensitivity C Diarrhea D Myalgia E Cumulative sensorimotor polyneuropathy 14 Which of the following are possible side effects of irinotecan? (more than one answer is possible) A Alopecia B Fatigue C Diarrhea D Neutropenia E Cumulative sensorimotor polyneuropathy 15 Which one of the following statements does not apply to the tumor marker CA 19-9? A Can be elevated in cholangitis B Is usually elevated in cholangiocellular carcinoma C May help to differentiate primary sclerosing cholangitis from superimposed cholangiocellular carcinoma D Is usually elevated in colorectal cancer E Is usually elevated in pancreatic cancer

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35 Rivoire M, De Cian F, Meeus P, Negrier S, Sebban H, Kaemmerlen P. Combination of neoadjuvant chemotherapy with cryotherapy and surgical resection for the treatment of unresectable liver metastases from colorectal carcinoma. Cancer 2002;95:2283–92. 36 Ychou M, Viret F, Kramar A, et al. Tritherapy with fluorouracil/ leucovorin, irinotecan and oxaliplatin (FOLFIRINOX): a phase II study in colorectal cancer patients with non-resectable liver metastases. Cancer Chemother Pharmacol 2008;62:195–201. 37 Masi G, Cupini S, Marcucci L, et al. Treatment with 5fluorouracil/folinic acid, oxaliplatin, and irinotecan enables surgical resection of metastases in patients with initially unresectable metastatic colorectal cancer. Ann Surg Oncol 2006;13: 58–65. 38 Souglakos J, Androulakis N, Syrigos K, et al. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer 2006;94:798–805. 39 Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 2007;25:1670–6. 40 Benoist S, Brouquet A, Penna C, et al. Complete response of colorectal liver metastases after chemotherapy: does it mean cure? J Clin Oncol 2006;24:3939–45. 41 Lai CL, Wu PC, Chan GC, Lok AS, Lin HJ. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer 1988;62:479–83. 42 Yeo W, Mok TS, Zee B, et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/ doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 2005;97: 1532–8. 43 Kouroumalis E, Skordilis P, Thermos K, Vasilaki A, Moschandrea J, Manousos ON. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut 1998;42:442–7. 44 Becker G, Allgaier HP, Olschewski M, et al. Long-acting octreotide versus placebo for treatment of advanced HCC: a randomized controlled double-blind study. Hepatology 2007;45:9–15. 45 Siveke JT, Herberhold C, Folwaczny C. Complete regression of advanced HCC with long acting octreotide. Gut 2003;52: 1531. 46 Barbare JC, Bouche O, Bonnetain F, et al. Randomized controlled trial of tamoxifen in advanced hepatocellular carcinoma. J Clin Oncol 2005;23:4338–46. 47 Hsu C, Yang, T, Toh T. Modified-dose capecitabine + bevacizumab for the treatment of advanced/metastatic hepatocellular carcinoma (HCC): A phase II, single-arm study. J Clin Oncol 2007;25:a15190. 48 Sun W, Haller DG, Mykulowycz K. Combination of capecitabine, oxaliplatin with bevacizumab in treatment of advanced hepatocellular carcinoma (HCC): A phase II study. J Clin Oncol 2007;25:a4574.

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49 Zhu AX, Blaszkowsky LS, Ryan DP, et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006;24:1898–903. 50 Thomas MB, Chadha R, Iwasaki M. The combination of bevacizumab (B) and erlotinib (E) shows significant biological activity in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol 2007;25:a4567. 51 Patt YZ, Hassan MM, Lozano RD, et al. Phase II trial of systemic continuous fluorouracil and subcutaneous recombinant interferon Alfa-2b for treatment of hepatocellular carcinoma. J Clin Oncol 2003;21:421–7. 52 Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–90. 53 Cheng A, Kang Y, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebocontrolled trial. Lancet Oncol 2009;10:25–34. 54 Philip PA, Mahoney MR, Allmer C, et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 2005;23:6657–63. 55 Thomas MB, Chadha R, Glover K, et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer 2007;110:1059–67. 56 Glimelius B, Hoffman K, Sjoden PO, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 1996;7:593–600. 57 Rao S, Cunningham D, Hawkins RE, et al. Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer. Br J Cancer 2005;92:1650-4. 58 Ducreux M, Van Cutsem E, Van Laethem JL, et al. A randomised phase II trial of weekly high-dose 5-fluorouracil with and without folinic acid and cisplatin in patients with advanced biliary tract carcinoma: results of the 40955 EORTC trial. Eur J Cancer 2005;41:398–403. 59 Kornek GV, Schuell B, Laengle F, et al. Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial. Ann Oncol 2004;15:478–83. 60 Knox JJ, Hedley D, Oza A, Siu LL, Pond GR, Moore MJ. Gemcitabine concurrent with continuous infusional 5-fluorouracil in advanced biliary cancers: a review of the Princess Margaret Hospital experience. Ann Oncol 2004;15:770–4. 61 Kuhn R, Hribaschek A, Eichelmann K, Rudolph S, Fahlke J, Ridwelski K. Outpatient therapy with gemcitabine and docetaxel for gallbladder, biliary, and cholangio-carcinomas. Invest New Drugs 2002;20:351–6. 62 Thongprasert S, Napapan S, Charoentum C, Moonprakan S. Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma. Ann Oncol 2005;16:279–81. 63 Adamo V, Magno C, Spitaleri G, et al. Phase II study of gemcitabine and cisplatin in patients with advanced or metastatic bladder cancer: long-term follow-up of a 3-week regimen. Oncology 2005;69:391–8. 64 Andre T, Tournigand C, Rosmorduc O, et al. Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann Oncol 2004;15:1339–43.

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65 Knox JJ, Hedley D, Oza A, et al. Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial. J Clin Oncol 2005;23:2332–8. 66 Riechelmann RP, Townsley CA, Chin SN, Pond GR, Knox JJ. Expanded phase II trial of gemcitabine and capecitabine for advanced biliary cancer. Cancer 2007;110:1307–12. 67 Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer 2007;96:896–902. 68 Paule B, Herelle MO, Rage E, et al. Cetuximab plus GemcitabineOxaliplatin (GEMOX) in Patients with Refractory Advanced Intrahepatic Cholangiocarcinomas. Oncology 2007;72:105–10. 69 Clark J, Meyerhardt, JA, Sahani, DV. Phase II study of gemcitabine, oxaliplatin in combination with bevacizumab (GEMOXB) in patients with unresectable or metastatic biliary tract and gallbladder cancers. J Clin Oncol 2007;25:a4625. 70 Moertel CG, Hanley JA, Johnson LA. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med 1980;303:1189– 94. 71 Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992;326:519–23. 72 McCollum AD, Kulke MH, Ryan DP, et al. Lack of efficacy of streptozocin and doxorubicin in patients with advanced pancreatic endocrine tumors. Am J Clin Oncol 2004;27:485–8. 73 Cheng PN, Saltz LB. Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma. Cancer 1999;866:944–8. 74 Ramanathan RK, Cnaan A, Hahn RG, Carbone PP, Haller DG. Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282. Ann Oncol 2001;12:1139–43. 75 Bajetta E, Rimassa L, Carnaghi C, et al. 5-Fluorouracil, dacarbazine, and epirubicin in the treatment of patients with neuroendocrine tumors. Cancer 1998;83:372–8. 76 Kulke MH, Stuart K, Enzinger PC, et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 2006;24:401–6. 77 Engstrom PF, Lavin PT, Moertel CG, Folsch E, Douglass HO Jr. Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. J Clin Oncol 1984;2:1255–9. 78 Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG. Phase II/ III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol 2005;23:4897– 904. 79 Kvols LK, Moertel CG, O’Connell MJ, Schutt AJ, Rubin J, Hahn RG. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med 1986;315:663–6. 80 Faiss S, Pape UF, Bohmig M, et al. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors – the Interna-

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tional Lanreotide and Interferon Alfa Study Group. J Clin Oncol 2003;21:2689–96. Oberg K. Interferon-alpha versus somatostatin or the combination of both in gastro-enteropancreatic tumours. Digestion 1996;57 (Suppl 1):81–3. Moertel CG, Kvols LK, O’Connell MJ, Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 1991;68:227–32. Mitry E, Baudin E, Ducreux M, et al. Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin. Br J Cancer 1999;81:1351–5. Haberle B, Bode U, von Schweinitz D. [Differentiated treatment protocols for high- and standard-risk hepatoblastoma–an interim report of the German Liver Tumor Study HB99]. Klin Padiatr 2003;215:159–65. Kelly H, O’Neil BH. Response of epithelioid haemangioendothelioma to liposomal doxorubicin. Lancet Oncol 2005;6:813–5. Maindrault-Goebel F, Louvet C, Andre T, et al. Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6). GERCOR. Eur J Cancer 1999;35:1338–42. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22: 229–37. Kohne CH, van Cutsem E, Wils J, et al. Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol 2005;23:4856–65. Selzner N, Pestalozzi BC, Kadry Z, Selzner M, Wildermuth S, Clavien PA. Downstaging colorectal liver metastases by concomitant unilateral portal vein ligation and selective intraarterial chemotherapy. Br J Surg 2006;93:587–92. Kemeny N, Jarnagin W, Paty P, et al. Phase I trial of systemic oxaliplatin combination chemotherapy with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer. J Clin Oncol 2005;23:4888–96. Kubicka S, Rudolph KL, Tietze MK, Lorenz M, Manns M. Phase II study of systemic gemcitabine chemotherapy for advanced unresectable hepatobiliary carcinomas. Hepatogastroenterology 2001;48:783–9. Park JS, Oh SY, Kim SH, et al. Single-agent gemcitabine in the treatment of advanced biliary tract cancers: a phase II study. Jpn J Clin Oncol 2005;35:68–73. Tsavaris N, Kosmas C, Gouveris P, et al. Weekly gemcitabine for the treatment of biliary tract and gallbladder cancer. Invest New Drugs 2004;22:193–8. Kiba T, Nishimura T, Matsumoto S, et al. Single-agent gemcitabine for biliary tract cancers. Study outcomes and systematic review of the literature. Oncology 2006;70:358–65. Giuliani F, Gebbia V, Maiello E, Borsellino N, Bajardi E, Colucci G. Gemcitabine and cisplatin for inoperable and/or metastatic biliary tree carcinomas: a multicenter phase II study of the Gruppo Oncologico dell’Italia Meridionale (GOIM). Ann Oncol 2006;17 (Suppl 7):vii3–vii7.

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Self-assessment answers 1 2 3 4 5 6

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E B, C C B, C, D B, D, E B B, E A, B, C, D D

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External Beam Radiation Therapy for Liver Tumors Rakesh Reddy and A. Bapsi Chakravarthy Department of Radiation Oncology, Vanderbilt University, Nashville, TN, USA

Until recently, external beam radiation therapy could only play a very limited role in the treatment of liver tumors, as the entire liver can tolerate just 30–33 Gy of radiation. Solid tumors, in general, require at least 60 Gy to achieve local control in tumors 1–2 cm in size, and 50 Gy for microscopic disease. Therefore, it was not surprising that in years past the role of external beam radiation was limited to the palliation of pain secondary to liver tumors. New technologic advances in imaging as well as the delivery of radiation now allow the delivery of up to 100 Gy to the tumor while sparing the surrounding tissue. Therefore, external beam radiation is increasingly being recognized as a potentially curative treatment option in patients who are not surgical candidates [1, 2]. The principals described in this chapter apply to both primary tumors of the liver, such as hepatocellular carcinoma, as well as to secondary tumors such as colorectal cancer that has metastasized to the liver. This chapter will discuss the role of external beam radiation in these two clinical settings.

Advances in the delivery of radiation Two-dimensional treatment planning The earliest form of external beam radiation to the liver involved setting up the patient on a conventional simulator and taking diagnostic quality orthogonal films. Using these orthogonal films and the bony anatomy as landmarks, the physician would draw in the tumor volume on these films. Blocks would then be hand-drawn based on the physician’s clinical “estimate” of where the tumor was in relationship to the bony anatomy. Lead blocks would be poured which would then be mounted on the therapy machine to help block out as much normal tissue as possible. At the time of conventional simulation a wire would be placed around the patient to determine their body contour so as to allow the

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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tumor and normal tissue to be drawn manually into this outline of the external surface. At the time of simulation fluoroscopic films would be used to determine the diaphragmatic excursion and the blocks would be placed so as to allow the tumor to be treated throughout the breathing cycle. This necessitated using larger volumes to ensure that the entire tumor was treated. Once computed tomography (CT) scanners came into widespread use, the tumors were traced from the CT scan, done usually in radiology, to the orthogonal simulation films, which were obtained several days later in the radiation oncology facility. Although this improved the ability to visualize the tumor as well as the surrounding normal tissues, the planning still was performed manually using a few external contours.

Three-dimensional conformal treatment planning With the development of CT-based simulators, patients could be placed in the position in which they would be treated on the therapy machines. Both the external contour as well as the internal organs (tumor and normal tissue) could be drawn onto this reconstructed image and a complete three-dimensional (3D) representation could be used for treatment planning. The new planning software would allow beam angles that were not limited to the axial plane, and beams could come in from any angle. The use of this planning software required standardized vocabulary which was based on reports from the International Commission on Reporting of Units (ICRU) [3]. The first step is to outline the tumor which is defined as the gross tumor volume (GTV). A defined margin of tissue which contains the microscopic disease is then defined. This is usually approximately 1–1.5 cm around the gross tumor volume. This is defined as the clinical target volume (CTV). The CTV in liver tumors is usually between 0.5 cm and 1.0 cm in all three dimensions. Improvements in imaging, including advancements in CT scans as well as magnetic resonance imaging (MRI) scanners, have allowed better delineation of the tumor volume. Both GTV and CTV are determined by the disease and therefore cannot be improved upon by further improve-

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ments in dose delivery. Despite improvements in patient positioning, an additional margin needs to be added because of the day-to-day variation in patient set-up as well as physiologic movement such as respiration. This is defined as the internal target volume (ITV). In the case of liver tumors there is marked superior and inferior movement with breathing. In general, ITV in the transverse plane is 0.6–1 cm and 1.0–1.5 cm in the longitudinal plane. This margin can be significantly reduced by decreasing internal organ motion using a variety of methods. This includes both immobilization methods as well as beam applications that are coordinated with breathing. The planning target volume (PTV) is the sum of GTV + CTV + ITV. Three-dimensional planning software is able to display not only these volumes in 3D space, but also the distribution of radiation dose within any defined volume, including both tumor and surrounding critical normal structures. A dose–volume histogram (DVH) is calculated by dividing each structure of interest into 1-mm3 volume elements or voxels. The dose to each voxel can be plotted out as a percentage of the total volume or a DVH. This allows multiple fields to be used from a variety of angles to help decrease dose to surrounding critical structures. Figures 11.1–11.3 illustrate how adding multiple fields results in improved dose distribution. Although the dose to the tumor remains almost the same, there is marked reduction in dose to liver, kidney, and cord with the addition of multiple fields.

Four-dimensional conformal treatment planning Following an accurate delineation of tumor volume, methods are required to deliver this accurately as well. Since the liver moves at least 1–2 cm during respiration (superior to inferior direction), it is critical that treatment planning systems take this into account [4–6]. There are currently many ways to account for respiratory motion. These include having the patient hold their breath after establishing the position of the liver using the dome of the diaphragm as seen on fluoroscopy [7]. Another method is to use active breath-hold using a mechanical device that is set to turn off the treatment machine if the patient’s breathing excursion falls outside prespecified limits [8, 9]. Further modifications on active breath-hold includes use of a respiratory tracer to trigger the radiation therapy machine to turn on only during one phase of the respiratory cycle [10]. Finally, fiducial markers (gold seeds) implanted into or near the tumor can be used to create a coordinate system that can be used for real-time tracking of the tumor via respiratory gating or robotic controls that allow for “track and shoot.”

Intensity-modulated radiation therapy The next improvement in treatment planning software and hardware came with intensity-modulated radiation therapy (IMRT). With the advent of IMRT the computer is able to shape dose distributions based on limitations to both tumor

External Beam Radiation Therapy for Liver Tumors

and surrounding normal tissue specified by the radiation oncologist. It is now possible to deliver tumor doses to the target volume while maintaining low doses to the critical organs by allowing the beam intensity to vary across shaped fields. Beam directions and beam shapes can be selected to conform to the shape of the projected target and minimize dose to critical normal structures with the use of beam’s eye viewing of volumes defined on a treatment planning CT scan. Although inverse planning using IMRT results in better dose distributions, it comes at the expense of additional time and resources. Calculations for IMRT plans are done for either static or dynamic beam delivery methods using multileaf collimators. New planning algorithms are being designed to reduce the time needed to plan, implement, and verify these treatments.

Stereotactic body radiotherapy Stereotactic body radiotherapy (SBRT) is another method of delivering larger doses to a small volume while sparing the surrounding normal tissue. Techniques that have been developed in the treatment of brain tumors are now being used to treat tumors elsewhere in the body, including the liver. This technique uses either a single dose or a small number of fractions with a high degree of precision within the body. An example of a patient who received SBRT is shown in Figures 11.1d, 11.2c and 11.3c, showing the fields utilized, the isodose curves, and the DVH of such an approach, respectively. Unlike the brain where the skull allows for rigid immobilization that can be extremely precise, treatment of intrahepatic tumors with either IMRT or SBRT is associated with difficulties in immobilization. Considerable organ motion occurs during respiration. Active breathing control, respiratory gating and tracking techniques, shallow breathing with an oxygen supply, and a double-vacuum body fixation system, online imaging and set-up adjustment have been used to improve targeting between fractions during liver radiotherapy. Studies are ongoing to improve set-up uncertainty and organ motion.

Image-guided radiotherapy The next step in improving accuracy has been to incorporate imaging into daily treatment. Linear accelerators can now not only generate megavoltage X-rays but also kilovoltage X-rays. This allows the diagnostic quality images to be visualized just prior to the actual treatment to allow precise definition of the isocenter. Fiducial markers can be set such that the treatment machines will only treat within a prespecified excursion of this fiducial marker. With the advent of new software as well as imaging capabilities, real-time tumor tracking is becoming a reality [11]. Unfortunately, even with these in-room CT scans or in-room kilovoltage machines, it is difficult to target the tumor as liver tumors

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Figure 11.1 Beam’s-eye view of a patient with metastatic colorectal cancer treated using three-dimensional conformal external beam therapy. (a) Anteroposterior field, (b) posteroanterior field, (c) right lateral field, and (d) multiple fields for stereotactic body radiosurgery.

are usually isointense and daily contrast injections are not clinically feasible.

Charged particle irradiation Despite improvements in conformal radiation, the dose distribution is limited by the nature of photon beam therapy, which involves some of the dose being deposited as the beam approaches the target, as well as when it goes beyond

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the target. Charged particles, on the other hand, are able to deliver dose to the target without any exit dose to normal tissue. These charged particles deposit very little energy as they enter the patient and proceed to the target. They deposit the bulk of their energy within the target with a sharp fall off in dose as they again exit the target. This peak dose (the Bragg peak) can be modulated to adapt to the thickness of the patient and the size of the tumor. These

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(a)

External Beam Radiation Therapy for Liver Tumors

(b)

(c) Figure 11.2 Isodose curves of the same patient using (a) two-field plan using anteroposterior–posteroanterior fields, (b) three-field plan using anteroposterior–posteroanterior and right lateral fields, and (c) stereotactic body radiosurgery using multiple fields. With increasing number of fields, the dose distribution to the tumor does not change much, but it minimizes the dose to the liver and kidneys.

heavy particles also have very little lateral spread of energy, providing even more protection of the surrounding normal tissue. Proton or heavy-ion radiation therapy is another method of delivering radiation to precisely the target or tumor with little or no dose around the intended target volume. In addition to these physical attributes, heavier ions also have the advantage of more biologic effect for a given dose of radiation. With this approach, local control is excel-

lent, but it is limited to a few centers in the world and is very expensive [12–15].

Additional radiation techniques to spare liver function In addition to external beam, there are other techniques that deliver large doses of radiation to a very small volume while sparing the remainder of the liver. These include the use of

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Figure 11.3 Cumulative dose–volume histograms (DVHs) for the proposed treatment plans: a) two-field plan using anteroposterior–posteroanterior fields, (b) three-field plan using anteroposterior–posteroanterior and right lateral fields, and (c) stereotactic body radiosurgery using multiple fields. The cumulative DVHs for the liver and both kidneys are shown. The figure displays the fractional volume of normal tissue (ordinate) that receives radiation greater than or equal to a specified single dose fraction (abscissa). Red line, tumor volume; purple line, exposure of the liver; green line, right kidney; blue line, left kidney; brown line, spinal cord.

radioactive isotopes that emit radiation. This can be accomplished using external catheters through which a radioactive source emits radiation. This used to be very difficult when only low dose rate sources were available, which required the patient to remain in an isolated room with lead shielding to minimize radiation to hospital staff and others. Now, with the advent of high dose rate remote afterloaders, it is possible to treat patients using intraluminal catheters that remain in place, but the patient needs to come once or twice a day to the radiation facility to receive treatment as an outpatient. Unsealed sources such as iodine-131 or yttrium92 microspheres have also been used in the treatment of liver tumors. These techniques are discussed in greater detail in Chapter 12.

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Hepatocellular carcinomas Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world and the third most common cause of global cancer death. Although it is primarily a disease of the developing world, it is increasing in incidence in the Western world. In 2007, there were an estimated 19 160 new cases and 16 780 deaths from liver and intrahepatic bile duct cancer in the United States. The increasing incidence of HCC as well as a shift toward a younger population is postulated to be related to the increasing spread of hepatitis C [16] (see Chapter 5). HCC is a potentially curable disease when it can be surgically resected. Unfortunately, only a small minority of

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patients present with resectable disease (see Chapter 16). A very select group of patients are eligible for liver transplantation [2]. For patients for whom surgery or transplantation is not an option, there are a number of treatment options available, including external beam radiation, chemotherapy, hepatic artery ligation or embolization, percutaneous ethanol injection, radiofrequency ablation, cryotherapy, as well as the use of radiolabeled antibodies. Alpha-fetoprotein (AFP) is an important biologic marker that can be used for diagnosis and follow-up of this disease. Almost three-quarters of patients will have elevated levels of AFP at time of diagnosis. AFP levels have also been shown to be important for prognosis with the median survival of patients with AFP-negative tumors being significantly longer than for those with AFP-positive tumors [17] (see Chapter 8). Primary tumors of the liver are predominantly adenocarcinomas and are of two major cell types: HCCs or cholangiocarcinomas. HCCs are the more common liver cancer. The fibrolamellar variant is a very rare subtype, and it is important to distinguish this from the more common HCC because it can be cured with surgery alone. The fibrolamellar variant presents largely in young women, and it is important to distinguish it as it can often be cured if resected. Cholangiocarcinomas develop from the intrahepatic bile ducts (see Chapter 4). Liver cancers are staged using the American Joint Committee on Cancer (AJCC) criteria, which use tumor characteristics, nodal involvement, and distant metastases to group patients into four stages. The T classification is based on the presence or absence of vascular invasion (either radiologically or pathologically), the number of tumor nodules, size of the largest tumor, as well as invasion of adjacent organs (other than gallbladder) or perforation of the visceral peritoneum. For treatment purposes, patients are either localized and surgically resectable, localized and surgically unresectable, or present with distant disease. All patients should be evaluated for surgical resection or transplantation. If these are not viable options, other localized options, including external beam radiation, can be considered. Patients can have localized disease and yet be unresectable due to the location of the tumor, medical conditions, including cirrhosis, or bilateral tumors. Such patients are candidates for a variety of local treatment options, including radiofrequency ablation (RFA), which involves the application of radiofrequency thermal energy to the lesion. As the temperature within the tissue is elevated beyond 60 °C, cells begin to die. Another local treatment option is percutaneous ethanol or acetic acid ablation. Prior to RFA, these were often the local treatments of choice. Although they are low cost, require minimal equipment, and have good results, the ease and efficacy of RFA has supplanted the use of ethanol/ acetic acid ablation in most centers. Given that the blood supply of HCC is primarily from the hepatic artery, a number of techniques have been developed to deliver chemotherapy

External Beam Radiation Therapy for Liver Tumors

or a material to occlude the hepatic artery, thereby cutting off the blood supply of the tumor. Although both chemotherapy and bland arterial embolization have been used in the past, currently both are being done in a single procedure referred to as transarterial chemoembolization (TACE). In this procedure a mixture of poppy seed oil (lipiodol) and a chemotherapeutic drug is selectively delivered to the feeding circulation of the tumor via a catheter inserted into the hepatic artery or one of its branches. Gelatin, collagen, and alcohol have all been injected in an attempt to induce tumor necrosis (see Chapter 13). There are a number of potential toxicities that can be caused by radiation to the liver. Conventional external beam radiation to the whole liver can result in a high risk of fatal radiation-induced liver disease (RILD), often referred to as radiation hepatitis. RILD is a syndrome characterized by the development of anicteric ascites and typically occurs 2–12 weeks after hepatic irradiation. It has a mortality rate of nearly 50%. The pathology of RILD demonstrates venoocclusive disease and recent evidence suggests that elevated transforming growth factor beta (TGF-β) may play a role in the development of this disease [18]. Gross examination of the liver in RILD reveals marked congestion mostly in the central portion of each lobule with foci of necrosis in the center of the affected areas. Microscopic examination shows severe congestion of the sinusoids in the central portion of the lobules with atrophy of the inner portion of the liver plates. Liver enzymes can also be elevated in RILD. In patients with HCC, radiation can result in elevation of transaminases, reactivation of hepatitis, liver decompensation, thrombocytopenia, biliary obstruction, and stricture. Gastrointestinal side effects include potential obstruction, bleeding, and fistula formation. Liver tolerance to radiation is a function of both the volume of liver irradiated as well as the dose of radiation given. No cases of RILD were observed if the mean liver dose was less than 31 Gy [19]. In addition to liver volume, there are a number of other parameters that predict for reduced tolerance. These include tumor-related factors such as whether this is a primary liver tumor or metastases from colorectal tumors. The patient’s baseline liver function, as well as the use of concurrent chemotherapy, will determine liver toxicity. Liver toxicity varies with the patient population as well as the radiation technique’s fractionation schemes and total dose utilized to treat these tumors. Hyperfractionated radiation (giving smaller doses, twice a day) allows the same biologic dose of radiation to be used while sparing normal tissue. Clinical trials with unresectable liver cancers have shown that conformal hyperfractionated radiation using 1.5 Gy twice a day for 6–8 weeks and concurrent hepatic arterial fluorodeoxyuridine is well tolerated [20, 21]. The use of doses that were adjusted based on the volume of liver being irradiated resulted in doses as high as 90 Gy in some patients with median survival of 15.2 months.

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There was a dose–response associated with radiation. Patients treated with doses above 75 Gy had a more durable local control rate [20]. Although DVHs can be used to determine safe doses, these models have not been validated in all patient populations. Tolerance to radiation is based not only on the amount of liver being irradiated but also on the degree of underlying liver disease. Patients with hepatitis B as well as Child–Pugh class B disease have a significantly higher risk of RILD [22]. Given the high likelihood of disease recurrence outside the high dose volume, it is reasonable to combine radiation with treatments that address the remainder of the liver, such as TACE. TACE is a widely used nonsurgical treatment for HCC. It allows a large dose of chemotherapy to be delivered to the tumor via the hepatic artery after occluding the tumor’s vascular blood via the hepatic artery. Retrospective studies have suggested that TACE can be combined with radiation to improve local control rates [23–25]. Since most HCC tumors develop vascular shunting, it is not possible to occlude all the feeding vessels and this can limit the efficacy of TACE. In addition to combining radiation with local chemotherapy (TACE), it can also be combined with regional or systemic therapy. Regional chemotherapy can be delivered via hepatic artery infusion of chemotherapy. Conformal radiation (1.5 Gy twice daily to a maximum of 90 Gy) delivered with hepatic arterial fluorodeoxyuridine for advanced unresectable hepatobiliary carcinoma produced good results with a median survival of 11 months and 1-year survival rate of 47% [26]. Phase I/II studies have been completed using SBRT for HCCs, cholangiocarcinomas, and liver metastases, demonstrating the feasibility, safety, and efficacy of this approach [27]. In a more recent phase I study, researchers combined not only the advances in radiation techniques to deliver conformal doses to the target, but prescribed doses dependent on the volume of liver irradiated as well as the estimated risk of liver toxicity based on a normal tissue complication model. These approaches will need to be studied in larger trials before being adopted in routine clinical care [28]. If detected early, HCC can be treated with curative surgery or transplantation. If curative surgical options are not available due to the size and/or location of the tumor, ablative treatment options using radiation should be considered. Radiation alone using 3D conformal techniques or hypofractionated stereotactic body radiosurgery will allow curative doses to be delivered to precise target volumes while sparing surrounding normal tissue. Future directions include the use of proton beam or carbon ion beam radiation therapy, which may be able to offer curative options to nonsurgical patients. Combining radiation with TACE, regional or systemic chemotherapy can improve on the results of radiation alone.

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Colorectal cancer metastatic to the liver At present surgery is the only potentially curative treatment option for patients with liver metastases from colorectal cancer. Improved surgical techniques and better systemic treatments have resulted in prolonged disease-free survival with 5-year rates varying from 21% to 48%. For patients who are not candidates for surgery based on the tumor size, location or comorbidities, a number of local ablative techniques are available (see Chapter 17). Patients who present with a single liver metastasis from cancers of the colon or rectum should first be considered for surgery. If surgery is not an option, systemic chemotherapy is the next best tool in the treatment of unresectable metastatic disease. Following chemotherapy, resection can be reconsidered. The role of hepatic artery infusion alone or in combination with systemic chemotherapy remains an option in centers that have experience with this treatment option. Finally, if the patient is not a candidate for palliative non-cross resistant chemotherapy options, local treatment options such as RFA or conformal highdose radiation therapy may be considered. The principles described above, including 3D and 4D conformal techniques, as well as hypofractionated high dose irradiation using stereotactic body radiosurgery, are currently being investigated.

Conclusion Surgical resection remains the optimal treatment strategy for hepatic malignancies; however, the large majority of patients are not candidates for resection. As a result, a variety of liver-directed strategies have been developed. The choice of treatment depends on the tumor type, size, and number of lesions, anatomic location of the tumor and its proximity to large vessels, as well as the patient’s liver function and other comorbidities. High dose conformal radiation therapy can be used safely to treat liver tumors, including both primary HCCs as well as colorectal cancers that have metastasized to the liver. Careful treatment planning allows for local tumor control while maintaining normal liver function in the majority of patients. Careful patient selection is key to the safe use of these techniques as the risk of potentially life-threatening radiation-induced side effects increases with larger tumor size, which results in higher volumes of normal liver irradiation. The baseline liver function also determines how much liver can be safely irradiated. The management of liver tumors now requires a multidisciplinary approach so that each patient is selected for the most appropriate treatment modality or combination of modalities.

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Self-assessment questions 7

1 At standard fractionation of 200 cGy per day, the whole liver can tolerate: A 3000 cGy B 4000 cGy C 5000 cGy D 6000 cGy 2 Patients with colorectal cancer metastatic to the liver have a higher tolerance to radiation than patients with primary tumors of the liver. True or false? 3 Patients who present with single liver metastases from colorectal cancers should first be considered for radiation therapy. True or false? 4 Liver tolerance is a function of which one of the following: A Volume of liver treated B Total dose of radiation delivered C Patient’s baseline liver function D Use of concurrent chemotherapy E All of the above 5 In treating liver tumors the planning target volume needs to include which one of the following: A Gross tumor volume B Clinical target volume (tumor with surrounding microscopic disease) C Internal target volume (tumor with superior–inferior excursion due to respiration D All of the above

References 1 Hawkins MA, Dawson LA. Radiation therapy for hepatocellular carcinoma: from palliation to cure. Cancer 2006;106:1653–63. 2 Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693–9. 3 ICRU. Prescribing, Recording, and Reporting Photon Beam Therapy. (Suppl. to ICRU report 50), Bethesda, MD: The International Commission on Radiation Units and Measurements, 1999. 4 Beddar AS, Kristofer K, Tina Marie B, et al. Correlation between internal fiducial tumor motion and external marker motion for liver tumors imaged with 4D-CT. Int J Radiat Oncol Biol Phys 2007;67:630–8. 5 Edward DB, Andrew W, Hungcheng C, et al. Abdominal organ motion measured using 4D CT. Int J Radiat Oncol Biol Phys 2006;65:554–60. 6 David PG, Johanna B, Gregory CS, et al. The correlation between internal and external markers for abdominal tumors: Implica-

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tions for respiratory gating. Int J Radiat Oncol Biol Phys 2005; 61:1551–8. James MB, Laura AD, Sahira K, et al. Determination of ventilatory liver movement via radiographic evaluation of diaphragm position. Int J Radiat Oncol Biol Phys 2001;51:267–270. Dawson LA, Eccles C, Bissonnette JP, et al. Accuracy of daily image guidance for hypofractionated liver radiotherapy with active breathing control. Int J Radiat Oncol Biol Phys 2005; 62:1247–52. Eccles C, Brock KK, Bissonnette JP, et al. Reproducibility of liver position using active breathing coordinator for liver cancer radiotherapy. Int J Radiat Oncol Biol Phys 2006;64:751–9. Wagman R, Yorke E, Ford E, et al. Respiratory gating for liver tumors: use in dose escalation. Int J Radiat Oncol Biol Phys 2003;55:659–68. Taguchi H, Sakuhara Y, Hige S, et al. Intercepting radiotherapy using a real-time tumor-tracking radiotherapy system for highly selected patients with hepatocellular carcinoma unresectable with other modalities. Int J Radiat Oncol Biol Phys 2007; 69:376–80. Chiba T, Tokuuye K, Matsuzaki Y, et al. Proton beam therapy for hepatocellular carcinoma: a retrospective review of 162 patients. Clin Cancer Res 2005;11:3799–805. Bush DA, Hillebrand DJ, Slater JM, et al. High-dose proton beam radiotherapy of hepatocellular carcinoma: preliminary results of a phase II trial. Gastroenterology 2004;127:S189–93. Kawashima M, Furuse J, Nishio T, et al. Phase II study of radiotherapy employing proton beam for hepatocellular carcinoma. J Clin Oncol 2005;23:1839–46. Kato H, Tsujii H, Miyamoto T, et al. Results of the first prospective study of carbon ion radiotherapy for hepatocellular carcinoma with liver cirrhosis. Int J Radiat Oncol Biol Phys 2004; 59:1468–76. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745–50. Stillwagon GB, Order SE, Guse C, et al. Prognostic factors in unresectable hepatocellular cancer: Radiation Therapy Oncology Group Study 83-01. Int J Radiat Oncol Biol Phys 1991;20:65– 71. Lawrence TS, Robertson JM, Anscher MS, et al. Hepatic toxicity resulting from cancer treatment. Int J Radiat Oncol Biol Phys 1995;31:1237–48. Dawson LA, Normolle D, Balter JM, et al. Analysis of radiationinduced liver disease using the Lyman NTCP model. Int J Radiat Oncol Biol Phys 2002;53:810–21. Ben-Josef E, Normolle D, Ensminger WD, et al. Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies. J Clin Oncol 2005;23:8739–8747. Robertson JM, Lawrence TS, Dworzanin LM, et al. Treatment of primary hepatobiliary cancers with conformal radiation therapy and regional chemotherapy. J Clin Oncol 1993;11:1286–93. Kim JH, Park JW, Kim TH, et al. Hepatitis B virus reactivation after three-dimensional conformal radiotherapy in patients with hepatitis B virus-related hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2007;69:813–9. Seong J, Keum KC, Han KH, et al. Combined transcatheter arterial chemoembolization and local radiotherapy of unresectable

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hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 1999; 43:393–7. Guo WJ, Yu EX, Liu LM, et al. Comparison between chemoembolization combined with radiotherapy and chemoembolization alone for large hepatocellular carcinoma. World J Gastroenterol 2003;9:1697–701. Cheng JC, Chuang VP, Cheng SH, et al. Local radiotherapy with or without transcatheter arterial chemoembolization for patients with unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2000;47:435–42. Dawson LA, McGinn CJ, Normolle D, et al. Escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies. J Clin Oncol 2000; 18:2210–8. Herfarth KK, Debus J, Lohr F, et al. Stereotactic single-dose radiation therapy of liver tumors: results of a phase I/II trial. J Clin Oncol 2001;19:164–70.

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28 Tse RV, Hawkins M, Lockwood G, et al. Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol 2008;26:657–64.

Self-assessment answers 1 A 2 True 3 False (patients who present with single liver metastases should be considered first for surgery) 4 E 5 D

12

Internal Radiation Therapy for Liver Tumors Ahsun Riaz1, Laura Kulik2, Michael Abecassis3, and Riad Salem4 1 Department of Radiology, Section of Interventional Radiology, Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA 2 Division of Hepatology, Department of Medicine, Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA 3 Division of Organ Transplantation, Northwestern University, Chicago, IL, USA 4 Department of Radiology, Section of Interventional Radiology, Robert H Lurie Comprehensive Cancer Center, and Division of Organ Transplantation, Northwestern University, Chicago, IL, USA

Introduction Interventional oncology is a field that has established its role in the management of liver tumors. The minimization of systemic toxicity and a favorable outcome make it a very promising approach. This chapter provides an overview of the general concepts associated with internal radiation and its specific use in various primary and secondary malignancies of the liver.

Vascular anatomy of the liver and its tumors The parenchyma of the liver is predominantly supplied by the portal vein. This unique vascularization allows for the hepatocytes to carry out their metabolic functions on the numerous substances absorbed from the gastrointestinal tract. It also makes the liver a common organ for malignancies to metastasize to. The proper hepatic artery supplying the liver is a continuation of the common hepatic artery, which itself is a branch of the celiac trunk. The proper hepatic artery branches into the right and left hepatic arteries, which supply the corresponding lobes of the liver. The cystic artery supplying the gallbladder usually arises from the right hepatic artery. The right and left hepatic arteries give rise to the segmental branches. These eventually branch into the small vessels found in the portal triads. The hepatic tumors are predominantly supplied by the branches of the hepatic artery. They are hypervascular structures predominantly supplied by the arteries of the organ

they are parasitizing. It should be kept in mind that the vasculature to malignant tumors often arises from the hepatic artery as well as from parasitization from extrahepatic sites. Hepatic tumors in one segment of the liver may become vascularized from vessels of adjacent segments or adjacent structures.

History of internal radiation Internal radiation using yttrium-90 was first performed in the 1960s but its use has increased in the past 10 years. The use of external radiation for liver tumors traditionally has had limited value due to the sensitivity of the normal parenchyma to the tumoricidal radiation dose [1, 2]. A dose greater than 35 Gy has led to the development of a syndrome consisting of ascites, hepatomegaly, and elevation of liver enzymes. Thus, internal radiation is a mode of providing localized radiotherapy to the tumor. A dose of up to 150 Gy can be administered without the complications of external radiation. The use of the hepatic arterial system to approach the tumor and then inject the microspheres containing the radioactive substance ensures maximum delivery of the dose to the tumor and minimum toxicity to the normal parenchyma of the liver. Internal radiation has been shown to have promising outcomes in primary and secondary hepatic malignancies by numerous investigators. The use of yttrium90 (90Y), as well as other radionuclides, will be discussed in detail. 90Y is available worldwide clinically and its use in the management of liver tumors has been increasing in the past decade. The radionuclides are summarized in Table 12.1.

Yttrium-90 microspheres Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

The radioactive element most commonly in use for internal radiation is 90Y. It is a pure beta emitter. 90Y has a half-life

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Table 12.1 Radionuclides for internal radiation.

Radionuclide Half-life (hours) Maximum beta emission (MeV) Maximum gamma emission (keV) Material Size of particle (μm) Embolic effect

TheraSphere®

SIR-Spheres®

131

188

Re HDDLipiodol

32

Milican

166

Yttrium-90 64.2 2.28

Yttrium-90 64.2 2.28

Iodine-131 192.5 0.606

Rhenium-188 16.9 2.1

Phosphorus-32 342.7 1.7

Holmium-166 26.8 1.77

Holmium-166 26.8 1.77

0

0

364

155

0

80.6

80.6

Glass microsphere 20–30 Mild

Resin microsphere 20–60 Moderate

Iodized oil NA High

Iodized oil NA High

Glass microsphere 46–76 Moderate

Chitosan NA High

Poly(L-lactic Acid) 25–35 Mild

I-Lipiodol

P-GMS

HoMS

NA, not applicable.

of 64.2 h. It decays into the stable element zirconium-90. The range of tissue penetration of the emissions is 2.5–11 mm.

Pretreatment evaluation The diagnosis of the hepatic tumors is discussed in Section 2. The laboratory work-up is important to assess the pretreatment functional status of the liver. The clinical evaluation is required to stratify the patients according to the Eastern Cooperative Oncology Group (ECOG) performance status. Patients with an ECOG performance status of greater than 2 are not considered ideal candidates for this treatment. The administration of internal radiation is a complex process. Diagnostic mesenteric angiography is necessary to ensure that complications are minimized. The aortogram, superior mesenteric angiogram, and celiac trunk angiogram allow the interventional radiologist the opportunity to study the vascular anatomy of the liver in detail. The patency of the portal vein and the presence of arterioportal shunting are assessed. The inadvertent spread of the microspheres is prevented by a meticulous study of the vascular anatomy of the liver and collateral nontarget flow [3]. Coil embolization of nontarget vessels may be necessitated to decrease the unintended deposition of microspheres. Some examples of vessels that may need to be embolized are the inferior esophageal, left inferior phrenic, accessory left gastric, supraduodenal, and retroduodenal arteries. The virtual lack of complications of coil embolization and the grave clinical consequences associated with the inadvertent deposition of microspheres in the stomach, duodenum, or pancreas favor prophylactic coil embolization before radioembolization in select cases. Technetium-99-labeled macroaggregated albumin (99TcMAA) is used to assess splanchnic shunting and pulmonary shunting. This pretreatment nuclear scan is important to prevent complications associated with treatment. The prox-

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imity of the duodenum and stomach to the liver may make it difficult to assess shunting to these portions of the gastrointestinal tract by using nuclear medicine scans alone. Thus, it is important to correlate the findings of angiography to the findings of the 99Tc-MAA scan. The lung shunt fraction (LSF) is used to calculate the dose delivered to the lungs, and adjustment for this parameter minimizes the risk of radiation pneumonitis that may be seen after radioembolization. All the hepatic vessels are assessed during the angiogram and the arteries feeding the tumor are studied in detail. As the tumor may parasitize blood flow from surrounding vessels, it is necessary to study its vascular supply in detail. Failure to recognize a vessel supplying the tumor may lead to the incomplete targeting of the lesion and failure of treatment. There are two forms available. TheraSphere® (MDS Nordion, Ottawa, Canada) consists of glass microspheres that are nonbiodegradable and have a diameter between 20 and 30 μm. It was approved by the FDA in 1999 and recently has been approved for use in hepatocellular carcinoma (HCC) patients with portal vein thrombosis (PVT). Vials of six different activities are available. The only difference in the vials is the number of spheres: 1.2 million microspheres are present in a vial with an activity of 3 GBq, and. each microsphere has an activity of 2500 Bq at the time of calibration. The activity of the vial varies inversely with the time elapsed after calibration. SIR-Spheres consist of resin microspheres that are biodegradable. The spheres have slightly increased diameter and lower specific gravity per microsphere than TheraSphere®. The use of SIR-Spheres was approved by the FDA for metastatic colorectal cancer to the liver in 2002. The use of internal radiation using 90Y-microspheres is also known as transcatheter radioembolization. It is necessary to point out here that the embolic effect of the microscopic

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spheres is minimal. The small size allows deep penetration into the tumor and theoretically increased efficacy.

Dose calculation for TheraSphere® The calculation of the dose requires the use of 3D reconstruction of the target site to calculate the volume of the liver to be infused. The volume in cubic centimeters is then used to calculate the mass in grams by multiplying it by a factor of 1.03. The activity (A) in gigaBecquerels (GBq) administered to the target area of the liver, assuming uniform distribution of microspheres, is calculated using the following formula: A = D × m 50 where D is the dose administered in Gray (Gy) and m is the mass in kilograms (kg). Using this formula, it can be said that a dose of 50 Gy will be administered to 1 kg of tissue, if 1 GBq of 90Y is given. The dose given to the treated mass also depends on the percentage residual activity (R) in the vial after treatment and the LSF which is calculated beforehand. These factors are accounted for in the following formula: D = A × 50 × (1 − LSF ) × (1 − R ) m

Dose calculation for SIR-Spheres® The most commonly used model of dosimetry for SIRSpheres® is based on whole liver infusion. The calculated GBq of the whole liver is multiplied by the percentage of the target site as a proportion of the whole liver. The formula for dosimetry of SIR-Spheres® is as follows: A = BSA − 0.2 + (% tumor burden 100 ) where A is the activity in gigaBecquerels, BSA is the body surface area in meters squared (m2), and % tumor burden is the percentage of the liver that is involved by tumor.

Transcatheter

90

Y radioembolization

The technical details associated with the actual procedure are beyond the scope of this chapter. It is a transcatheter therapy performed by interventional radiologists. The tumor is approached using its arterial supply and the vial is injected into the vessel feeding the tumor. The distribution of the tumor is the factor that allows the treatment to be selective i.e. to one lobe, or super-selective, i.e. to one segment. The apparatus for the administration of 90Y is designed to minimize the radiation exposure to the persons involved in the procedure. A physicist is present throughout the case to ensure that proper protocols are followed to minimize accidental radiation exposure. The procedure is performed on an outpatient basis and the patient is discharged on the same day [4].

Internal Radiation Therapy for Liver Tumors

Post-treatment assessment The response to treatment can be monitored clinically and radiologically. The regular follow-up laboratory work-up includes the hepatic panel and tumor markers, such as alphafetoprotein (AFP) in the case of HCC, to look for any toxicity due to treatment or clinical improvement in the patient. The first radiologic study is done 1 month after treatment to assess response or lack thereof. The patients are then followed with scans every 3 months to assess response to treatment or progression of disease. The use of the World Health Organization (WHO) size criteria and the European Association for the Study of the Liver (EASL) necrosis criteria are used to assess response in the target lesions [5]. The conventional anatomic imaging studies are not able to assess tumor response until 6 weeks have elapsed after treatment. The use of functional magnetic resonance imaging (MRI) may have a role in earlier detection of tumor response [6].

Other radionuclides Iodine-131 labeled iodized oil (lipiodol) Lipiodol is a poppy seed oil containing 38% iodine by weight. Lipiodol is concentrated in the tumor and is retained for weeks while normal hepatocytes are able to remove it in 7 days. There is stasis associated with lipiodol and hence there is an embolic effect associated with this conjugate. It is a radio-opaque substance and is visualized on posttreatment computed tomography (CT) scans in the target lesion. The use of 131I-lipiodol has been studied in a prospective trial and compared in efficacy to chemoembolization [7]. This radionuclide is a beta and gamma emitter. The iodine moiety of lipiodol can be substituted for the radionuclide 131I. It has a half-life of 8 days. Angiography is performed and 131I-lipiodol is administered after studying the vascular anatomy of the liver. The dose is usually given via a 3 mL injection in the main hepatic artery if the vascular anatomy is found to be normal. Extreme caution has to be taken during administration as dissolution of the plastic catheters has been noted. The thyroid gland, due to its use of iodine to synthesize thyroid hormones, is susceptible to the toxicity of 131I and is blocked before and after the treatment to minimize this. The radionuclide is excreted in urine and thus the patient has to be hospitalized for 6 days after treatment as a radioactivity safety measure. Patients are told to refrain from possible conception until 6 months after treatment. The outcomes of 131I-lipiodol are comparable to those of transarterial chemoembolization (TACE), but there is a significant decreased incidence of serious adverse effects with the use of this radionuclide as compared to using TACE. The hospitalization required after the procedure decreases its cost-effectiveness [7].

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Rhenium-188 HDD-labeled iodized oil Transarterial radionuclide therapy (TART) with rhenium188 (188Re) 4-hexadecyl-1, 2, 9, 9-tetramethyl-4, 7-diaza-1, 10-decanethiol (HDD)-labeled iodized oil has been recently studied for use in inoperable HCC. 188Re has a shorter halflife (16.9 h), and high beta energy (maximum: 2.1 MeV) and low gamma energy (155 keV) emissions, and is available through a tungsten-188 (188W–188Re) generator [8]. The iodized oil, i.e. lipiodol, is discussed above. The quantity of 188Re HDD iodized oil (lipiodol) administered is based on the radiation absorbed dose (RAD) to critical organs, which is calculated after administration of a test dose of the radioconjugate, transarterially [8]. The critical organs include the bone marrow, lung, and the normal liver, and the dose limitations to them are 1.5 Gy, 12 Gy, and 30 Gy respectively. A scout dose of 185 MBq activity of the radioconjugate is injected and a whole body nuclear scan is performed to calculate the RAD to the critical organs. The dose is then calculated and administered on the same day. The incidence of serious adverse events is low. A survival benefit in HCC patients has been reported [8]. Its easy availability and published data make it appear a promising mode of treatment of HCC. However, at the time of writing, there is insufficient data to recommend the use of this radionuclide in metastatic disease to the liver.

Phosphorus-32 glass microspheres Phosphorus-32 (32P) is a radioisotope which emits high energy beta particles during decay. It has a half-life of 14.28 days and a maximum tissue penetration of 8 mm with an average of 3.2 mm [9]. It is administered as an integral constituent of nonbiodegradable glass microspheres (GMS). The dose is calculated using the following formula based on the pharmacokinetics and distribution of 32P-GMS:

[10]. Chitosan is a unique substance derived from chitin. It has the ability to liquefy in an acidic environment and form a gel in basic environments. The gel has embolic effects. The use of holmium-165 poly (L-lactic acid) microspheres has been shown to be safe in animal models. Its use in humans has not been studied as of yet.

Complications of internal radiation Postembolization syndrome Patients may experience a mild postembolic syndrome which consists of the following clinical complications after radioembolization: fatigue, nausea, vomiting, anorexia, fever, abdominal discomfort, and cachexia. These are usually not severe enough to require hospitalization. Some serious adverse events related to radioembolization are explained below.

Hepatobiliary toxicity Hepatic injury Radiation-induced liver disease usually occurs between 4 and 8 weeks after radioembolization. The hepatic toxicity is measured by a change in the liver enzymes and metabolites, i.e. alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, albumin, and bilirubin. Using these criteria to assess toxicity to the liver following radioembolization, the toxicity rates have been between 15% and 20% [11, 12]. The clinical appearance of ascites and jaundice may be seen. The histologic hallmark of venoocclusive disease may be seen in severe cases. The hepatic toxicity may be severe and lead to significant morbidity and mortality [11]. The presence of various factors, such as a deranged hepatic function at baseline, age, and activity delivered may predispose patients to the hepatotoxic effects of radioembolization.

D = 20 × A m

Biliary injury where D is the dose in Gray, A is the activity in gigaBecquerels, and m is the mass in kilograms. The administration is via a transarterial approach, after angiography has been performed to study the vascular anatomy of the liver. The half-life of this radionuclide gives it the advantage of a lower dose being required and a potential to have a decreased radiation to handlers as compared to the other available radionuclides. It has been shown to be tolerated well in animal and human trials. Its role in the management of liver tumors is yet to be established.

Milican/holmium-166 microspheres (HoMS) The use of holmium/chitosan complex (Milican, Dong Wha Pharmaceutical Co, Seoul, Korea) has been shown to be effective in treating small HCC in a novel study from Korea

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The biliary tract is also susceptible to toxicity by radioembolization. According to Atassi et al, less than 2% of patients required intervention for the biliary toxicity induced by radioembolization [6]. These included drainage of three bilomas, one abscess, and two cholecystectomies. Radiation-induced cholangitis has been reported following 90Y administration as well [6].

Portal hypertension Radioembolization has been shown to cause fibrosis that may lead to portal hypertension by changing volume of the treated lobe. The time for development of portal hypertension is variable [13]. It is more often associated with bi-lobar treatment and its incidence is increased in patients who have chemotherapy-associated steatohepatitis (CASH). The presence of pre-existing cirrhosis leading to portal hypertension

CHAPTER 12

in most HCC patients makes them more susceptible to the aggravation of this complication as well.

Radiation pneumonitis Caution has to be taken when the LSF is greater than 13% [14]. A restrictive pulmonary dysfunction is seen after radioembolization in a few cases with a predisposing high LSF if treated with resin microspheres. The LSF is used to calculate the dose that would be administered to the lung and an absolute contraindication to radioembolization is the predicted administration of a dose greater than or equal to 30 Gy to the lungs in a single treatment, or greater than 50 Gy as a cumulative dose after multiple treatments [15]. The presence of radiation pneumonitis can be diagnosed clinically and on finding consolidation on chest X-rays.

Gastrointestinal complications Gastrointestinal complications after radioembolization have been reported. The inadvertent spread of microspheres to the gastrointestinal tract is responsible for complications such as ulceration [16, 17]. This complication is severe and may require surgery for treatment. It can be prevented by meticulous mapping of the blood vessels to look for aberrant vasculature arising from branches of the hepatic artery which supply the gastrointestinal tract. The prophylactic use of proton pump inhibitors is recommended.

Vascular injury Transcatheter 90Y radioembolization is an invasive procedure. The incidence of vascular injury is very low and mostly has been seen in patients who were already on systemic chemotherapy [18]. This might cause a weakening of the vessel wall leading to a susceptibility to injury. The adverse events present after radioembolization occur rarely and are manageable. Their occurrence can be minimized by careful assessment of angiographic findings before treatment.

Role of radioembolization in the management of primary liver tumors The use of radioembolization has been extensively studied for the treatment of the most common primary malignant tumor, i.e. hepatocellular carcinoma (HCC). Its use in the management of cholangiocarcinoma has also been studied and will be discussed briefly.

Hepatocellular carcinoma Patient selection Chapter 5 discusses the various diagnostic criteria for HCC and the staging systems available for this cancer. The management of HCC is now a multidisciplinary task with the

Internal Radiation Therapy for Liver Tumors

involvement of hepatologists, oncologists, transplant surgeons, and interventional radiologists. Patients should be selected for radioembolization after a consensus of the team. As discussed below, the role of radioembolization is not limited by the stage of the disease. Patients with distant metastases are the only ones who have not been shown to have a survival benefit after treatment.

Indications and efficacy Patients within transplant criteria The patients within Milan criteria, i.e. single lesion less than 5 cm or less than or equal to three lesions all less than 3 cm, are eligible for transplantation. Resection is possible if liver cirrhosis is well-compensated. The use of surgical options is the gold standard of treatment for these patients. The limited availability of donor organs for orthotopic liver transplantation (OLT) and the drop out of patients due to tumor progression limits the number of patients who initially were within transplant criteria and are able to undergo OLT. Ablation has a limited role due to the risk of tract seeding in these patients. The use of radioembolization has been shown to limit progression of the disease. This allows the patient more time to wait for donor organs [19] and thus increases their chance of undergoing OLT. Thus, it has a role of bridging the patient to OLT.

Patients beyond transplant criteria The patients who are outside transplant criteria but do not have malignant PVT or metastatic HCC are also candidates for radioembolization. The use of radioembolization in these patients has been shown to downstage the disease to within transplant criteria. This use allows the patients who were initially outside Milan criteria to be eligible for transplant. There is an increase in overall survival in these patients as well [19]. The recurrence-free survival and overall survival after OLT in downstaged patients is yet to be compared to those of patients who were already within transplant criteria to determine the efficacy of downstaging. Patients with advanced disease Patients with PVT have been shown to have a good response to treatment after radioembolization [20]. The presence of malignant PVT excludes these patients from the transplant criteria, whereas its presence is not a contraindication to internal radiation with 90Y. Systemic therapy with sorafenib has been shown to give a significant improvement in survival in patients with advanced disease [21]. Embolic forms of treatment are relatively contraindicated in patients with malignant PVT as this may lead to compromise of the vascular supply of normal hepatic parenchyma. 90Y can be used in these cases due to its minimal embolic effect [20]. A survival benefit (10.1–13.4 months from treatment) has been shown with the use of radioembolization in patients with malignant vascular involvement [20]. The presence of

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distant metastases, i.e. lung and adrenals, is a contraindication to this treatment, as a survival benefit has not been shown for this subset of patients. Internal radiation for the treatment of HCC has been shown to be a safe and effective method. The response rate and improvement in survival have established its role in many centers around the world for the management of HCC.

Intrahepatic cholangiocarcinoma The basics of cholangiocarcinoma are discussed in Chapter 6. Resection is an option in patients who have resectable disease and has been shown to modestly improve survival. The use of TACE for cholangiocarcinoma has been studied and an improvement in survival has been shown, but the rate of toxicity remains high. The use of internal radiation has been shown to be effective in the treatment of HCC but its role in the management of intrahepatic cholangiocarcinoma (ICC) has not been extensively studied. A pilot study analyzing the use of 90Y in 24 patients with biopsy-proven ICC has shown a favorable response to treatment and favorable survival outcomes [22]. Patients with a better performance status according to the ECOG had a significantly improved survival in this study.

Role of radioembolization in the management of secondary liver tumors Metastatic disease to the liver is common due to its unique anatomy. The presence of multiple metastasis and comorbidities limits the role of surgical resection in these patients [23]. The use of internal radiation alone and as a conjunct to systemic chemotherapy has been well published.

Metastatic colorectal carcinoma Resection is the only curative option available for colorectal cancer that has metastasized to the liver. Less than 10% have disease that is resectable [23]. Systemic chemotherapy for this disease is beyond the scope of this chapter but some commonly used chemotherapeutic agents are fluorouracil (5-FU), oxaliplatin, irinotecan (CPT-11), bevacizumab, cetuximab, and capecitabine. The favorable role of internal radiation in the treatment of metastatic colorectal carcinoma to the liver has been published.

Patient selection The selection of patients for internal radiation with metastatic disease to the colon is very similar to that of HCC. Patients who have unresectable disease and are on systemic chemotherapy or have failed to respond to first- or secondline chemotherapeutic agents are considered as candidates for internal radiation. The value of carcinoembryonic agent (CEA) is measured and radiologic studies are performed

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before and after treatment to assess response to treatment. Fluoro-deoxyglucose positron emission tomography (FDGPET) has been shown to have better sensitivity in assessing tumor response to internal radiation for treatment of metastatic colorectal carcinoma than CT.

Efficacy of internal radiation The effect of systemic chemotherapy alone has been compared to its combined effect with internal radiation. The combination in a randomized control trial has been shown to have a significantly better tumor response, a longer time to progression, survival benefit, and an acceptable safety profile [24]. The use of internal radiation alone has also been published in many series and has shown promising results [25]. Dose escalation studies have shown a better response with increasing doses [26].

Metastatic neuroendocrine tumors Metastatic disease to the liver from a neuroendocrine tumor is common. The production of hormones leads to a variety of symptoms. Carcinoid, VIPomas, gastrinomas, and somatostatinomas are some examples. Systemic chemotherapy and ablative procedures have been shown to have a modest benefit in these patients. Patients with unresectable disease are candidates for internal radiation. Clinical improvement, chromogranin A, and imaging studies before and after treatment are used to assess response to internal radiation. Radioembolization of metastatic disease to the liver from a neuroendocrine neoplasia has been shown to be effective and safe. A prolonged response to treatment, i.e. greater than 2 years, has also been seen [27, 28].

Metastatic mixed neoplasia The presence of hepatic metastases from primary neoplasia other than the ones listed above will be discussed under the heading of mixed neoplasia. The following secondary tumors have been treated using internal radiation but only metastatic breast cancer has been studied in detail.

Internal radiation to metastatic breast cancer to liver Breast cancer is the most common cancer in women. It has a tendency to metastasize to the liver. Internal radiation is an efficacious treatment for unresectable breast cancer metastasis to the liver [29]. There is a significant radiologic response after internal radiation, but the survival benefit of this treatment in these patients has not been established [30].

Other secondary liver tumors Internal radiation has been used to treat secondary liver tumors from various primary sources. This mode of treatment is an effective alternative for patients who have failed

CHAPTER 12

chemotherapy or have become chemorefractory [31]. The data suggest a similar benefit in survival and tumor response in metastatic liver tumors from the mixed neoplasia.

Conclusion Internal radiation represents an innovative treatment approach that has gained increased awareness and clinical use during the past 15 years. The minimal toxicity and the ability to discharge the patient on an outpatient basis make the therapy an attractive alternative in the treatment of primary and metastatic liver malignancies. Patients are able to resume normal activities shortly following treatment with minimal side effects. Treatment planning requires certain steps including: (1) calculation of target liver mass to be infused and tumor burden; (2) visceral angiography to map out tumor-perfusing vessels and embolize collaterals; (3) assessment of pulmonary shunt; (4) determination of the optimal therapeutic dose; (5) room preparation; (6) radiation monitoring and safety procedures; and (7) calculation of residual activity and efficiency of radiation delivery. Careful patient selection and preparation for internal radiation will result in an optimal risk-to-benefit ratio for the patient. For patients presenting with HCC, the treatment of advancing disease must be balanced against the oftencompromised functional liver reserve due to underlying cirrhosis. Selection of patients with adequate hepatic reserve and good functional status will maximize the beneficial therapeutic effect of this therapy with minimal risk to normal liver parenchyma. This treatment has also been shown to be beneficial for patients presenting with metastatic disease who have intrahepatic progression despite standard of care chemotherapy. The clinical benefit and potential for enhancing patients’ quality of life associated with radioembolization represents an exciting opportunity for all disciplines involved in the management of liver tumors, including hepatobiliary, surgical, radiation, and interventional oncology.

Self-assessment questions

1 A 60-year-old obese male presents with persistent right upper quadrant pain but without jaundice and requires hospitalization, 2 weeks after internal radiation with 90Y to a right lobe tumor necessitating whole right lobe infusion. Which one of the following is the most probable cause of this symptom? A Acute calculous cholecystitis B Costochondritis C Ascending cholangitis D Radiation induced cholecystitis E Pneumonia

Internal Radiation Therapy for Liver Tumors

2 The most important use of the 99Tc-MAA scan before internal radiation is in the prevention of: A Radiation-induced hepatitis B Radiation-induced cholecystitis C Radiation pneumonitis D Radiation-induced gastrointestinal ulcers E Radiation-induced lymphopenia 3 Internal radiation does not usually lead to opportunistic infections because it never causes lymphopenia. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 4 Which of the following could most probably supply a tumor in segment 4a of the liver? (more than one answer is possible) A Left hepatic artery B Right hepatic artery C Splenic artery D Cystic artery E Portal vein 5 A gamma probe has the ability to detect which of the following radionuclides? A Yttrium-90 B Iodine-131 C Phosphorus-32 D Rhenium-188 E Holmium-166

References 1 Ingold JA, Reed GB, Kaplan HS, Bagshaw MA. Radiation hepatitis. Am J Roentgenol Radium Ther Nucl Med 1965;93:200–8. 2 Geschwind JF, Salem R, Carr BI, et al. Yttrium-90 microspheres for the treatment of hepatocellular carcinoma. Gastroenterology 2004;127 (5 Suppl 1):S194–S205. 3 Covey AM, Brody LA, Maluccio MA, Getrajdman GI, Brown KT. Variant hepatic arterial anatomy revisited: digital subtraction angiography performed in 600 patients. Radiology 2002;224: 542–7. 4 Salem R, Thurston KG, Carr BI, Goin JE, Geschwind JF. Yttrium90 microspheres: radiation therapy for unresectable liver cancer. J Vasc Interv Radiol 2002;13 (9 Suppl):S223–9. 5 Ibrahim SM, Nikolaidis P, Miller FH, et al. Radiologic findings following Y90 radioembolization for primary liver malignancies. Abdom Imaging 2009;34: 566–81. 6 Rhee TK, Naik NK, Deng J, et al. Tumor response after yttrium90 radioembolization for hepatocellular carcinoma: comparison

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7

8

9

10

11

12

13

14

15 16

17

18

19

20

Systemic and Regional Therapies

of diffusion-weighted functional MR imaging with anatomic MR imaging. J Vasc Interv Radiol 2008;19:1180–6. Raoul JL, Guyader D, Bretagne JF, et al. Prospective randomized trial of chemoembolization versus intra-arterial injection of 131I-labeled-iodized oil in the treatment of hepatocellular carcinoma. Hepatology 1997;26:1156–61. Kumar A, Srivastava DN, Chau TT, et al. Inoperable hepatocellular carcinoma: transarterial 188Re HDD-labeled iodized oil for treatment – prospective multicenter clinical trial. Radiology 2007;243:509–19. Wong JY, Somlo G, Odom-Maryon T, et al. Initial clinical experience evaluating yttrium-90-chimeric T84.66 anticarcinoembryonic antigen antibody and autologous hematopoietic stem cell support in patients with carcinoembryonic antigen-producing metastatic breast cancer. Clin Cancer Res 1999;5 (10 Suppl): 3224s–31s. Kim JK, Han KH, Lee JT, et al. Long-term clinical outcome of phase IIb clinical trial of percutaneous injection with holmium166/chitosan complex (Milican) for the treatment of small hepatocellular carcinoma. Clin Cancer Res 2006;12:543–8. Sangro B, Gil-Alzugaray B, Rodriguez J, et al. Liver disease induced by radioembolization of liver tumors: description and possible risk factors. Cancer 2008;112:1538–46. Young JY, Rhee TK, Atassi B, et al. Radiation dose limits and liver toxicities resulting from multiple yttrium-90 radioembolization treatments for hepatocellular carcinoma. J Vasc Interv Radiol 2007;18:1375–82. Jakobs TF, Saleem S, Atassi B, et al. Fibrosis, portal hypertension, and hepatic volume changes induced by intra-arterial radiotherapy with (90)yttrium microspheres. Dig Dis Sci 2008;53: 2556–63. Leung TW, Lau WY, Ho SK, et al. Radiation pneumonitis after selective internal radiation treatment with intraarterial 90yttrium-microspheres for inoperable hepatic tumors. Int J Radiat Oncol Biol Phys 1995;33:919–24. TheraSphere Yttrium-90 microspheres package insert. Kanata: MDS Nordion, 2004. Murthy R, Brown DB, Salem R, et al. Gastrointestinal complications associated with hepatic arterial Yttrium-90 microsphere therapy. J Vasc Interv Radiol 2007;18:553–61; quiz 62. Carretero C, Munoz-Navas M, Betes M, et al. Gastroduodenal injury after radioembolization of hepatic tumors. Am J Gastroenterol 2007;102:1216–20. Murthy R, Eng C, Krishnan S, et al. Hepatic yttrium-90 radioembolotherapy in metastatic colorectal cancer treated with cetuximab or bevacizumab. J Vasc Interv Radiol 2007;18:1588–91. Kulik LM, Atassi B, van Holsbeeck L, et al. Yttrium-90 microspheres (TheraSphere(R)) treatment of unresectable hepatocellular carcinoma: Downstaging to resection, RFA and bridge to transplantation. J Surg Oncol 2006;94:572–86. Kulik LM, Carr BI, Mulcahy MF, et al. Safety and efficacy of (90) Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology 2007;47:71–81.

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21 Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–90. 22 Ibrahim SM, Mulcahy MF, Lewandowski RJ, et al. Treatment of unresectable cholangiocarcinoma using yttrium-90 microspheres: results from a pilot study. Cancer 2008;113:2119–28. 23 Welsh JS, Kennedy AS, Thomadsen B. Selective internal radiation therapy (SIRT) for liver metastases secondary to colorectal adenocarcinoma. Int J Radiat Oncol Biol Phys 2006;66 (2 Suppl): S62–73. 24 Gray B, Van Hazel G, Hope M, et al. Randomised trial of SIRSpheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Ann Oncol 2001;12:1711–20. 25 Kennedy A, Coldwell D, Nutting C, Overton C, Sailer S. Liver brachytherapy for unresectable colorectal metastases: US results 2000–2004. ASCO 2005 Gastrointestinal Cancers Symposium, Miami, Florida, a145. 26 Goin JE, Dancey JE, Hermann GA, Sickles CJ, Roberts CA, MacDonald JS. Treatment of unresectable metastatic colorectal carcinoma to the liver with intrahepatic Y-90 microspheres: a dose-ranging study. World J Nucl Med 2003;2:216–25. 27 Rhee TK, Lewandowski RJ, Liu DM, et al. 90Y Radioembolization for metastatic neuroendocrine liver tumors: preliminary results from a multi-institutional experience. Ann Surg 2008;247:1029–35. 28 Kennedy AS, Dezarn WA, McNeillie P, et al. Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: early results in 148 patients. Am J Clin Oncol 2008;31:271–9. 29 Coldwell D, Nutting C, Kennedy AK. Treatment of hepatic metastases from breast cancer with Yttrium-90 SIR-Spheres radioembolization. Society of Interventional Radiology Annual Meeting, 2005 March 31-April 5. New Orleans, LA, 2005. 30 Jakobs TF, Hoffmann RT, Fischer T, et al. Radioembolization in patients with hepatic metastases from breast cancer. J Vasc Interv Radiol 2008;19:683–90. 31 Sato KT, Lewandowski RJ, Mulcahy MF, et al. Unresectable chemorefractory liver metastases: radioembolization with 90Y microspheres – safety, efficacy, and survival. Radiology 2008;247:507–15.

Self-assessment answers 1 2 3 4 5

D C B A, B B, D, E

13

Transarterial Embolization for Patients with Hepatocellular Carcinoma Jordi Bruix, Carmen Ayuso, and Maria I. Real Barcelona-Clinic-Liver-Cancer (BCLC) Group, Liver Unit and Radiology Department, Hospital Clínic, University of Barcelona, Centro de Investigaciones Biomédicas en Red, Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

Hepatocellular carcinoma (HCC) is a neoplasm whose progression is closely associated with neoangiogenic activity. At very early stages the tumor is not highly vascularized and receives its blood supply from both the portal vein and the hepatic artery. However, when the neoplasm grows into a more advanced stage (usually measuring >2 cm in diameter), the supply is mostly dependent on the hepatic artery This characteristic represents the anatomic basis for the radiologic characteristics that are used to diagnose the disease by imaging techniques, such as ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) with contrast [1]. Thereby, enhanced contrast uptake in the arterial phase followed by washout in the venous phase, as seen in any dynamic imaging technique, in a mass greater than 2 cm in a cirrhotic liver is considered diagnostic of HCC [1]. In addition to its use for diagnostic purposes, this specific arterial vascular profile provides the basis for the development of arterial obstruction as an effective therapy. Acute arterial obstruction results in ischemic tumor necrosis with a high rate of objective responses. However, despite this significant decrease in tumor load, the beneficial impact on patient survival has been highly controversial. In this chapter, we will review the potential role of transarterial embolization (TAE) in the management of patients with HCC, and the different techniques that can be applied to obstruct the arterial blood flow, and finally discuss the therapeutic efficacy and evidence supporting a beneficial impact on survival.

Therapeutic strategy in patients with hepatocellular carcinoma and role of transarterial chemoembolization The selection of the most appropriate therapeutic option depends not only on tumor burden, but also on liver function and general health of the patient. The Barcelona Clinic

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

Liver Cancer (BCLC) staging system takes into account all these factors, and establishes prognosis and guides the therapeutic approach [1] (Figure 13.1). Only patients diagnosed at an early stage are optimal candidates to receive potentially curative therapy, such as surgical resection, liver transplantation, or percutaneous ablation. The optimal candidates for these options are patients with solitary HCC of 5 cm or less, or with up to three nodules each of them less than 3 cm, without vascular invasion or extrahepatic spread, and 5-year survival after treatment ranging between 50% and 75% is expected in well-selected patients [1, 2]. However, despite the universal implementation of surveillance programs, 60–70% of the patients with HCC cannot benefit from curative treatment. If liver function and physical status are preserved, and the tumor has not invaded the portal vein or spread outside the liver, they can benefit from transarterial chemoembolization (TACE) [3–5]. Thus, this treatment is indicated in patients with intermediate tumor stage (stage B, BCLC), which includes small multifocal to large HCC. Its main contraindication is the absence of portal blood flow (because of vein thrombosis, portosystemic anastomoses, or hepatofugal flow) and, as mentioned above, it is not indicated in the presence of extrahepatic tumor spread or when the patient presents with end-stage liver disease (Child–Pugh class C) and/or clinical symptoms of terminal cancer stage [1, 6] (Figure 13.1). While surgical resection and percutaneous ablation may be applied without significant delay, it is well-known that there is a steadily increasing waiting time between listing for transplantation and the procedure itself. This may allow the tumor to progress and prompt the exclusion of patients from the waiting list and/or their death [7]. TACE is one of the treatment options that has been applied in this scenario and currently constitutes the most widely applied therapy in HCC patients waiting for liver transplantation. However, as we will comment below, there is no unequivocal evidence that this policy provides any benefit. It has also been proposed that effective chemoembolization could reduce tumor burden in patients who exceed the conventional Milano criteria for liver transplantation [8]. However, this approach is far from being clearly shown to be effective. No study has

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SECTION 3

HCC

Stage 0 Child A; PS 0

Stage D Okuda 3; Child C; PS > 2

Stage A–C Okuda 1–2; Child A–B; PS 0–2

Very early stage 0 Single < 2 cm carcinoma in situ

Early stage A Single or 3 nodules < 3 cm PS 0

Intermediate stage Multinodular; PS 0

Advanced stage C Portal invasion, N1, M1, PS 1–2

Terminal stage D

3 nodules ≤ 3 cm

Single

Portal pressure bilirubin

Increased

Normal

Associated diseases

No

Resection

Liver transplantation

Curative treatment (30%) 5-year survival: 50–70%

Yes

PEI/RF

Chemoembolization

Sorafenib

Randomized controlled trials (30%) 3-year survival: 20–40%

Symptomatic TTO (30%) 1-year survival: 10%

Figure 13.1 Strategy for staging and treatment assignment in patients diagnosed with hepatocellular carcinoma (HCC) according to the Barcelona Clinic Liver Cancer (BCLC) proposal. PEI, percutaneous ethanol injection; PS, performance status; RF, radiofrequency; TTO, time trade off. (Reproduced from Llovet et al, J Natl Cancer Inst 2008;100:698, with permission from Oxford University Press).

clearly defined how staging prior to therapy has been done and how staging is assessed after therapy. Indeed, it is common to combine TACE with radiofrequency and/or surgery, and in addition, the follow-up after therapy is usually short. Taking into account that tumor burden is a surrogate of tumor spread prior to therapy, the reduction in burden should not be expected to reduce the already acquired risk. It is assumed that tumors that can be downstaged reflect a better biology, but with the current data, this assumption cannot be proven. For patients with more advanced HCC, the sole option that has been shown to be effective is sorafenib [9]. This is a multikinase inhibitor that has antiproliferative and antiangiogenic effects that result in slower tumor progression rate and improved survival [9]. Hence, today all evolutionary stages of HCC have a treatment option with positive impact on survival (see also Chapter 26).

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Techniques to obstruct the hepatic artery blood flow The hepatic artery blood flow may be obstructed by surgical ligation or by injection of an obstructing agent in the vascular lumen. The first approach is clearly more invasive and it is solely performed when a hemoperitoneum due to ruptured HCC is discovered in the operating room. Hepatic artery ligation stops the bleeding but has a very high rate of postoperative mortality. Since the same hemostatic success might be achieved by TAE, this should be considered the optimal approach in patients with ruptured HCC [10]. The hepatic artery obstruction during angiography is known as transarterial, or transcatheter arterial, embolization (TAE). When TAE is combined with the earlier injection into the hepatic artery of chemotherapeutic agents, usually

CHAPTER 13

Transarterial Embolization for Patients with Hepatocellular Carcinoma

mixed with lipiodol, the procedure is known as transarterial chemoembolization (TACE). Chemotherapy has to be injected prior to arterial obstruction. With the aim of increasing the selective delivery of chemotherapy into the tumor, it is very common to suspend the antineoplastic agent into lipiodol, an oily contrast agent that was used in lymphographic studies. This contrast is selectively retained within the tumor and thus, it expands the exposure of the neoplastic cells to chemotherapy [11– 13] (Figure 13.2). The chemotherapy agent, mixed with

lipiodol, has to be injected selectively into the tumoral arteries. Once the chemotherapy has been delivered, an occlusive agent is released to obstruct the tumoral vessels. The procedure should be as selective as possible to limit injury to the nontumoral liver. The dose of chemotherapy to be administered has to be adjusted according to the liver function. Several chemotherapeutic agents have been injected into the hepatic artery in patients. The most common and effective are adriamycin and cisplatin [14].

(a)

Figure 13.2 Hepatocellular carcinoma within a cirrhotic liver. Two distinct tumor sites are recognized in the right and left lobe (a) at baseline angiography and (b, c) at baseline CT. (d, e) After performing TACE using lipiodol–doxorubicin and gelfoam, both nodules show a reduction in size and lipiodol deposition that prevents the recognition of contrast uptake within the tumor. Hence, efficacy and presence of residual viable tumor tissue is best assessed by dynamic MRI.

(b)

(c)

(d)

(e)

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(a)

(b)

Figure 13.3 Large, multinodular hepatocellular carcinoma affecting both lobes. (a) Multiple tumor sites with increased arterial blood flow. (b) The venous phase shows segmentary portal vein thrombosis in the right lobe. This feature reflects advanced tumor stage and should be seen as a contraindication for transarterial chemoembolization.

The obstruction of the hepatic artery may be achieved by the injection or placement of several agents. Most authors use gelfoam carefully prepared as 1-mm cubes. Gelfoam powder has also been used with the aim of achieving a more distal embolization, but this has been associated with the appearance of biliary strictures and thus should be avoided [15]. Some investigators have injected polyvinyl alcohol [16], alcohol [17], starch microspheres [18], metallic coils [19], or even autologous blood clots [20]. Polyvinyl alcohol aims to achieve a more distal obstruction and may be used to embolize tumoral vessels selectively or even collaterals that have been formed after repeated embolizations. Starch microspheres represent a less deleterious agent for the hepatic artery branches and have the benefit of inducing a transient obstruction since they are degraded in a short period of time. However, their antitumoral effect is less intense than with gelfoam and thus they have not been widely used. The use of metallic coils is also controversial. They are placed less distally than gelfoam and thus they obstruct larger vessels that will develop collaterals in a short period of time. In addition, while gelfoam allows the repeated obstruction of the vessel feeding the tumor, the placement of coils may sometimes preclude the repetition of the treatment during follow-up. According to all these data, most authors use gelfoam cubes as the sole embolizing agent and select for the procedure patients with advanced tumors with patent hepatopetal portal blood flow. As stated above, the procedure is indicated when the portal blood flow is patent. In the absence of portal blood flow due to portosystemic anastomosis (splenorenal or

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portocaval), TACE should not be recommended (Figure 13.3). Subjects with thrombosis of a lobar or segmentary branch constitute poor candidates for the procedure since it will prompt necrosis of the tumor and of the nontumoral liver left without blood supply, and this may lead to death due to liver failure. A highly selective TACE could be attempted in patients with segmental portal thrombosis due to tumor invasion. However, it has to be kept in mind that vascular invasion reflects advanced disease with distant spread. Hence, despite potential immediate efficacy, there is no evidence of favorable impact on survival. Some authors combine arterial with simultaneous portal obstruction for small HCC but no randomized controlled trial has assessed the combined approach versus the benefits of conventional TACE [21–23]. The procedure is performed percutaneously in the angiographic suite. Usually a femoral approach is employed using the Seldinger method. Diagnostic visceral angiography is first performed to determine the arterial supply to the liver, the variant arterial anatomy, and the patency of the portal vein. The gastroduodenal, cystic, and gastric arteries should be carefully noted to avoid the backward flow of chemoembolization material to these arterial vessels. The selective angiography of the hepatic artery followed by angiography of the right or left hepatic artery is then studied to evaluate the tumoral vessels. Patients with unifocal lesions should be treated by selective chemoembolization, in which a catheter or microcatheter is placed selectively in the tumoral vessels. Patients with multiple lesions should be treated with lobar embolization.

CHAPTER 13

Transarterial Embolization for Patients with Hepatocellular Carcinoma

The obstruction of the artery induces acute ischemia of the HCC, which is associated with the so-called postembolization syndrome. This affects more than 50% of patients and consists of fever, abdominal pain located in the right hypochondrium, and a moderate degree of ileus accompanied by nausea and sometimes vomiting. Patients have therefore to fast and hydration through a venous line is mandatory. Prophylactic antibiotics are not routinely used since the fever is due to tissue necrosis and in fact, it is a predictor of a positive response to treatment. Nonetheless, some patients may develop infectious complications and thus, in the presence of prolonged fever or septic symptoms, a prompt medical evaluation through blood cultures and conventional examinations is mandatory to rule out severe complications such as hepatic abscess and ischemic cholecystitis. The postembolization syndrome is usually self-limiting in less than 48 h and patients can be discharged from hospital [24, 25].

Therapeutic efficacy of transarterial (chemo)embolization: impact on tumor progression and survival Arterial obstruction with or without associated chemotherapy achieves an extensive tumor necrosis in most patients. This is evidenced both by the decrease in the concentration of tumoral markers, identification of large intratumoral necrotic areas, and reduction in tumor burden. The techniques used to assess the therapeutic response are dynamic CT and MRI [1, 26] (Figure 13.4). CT constitutes the most common tool used to assess the response to treatment, but if lipiodol is injected, its deposition within the tumor may impede the recognition of nonenhanced necrotic tumor areas. During the first days after hepatic artery obstruction, it is possible to identify bubbles inside the tumor by US or CT. This reflects tissue liquefaction and should not prompt the diagnosis of intrahepatic abscess. To estimate the decrease in tumor load and not just size reduction, the evaluation of the treatment response should take into account the induction of intratumoral necrotic areas [1]. Thereby, according to the conventional World Health Organization (WHO) criteria [27], the reported rates of objective responses range between 15% and 55% [14, 19, 28–37]. Prospective studies have shown that the probability of tumor progression (defined by WHO criteria) is significantly lower in patients treated by TAE/TACE than in untreated controls [28, 29]. The efficacy of TAE/TACE assessed in several randomized controlled trials is summarized in Table 13.1. Reduced progression rate results in a lower risk of vascular invasion and this is a relevant aspect when considering that the appearance of vascular invasion while waiting for liver transplantation may impede the procedure. However, despite achieving an extensive initial necrosis in most cases, during the follow-up the residual tumor cells

recover their vascular supply and the neoplasm progresses again. Ultimately, almost 70–80% of patients treated by TACE will die of tumor progression rather than liver failure [14]. Despite the noteworthy rate of objective responses to treatment, the effects on the survival of patients have been highly controversial until very recently. There are a large number of cohort studies confirming that TAE/TACE bears a high antitumoral efficacy and almost all suggest an improvement in survival [14, 19, 30, 31, 34–37]. In a recent Japanese survey, the 5-year survival rate was higher than 30% [38]. However, until a few years ago, there was no evidence of the survival benefit of TACE/TAE with respect to conservative treatment. In 2002, two randomized controlled trials, reported from Barcelona and from Asia, showed a significant improvement in survival comparing TACE/TAE with conservative treatment [3, 5]. The study reported from Barcelona compared TACE with gelatin sponge and doxorubicin, TAE with gelatin sponge, and the best conservative management. An interim analysis showed that chemoembolization had survival benefits compared with conservative treatment, and survival rates at 1 and 2 years were 82% and 63% for TACE, 75% and 50% for TAE, and 63% and 27% for controls, respectively. In addition, treatment allocation was the only variable independently related to survival [3]. Further support for the benefits of TACE was obtained through cumulative meta-analysis assessing all the studies undertaken between 1978 and 2002. Seventeen randomized controlled trials evaluated TAE or TACE, and 10 transarterial chemotherapy [3, 5, 28, 29, 32, 39–47]). Nevertheless, only seven randomized controlled trials were adequate for the meta-analysis [3, 5, 28, 29, 32, 45, 47] as they included a control arm of conservative management or suboptimal treatment. Metaanalysis of these seven trials comparing TAE/TACE with conservative management showed a beneficial survival effect of embolization versus chemoembolization in comparison with a control group [4]. Of these trials, six (503 patients) reported 2-year death rate, four assessed TACE (one with doxorubicin [3], and three with cisplatin [5, 28, 32]), and three evaluated embolization alone [3, 29, 45]. The embolization agent was gelfoam in all studies. The mean number of treatment sessions ranged between 1 and 4.5 courses. An objective response rate of 35% (16–61%) was observed in these trials. Two studies identified survival benefit favoring treatment [3, 5] and two described a trend favoring survival benefit [28, 45]. In one of these studies treatment response was the best independent predictor of survival [5]. The 2-year survival of the treated group was 41% versus 27% in the control group. Significant differences in survival were identified with chemoembolization but not with embolization alone [4]. The survival benefit of TACE seems clear, but only approximately 15% of HCC patients may be considered for chemoembolization, and not all of them will benefit from the

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(a)

(b)

(c)

(d)

(g)

Figure 13.4 Large hepatocellular carcinoma (HCC) located in the left hepatic lobe. (a) The arterial blood supply. (b) The portal vein is fully patent. (c, d) Selective catheterization of the tumor arteries with a microcatheter to achieve selective distal obstruction with prior injection of doxorubicin suspended in lipiodol. (e)The HCC at baseline CT scan. (f, g) Evolution at 6 and 12 months: tumor size has been sharply reduced while lipiodol is still retained within the tumor.

treatment. Independent predictors of survival in patients with HCC treated by TAE/TACE are tumor burden (tumor size, vascular invasion, and alpha-fetoprotein levels), liver functional impairment (Child–Pugh, bilirubin ascites), health status, and response to treatment [14]. In fact, the best candidates for TACE are those patients with preserved liver function and asymptomatic multinodular tumors without vascular invasion or extrahepatic spread. Despite TACE achieving impact on survival in patients with HCC, there are several aspects of TACE that require active research to further refine the activity of this otherwise already effective therapy. New embolization agents need to be developed to increase antitumoral effects and to

strengthen the local action of cytostatic drugs. TACE elicits a high rate of objective response and therapeutic success results in delayed tumor progression and increased survival. Since improved survival depends on treatment response, the increase in efficacy of TACE should come from an enhancement of the response together with an expansion of its duration. A new class of embolization particles loaded with chemotherapy is under evaluation. These are polyvinyl alcohol microspheres that can be loaded with chemotherapeutic agents and delivered intra-arterially. The aim of these new particles is to achieve a more permanent embolization, while simultaneously releasing the chemotherapy at a slow pace.

(e)

144

(f)

Table 13.1 Response rate and survival of hepatocellular carcinoma (HCC) patients treated by transarterial embolization (TAE) or transarterial chemoembolization (TACE) in the setting of randomized controlled trials. Trial

Number response (%)

Arterial embolization/chemoembolization versus conservative management Lin et al [5] 63 TAE (ivalon + gelatin sponge powder/cubes) 21 TAE+ i.v. 5-fluorouracil 21 i.v. 5-fluorouracil 21 Pelletier et al [47] 42 TACE (gelatin sponge powder, doxorubicin) 21 Conservative management 21 GETCH [28] 96 TACE (gelatin sponge particles, cisplatin) 50 Conservative management 46 Bruix et al [29] 80 TAE (gelatin sponge) + coils 40 Conservative management 40 Pelletier et al [32] 73 TACE (gelatin sponge, cisplatin) + tamoxifen 37 Tamoxifen 36 Lo et al [5] 79 TACE (gelatin sponge, cisplatin) 40 Conservative management 39 Llovet et al [3] 112 TAE (gelatin sponge) 37 TACE gelatin sponge, doxorubicin] 40 Conservative management 35 Arterial embolization/chemoembolization versus active treatment Kasugai et al [43] 97 TACE (gelatin sponge, cisplatin) 52 TACE (gelatin sponge, doxorubicin) 25 TACE (doxorubicin 0.6–1 mg/kg + gelatin sponge) 20 Kawai et al [44] 232 TAE (gelatin sponge, lipiodol) 109 TACE (gelatin sponge + lipiodol + doxorubicin) 123 Okamura et al [46] 117 TACE (epirubicin + lipiodol + gelatin sponge) 58 TACE (doxorubicin + lipiodol + gelatin sponge) 59 Kawai et al [57] 216 TACE (epirrubicin + lipiodol + gelatin sponge) 208 TACE (doxorubicin + lipiodol + gelatin sponge) 208 Chang et al [39] 46 TACE (cisplatin + lipiodol + gelatin sponge) 22 TAE (lipiodol + gelatin sponge) 24 Hatanaka et al [41] 272 TACE (cisplatin or doxorubicin + gelatin sponge) 60 TACE (cisplatin or doxorubicin + lipiodol + gelatin sponge) 78 TACE [cisplatin or doxorubicin + lipiodol] 134 Ikeda et al [42] 40 TAE (gelatin sponge) + 5-DFUR 20 TAE (gelatin sponge) 20 Chen et al [40] 473 TACE (epirubicin + mitomycin + lipiodol + gelatin sponge) Child–Pugh A 203 Child–Pugh B 13 TACE (epirubicin + mitomycin + lipiodol < 20 mL + gelatin sponge) Child–Pugh A 238 Child–Pugh B 19 NA, not available; 5-DRUR, 5′-deoxy-5-fluorouridine.

Objective

Survival (%) 1 year

2 year

61 47 9.5

42 20 13

25 20 13

33 0

24 33

NA NA

16 5

62 43

38 26

55 0

70 72

49 50

24 5

51 55

24 26

27 2.6

57 32

31 11

43 35 0

75 82 63

50 63 27

38 13 11

71 55 35

45 40 5

27 27

74 65

51 42

19 22

86 84

NA NA

NA NA

69 74

4 57

68 67

52 72

26 39

NA NA NA

80 86 66

65 55 50

70 60

75 85

64 66

NA NA

79 42

52 21

NA NA

59 47

27 24 145

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Systemic and Regional Therapies

(a)

(b)

(c) Figure 13.5 Hepatocellular carcinoma (HCC) protruding from the right lobe treated by drug eluting beads-based transarterial chemoembolization. (a, b) The HCC at baseline CT pretreatment. Hyperdense HCC lesion in the right hepatic lobe. (c) The hepatic artery branches that feed the tumor prior to the procedure. (d, e) Evolution after therapy: the absence of contrast uptake reflects complete tumor necrosis. Note that the absence of lipiodol allows a confident evaluation of the potential residual disease. Fig. a-b: CT pre-treatment.

(d)

Thereby, the dose of chemotherapy can be increased with higher exposure of tumor cells to the agent. However, since chemotherapy is slowly released, the delivery is highly selective to the tumor itself and the passage to the systemic circulation is diminished. As a result, the side effects are reduced. In 2007 we reported a phase II study using drug-eluting beads (DEB) loaded with doxorubicin in patients with HCC. The results confirmed the expectations: the objective response rate at 6 months was 75%, and we registered a low rate of systemic side effects due to reduced passage of chemotherapy to the systemic circulation as reflected by the phar-

146

(e)

macokinetic assessment [48] (Figure 13.5). Accordingly, DEB-based chemoembolization appears to be highly effective and well tolerated. However, its superiority versus conventional gelfoam-based TACE in terms of patient survival would need to be tested within a randomized controlled trial. The refinement of the selection of patients for treatment, the development of new embolization agents and better chemotherapeutic drugs, and the sequential application of different therapeutic tools should finally solve the present uncertainty and allow treatment to be tailored to each patient and achieve a clear-cut benefit in survival.

CHAPTER 13

Transarterial Embolization for Patients with Hepatocellular Carcinoma

Transarterial embolization as coadjuvant treatment prior to resection and transplantation The significant antitumoral effect of TAE and TACE has prompted their use prior to conventional surgical resection of HCC and upon listing HCC patients for liver transplantation. Treatment in surgical candidates aims to reduce tumor burden, facilitate resection, and diminish recurrence after successful operation. However, there is no evidence that these endpoints have been achieved. Some patients may deteriorate after TAE/TACE and this may even impede surgery. There are studies suggesting that surgery may be more difficult and be associated with higher transfusional needs after this coadjuvant approach [49, 50]. Furthermore, as commented above, some studies suggest that treatment itself may disseminate the disease [51]. Finally, small randomized controlled trials have suggested that this approach does not provide any benefit to survival [52]. Accordingly, there is no basis to support the use of TACE as coadjuvant treatment prior to surgical resection. In patients listed for liver transplantation the situation is highly controversial, but due to the therapeutic efficacy of TACE and the absence of any other useful approach, it is a common policy to indicate treatment with ablation or TACE if the waiting time between listing and transplantation is expected to exceed 4–6 months. The shortage of donors has lead to a steadily increasing waiting time during which the tumors may progress and lead to exclusion and/or death. To avoid this adverse circumstance, most transplant programs apply antineoplastic treatment upon listing, and suggest that the application of treatment has been beneficial. Unfortunately, the results of liver transplantation merely reflect the outcome of those patients who have been transplanted and in most instances there is no information about the treated patients who have been lost while waiting. We have recently quantified the risk of exclusion, established its relationship with the length of the waiting time, and shown that the intention-to-treat analysis of liver transplantation is mandatory to clearly reflect the survival of patients listed for transplantation [7]. The benefits of treatment should be demonstrated through a randomized controlled trial comparing therapy versus a control group, but no such trial has been reported to date [1, 53]. The available phase II trials that suggest a benefit of therapy may be biased because of the application of very restrictive criteria and/or the lack of a long enough waiting time. It could also be suggested that a favorable response to TAE or TACE serves to identify those individuals with less advanced/aggressive neoplasm [54]. Alternatively, those who do not respond could be considered as high risk candidates who perhaps should be excluded from the program. However, it has to be stressed that there is no evidence for using these criteria.

A randomized controlled trial with an untreated control arm will probably be impossible to conduct and in its absence, the estimation of the benefits of therapy will have to be derived from statistical modeling, as has been done for other adjuvant therapies [55] and for living donation [56]. This virtual evaluation has to be derived from data in the real clinical setting, further emphasizing the need to report the progress of candidates for transplantation from the time of listing, detailing the efficacy of the treatments that may have been applied.

Conclusion TAE with and without associated chemotherapy has been used for years in patients with HCC diagnosed at an intermediate stage. Both approaches have a significant antineoplastic effect, with more than half of patients presenting objective therapeutic responses with a reduction in the tumor progression rate. In spite of its wide use in the last two decades, its survival benefit was not clearly proven until recently, when two randomized controlled trials and a metaanalysis of pooled data demonstrated a significant survival benefit favoring TACE. The procedure is highly efficacious in patients with preserved liver function, absence of extrahepatic spread or vascular invasion, and no significant cancer-related symptoms. These well selected candidates are classified as of intermediate stage in the BCLC staging system, and represent only 15% of patients with HCC. Additional investigations should be published to unequivocally confirm the value of this therapy and ongoing investigations should explore the usefulness of better embolic materials and of more effective antineoplastic agents. There is no evidence that this therapy is of any use prior to surgical resection and it has been suggested that it might even be deleterious. Thus, its use in this setting should not be advised. In patients waiting for liver transplantation, the benefits of treatment have not been assessed through prospective controlled investigations. Phase II trials suggest that some patients may benefit from this strategy but large prospective investigations with accurate pretreatment staging and extensive follow-up are urgently needed in this field.

Self-assessment questions 1 Which one of the following statements regarding TACE for hepatocellular carcinoma (HCC) is true? A Is the first therapeutic option in patients with solitary HCC < 2 cm B Induces tumor necrosis but has no impact on survival C Is contraindicated in patients with hepatitis B virus infection

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D Is the first-line treatment in patients with intermediate HCC as per BCLC staging E Should always be combined with sorafenib 2 TACE has no proven impact on survival or is contraindicated in which one of the following? A In the absence of portal blood flow B In Child–Pugh class C patients C In the presence of extrahepatic spread D In patients with impaired performance status E In all of the above 3 Which one of the following statements regarding downstaging by TACE in an attempt to enlist patients for transplantation is true? A Is an approach with established efficacy B Has been tested in proper prospective trials C Is still controversial because of lack of validated staging and large follow-up investigations D Should be part of the standard of care in HCC patients E Is only viable if patients meet Milan criteria at baseline 4 The efficacy of TACE is assessed by which one of the following? A The reduction in alpha-fetoprotein B The degree of tumor necrosis on dynamic imaging C RECIST criteria D Improvement in symptoms E Delay in tumor progression 5 Which one of the following statements concerning the treatment schedule for TACE is true? A TACE should be performed only once B TACE should be repeated even if there is no therapeutic response C It is known that the best approach is to treat by TACE every 2 months D There is a need to define which is the best treatment schedule E It is established that no more than one tumor can be treated at each TACE session

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52

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Self-assessment answers 1 2 3 4 5

D E C B D

14

Selective Continuous Intra-arterial Chemotherapy for Liver Tumors Fidel D. Huitzil-Melendez1, Stefan Breitenstein2, and Nancy Kemeny3 1

Departamento de Hematología y Oncología, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán,” Mexico City, Mexico 2 Swiss Hepato-Pancreato-Biliary and Transplantation Center, Department of Surgery, University Hospital Zurich, Zurich, Switzerland 3 Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY, USA

Background Chemotherapy into the hepatic artery (HAC) was developed in the early 1960s to treat large, unresectable, hepatic colorectal metastases [1–3]. Historically, drugs were applied either through angiographically placed catheters using the Seldinger technique, or implanted catheters passing through the abdominal wall, or later, port catheters (Port-A-Cath, Jet Port). These methods demonstrated the feasibility of this approach, but were associated with multiple complications, including catheter migration and hepatic artery thrombosis; additionally, it was necessary for patients to visit the hospital on an almost daily basis for the administration of chemotherapy. The use of totally implantable pumps, initially developed for continuous administration of insulin in diabetic patients, has significantly decreased the rate of complications, with longer preservation of hepatic artery patency. The rationale for using HAC was based on several observations. First, it was discovered that although blood supply to the liver arises from both the hepatic artery and the portal vein, most hepatic tumors are almost exclusively perfused by branches derived from the hepatic artery [4, 5]. Therefore, directing a local infusion of chemotherapy through the hepatic artery may expose the malignant cells to higher drug concentrations while sparing normal liver tissue [6]. Second, prolonged exposure to continuous infusion of pyrimidine derivatives [fluorouracil (FU) and floxuridine (FUDR)], which are cell cycle dependent, leads to increased response rates. Third, radioactive FUDR is found in equal quantities in normal liver parenchyma and liver tumors after portal vein and hepatic artery injection, whereas it is concentrated 15-fold in hepatic metastases after hepatic artery injection [7], and 400-fold compared with systemic injection [8].

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

Finally, FUDR, an active metabolite of 5-FU, has the advantage of being rapidly metabolized with a 94–99% extraction rate within the liver on the first pass, thereby preventing systemic toxicity [9].

Pump mechanics HAC gained popularity in the 1980s with the development of totally implantable infusion pumps [10–12]. These devices have enabled a better quality of life in and given freedom of movement to patients without the need for repeated hospitalization. The surgical placement of the pump, initially an open procedure requiring laparotomy and complete anesthesia, can now also be performed under laparoscopy with one-day hospitalization (Ravi Chari, personal communication). Surgical placement of the pump ensures an accurate and reliable delivery of chemotherapy. Implantable pumps are powered by the vapor pressure exerted by a fluorocarbon derivative contained in a sealed chamber; a steady flow rate with an essentially inexhaustible power supply is thus generated. The models currently available are the Arrow 3000-16, 3000-30, and 3000-50 (Codman 3000, Johnson & Johnson, Raynham, MA) and the Medtronic IsoMed Constant Flow Pump and Medtronic SynchroMed EL (Medtronic Minneapolis, MI). The Arrow and Medtronic pumps are depicted in Figure 14.1, and their cross-sections are shown in Figure 14.2. The specifications of both pump models are summarized in Table 14.1. The pump flow rate is determined by the difference between the reservoir pressure at the catheter exit site multiplied by the pump flow constant, and divided by the viscosity of the fluid. The flow rate is affected by the arterial blood pressure, with an increase of 10 mmHg reducing flow by 3% and vice versa. High altitude increases pump flow, e.g. pump flow rate increases by 45% between sea level and an altitude of 2000 m. Body temperature also affects the vapor

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pressure of the main chamber, with a 10% adjustment in flow for each degree Celsius.

A subcostal abdominal incision is used for pump placement. The remainder of the abdomen is explored and the vascular anatomy confirmed. With a standard anatomy, control of the common hepatic and proper hepatic arteries is obtained and the catheter is placed in the gastroduodenal artery (Figure 14.4). The catheter is normally placed so that its tip is at the origin of the gastroduodenal artery and the artery is ligated proximally. If the tip extends too far into the hepatic artery, it may promote thrombosis. A cholecystectomy is performed routinely to prevent chemotherapyinduced toxic cholecystitis. Variants of the arterial anatomy are frequent. Researchers at the University of Michigan reported on 111 patients, in whom 13 anatomic variants were noted [13]. The anatomy was standard in 64 of the 111 patients. Trifurcation of the left common hepatic artery, the right hepatic artery, and the gastroduodenal artery was the most common variant, occurring in 16 of the 111 patients. Replaced right hepatic artery occurred in 11 of the 111 patients. The gastroduodenal artery was used for single catheter placement in 55% of the patients. The second most common artery used for single catheter placement was the splenic artery. This type of placement requires careful ligature of all splenic artery and celiac axis branches except hepatic branches to avoid aberrant perfusion. Several alternative cannulation techniques in the presence of anatomic variants have been described [14]. The pump is placed in a subcutaneous pocket made through a separate transverse skin incision. The incision is made approximately 2–3 cm below the initial incision between the skin and fascia, usually on the lower right side of the abdomen. It is important that the skin incision does not lie directly over the membranes of the main chamber or side port. The pump should be placed high enough to avoid exerting pressure on the anterosuperior iliac spine in a sitting position. The complete perfusion of the liver should be confirmed intraoperatively by using fluorescein dye injection and a Wood’s lamp (Figure 14.5). Methylene blue dye may also be used to assist in this evaluation. An additional baseline evaluation of the pump can be obtained approximately 3–4 days postoperatively using a liver spleen scan and compared with a pump scan performed through the side port the following day [15].

Technical considerations

Technical complications

Careful evaluation of prospective patients is required before implantable pumps are placed. Appropriate preoperative evaluation maximizes the efficacy of the therapy. The anatomy and flow direction are best defined with selective hepatic, celiac, and superior mesenteric arteriograms (Figure 14.3). A contraindication for HAC is the presence of extrahepatic disease (see Chapter 10).

The controversy surrounding the placement of totally implantable pumps for HAC comes partly from the technical complications associated with pump placement. The mortality rate is less than 1% [16]. The largest single-institution experience regarding technical complications of HAC involving 544 patients was published in 2005 by Allen et al [17]. The incidence of pump failure was 9% at 1 year and 16%

(a)

(b) Figure 14.1 (a) IsoMed implantable pumps. (b) Codman 3000 implantable pump.

152

CHAPTER 14

Selective Continuous Intra-arterial Chemotherapy for Liver Tumors Center reservoir fill port

(a)

Suture loop

Screened catheter access port

Filter

Reservoir propellant chamber

Drug reservoir

Bellows

(b) Noncoring needle with tubing set

Special bolus needle Side hole

Septum

Safety valve open Bolus safety valve Bolus path Outlet catheter

Refill path Flow restrictor

Filter

30 mL drug reservoir

Needle stop

Propellant chamber

Figure 14.2 Cross-sectional view of (a) the IsoMed pump and (b) the Codman 3000 pump. (Reproduced from Meditronic Inc, with permission.)

Table 14.1 Specifications of implantable pumps. Model IsoMed 20 35 60 SynchroMed EL 10 18 Arrow 300 30 16 50

Side port

Diameter (mm)

Thickness (mm)

Reservoir (mm)

Empty weight (g)

Yes Yes Yes

77 77 77

17 22 30

20 35 60

113 116 120

Yes Yes

70.4 70.4

– –

10 18

165 185

No No No

78 61 86

37 32 37

30 16 50

137 98 173

at 2 years. Pump complications occurred in 120 (22%) patients. Complications occurring early after operation (<30 days) were more likely to be salvaged than those occurring late (70% versus 30%; p < 0.001). Increased pump complication rates occurred in the setting of variant arterial anatomy (28% versus 19%; p = 0.02), and when the catheter was

inserted into a vessel other than the gastroduodenal artery (42% versus 21%; p = 0.004) [17]. The most commonly reported complications are pump pocket hematoma and seroma (0.3–15%). When a seroma occurs, the pocket should be aspirated and samples sent for culture and sensitivity. If no infection is present, repeated

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d

a b

c

Figure 14.5 Liver perfusion confirmed with Wood’s lamp after fluorescein bolus injection into the pump. Figure 14.3 Arteriogram of the celiac trunk showing a standard anatomy: celiac trunk (a), splenic artery (b), gastroduodenal artery (c), and bifurcation of the hepatic artery (d).

Clinical applications

c

b

a

The potential clinical applications of HAI chemotherapy in the management of liver tumors are diverse. For patients with unresectable disease, HAI therapy may downstage disease, allowing secondary resection. If resection cannot be achieved, HAI may still improve results over systemic chemotherapy alone. For patients completely resected, HAI chemotherapy combined with systemic chemotherapy may decrease recurrence rates and improve survival. The clinical applications of HAI for colorectal cancer will be discussed, followed by some results with liver malignancies.

Pharmacologic considerations Figure 14.4 Intra-arterial placement of the catheter: with the catheter tip at the origin of the gastroduodenal artery (a), common hepatic artery (b), and hilus of the liver (c).

aspirations should resolve the fluid collection. Pump removal is required in cases of pocket infection, while the intraabdominal catheter may be maintained and temporarily connected to an arterial port. Occasionally this technique may allow a new pump to be connected to the same arterial access and HAC treatment can be maintained. Placement of hepatic arterial infusion (HAI) pumps is a complex procedure requiring experience. There is a definite learning curve. Allen et al showed significantly increased pump complications during the early study period (1986– 1993, 25%) compared with the later period (1994–2001, 18%; p = 0.05) [17]. In a review of complications of pump placement published by Curley et al, there was a five-fold increase in complications when the surgeon had placed fewer than 10 pumps [18].

154

Floxuridine (FUDR) remains the best drug for selective continuous infusion of intra-arterial chemotherapy despite the recent availability of new drugs for the treatment of advanced colorectal cancer, including oxaliplatin, irinotecan, bevacizumab, cetuximab, and panitumumab. This is explained by the unique pharmacologic profile of FUDR. A clear understanding of the pharmacokinetic and pharmacodynamic principles of regional chemotherapy is necessary to better interpret and design clinical trials testing the value of intraarterial chemotherapy in the management of liver tumors. The value of regional delivery of any specific drug can be anticipated based on the extent to which such a drug fulfils the following principles [19].

Regional delivery of the drug leads to increased local concentrations Collins formula has established that increased local concentrations are dependent on the ratio of the total body clearance of a particular drug (CLTB) to the regional exchange (Q) for a particular body compartment: CLTB/Q. Therefore, drugs delivered via the hepatic artery will achieve increased local

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Selective Continuous Intra-arterial Chemotherapy for Liver Tumors

concentrations only if their CLTB is high, as regional exchange is constant. On the other hand, total body clearance is a constant pharmacokinetic parameter that relates the rate of elimination of a drug to the plasma concentration of the drug. Higher elimination of the drug at a given plasma concentration is a desirable feature for drugs to be delivered via the hepatic artery. The intra-arterial chemotherapy delivery can also be considered as a model of high-dose chemotherapy. In this regard, it is important that clearance of a drug remains constant if high doses are delivered. This is the case for drugs that exhibit first-order kinetics and will have only one clearance value independent of the plasma concentration of the drug. Other drugs, however, may exhibit zero-order kinetics, and their clearance will actually decrease as the enzyme systems become saturated and the elimination rate becomes constant. In summary, ideal drugs for hepatic artery delivery are those with high total body clearance and first-order kinetics. The CLTB for FUDR is 15–25 L/min, and it exhibits first-order kinetics and compares favorably to any other active drug for the treatment of patients with advanced colorectal cancer. This pharmacokinetic profile contrasts with that of 5-FU, for example: its CLTB is only 0.5–2 L/min and it does not exhibit first-order kinetics.

Increased local concentrations lead to increased therapeutic response A sigmoidal steep dose–response curve is characteristic of most cytotoxic drugs and patients are usually treated to the maximal tolerated dose [20]. (For therapeutic antibiotics this is not true.) Therefore, cytotoxic drugs such as FUDR are more suitable for intra-arterial chemotherapy since the higher doses delivered regionally can actually improve the therapeutic response.

drug in advanced colorectal cancer. 5-FU has a much lower extraction rate (55%) [21]. Collins developed a formula that evaluates the combined advantage of regional therapy in terms of increased local concentration/efficacy and decreased systemic exposure for any given drug [19]: Advantage =

1 + Total body clearance of a drug Hepatic artery flow rate (1 − Fraction of drug extracted across the liver )

Colorectal cancer: unresectable liver metastases Patients afflicted by colorectal cancer experience significant morbidity and mortality related to the development of liver metastases: approximately 60–70% of patients with colorectal cancer will develop hepatic metastases and the liver metastases may be present at initial disease in 15–20% patients [22]. However, approximately 80% of patients with colorectal liver metastases present with unresectable disease [23]. Besides advances in surgical techniques that allow a higher proportion of patients to be considered for a curative resection [24], both systemic chemotherapy and regional chemotherapy have the potential to improve survival through increased response rates and increased resection rates with curative potential after downstaging (Figure 14.6). At the time when only fluoropyrimidines were available for the treatment of colorectal cancer, it was clearly demonstrated that the administration of the drug through the hepatic artery resulted in superior response rates compared to the systemic administration of the drug. A meta-analysis of 10 randomized trials [25–34] confirmed that hepatic artery administration of chemotherapy more than doubled response rates compared to systemic therapy (relative risk

The hepatic extraction ratio reflects the extent of metabolism or elimination of a drug as a first-pass effect [21]. It is estimated as:

( Hepatic arterial level of a drug − Hepatic venous level of a drug ) Hepatic arterial level The hepatic extraction ratio can exhibit first- or zero-order kinetics. Drugs suitable for hepatic artery administration will be those with a high hepatic extraction ratio that exhibit first-order kinetics, so higher doses can be administered while maintaining decreased systemic exposure. This will ultimately result in decreased systemic toxicity and improved therapeutic index. The hepatic extraction for FUDR after hepatic artery administration is 95%, and it exhibits firstorder kinetics and compares favorably to any other active

Survival distribution function

Regional delivery of the drug leads to decreased systemic exposure 1.00

0.75

0.50

0.25

0.00 0 Strata

10

20

30

40

Previous, Chemo = N Previous, Chemo = Y

50

60

70

80

Censored Previous, Chemo = N Censored Previous, Chemo = Y

Figure 14.6 Overall survival after resection of colorectal liver metastases and adjuvant therapy with floxuridine-based hepatic arterial infusion (HAI-FUDR) chemotherapy. N, no; Y, yes.

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Table 14.2 Randomized clinical trials comparing fluoropyrimidine-based hepatic arterial infusion (HAI) versus systemic therapy for colorectal liver metastasis. Authors

Treatment arms

Chang et al [25]

HAI: FUDR SYS: FUDR HAI: FUDR SYS: FUDR HAI: FUDR SYS: FUDR

Kemeny et al [26] Hohn et al [27]

Martin et al [28] Wagman et al [29] Rougier et al [30] Allen-Mersh et al [31] Lorenz & Muller [32]

Kerr et al [33] Kemeny et al [34]

n

Response rate (%)

Median overall survival (months)

Comments

32 32 48 51 67 76

62 17 53 21 42 9

17 12 17 12 16.5 15.8

Extrahepatic disease (+) Inappropriate HAI-FUDR dose (+) Cross-over allowed

HAI: FUDR SYS: 5-FU + LV HAI: FUDR SYS: 5-FU HAI: FUDR SYS: 5-FU or BSC HAI: FUDR SYS: 5-FU or BSC HAI: FUDR HAI: 5-FU + LV SYS: 5-FU + LV

39 35 31 10 81 82 51 49 54 57 57

48 21 55 20 41 9

43 45 27

12.6 10.5 13.8 11.6 15 11 13.5 7.5 12.7 18.7 17.6

HAI: 5-FU + LV SYS: 5-FU + LV HAI: FUDR + Dex SYS: 5-FU + LV

145 145 68 67

22 19 47 24

14.7 14.8 24.4 20

NR

Extrahepatic disease (+) Cross-over allowed Inappropriate initial HAI-FUDR dose Extrahepatic disease (+) Inappropriate HAI-FUDR dose Cross-over allowed Inappropriate HAI-FUDR dosage

Ports were used Inappropriate FUDR dose adjustment algorithm Cross-over allowed Ports were used FUDR not used for HAI Only study that used intra-arterial Dex

BSC, best supportive care; Dex, dexamethasone; FUDR, floxuridine; 5-FU, 5-fluorouracil; LV, leucovorin; SYS, systemic chemotherapy.

of tumor response = 2.2; 95% CI 1.80–2.84) [35]. Importantly, an almost linear correlation between response rate and resectability has been documented for patients with isolated unresectable colorectal liver metastases (r = 0.96; p = 0.002) [36]. Not all the trials included in the metaanalysis were designed or powered to evaluate a survival advantage of HAI over systemic chemotherapy. Significant heterogeneity was observed among the trials included in the meta-analysis. Table 14.2 summarizes the 10 randomized controlled trials [25–34] and highlights variables that may explain suboptimal survival outcomes among patients treated with regional chemotherapy: utilization of drugs other than FUDR for intra-arterial administration, inappropriate FUDR dosage and dose-reduction algorithms, utilization of ports instead of implantable pumps, inclusion of patients with extrahepatic disease, and cross-over to the HAI arm after tumor progression on systemic therapy. Since these randomized controlled trials were conducted, and probably as a consequence of the critical evaluation of their results, we have learned how to better deliver intraarterial chemotherapy. Table 14.3 summarizes key elements

156

Table 14.3 Recommendations for optimal results with regional chemotherapy in the treatment of colorectal liver metastases. 1. Patient selection: liver-only metastases 2. Chemotherapy agent via hepatic artery: FUDR + dexamethasone 2 weeks continuous infusion every 4 weeks 3. Dosing: FUDR = (0.12 mg × kg × 30 mL)/(pump flow rate mL/day) Dexamethasone: 25 mg fconsider pump flow rateCT scansnged exposure to FUDR as the treatment needs to be discontinued less frequently quality CT scans 4. Aggressive dose adjustment algorithm: to prevent biliary toxicity and enhance FUDR delivery 5. Mechanism of drug delivery via hepatic artery: implantable pump placed by an experienced surgeon 6. Combine with systemic chemotherapy 7. Re-evaluate resectability every 2 months by an experienced multidisciplinary team

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Selective Continuous Intra-arterial Chemotherapy for Liver Tumors

to obtain optimal results when treating patients with HAC. Regarding patient selection, the presence of extrahepatic disease is a powerful adverse prognostic factor. High-quality computed tomography (CT) scans and/or positron emission tomography (PET)/CT scans may help improve the selection of candidates suitable for regional therapy. Regarding the drug to be administered via the hepatic artery, we have discussed above the superior pharmacologic profile of FUDR. Biliary toxicity can be minimized with appropriate FUDR dosing [34], the use of an aggressive dose-adjustment algorithm [37], and the addition of dexamethasone via the hepatic artery [38]. These recommendations will not only result in decreased toxicity but will also enhance FUDR delivery. Systemic therapy for advanced colorectal cancer has also improved. The availability of oxaliplatin, irinotecan, and biologic agents used in combination regimens has resulted in increased response rates and resection rates for patients with metastatic disease to the liver. Two-drug combination regimens, such as 5-FU and oxaliplatin, resulted in a 14% conversion rate in patients with initially unresectable liver metastases in a large cohort of unselected patients (n = 701) [39]. The FOLFOX regimen in previously chemotherapynaïve patients produced a 60% response, and 40% were able to undergo resection [40]. Three-drug regimens combining 5-FU, irinotecan, and oxaliplatin resulted in a 26– 37.5% resectability rate in the first-line setting in small prospective trials [41, 42]. More recently, the addition of cetuximab to a chemotherapy regimen after first-line chemotherapy failure resulted in a 7% resectability rate in previously treated patients [43]. Patients with unresectable liver metastases from colorectal cancer treated exclusively with regional therapy have improved hepatic progression-free survival but decreased extrahepatic progression-free survival [34]. Not surprisingly, improvements in the outcome for patients with unresectable colorectal liver metastases treated with HAI-FUDR have come from the addition of systemic chemotherapy. Initial phase I clinical trials defined the appropriate dosages to be

used when combining HAI-FUDR with systemic chemotherapy. For a combination with systemic irinotecan, the maximum tolerated dose was 100 mg/m2 of irinotecan weekly for 3 weeks every 4 weeks with concurrent HAIFUDR [(0.16 mg/kg/day × pump volume)/(pump flow rate mL/day)] plus dexamethasone for 14 days of a 28-day cycle [44]. The dose-limiting toxicities were diarrhea and neutropenia. For a combination with systemic irinotecan and oxaliplatin, the maximum tolerated dose was oxaliplatin 85–100 mg/m2 and irinotecan 150 mg/m2 every 2 weeks concurrent with FUDR [(0.12 mg/kg/day × pump volume)/ (pump flow rate mL/day)] and dexamethasone [45]. Grade 3 and 4 toxicities included diarrhea (24%), neutropenia (10%), neurotoxicity (24%), and hyperbilirubinemia greater than 3 mg/dL (5%). Table 14.4 summarizes response rate, resection rate, and survival of patients with unresectable liver metastases treated with different regimens of HAI-FUDR ± systemic chemotherapy. Response rate and resection rate for patients with initially unresectable colorectal liver metastases treated with HAI-FUDR + dexamethasone + leucovorin in the second-line setting were 39% and 26%, respectively [46]. The response rate for a combination of HAI-FUDR/ dexamethasone with systemic irinotecan was 74% [44]. The same regimen yielded only a 43% response rate and an 18% resection rate in patients previously treated with systemic oxaliplatin [47]. The observed response rate for a combination of HAI-FUDR/dexamethasone with systemic oxaliplatin and irinotecan in 49 patients with unresectable liver metastases was 92%; complete response rate was 8%. The associated resection rate was 47%. Median overall survival for chemotherapy-naïve patients was 50 months. For previously treated patients, the median overall survival was 35 months [48]. To put these results into perspective, it should be noted that the patient population was characterized by the presence of several adverse prognostic factors: 73% of patients had more than five liver lesions, 98% had bilobar disease, and 86% had six or more liver segments

Table 14.4 Response rates and resection rates observed in patients with unresectable liver metastases from colorectal cancer after treatment with floxuridine-based hepatic arterial infusion (HAI-FUDR) + dexamethasone (Dex) alone or in combination with systemic chemotherapy. Authors

N

Treatment arm

Clavien et al [46] Kemeny et al [44] Gallagher et al [47] Kemeny et al [48]

23 46 39 49

HAI-FUDR HAI-FUDR HAI-FUDR HAI-FUDR

+ + + +

Dex Dex Dex Dex

+ + + +

LV sys irinotecan sys irinotecan sys irinotecan + oxaliplatin

Previously treated (%)

Response rate (%)

Resection rate (%)

Median survival (months)

100 100 100 53

39 74 43 92

26 NR 18 47

20 20 39.8

LV, leucovorin; sys, systemic.

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involved. Of note, 53% had been previously treated with chemotherapy. Alternative approaches have been reported. Patients with isolated liver metastases from colorectal cancer were treated with hepatic arterial oxaliplatin and systemic bi-weekly 5-FU and leucovorin. Median overall survival was 27 months [49]. The advantage of regional compared to systemic administration of the oxaliplatin is unclear. As such, in the treatment of patients with liver metastases from colorectal cancer, the clinical question has been updated. Does combination treatment with HAI-FUDR, oxaliplatin, and irinotecan improve response rates, resection rates, and survival when compared to the best systemic chemotherapy + biologic therapy? Does combination treatment with HAI-FUDR, oxaliplatin, and irinotecan improve outcomes when compared to three-drug systemic chemotherapy? Well-designed randomized controlled clinical trials are needed.

Colorectal cancer: adjuvant therapy after resection of liver metastases Patterns of recurrence after resection of liver metastases from colorectal cancer demonstrate that the liver is involved in 43–60% of the cases, while extrahepatic recurrence is observed in 30–60% of patients [50, 51]. A clinical risk score can estimate the probability of recurrent disease after resection of colorectal liver metastases [52]. Adverse prognostic factors include: (1) a node-positive primary; (2) disease-free interval from primary to development of metastases less than 12 months; (3) more than one hepatic tumor; (4) largest tumor greater than 5 cm; and (5) carcinoembryonic antigen (CEA) level greater 200 ng/mL. Even patients with no adverse prognostic factors have a 40% probability of death at 5 years. The probability increases to 86% for patients with five adverse prognostic factors. As such, all patients who have undergone resection of liver metastases from colorectal cancer are candidates for adjuvant therapy based on the high risk of recurrence. In addition, the adjuvant strategy to be offered should decrease the risk of both hepatic and systemic recurrence. Systemic chemotherapy has shown a trend towards improved disease-free survival and overall survival when used in the adjuvant setting after resection of colorectal metastases. A pooled analysis of two randomized control trials that evaluated adjuvant bolus 5-FU for 6 months after liver resection versus surgery alone (n = 278) demonstrated a trend towards improved progression-free survival (hazard ratio 1.32; 95% CI 1.00–1.76) and overall survival (hazard ratio 1.32; 95% CI 0.95–1.82) [53]. The value of regional therapy has been evaluated in the adjuvant setting after resection of colorectal liver metastases. Table 14.5 summarizes the randomized controlled trials [16, 54–57] and highlights differences between clinical trials that

158

may explain the different outcomes: drug used for HAI, device used for drug delivery, primary endpoint, actual duration of treatment, actual proportion of patients treated, whether or not systemic chemotherapy was allowed in the experimental or control arm, and timing of randomization. The two largest studies by Lorenz et al and Memorial Sloan-Kettering Cancer Center (MSKCC) [16, 55] give conflicting results: the use of 5-FU as opposed to FUDR, ports instead of implantable pumps, and preoperative randomization as opposed to intraoperative randomization may explain negative results in the former study. Of note, the MSKCC study confirms the benefit of the addition of HAI-FUDR/ dexamethasone to a systemic chemotherapy regimen (5-FU/ LV) [HAI + SYS versus SYS alone] [16]. There was a clear improvement in hepatic disease-free survival and diseasefree survival with both regional and with the combination of regional and systemic therapy. The endpoint of the MSKCC study was 2-year survival which was increased to 86% with HAI + SYS versus 72% with SYS alone (p = 0.03). Updated overall survival data have shown a median survival of 68 months for the HAI + SYS and 58 months for SYS alone; 10-year survival is 41% for HAI + SYS and 27% for SYS alone [58]. FOLFOX is a more active chemotherapy regimen both in the adjuvant setting and in advanced colorectal cancer compared to 5-FU/LV. Recently, perioperative FOLFOX has demonstrated a trend towards improved disease-free survival in patients with resectable liver metastases from colorectal cancer compared to no chemotherapy before or after surgery [59]. The 3-year progression-free survival was 36% versus 28% for the treated and untreated groups, respectively (p = 0.04). This study included pre- and post-operative systemic therapy so it is unclear whether pre- or posttherapy or both made the difference. Table 14.6 summarizes adjuvant studies conducted at MSKCC testing HAI-FUDR/dexamethasone ± systemic therapy. A pooled analysis of four adjuvant trials at MSKCC demonstrates a 70% 5-year survival for patients with 0–2 clinical risk score. Adjuvant HAI-FUDR/dexamethasone plus systemic oxaliplatin + 5-FU produced an 88% 4- and 5-year survival after liver resection [60]. The combination of HAIFUDR and dexamethasone with modern systemic chemotherapy regimens constitutes a step forward in the development of adjuvant treatment strategies. Randomized controlled trials testing HAI-FUDR plus modern oxaliplatinbased systemic chemotherapy versus adjuvant systemic 5-FU/LV or FOLFOX or HAI-FUDR + 5-FU/LV are also needed.

Primary liver malignancies The biologic behavior of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma is characterized by prolonged intervals in which the disease is confined to the liver, making these malignancies amenable to local or

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Selective Continuous Intra-arterial Chemotherapy for Liver Tumors

Table 14.5 Randomized trials of hepatic arterial infusion (HAI) versus systemic therapy or control as adjuvant treatment after resection of colorectal liver metastases. Authors

N

Treatment arm

Primary endpoint

Comments

Lorenz et al [55]

226

HAI: 5-FU/LV Control: −

Drug delivery by port Preoperative randomization 24 of 113 patients did not receive HAI

Kemeny et al [16]

156

HAI: FUDR + Dex + sys 5-FU/LV Control: sys 5-FU/LV

Tono et al [54]

19

HAI: 5-FU followed by oral 5-FU to complete 2 years Control: oral 5-FU for 2 years

Kemeny et al [56]

75

HAI: FUDR + sys FU Control: −

Lygidakis et al [57]

122

HAI: mitomycin C + 5-FU + LV + IL-2 (half dose HAI, half dose systemic) Control: same regimen IV

Median OS: 34.5 vs 40.8 months (p = 0.1519) 2-year survival rate: 60% vs 45% 86% vs 72% (p = 0.03) Median DFS: 62.6 vs 13.8 months (p = 0.045) Median OS: 62.6 vs 39.9 months (p = 0.2686) 4-year recurrence free rate: 45.7% vs 25.2% (p = 0.04) Median OS: 79 vs 66 months (p = 0.04)

Implantable pumps used Intraoperative randomization 6 of 74 patients did not receive HAI Drug delivery by port Intraoperative randomization No statistical hypothesis formulated

Implantable pump Preoperative randomization No intention to treat analysis 23 of 53 patients did not receive HAI

Dex, dexamethasone; FUDR, floxuridine; 5-FU, 5-fluorouracil; LV, leucovorin; sys, systemic; IL-2, interleukin 2, OS, overall survival; DFS, disease-free survival.

Table 14.6 Adjuvant treatment with hepatic arterial infusion of floxuridine (HAI-FUDR) + modern systemic chemotherapy regimens after resection of colorectal liver metastases: Memorial Sloan-Kettering Cancer Center cohorts. Treatment HAI-FUDR HAI-FUDR HAI-FUDR HAI-FUDR Total

+ + + +

sys 5-FU/LV sys irinotecan sys FOLFOX systemic irinotecan or FOLFOX ± bevacizumab

N

Median follow-up (months)

5-year survival (%)

74 103 35 45 247

167 86 48 27 4.7 years

60 59 88 Too early 1 metastasis: 75 2–4 metastases: 65 >5 metastases: 35 CRS 0–2: 70 CRS 3–5: 52

5-FU, 5-fluorouracil; LV, leucovorin; CRS, clinical risk score.

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regional therapeutic strategies. Systemic chemotherapy results in poor response rates and biologic therapy offers only a modest survival advantage in patients with HCC [61]. In patients with intrahepatic cholangiocarcinoma, systemic chemotherapy offers mostly stability of disease [62]. HAIFUDR has been tested in unresectable primary liver malignancies. At MSKCC, 34 patients with unresectable intrahepatic cholangiocarcinoma and hepatocarcinoma with disease confined to the liver were treated with HAI-FUDR at 0.16 mg/kg/day + dexamethasone from days 1 to 14, followed by heparanized saline from days 15 to 28. Cycles were repeated every 28 days. The partial response rate was 47%. Overall survival was 29.5 months. One patient was able to be resected after response to treatment and complete pathologic response was documented. Three grade 3 complications (one each: elevated bilirubin, pain, gastrointestinal) and two grade 4 complications (elevated bilirubin) were reported [63]. These results compare favorably to patients with intrahepatic cholangiocarcinoma treated with capecitabine and oxaliplatin where objective responses were lower and median survival was 5.2 months.

Conclusion The current management of metastatic liver cancer is multidisciplinary. Hepatic arterial infusion of chemotherapy adds to the therapeutic armamentarium that includes surgery, ablative techniques, systemic chemotherapy, biologic therapy, and radiotherapy. Further improvements of systemic chemotherapy may also improve the results of treatment strategies that combine HAI-FUDR with the best systemic treatment available. Given the recent availability of a predictive test for response to cetuximab therapy, wildtype K-Ras patients may be candidates for first-line cetuximab therapy. A randomized trial has been reported. Wild-type K-Ras patients with unresectable liver metastases treated with FOLFOX or FOLFIRI plus cetuximab experienced a 34% complete resection rate [64]. However, for patients with mutant K-Ras, first- and second-line therapies are now less available but HAI therapy is still an option for them. The role of regional chemotherapy in the management of primary liver malignancies is less explored, but initial results make a case for further investigation. In the future there will hopefully be a closer association of surgeons, medical oncologists, and interventional radiologists to define the best therapies for the treatment of liver metastases.

Self-assessment questions 1 The flow rate of the pump is affected by which of the following? (more than one answer is possible)

160

A B C D

Arterial blood pressure Central venous pressure Body temperature Heart rate

2 Which one of the following is the optimal placement of the catheter for intra-arterial chemotherapy? A Common hepatic artery B Proper hepatic artery C Gastroduodenal artery D Splenic artery 3 Which of the following pharmacokinetic characteristics of FUDR do not make it an ideal drug for HAI infusion? (more than one answer is possible) A High total body clearance (15–25 L/min) B Zero-order kinetics C High hepatic extraction ratio when administered via the hepatic artery (95%) D Increased biliary toxicity 4 Which of the following results have not been associated with HAI-FUDR in patients with unresectable liver metastases? (more than one answer is possible) A More than double probability of response when compared to systemic administration of fluoropyrimidines (relative risk of response 2.2) B Addition of dexamethasone increases biliary toxicity C HAI-FUDR + dexamethasone in pretreated patients results in a 26% resection rate D HAI-FUDR + dexamethasone + systemic irinotecan results in a 74% response rate in pretreated patients E HAI-FUDR+ dexamethasone + systemic irinotecan and oxaliplatin results in a 92% response rate and a 47% resection rate 5 Which of the following results have not been reported for adjuvant HAI-FUDR after resection of colorectal liver metastases? (more than one answer is possible) A Adjuvant HAI-FUDR + systemic 5-FU/leucovorin results in 60% 5-year survival B Adjuvant HAI-FUDR + systemic irinotecan has been associated with the best survival C Adjuvant HAI-FUDR + systemic FOLFOX results in 88% 5-year survival D Adjuvant HAI-FUDR is not effective for patients with high clinical risk score

References 1 Brennan MJ, Tally RW, Drake EH, Vaitkevicius VK, Poznanski AK, Brush BE. 5-Fluorouracil treatment of liver metastases by continuous hepatic artery infusion via Cournand catheter:

CHAPTER 14

2

3

4

5 6 7

8 9

10

11

12

13

14

15

16

17

18

19 20

Selective Continuous Intra-arterial Chemotherapy for Liver Tumors

Results and suitability for intensive postsurgical adjuvant chemotherapy. Ann Surg 1963;158:405–19. Clarkson B, Young C, Dierick W, et al. Effects of continuous hepatic artery infusion of antimetabolites on primary and metastatic cancer of the liver. Cancer 1962;15:472–88. Klopp CT, Alford TC, Bateman J, Berry GN, Winship T. Fractionated intra-arterial cancer; chemotherapy with methyl bis amine hydrochloride; a preliminary report. Ann Surg 1950; 132:811–32. Ackerman NB. The blood supply of experimental liver metastases. IV. Changes in vascularity with increasing tumor growth. Surgery 1974;75:589–96. Breedis C, Young G. The blood supply of neoplasms in the liver. Am J Pathol 1954;30:969–77. Ensminger WD, Gyves JW. Clinical pharmacology of hepatic arterial chemotherapy. Semin Oncol 1983;10:176–82. Sigurdson ER, Ridge JA, Kemeny N, Daly JM. Tumor and liver drug uptake following hepatic artery and portal vein infusion. J Clin Oncol 1987;5:1836–40. Ensminger WD, Gyves JW. Regional chemotherapy of neoplastic diseases. Pharmacol Ther 1983;21:277–93. Ensminger WD, Rosowsky A, Raso V, et al. A clinical-pharmacological evaluation of hepatic arterial infusions of 5-fluoro-2′deoxyuridine and 5-fluorouracil. Cancer Res 1978;38:3784–92. Blackshear PJ, Dorman FD, Blackshear PL Jr, Varco RL, Buchwald H. A permanently implantable self-recycling low flow constant rate multipurpose infusion pump of simple design. Surg Forum 1970;21:136–7. Blackshear PJ, Dorman FD, Blackshear PL Jr, Varco RL, Buchwald H. The design and initial testing of an implantable infusion pump. Surg Gynecol Obstet 1972;134:51–6. Blackshear PJ, Rohde TD, Varco RL, Buchwald H. One year of continuous heparinization in the dog using a totally implantable infusion pump. Surg Gynecol Obstet 1975;141:176–86. Niederhuber JE, Ensminger WD. Surgical considerations in the management of hepatic neoplasia. Semin Oncol 1983;10: 135–47. Curley SA, Hohn DC, Roh MS. Hepatic artery infusion pumps: cannulation techniques and other surgical considerations. Langenbecks Arch Chir 1990;375: 119–24. Kaplan WD, Come SE, Takvorian RW, et al. Pulmonary uptake of technetium 99m macroaggregated albumin: a predictor of gastrointestinal toxicity during hepatic artery perfusion. J Clin Oncol 1984;2:1266–9. Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999;341:2039–48. Allen PJ, Nissan A, Picon AI, et al. Technical complications and durability of hepatic artery infusion pumps for unresectable colorectal liver metastases: an institutional experience of 544 consecutive cases. J Am Coll Surg 2005;201:57–65. Curley SA, Chase JL, Roh MS, Hohn DC. Technical considerations and complications associated with the placement of 180 implantable hepatic arterial infusion devices. Surgery 1993;114: 928–35. Collins JM. Pharmacologic rationale for regional drug delivery. J Clin Oncol 1984;2:498–504. Arteaga CL, Baselga J. Clinical trial design and end points for epidermal growth factor receptor-targeted therapies: implica-

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tions for drug development and practice. Clin Cancer Res 2003;9:1579–89. Ensminger WD. Intrahepatic arterial infusion of chemotherapy: pharmacologic principles. Semin Oncol 2002;29:119– 25. Steele G Jr, Ravikumar TS. Resection of hepatic metastases from colorectal cancer. Biologic perspective. Ann Surg 1989;210:127–38. Wagner JS, Adson MA, Van Heerden JA, Adson MH, Ilstrup DM. The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann Surg 1984;199:502–8. Clavien PA, Petrowsky H, DeOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 2007;356:1545–59. Chang AE, Schneider PD, Sugarbaker PH, Simpson C, Culnane M, Steinberg SM. A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Ann Surg 1987;206:685–93. Kemeny N, Daly J, Reichman B, Geller N, Botet J, Oderman P. Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma. A randomized trial. Ann Intern Med 1987;107:459–65. Hohn DC, Stagg RJ, Friedman MA, et al. A randomized trial of continuous intravenous versus hepatic intraarterial floxuridine in patients with colorectal cancer metastatic to the liver: the Northern California Oncology Group trial. J Clin Oncol 1989; 7:1646–54. Martin JK Jr, O’Connell MJ, Wieand HS, et al. Intra-arterial floxuridine vs systemic fluorouracil for hepatic metastases from colorectal cancer. A randomized trial. Arch Surg 1990;125: 1022–7. Wagman LD, Kemeny MM, Leong L, et al. A prospective, randomized evaluation of the treatment of colorectal cancer metastatic to the liver. J Clin Oncol 1990;8: 1885–93. Rougier P, Laplanche A, Huguier M, et al. Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial. J Clin Oncol 1992;10:1112–8. Allen-Mersh TG, Earlam S, Fordy C, Abrams K, Houghton J. Quality of life and survival with continuous hepatic-artery floxuridine infusion for colorectal liver metastases. Lancet 1994;344:1255–60. Lorenz M, Muller HH. Randomized, multicenter trial of fluorouracil plus leucovorin administered either via hepatic arterial or intravenous infusion versus fluorodeoxyuridine administered via hepatic arterial infusion in patients with nonresectable liver metastases from colorectal carcinoma. J Clin Oncol 2000;18:243–54. Kerr DJ, McArdle CS, Ledermann J, et al. Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial. Lancet 2003;361:368–73. Kemeny NE, Niedzwiecki D, Hollis DR, et al. Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol 2006; 24:1395–403.

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35 Mocellin S, Pilati P, Lise M, Nitti D. Meta-analysis of hepatic arterial infusion for unresectable liver metastases from colorectal cancer: the end of an era? J Clin Oncol 2007;25:5649–54. 36 Folprecht G, Grothey A, Alberts S, Raab HR, Köhne CH. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol 2005;16:1311–9. 37 Kemeny N, Jarnagin W, Gonen M, et al. Phase I/II study of hepatic arterial therapy with floxuridine and dexamethasone in combination with intravenous irinotecan as adjuvant treatment after resection of hepatic metastases from colorectal cancer. J Clin Oncol 2003;21:3303–9. 38 Kemeny N, Conti JA, Cohen A, et al. Phase II study of hepatic arterial floxuridine, leucovorin, and dexamethasone for unresectable liver metastases from colorectal carcinoma. J Clin Oncol 1994;12:2288–95. 39 Adam R, Avisar E, Ariche A, et al. Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 2001;8:347–53. 40 Alberts SR, Horvath WL, Sternfeld WC, et al. Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase II study. J Clin Oncol 2005;23:9243–9. 41 Abad A, et al. Resectability of liver metastases (LM) in patients with advanced colorectal cancer (ACRA) after treatment with the combination of oxaliplatin (OXA), irinotecan (IRI) and 5FU. Final results of a phase II study. ASCO Annual Meeting 2005, Orlando, Florida. 42 Quenet F, et al. Resection of previously unresectable liver metastases from colorectal cancer (LMCRC) after chemotherapy (CT) with CPT-11/L-OHP/LV5FU (Folfirinox): A prospective phase II trial. ASCO Annual Meeting 2004, New Orleans, Louisiana, USA. 43 Adam R, Aloia T, Lévi F, et al. Hepatic resection after rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy. J Clin Oncol 2007;25:4593–602. 44 Kemeny NN, et al. Phase I study of hepatic arterial infusion of floxuridine and dexamethasone with systemic irinotecan for unresectable hepatic metastases from colorectal cancer. J Clin Oncol 2001;19:2687–95. 45 Kemeny N, Jarnagin W, Paty P, et al. Phase I trial of systemic oxaliplatin combination chemotherapy with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer. J Clin Oncol 2005;23:4888–96. 46 Clavien PA, Selzner N, Morse M, Selzner M, Paulson E. Downstaging of hepatocellular carcinoma and liver metastases from colorectal cancer by selective intra-arterial chemotherapy. Surgery 2002;131:433–42. 47 Gallagher DJ, Capanu M, Raggio G, Kemeny N. Hepatic arterial infusion plus systemic irinotecan in patients with unresectable hepatic metastases from colorectal cancer previously treated with systemic oxaliplatin: a retrospective analysis. Ann Oncol 2007;18:1995–9. 48 Kemeny N, Huitzil Melendez FD, Capanu M, et al. Conversion to resectability using hepatic artery infusion plus systemic chem-

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58 59

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61 62

otherapy for the treatment of unresectable liver metastases from colorectal carcinoma. J Clin Oncol 2009;27:3465–71. Ducreux M, Ychou M, Laplanche A, et al. Hepatic arterial oxaliplatin infusion plus intravenous chemotherapy in colorectal cancer with inoperable hepatic metastases: a trial of the gastrointestinal group of the Federation Nationale des Centres de Lutte Contre le Cancer. J Clin Oncol 2005;23:4881–7. Topal B, Kaufman L, Aerts R, Penninckx F, et al. Patterns of failure following curative resection of colorectal liver metastases. Eur J Surg Oncol 2003;29:248–53. Fong Y. Surgical therapy of hepatic colorectal metastasis. CA Cancer J Clin 1999;49:231–55. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230:309–18; discussion 318–21. Mitry E, Fields AL, Bleiberg H, et al. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol 2008,26:4906–11. Tono T, Hasuike Y, Ohzato H, Takatsuka Y, Kikkawa N. Limited but definite efficacy of prophylactic hepatic arterial infusion chemotherapy after curative resection of colorectal liver metastases: A randomized study. Cancer 2000;88:1549–56. Lorenz M, Müller HH, Schramm H, et al. Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen). Ann Surg 1998;228:756–62. Kemeny M, Adak S, Gray B, et al. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy – an intergroup study. J Clin Oncol 2002;20:1499–505. Lygidakis NJ, Sgourakis G, Vlachos L, et al. Metastatic liver disease of colorectal origin: the value of locoregional immunochemotherapy combined with systemic chemotherapy following liver resection. Results of a prospective randomized study. Hepatogastroenterology 2001;48:1685–91. Kemeny NE, Gonen M. Hepatic arterial infusion after liver resection. N Engl J Med 2005;352:734–5. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008; 371:1007–16. Kemeny N, Capanu M, D’Angelica M, et al. Phase I trial of adjuvant hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone plus systemic oxaliplatin, 5-fluorouracil and leucovorin in patients with resected liver metastases from colorectal cancer. J Clin Oncol 2009;27:3465–71 Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–90. Nehls O, Oettle H, Hartmann JT, et al. Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial. Br J Cancer 2008;98:309–15.

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63 Jarnagin WR, Gultekin DH, Gönen M, et al. Hepatic arterial infusional (HAI) therapy in patients with unresectable primary liver cancer: Use of dynamic contrast enhanced MRI to evaluate response. J Clin Oncol 26(Suppl 20):abstr 4597. 64 Folprecht G, Harmann JT, et al. Randomized multicenter study of cetuximab plus folfox or plus folfiri in neoadjuvant treatment of non-resectable colorectal liver metastases (CELIM-study). Ann Oncol 2008;19(Suppl 8):abstr 510PD.

Self-assessment answers 1 2 3 4 5

A, C A, A, A,

C C C, D, E C

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15

Isolated Hepatic Perfusion and Percutaneous Hepatic Perfusion Charles K. Heller III1, James F. Pingpank2, and Steven K. Libutti3 1

Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA 3 Department of Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, New York, NY, USA 2

Patients with unresectable liver tumors pose a treatment challenge for physicians. Options for patients with these tumors are systemic treatments, regional therapies, or local ablative therapy, such as cryotherapy, radiofrequency ablation (RFA) or ethanol injection. Additionally, infusional therapy like hepatic arterial infusion (HAI), chemoembolization, isolated hepatic perfusion (IHP), or more recently, percutaneous hepatic perfusion (PHP) may also play a role. This chapter will focus on isolated hepatic perfusion in the context of different cancer histologies, the agents used, and the experience gained at centers specialized in this procedure. It will also focus on interventional percutaneous perfusion of the liver and outcomes to date, as well as future directions.

Isolated hepatic perfusion The rationale for IHP begins with its ability to deliver an isolated treatment to the diseased liver, while sparing the rest of the body. The patients selected for IHP have cancer that is otherwise unresectable. The goal is to maximize the delivery of the therapy to the tumors and to minimize systemic toxicity. The liver can tolerate significantly higher doses of chemotherapy than other organs such as the gastrointestinal tract and the bone marrow. Since the liver is the sole or dominant site of disease in many metastatic settings, as well as in hepatocellular carcinoma (HCC), a regional strategy is a rational approach. The liver has a unique blood supply which makes it a favorable site for regional therapy. This is accomplished by delivering chemotherapy via complete separation of the regional hepatic and systemic circulation. As part of a preoperative work-up for the procedure, patients have standard imaging to rule out other sites of disease. If they have had previous HAI or chemoemboliza-

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

164

tion, an arteriogram (or magnetic resonance angiogram) is performed to confirm anatomic vascular relationships. Also, in order to be considered eligible for the procedure, patients must have enough healthy liver parenchyma to undergo the procedure. Some patients require a liver biopsy to confirm that the liver has not entirely been replaced with cancer. An exploratory laparotomy is carried out through a bilateral subcostal incision in order to detect the presence of carcinomatosis or other occult extrahepatic disease that would be a contraindication to proceeding. If encountered, periportal lymph nodes are resected and do not exclude treatment. The liver is mobilized to ensure complete vascular isolation and to avoid systemic leak. The retrohepatic inferior vena cava (IVC) is dissected from the level of the renal veins to the diaphragm and systemic venous tributaries are ligated. A cholecystectomy is performed to prophylactically guard against chemical cholecystitis. The patient is anticoagulated with heparin and activated clotting time is monitored to maintain therapeutic levels above 200 s throughout the procedure. After anticoagulation a venovenous bypass system is set up by cannulating the saphenous, portal, and axillary veins in order to maintain systemic circulation. The liver is then prepared to be perfused via an extracorporeal circuit with roller pump, heat exchanger, and oxygenator (Figure 15.1). Next, the IHP circuit is constructed. The perfusion inflow circuit is connected to a cannula in the gastroduodenal artery and outflow is established by a cannula in the right femoral vein. The agent can then be perfused at relatively stable dosing and temperature parameters. This isolation also makes it possible to achieve clinically relevant degrees of hyperthermia. Some studies have supported the concept that hyperthermia can kill tumor cells at tissue temperatures that are not toxic to normal cells [1, 2]. Under hyperthermic treatment the hepatic tissue is maintained between 39.5 and 40 °C. After the perfusion has finished, the liver is flushed with both colloid and crystalloid. Blood flow is then quickly reestablished to the liver. Circulating levels of drug are minimal or absent after treatment. Multiple agents have been tested in the past, including doxorubicin, cisplatin, mitomycin C, floxuridine (FUDR),

CHAPTER 15

Isolated Hepatic Perfusion and Percutaneous Hepatic Perfusion

Axillary vein

Outflow IVC

Gastroduodenal artery Superior mesenteric vein Inflow

Perfusion circuit

Veno–venous bypass

Saphenous vein

interferon-alpha (IFN-α), and adriamycin [3–5]. Over the past two decades at the National Cancer Institute (NCI), melphalan hydrochloride has been found to be superior in this form of therapy. It belongs to the class of nitrogen mustard alkylating agents and it has a steep dose–response curve over a short exposure time. It is also effective against many of the cancers that metastasize to the liver. All of these characteristics make this agent useful in IHP. Under surgical isolation, a dose of 1.5 mg/kg has been determined to be safe and effective for treating hepatic metastases. An important feature of IHP is that it can deliver high enough drug levels in the liver for a sustained period of time to achieve an effect. The maximal tolerated dose of the therapeutic agent is limited by the tissue tolerance of the liver. The maximum tolerated dose of melphalan was deter-

Figure 15.1 The isolated hepatic perfusion circuit. Arterial inflow is via the cannulated gastroduodenal artery, while venous outflow is collected from the hepatic veins via a cannula placed in the inferior vena cava (IVC). A veno–venous bypass circuit shunts blood from the portal vein and infrahepatic IVC to the systemic circulation.

mined during an NCI phase I clinical trial where the doselimiting toxicity of veno-occlusive disease (VOD) and coagulopathy was observed at 2 mg/kg. Tumors in the liver derive the majority of their blood flow from the arterial system. Normal hepatocytes receive 25% of their blood supply from the hepatic artery and the rest through the portal circulation [6–8]. This method of delivery treats the entire organ, even subclinical micrometastases, unlike local ablative or embolization procedures which can only target measurable tumors. Using this technique, overall objective response rates have been obtained when treating many different cancers. The most common toxicities are increased creatinine, increased transaminase levels, thrombocytopenia, and weight gain, which are transient and resolve with minimal

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Table 15.1 Summary of isolated hepatic perfusion trials (adapted from [47]). Authors

Year

Ausman [31], Ausman & Aust [38] Aigner et al [39] Skibba & Quebbeman [40] Schwemmle et al [41]

1961

n

Agent

Dose

Temperature (°C)

Results

5

Nitrogen mustard

0.2–0.4 mg/kg

37

No response data

1984 1986 1987

32 8 50

Median survival 8 months 5/6 responders CR: 9% PR: 68%

1998

29

40

20% PR

Marinelli et al [43] van Zuidewign et al [49] Devries et al [50]

1996 1993 1995

9 24 9

37 37 41

21% RR 41% RR 5/6 PR

Hafstrom et al [44]

1998

11

39

3/11 PR

Oldhafer et al [45, 46]

1998

6

700–1100mg – 300–1250 mg 5–50 mg 50 mg 0.5 mg/kg 0.5 mg/kg 30 mg/m2 0.5–4 mg/kg 1 mg/kg 0.4 mg 0.8 mg 0.5 mg/kg 30–200 μg 60–140 mg 200–300 μg

39.5–40 42–42.5 39–39.5

Hafstrom & Naredi [42]

5-FU Hyperthermia only 5-FU Mitomycin C Cisplatin Melphalan Cisplatin Mitomycin C Melphalan Melphalan TNF TNF alone Melphalan TNF Melphalan TNF

40–41

1/6 CR 2/6 PR

PR, partial response; CR, complete response; RR, response rate; 5-FU, 5-fluorouracil; TNF, tumor necrosis factor.

intervention. The most serious toxicity that a patient can encounter is VOD and fulminant hepatic failure.

Clinical experience IHP was first clinically developed almost 50 years ago. Since then a small number of institutions have reported a limited series of trials using IHP alone or with hyperthermia. It was during these initial trials that the morbidity associated with the procedure was observed. In the early experience with IHP, due to small numbers of patients treated, it was not evident that the benefits outweighed the toxicity (Table 15.1). In 1998, a more modern experience with IHP was reported. Thirty-four patients with primarily colorectal cancer and a few mixed histologies were treated with the combination of melphalan and tumor necrosis factor (TNF). There was a 75% response rate with a 3% complete response, and a 72% partial response with a mean duration of response of 9 months [9]. Mortality was less than 5%. Another study compared melphalan alone versus melphalan plus TNF in 22 patients with ocular melanoma. Malignant melanoma represents one of the fastest growing cancers in the United States with over 62 000 new cases per year [10]. Primary ocular melanoma represents approximately 4.25% of all melanomas [11]. Despite advances in medical care, the mortality associated with ocular melanoma has not altered over the past 25 years [11]. Hepatic metastases occur in roughly half of patients with ocular melanoma. Once this occurs, median survival is months with overall 1-year survival around 10% [12]. Several chemotherapeutic options

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such as dacarbazine, cisplatin, or antiangiogenic agents have been administered; however, none has impacted survival. IHP has been used to treat liver metastases and tumor progression. Isolated hepatic metastases from ocular melanoma were treated with hyperthermic melphalan plus TNF. There was a 62% objective response rate with a 9.5% complete response and a 52% partial response [13]. In 2003, a followup study reported on 29 patients with ocular melanoma treated using melphalan alone at 1.5 mg/kg and found a 10% complete response and a 52% partial response [14]. Conventional management of patients with stage IV colorectal cancer has been directed at palliation. Chemotherapy is considered to be the standard treatment and, while improvements in median survival have been reported, there is little impact on overall 5-year survival. Current natural history studies report that patients with untreated liver metastases have a median survival of 5 months with almost no 5-year survival [15]. Metastasectomy of hepatic metastases has yielded survival rates ranging from 37% at 5 years to 22% at 10 years [16]. Standard of care for primary disease is well established; however, 25% of patients with colorectal cancer present with metastases at the time of staging [17, 18]. During the natural course of colorectal cancer up to 50% of patients will develop liver metastases and only 20% will be resectable at presentation [19]. For patients with unresectable colorectal metastases to the liver who have progressed through standard systemic therapies there remain few options. In one NCI study, 50 patients, primarily with colorectal cancer, were treated with IHP using melphalan plus TNF. There was a 75% response rate

CHAPTER 15

Isolated Hepatic Perfusion and Percutaneous Hepatic Perfusion

(2% complete response and 73% partial response) with a median time to recurrence of 6 months [20]. In another study, 51 patients underwent melphalan plus TNF versus melphalan alone followed by HAI of FUDR and leucovorin. This was started 6 weeks after surgery and given monthly for 14 days. The objective response rate was 76% with a median duration of 10.5 months. Median survival was 16 months for IHP alone and 14.5 months after IHP and HAI [21]. An additional study looked at seven patients with colorectal cancer who were treated by IHP after not responding to earlier regional HAI or systemic therapy. There were three cohorts consisting of melphalan alone, TNF alone, or melphalan plus TNF. There was an overall 71% objective response rate with median duration of response of 10 months. Two patients did not respond and both had been treated with TNF alone [22]. IHP can be effective in patients resistant to other therapies. Twenty-five patients with colorectal cancer who progressed after 5-flurouracil (5-FU), leucovorin, and irinotecan were retreated by IHP with melphalan and had an objective response rate of 64%. These data suggest that this particular agent delivered to the liver could be an effective second-line regional therapy after many of the current first- and secondline systemic chemotherapy regimens for colorectal cancer have failed. These trials are summarized in Table 15.2. Metastatic neuroendocrine tumors (MNET) isolated to the liver have also been studied using IHP. Between 1993 and 2003 13 patients with unresectable liver-only MNET received IHP with or without TNF. An overall response rate of 50% was seen with a median survival of 28 months [23]. Figure 15.2 shows the computed tomography (CT) scan of a single patient on the trial and demonstrates the response. IHP has been used also to treat primary HCC. Primary HCC is the most prevalent liver cancer in the world [24]. Currently, there are several approaches to treat patients

with HCC, however, surgical methods offer the only chance for cure. Surgical approaches include anatomic or nonanatomic resection as well as orthotopic liver transplantation. HCC is amenable to resection if the remaining hepatic remnant has adequate functional reserve, the operation is technically feasible, and there is no evidence of extrahepatic spread. Generally, indications for liver transplant in the HCC patient include tumors of less than 5 cm that are unresectable, less than three intrahepatic tumors, and absence of extrahepatic spread [24]. Recurrence is common in patients who undergo liver resection for HCC and may reflect the multicentricity of this disease or inadequacy of the resection. Five-year survival after resection in early-stage cancer is 60% [25]. Liver transplantation may yield 5-year survival rates approaching 70% and have a lower recurrence rate [25]. For some patients, high operative risk from cirrhosis and poor functional status preclude an operation. Other treatment options for HCC patients who are not operative candidates include chemoembolization, ethanol ablation, cryoablation, and RFA of lesions. Like many regional therapies, however, they are restricted by both the number and size of the lesions which they can safely treat. This patient population could potentially benefit from a whole organ therapy such as IHP. Compared to systemic chemotherapy, isolated perfusion has produced more promising results. Several agents, including doxorubicin, cisplatin, mitomycin C, FUDR, and IFN-α, have produced objective responses of 30–50% in these patients [26–29]. Early animal studies determined that adriamycin is an effective agent for this cancer [30]. A clinical pilot study confirmed that adriamcyin is an effective agent for patients with HCC. Tumor regression was seen and median survival was 12 months, whereas median survival in nonresponders was only 5 months [4]. IHP has been under clinical investigation for almost 50 years; however, it is still not widely practiced because it is a

Table 15.2 Recent National Institutes of Health experience with isolated hepatic perfusion (adapted from [47]). Authors

Year

n

Agent

Dose

Histology

Results

Alexander et al [9, 48] Alexander et al [13] Libutti et al [20]

1998

34

Melphalan/TNF

1.5 mg/kg and 1 mg

75% RR

2000

Melphalan Melphalan/TNF Melphalan/TNF

1.5–2.5 mg/kg and 1 mg

2000

11 11 50

Mixed histology (primarily colorectal) Ocular melanoma

75% RR

Bartlett et al [21]

2001

32

2002

Colorectal cancer

71% RR

Alexander et al [14]

2003

2 7 29

1.5 mg/kg and 1 mg 1.5mg/kg and 0.2 mg/kg/day and 15 mg/m2/day 0.6 mg, 1 mg 1.5 mg/kg ± 1 mg 1.5 mg/kg

76% RR all groups

Alexander et al [22]

Melphalan/TNF Melphalan/FUDR/ leucovorin TNF Melphalan/TNF Melphalan

Mixed histology (primarily colorectal) Colorectal

Ocular melanoma

10% CR 52% PR

1.5 mg/kg and 1 mg

62% RR both groups

PR, partial response; CR, complete response; RR, response rate, 5-FU, 5-fluorouracil; FUDR, floxuridine; TNF, tumor necrosis factor.

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Pre-IHP: May 2004

Post-IHP: October 2006 Figure 15.2 CT scans demonstrating the effect of isolated hepatic perfusion on neuroendocrine tumor metastatic to the liver at baseline (top row) and 2 years after treatment (bottom row).

demanding procedure with associated morbidity and its efficacy was questioned in early studies [31]. Regional delivery of high dose melphalan has been demonstrated to be safe and effective in stage IV disease confined to the liver for several different types of cancer. Experience has demonstrated that IHP using melphalan alone or in combination with TNF can have response rates of 50–70%, depending on the histology, with acceptable operative morbidity and mortality [32]. While the response rates of IHP are promising, the amount of effort and the resources needed to both perform surgery on these patients as well as care for them postoperatively has limited the acceptance of this procedure. IHP is an operation that can only be performed once. Additional attempts are limited by the potential loss of a viable arterial cannulation site for infusion and by postoperative adhesions around portal structures and the vena cava. The future of IHP may hold its greatest benefit in phase I clinical trials where complete separation of the portal and systemic circulations are achieved, or in a cancer where a one-time second-line therapy could improve survival.

Percutaneous hepatic perfusion With the advent of interventional procedures came the development of PHP, which has many advantages over IHP. One of the most important advantages possibly is the ability

168

for repeated dosing of an agent without the morbidity of an open surgical procedure. It also allows a higher concentration of drug to be delivered to the liver. One drawback, however, is that this does produces higher systemic drug levels and patients develop transient bone marrow toxicity secondary to the intervention. Phase II and III studies are currently underway at the National Institutes of Health (NIH) to evaluate PHP using melphalan in patients with metastatic disease to the liver. A detailed outline of the PHP procedure has been described [33]. The procedure requires all patients to be under general anesthesia with endotracheal tube intubation. Central venous access is obtained in bilateral jugular veins and the right femoral vein. The right femoral artery is cannulated for access to the visceral arterial system. Invasive systemic arterial monitoring is used for potential hemodynamic changes. The use of vasopressors is often required upon inflation of the balloons and the initiation of the charcoal filters. Insertion of a double balloon IVC catheter system (Delcath Systems Inc, New York, NY, USA) isolates the IVC above and below the hepatic veins but still allows some blood to flow through the central lumen of the catheter from the IVC to the right atrium (Figure 15.3a,b). Hepatic delivery of melphalan is accomplished via the hepatic artery through a percutaneously inserted catheter under standard fluoroscopic guidance. Hepatic venous outflow is collected and melphalan-dosed blood from the central lumen is pumped

CHAPTER 15

Isolated Hepatic Perfusion and Percutaneous Hepatic Perfusion

(b)

Blood flow

Filters (c)

Delcath double balloon catheter Flow probe Pump head

(a)

Delcath introducer set

Figure 15.3 The percutaneous hepatic perfusion (PHP) circuit. (a) Diagram of the Delcath Catheter System (Delcath Systems Inc, New York, NY, USA) and the set-up of the PHP circuit. (b) Depiction of the control of the hepatic venous outflow via a double balloon catheter in the retrohepatic inferior vena cava. (c) Fluoroscopic venogram of the occluded inferior vena cava.

through an extracorporeal exchange circuit and drug filtration cartridges. The filtered blood is returned to the systemic circulation via the cannulated internal jugular vein. An IVC venogram is performed to confirm there is no systemic leak (Figure 15.3c). Also, a complete visceral angiogram is done to check for small branches to the liver. Any small branches are embolized if present. Melphalan is given over a period of 30 min and, following infusion, the extracorporeal filtration circuit is allowed to run an additional 30 min. Cryoprecipitate and protamine are given at the end of the procedure to reverse the effects of heparin and all sheaths are removed. The patient is monitored in the intensive care unit for 12 h and then transferred to the floor. Most patients are discharged home on postoperative day 2.

Current experience In a phase I study PHP the initial melphalan dose was increased from 2 to 3.5 mg/kg, at which point dose-limiting toxicities were observed in two of six patients. The safe and

effective dose of melphalan was determined to be 3.0 mg/ kg. An overall objective response rate was observed in 30% of treated patients. A different study accrued 21 patients with MNETs to the liver. The PHP treatment course consisted of four perfusions every 28–35 days. Twenty patients received 36 treatments (median three per patient) and overall objective responses were seen in 12 of 16 evaluable patients (75%; complete response 2; partial response, 10) with one additional patient having a durable minor response for 43 months. An example of a response in one patient with poorly differentiated neuroendocrine tumor metastatic to the liver is shown in Figure 15.4. Reversible grade 3/4 bone marrow toxicities were observed in 78% of patients. The mean hospital stay was 2.5 days [34]. Hepatic metastases are seen in 25–90% of patients who present with MNETs. The presence or absence of liver metastases is the main determinant of overall prognosis. Response rates with melphalan and IHP have been reported to be as

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Pre-PHP: December 15, 2005

Post-PHP #2: April 11, 2006 Figure 15.4 CT scans of a patient with a poorly differentiated metastatic neuroendocrine tumor who demonstrated a clinical response after two percutaneous hepatic perfusion treatments. The baseline scans (top row) are compared to follow-up scans after a 6-month interval (bottom row), showing regression of disease.

high as 50% [23, 35]. Surgery with curative intent should be considered in patients with MNET whenever possible, but metastases are usually diffuse at diagnosis. The rate of progression of liver metastases is also important and should be taken into account when choosing a treatment strategy. Chemotherapy with 5-FU, anthracyclines, and streptozotocin has very little efficacy in treating these patients with hepatic metastases [36]. In another study of patients with metastatic melanoma to the liver, 15 patients received 48 treatments (mean 3.1 per patient). An objective response rate of 77% (complete response, 2; partial response, 8) was observed in 13 evaluable patients. The median hepatic progression-free survival in treated patients was 12 months. The mean hospital stay was 2.5 days per treatment.

Conclusion From its first description as a novel approach almost 50 years ago, IHP has evolved from an extensive open surgical procedure, to the emerging technique of PHP, which involves the use of percutaneous catheters. This procedure now takes place in an interventional radiology suite with minimal morbidities to the patient. The future of hepatic perfusion will continue to grow by testing the delivery of new agents and expanding the number of cancers it can treat. Recently, a

170

phase I study was completed at the University of Pittsburgh to evaluate oxaliplatin (with hyperthermia) using IHP plus HAI to treat patients with unresectable liver metastases from colorectal cancer. The overall response rate in this small phase I study was encouraging [37]. The question is raised as to where this treatment now fits with the current management of patients with colorectal cancer. In the future, it may be viewed in a treatment algorithm similar to resection of liver metastases. Testing biologic agents, new filter systems, and the addition of hyperthermia to PHP are also on the horizon. While complete response in some metastatic tumors may not be achievable, there are some patients who benefit from the sustained partial responses that PHP can offer. For diseases such as ocular melanoma with a short mean survival, this therapy could provide great benefit and possibly have a meaningful impact on survival. There are some patients with MNETs who have experienced durable 5-year responses following this treatment. The ability to retreat patients with many different cancers will be a great leap forward in the treatment of widespread metastases confined to the liver. This new interventional technique could be performed in hospital settings in the community with short hospitalizations and minimal morbidity. The benefits of PHP have resulted in its supplanting IHP as the procedure of choice for the isolated infusion of agents to the liver in patients with unresectable hepatic cancers.

CHAPTER 15

Isolated Hepatic Perfusion and Percutaneous Hepatic Perfusion

Self-assessment questions

References

1 For which one of the following reasons has isolated hepatic perfusion not been widely accepted into clinical practice? A There are not enough patients with disease located only in the liver B The response rates in the liver are no different from those from systemic chemotherapy C The procedure is technically demanding and can only be performed once D Most cancer histologies do not respond to this type of treatment E Patients are subject to long-term morbidity from liver and bone marrow toxicity

1 van der Zee J, Kroon BB, Nieweg OE, van de Merwe SA, Kampinga HH. Rationale for different approaches to combined melphalan and hyperthermia in regional isolated perfusion. Eur J Cancer 1997;33:1546–50. 2 Bates DA, Mackillop WJ. The effect of hyperthermia in combination with melphalan on drug-sensitive and drug-resistant CHO cells in vitro. Br J Cancer 1990;62:183–8. 3 Lazarus HM, Herzig RH, Graham-Pole J, et al. Intensive melphalan chemotherapy and cryopreserved autologous bone marrow transplantation for the treatment of refractory cancer. J Clin Oncol 1983;1:359–67. 4 Ku Y, Fukumoto T, Iwasaki T, et al. Clinical pilot study on highdose intraarterial chemotherapy with direct hemoperfusion under hepatic venous isolation in patients with advanced hepatocellular carcinoma. Surgery 1995;117:510–9. 5 Doll DC, Weiss RB, Issell BF. Mitomycin: ten years after approval for marketing. J Clin Oncol 1985;3:276–86. 6 Sigurdson ER, Ridge JA, Kemeny N, Daly JM. Tumor and liver drug uptake following hepatic artery and portal vein infusion. J Clin Oncol 1987;5:1836–40. 7 Breedis C, Young G. The blood supply of neoplasms in the liver. Am J Pathol 1954;30:969–77. 8 Lien WM, Ackerman NB. The blood supply of experimental liver metastases. II. A microcirculatory study of the normal and tumor vessels of the liver with the use of perfused silicone rubber. Surgery 1970;68:334–40. 9 Alexander HR Jr, Bartlett DL, Libutti SK, Fraker DL, Moser T, Rosenberg SA. Isolated hepatic perfusion with tumor necrosis factor and melphalan for unresectable cancers confined to the liver. J Clin Oncol 1998;16:1479–89. 10 Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71–96. 11 Singh AD, Damato B, Howard P, Harbour JW. Uveal melanoma: genetic aspects. Ophthalmol Clin North Am 2005;18:85–97, viii. 12 Grover A, Alexander HR Jr. The past decade of experience with isolated hepatic perfusion. Oncologist 2004;9:653–64. 13 Alexander HR, Libutti SK, Bartlett DL, Puhlmann M, Fraker DL, Bachenheimer LC. A phase I–II study of isolated hepatic perfusion using melphalan with or without tumor necrosis factor for patients with ocular melanoma metastatic to liver. Clin Cancer Res 2000;6:3062–70. 14 Alexander HR Jr, Libutti SK, Pingpank JF, et al. Hyperthermic isolated hepatic perfusion using melphalan for patients with ocular melanoma metastatic to liver. Clin Cancer Res 2003;9:6343–9. 15 McMillan DC, McArdle CS. Epidemiology of colorectal liver metastases. Surg Oncol 2007;16:3–5. 16 Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230:309–18; discussion 18–21. 17 Ragnhammar P, Hafstrom L, Nygren P, Glimelius B. A systematic overview of chemotherapy effects in colorectal cancer. Acta Oncol 2001;40:282–308. 18 Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000;343:905–14.

2 For which types of cancer have response rates for isolated hepatic perfusion been established to be greater than 60%? (more than one answer is possible) A Metastatic colorectal cancer B Renal cell cancer C Primary hepatic malignancies D Gastric adenocarcinoma E Ocular melanoma 3 Percutaneous hepatic perfusion may gain widespread acceptance as a treatment that can be applied multiple times because patients can have this done on an outpatient basis. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 4 Which of the following are common toxicities associated with isolated hepatic perfusion? (more than one answer is possible) A Cholecystitis B Increased creatinine C Veno-occlusive disease D Increased ALT/AST E Thrombocytopenia 5 Which dose of melphalan has been found to be safe and effective for isolated hepatic perfusion with or without tumor necrosis factor? A 2.5 mg/kg B 3.5 mg/kg C 1 mg/kg D 1.5 mg/kg E 0.5 mg/kg

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19 Lochan R, White SA, Manas DM. Liver resection for colorectal liver metastasis. Surg Oncol 2007;16:33–45. 20 Libutti SK, Barlett DL, Fraker DL, Alexander HR. Technique and results of hyperthermic isolated hepatic perfusion with tumor necrosis factor and melphalan for the treatment of unresectable hepatic malignancies. J Am Coll Surg 2000;191:519–30. 21 Bartlett DL, Libutti SK, Figg WD, Fraker DL, Alexander HR. Isolated hepatic perfusion for unresectable hepatic metastases from colorectal cancer. Surgery 2001;129:176–87. 22 Alexander HR Jr, Libutti SK, Bartlett DL, et al. Hepatic vascular isolation and perfusion for patients with progressive unresectable liver metastases from colorectal carcinoma refractory to previous systemic and regional chemotherapy. Cancer 2002;95:730–6. 23 Grover AC, Libutti SK, Pingpank JF, Helsabeck C, Beresnev T, Alexander HR Jr. Isolated hepatic perfusion for the treatment of patients with advanced liver metastases from pancreatic and gastrointestinal neuroendocrine neoplasms. Surgery 2004;136:1176–82. 24 Cormier JN, Thomas KT, Chari RS, Pinson CW. Management of hepatocellular carcinoma. J Gastrointest Surg 2006;10:761– 80. 25 Poon RT. Liver transplantation for solitary hepatocellular carcinoma less than 3 cm in diameter in Child A cirrhosis. Dig Dis 2007;25:334–40. 26 Kajanti M, Pyrhonen S, Mantyla M, Rissanen P. Intra-arterial and intravenous use of 4′ epidoxorubicin combined with 5-fluorouracil in primary hepatocellular carcinoma. A randomized comparison. Am J Clin Oncol 1992;15:37–40. 27 Atiq OT, Kemeny N, Niedzwiecki D, Botet J. Treatment of unresectable primary liver cancer with intrahepatic fluorodeoxyuridine and mitomycin C through an implantable pump. Cancer 1992;69:920–4. 28 Patt YZ, Yoffe B, Charnsangavej C, et al. Low serum alphafetoprotein level in patients with hepatocellular carcinoma as a predictor of response to 5-FU and interferon-alpha-2b. Cancer 1993;72:2574–82. 29 Sangro B, Rios R, Bilbao I, et al. Efficacy and toxicity of intraarterial cisplatin and etoposide for advanced hepatocellular carcinoma. Oncology 2002;62:293–8. 30 Curley SA, Byrd DR, Newman RA, et al. Reduction of systemic drug exposure after hepatic arterial infusion of doxorubicin with complete hepatic venous isolation and extracorporeal chemofiltration. Surgery 1993;114:579–85. 31 Ausman RK. Development of a technic for isolated perfusion of the liver. N Y State J Med 1961;61:3993–7. 32 Alexander HR Jr, Bartlett DL, Libutti SK. Current status of isolated hepatic perfusion with or without tumor necrosis factor for the treatment of unresectable cancers confined to liver. Oncologist 2000;5:416–24. 33 Pingpank JF, Libutti SK, Chang R, et al. Phase I study of hepatic arterial melphalan infusion and hepatic venous hemofiltration using percutaneously placed catheters in patients with unresectable hepatic malignancies. J Clin Oncol 2005;23:3465– 74. 34 Pingpank J, Alexander H, Libutti S, et al. Percutaneous hepatic perfusion (PHP) with melphalan for patients with metastatic neuroendocrine tumors (MNET) to the liver. HPB 2008;10 (Suppl 2):83.

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35 Lise M, Pilati P, Da Pian P, et al. Hyperthermic isolated liver perfusion for unresectable liver cancers: pilot study. J Chemother 2004;16 (Suppl 5):37–9. 36 O’Toole D, Ruszniewski P. Chemoembolization and other ablative therapies for liver metastases of gastrointestinal endocrine tumours. Best Pract Res Clin Gastroenterol 2005;19:585–94. 37 Zeh HJ 3rd, Brown CK, Holtzman MP, et al. A phase I study of hyperthermic isolated hepatic perfusion with oxaliplatin in the treatment of unresectable liver metastases from colorectal cancer. Ann Surg Oncol 2009;16:385–94. 38 Ausman RK, Aust JB. Studies in isolated perfusion chemotherapy. I. Nitrogen mustard. Ann Surg 1961;153:527–32. 39 Aigner KR, Walther H, Tonn JC, Link KH, Schoch P, Schwemmle K. [Isolated liver perfusion in advanced metastases of colorectal cancers]. Onkologie 1984;7:13–21. 40 Skibba JL, Quebbeman EJ. Tumoricidal effects and patient survival after hyperthermic liver perfusion. Arch Surg 1986;121:1266–71. 41 Schwemmle K, Link KH, Rieck B. Rationale and indications for perfusion in liver tumors: current data. World J Surg 1987;11:534–40. 42 Hafstrom L, Naredi P. Isolated hepatic perfusion with extracorporeal oxygenation using hyperthermia TNF alpha and melphalan: Swedish experience. Recent Results Cancer Res 1998;147:120–6. 43 Marinelli A, de Brauw LM, Beerman H, et al. Isolated liver perfusion with mitomycin C in the treatment of colorectal cancer metastases confined to the liver. Jpn J Clin Oncol 1996;26:341–50. 44 Hafstrom L, Naredi P, Lindner P, Holmberg S, Schersten T. Treatment of primary liver cancer. Eur J Surg 1998;164:569–74. 45 Oldhafer KJ, Lang H, Kuse ER, Martin MU. High-dose tumor necrosis factor-alpha leads to the systemic inflammatory response syndrome. Am J Med 1998;105:346–7. 46 Oldhafer KJ, Frerker MK, Lang H, et al. High-dose mitomycin C in isolated hyperthermic liver perfusion for unresectable liver metastases. J Invest Surg 1998;11:393–400. 47 Grover A, Alexander HR JR. The past decade of experience with isolated hepatic infusion. Oncologist 2004;9:653–64. 48 Alexander HR Jr, Bartlett DL, Libutti SK. Isolated hepatic perfusion: a potentially effective treatment for patients with metastatic or primary cancers confined to the liver. Cancer J Sci Am 1998;4:2–11. 49 van Zuidewign DBW, de Brauw LM, Marinelli A, et al. Isolated liver perfusion with mitomycin-C or melphalan in patients with hepatic metastases. Soc Surg Oncol 1993;46:198a. 50 Devries MR, Borel Rinkes IHM, Buurman WA, et al. Soluble TNF-alpha receptor induction by isolated hepatic perfusion with TNF-alpha and melphalan. Eur Surg Res 1995;27:108.

Self-assessment answers 1 2 3 4 5

C A, C, E B B, D, E D

4

Resection, Ablation or Transplantation for Liver Tumors

Introduction Jean-Nicolas Vauthey1 and Tadatoshi Takayama2 1 2

Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan

Liver resection may offer potential cure in patients with primary liver cancers such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma. At highvolume centers, resection for such indications is performed with low morbidity and mortality [1–4]. Survival rates of up to 50% at 5 years are now reported after resection of HCC in noncirrhotic and selected cirrhotic patients. Surgical resection is the only potentially curative treatment for perihilar cholangiocarcinomas but less than 50% of patients are resectable because these tumors are usually seen at an advanced stage. Liver resection and hepatoduodenal lymphadenectomy are performed in a subset of patients with gallbladder cancer. However, most resectable patients with gallbladder cancer are diagnosed incidentally at the time of simple cholecystectomy, or postoperatively after pathological examination of the cholecystectomy specimen [5]. In patients with colorectal liver metastases, liver resection is the treatment of choice, and the 5-year survival after resection is approaching 60% [6]. Multidisciplinary and multimodality approaches, including preoperative systemic chemotherapy, portal vein embolization, and innovative surgical techniques, have enabled a larger proportion of patients to undergo potentially curative treatment. The definition of resectability has shifted from criteria based on morphologic characteristics of metastases (number, size) to new criteria based on whether both intrahepatic and extrahepatic disease can be completely resected and whether such an approach is appropriate from an oncologic standpoint [7]. Radiofrequency ablation for hepatic colorectal metastases should be used only after resectability has been ruled out using advanced multidisciplinary approaches, combining systemic chemotherapy, portal vein embolization, and twostage hepatectomy [8]. A dilemma facing clinicians in the management of liver tumors, both primary and secondary, is the array of alternative techniques available to treat these

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

lesions. An effective local ablative modality should be one that can induce a high degree of tumor necrosis, with a margin, yet remain nontoxic to surrounding liver parenchyma or structures. One approach has been the use of chemical ablation with ethanol. Other approaches are based on hyperthermia with radiofrequency and microwave ablations. The use of organ transplantation to treat malignancies is unique to the liver. Liver transplantation was almost abandoned in patients with secondary liver tumors, with the exception of selective cases with neuroendocrine tumors, because results were poor. Liver transplantation for HCC has been revisited and selection criteria have been established to identify candidates with early stage HCC, who have the lowest risk of recurrence [9, 10]. How to lower high incidences of HCC recurrence after treatment, even if it would be confirmed curative, is of clinical importance. To date, no specific adjuvant therapy is highly recommended as a gold standard in current practice. Recently, a multikinase inhibitor was found to prolong survival in advanced HCC [11], and therefore the oral drug may be promising as adjuvant therapy following resection of HCC. The role of orthotopic liver transplantation for cholangiocarcinoma, while the early results were poor, has been revisited by the Mayo Clinic Group. Results have been very encouraging in a highly selective group of patients. In this section, the state of the art is reviewed for resection, ablation, and transplantation for liver tumors. The current criteria for resectability of HCC and liver metastases are discussed, as well as the results of resection, the indications for and results of percutaneous therapy, and the practice and results of liver transplantation.

References 1 Ishizawa T, Hasegawa K, Aoki T, et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 2008;134:1908–16. 2 Takayama T, Makuuchi M, Hirohashi S, et al. Early hepatocellular carcinoma as an entity with a high rate of surgical cure. Hepatology 1998;28:1241–6.

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3 Clavien P-A, Petrowsky H, de Oliveira M, et al. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 2007;356:1545–59. 4 Abdalla EK, Denys A, Hasegawa K, et al. Treatment of large and advanced hepatocellular carcinoma. Ann Surg Oncol 2008;15:979–85. 5 de Aretxabala X, Roa I, Burgos L, et al. Gallbladder cancer: an analysis of a series of 139 patients with invasion restricted to the subserosal layer. J Gastrointest Surg 2006;10:186–92. 6 Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 2005;241:715–724. 7 Vauthey JN, Zorzi D, Pawlik TM. Making unresectable hepatic colorectal metastases resectable – does it work? Semin Oncol 2005;32:S118–22.

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8 Blazer III DG, Kishi Y, Maru D, et al. Pathologic response to preoperative chemotherapy: a new outcome end point after resection of hepatic colorectal metastases. J Clin Oncol 2008;26:5230–1. 9 Mazzaferro V. Results of liver transplantation: with or without Milan criteria? Liver Transpl 2007;13:S44–7. 10 Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394–403. 11 Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–90.

16

Liver Resection of Primary Tumors: Hepatocellular Carcinoma, Cholangiocarcinoma, and Gallbladder Cancer Tadatoshi Takayama1 and Masatoshi Makuuchi2 1 2

Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan Department of Hepato-Biliary-Pancreatic Surgery, Japanese Red Cross Medical Center, Tokyo, Japan

Liver resection for primary tumors has been supported since the 1950s by a widespread appreciation of the surgical anatomy of the liver, as well as by the development of improved surgical techniques [1]. In 1654, Glisson described the structure of the major vessels of the liver in his Anatomia Hepatis. Subsequently, Rex (1888) and Cantlie (1897) defined the hepatic midline in the lobar anatomy. A major breakthrough was the segmental anatomy proposed by Couinaud (1957), who divided the liver into eight segments based on the distribution of the portal and hepatic veins [2]. Kumon (1985) clearly identified the dorsal sector of the liver, recognized as a small part of the parenchyma surrounding the vena cava [3]. The modern era of liver resection commenced with a shift from resection without reference to vascular anatomy to major resection through anatomic planes. In 1910, Wendel performed a right hepatectomy under semicontrolled conditions by ligating the right hepatic artery and hepatic duct before parenchymal transection. After four decades, the credit for the first anatomic right hepatectomy with preliminary hilar ligation was given to Honjo (1949) in Japan or Lortat-Jacob (1952) in France [1]. A more recent development is segmental resection, usually guided by an intraoperative ultrasonic device, allowing any Couinaud’s segment to be removed anatomically [4–6]. Liver resection has been proven to offer a potential cure for primary liver tumors, including hepatocellular carcinoma (HCC), cholangiocarcinoma, and gallbladder cancer. The operation for such common indications is now performed at high-volume centers throughout the world, with low morbidity and mortality.

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

Liver anatomy Liver resection requires precise knowledge about the surgical anatomy, terminology, and blood vessels of the liver (see Chapter 2). A clear understanding of these factors enables radical liver resection to be safely performed for many primary tumors.

Hepatic division In the 1950s, Couinaud [2] and Healey & Schroy [7] independently advocated two nomenclature systems for hepatic division based on the results of corrosion cast analyses. Both systems have been widely accepted throughout the world. Each system divided the liver into three levels. Couinaud defined the levels as (1) hemilivers, (2) sectors, and (3) segments, while Healey defined the levels as (1) lobes, (2) segments, and (3) areas (Figure 16.1). The caudate lobe as defined by Healey corresponds to Couinaud’s dorsal sector (or segment 1), and Healey subdivided segment 4 into two areas (medial superior and inferior areas). Although there are some inconsistencies between the two systems, surgeons have used either or both in their clinical practice. However, Couinaud’s nomenclature, based on the intrahepatic portal and hepatic venous system, is the most widely used concept in liver surgery. The liver is divided into right and left hemilivers along the middle hepatic vein (corresponding to the Rex–Cantlie line). Each hemiliver is subdivided into four sectors by the right and left hepatic veins (right/left lateral and paramedian sectors). The sectors (excluding the left lateral sector) are subdivided into eight segments including the caudate lobe (segments 1–8) according to the third-order branches of the intrahepatic portal pedicles. The liver segments are denoted in a clockwise fashion by Roman numerals, starting from the caudate lobe as segment 1. In Healey’s nomenclature, Couinaud’s hemilivers correspond to lobes, his sectors to segments, and his segments to

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Segment

Left

Right

Lobe

Posterior

Anterior

7, 6

8, 5

Area

Medical 4

Inferior vena cava

Healey & Schroy’s classification

Lateral 3, 2

Hepatic vein

2 8

7

4 3 1

6

5

Portal vein Segment Sector Hemiliver

7, 6

8, 5

4, 3

2

Right lateral

Right paramedian

Left paramedian

Left lateral

Right

Figure 16.1 Hepatic division according to Couinaud’s versus Healey’s classification.

Left

areas. The conceptual difference between the two nomenclatures lies in the left side of the liver. Couinaud divided the left portal vein into an umbilical branch and a segment 2 branch. Consequently, the left hemiliver was divided into the left paramedian sector (Couinaud’s segments 3 and 4) and the lateral sector (segment 2). Healey divided the left hepatic artery and bile duct into lateral and medial branches, causing the left lobe to be divided into the lateral segment (segments 2 and 3) and the medial segment (segment 4). The fact that the term “segment” is used in both concepts, but indicates different parts of the liver, has created confusion. In 2000, a committee of the International HepatoPancreatico-Biliary Association proposed the first universal terminology for liver anatomy and resection (the Brisbane 2000 system) [8]. This classification system aimed to simplify the description of different type of resections according to anatomically relevant structures. In this system, the anatomic terms for parts of the liver (hemiliver, section, and segment) correspond to the terms used to describe hepatic resection (hemihepatectomy, sectionectomy, and segmentectomy), with reference to Couinaud’s segments (segments 1–8). The watersheds for the first-order, second-order, and third-order divisions are referred to as the midplane, the intersectional planes, and the intersegmental planes, respectively. This system allows the use of the term “caudate lobe” (or segment 1), as it is a true lobe (see Chapter 2).

178

Couinaud’s classification

Portal vein Of the vessels related to the liver, the portal venous system is the most easily identifiable on imaging and is therefore a good surgical landmark. The first-order branches of the portal vein include the right and left main branches; the second-order branches include the right anterior and posterior sectorial branches, left umbilical branch, and caudate (segment 1) branch; and the third-order branches include the segmental (segments 2–8) branches (Figure 16.2) [9]. We named each third-order branch after its major feeding portion in the segmental domain (i.e. P8v is the portal branch of the ventral portion of segment 8) [4]. Portal mapping facilitates the surgeon’s understanding of the anatomic layout in each patient: all portal venous branches and hepatic veins can be traced by ultrasound with reference to the map. For subsequent liver resection, the relation between the target tumor and related intrahepatic vessels is of surgical importance, especially in segmentectomies [4].

Liver resection Indications A key determinant of a good outcome is the identification of patients most likely to benefit optimally from liver resection. Patients with primary liver tumors often have a history

CHAPTER 16

of chronic liver disease with decreased hepatic synthetic function, associated with low serum albumin levels and hyperbilirubinemia, as well as portal hypertension, causing ascites and pancytopenia. No widely accepted criteria for liver resection have been established in patients with HCC and cirrhosis. Several sets of criteria have been proposed; some are quantitative but may be complicated or unreproU-point

P8v P4s

P7d P1 P4sho

P8d

P2

P7l P3 P5v

P1 P4i

P5d

P1

P6l

P6v P-point

PV

Figure 16.2 Map of intrahepatic portal venous branches. P represents portal venous branch, numbers refer to the eight segments of the liver, and lowercase letters refer to the segmental branches named after their major feeding portions in the segment. PV, portal vein; U-/P-point, umbilical/posterior point; sho, short branches; v, ventral portion; d, dorsal portion; l, lateral portion; s, superior portion; i, inferior portion.

Liver Resection of Primary Tumors

ducible when used for routine preoperative assessment. Indications for liver resection seem to ultimately depend on the policy and expertise of each surgical team. However, the exclusion criteria for liver resection, such as the presence of bihemihepatic tumor dissemination or extrahepatic metastases (stage IV) and the presence of serious hepatic impairment associated with conditions such as ascites or jaundice (Child–Pugh class C) are now consistent. The type of liver resection must be customized for each patient according to hepatic function. The Child–Pugh grading continues to be the most useful evaluation system. The indocyanine green (ICG) clearance test is widely used to identify good candidates for liver resection in Asia [10], and portal pressure or the model for end-stage liver disease (MELD) score is used in Europe [11]. In Asia, the procedure for liver resection has been selected on the basis of Makuuchi’s criteria (Figure 16.3). The criteria defining the safe limits of liver resection are based on three variables: the absence or presence of ascites, the serum total bilirubin concentration, and the ICG clearance rate at 15 min. In patients without ascites who have a normal bilirubin level (≤1 mg/ dL), the ICG clearance rate is the main determinant of the resection procedure as follows: ICG clearance rate less than 10% – right hemihepatectomy; 10–19% – left hemihepatectomy or four types of right sectoriectomy; 20–29% – resection of one Couinaud’s segment; and more than 30% – limited resection. In addition, the resectable range should be adjusted on the basis of tumor size or liver deformity according to the relative volume on computed tomography (CT) scans. In our center, we used aspecial guideline to prevent liver failure due to excessive removal of the functioning hepatic

Ascites

No

Yes

Bilirubin

£ 17.0 μmol/L

ICG

<10%

Right hemihepatectomy

Figure 16.3 Makuuchi’s criteria for liver resection according to liver function.

18.7–32.3 μmol/L

≥ 34.0 μmol/L

Contraindicated

Limited resection

10–19%

Left hemihepatectomy Segments 7 + 6 resection Segments 8 + 5 resection Segments 8 + 7 resection Segments 6 + 5 resection

20–29%

Segmentectomy

≥ 30%

Limited resection

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parenchyma. We have achieved an operative mortality of 0% among 915 patients who underwent 1056 liver resections [12]. Our policy originated from the need to resect HCC both radically and safely, since most patients are functionally impaired, but asymptomatic. A similar guideline is presented in Chapter 25 (Fig. 25.1A).

Procedures Routine operative procedures essential for liver resection include intraoperative ultrasonography, vascular occlusion, hepatic parenchymal transection, and drainage after transection.

Ultrasonography Intraoperative ultrasonography (US) is an indispensable tool for deciding the optimal strategy for liver resection [13]. The roles of US in routine practice include the identification of intrahepatic vascular anatomy, the detection and diagnosis of tumors, and US-guided therapeutic procedures. US facilitates the discovery of smaller lesions that may be overlooked on preoperative imaging. When such lesions are too small to be diagnosed on US imaging, needle biopsy under US guidance is performed via the optimal route. During hepatic resection, the transection line can be demonstrated on US as a glittering line. The relation between the ongoing transection and target vessels or tumors can be visualized by occasional orientation of the line, thereby facilitating accurate resection of the liver.

Vascular occlusion Inflow occlusion (Pringle’s maneuver) during hepatic resection has been widely used to decrease bleeding and has been shown to be effective in a randomized controlled trial (RCT) [14]. Pringle’s maneuver for up to 60 min is considered safe in noncirrhotic patients, whereas a duration of less than 30 min is recommended for cirrhotic patients. Even in cirrhotic patients, this technique can be repeated intermittently, alternating between 15 min occlusion and 5 min release until the resection is completed. In fact, an RCT found that intermittent occlusion is more beneficial than continuous occlusion, especially in cirrhotic patients [15]. This is consistent with experimental data suggesting that short periods of ischemia (10–15 min) have protective effects on hepatocytes, a phenomenon called “preconditioning.” In 2000, Clavien et al demonstrated that ischemic preconditioning significantly reduces liver injury after major liver resection in humans [16], confirmed recently by an RCT [17]. We have therefore used Pringle’s maneuver even in livingdonor hepatectomies, with no negative effect on graft quality [18]. In addition, hemihepatic inflow occlusion (Makuuchi’s maneuver; 30 min occlusion with 5 min release) is recommended for patients scheduled to undergo a complicated hepatic resection, such as a right anterior sectioriectomy (bisegmentectomy 8 and 5). During liver resection, vascular

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occlusion can be applied without additional risks, and intermittent or hemihepatic occlusion is preferable in patients with cirrhosis [19]. Total vascular exclusion, usually done in liver transplantation, is an option that permits bloodless major hepatic resection and is achieved by clamping the porta hepatis as well as the suprahepatic and the infrahepatic vena cava. In patients who do not tolerate caval clamping because of cardiovascular instability, a complete or partial veno-venous bypass system can be used. The systemic shunt connects the portal vein and the inferior vena cava (IVC), through femoral access, to the axillary vein. In a partial veno-venous bypass, cannulation of the portal vein is omitted. However, total vascular exclusion seems to be required for liver resection in only patients with very large tumors or tumors that invade the vena cava [20]. Without this technique, we performed liver resection in 329 consecutive patients with no operative mortality, including those whose tumors involved the cavohepatic junction [21].

Hepatic transection In liver surgery, hepatic parenchymal transection is a technical priority because blood loss during the procedure is a powerful determinant of operative outcomes. At highvolume centers, liver resection has been reported to yield a median blood loss of 700–1200 mL, morbidity rates of 23– 46%, and mortality rates of less than 4% [22]. Hepatic parenchyma can be transected by conventional digitoclasia (finger fracture or clamp crushing) or by instrument-based techniques (ultrasonic or water jet dissector). The procedure used is likely to depend on the surgeon’s preference rather than on objective data. The ultrasonic dissector (Cavitron ultrasonic surgical aspiration [CUSA]), although more costly and time-consuming than digitoclasia, has gained wide acceptance because it may reduce bleeding during hepatic resection. Fan et al [23] reported a 30% reduction in blood loss after changing their technique from clamp crushing to CUSA, with only a 4% prolongation of execution time, consistent with the findings of other specialists. Reported benefits, however, were based on comparisons with historic controls, and conclusive evidence supporting either technique is lacking. We prefer to use the clamp crushing technique, since our RCT proved that CUSA offers no reduction in blood loss as compared with clamp crushing [22]. In that trial, we successfully performed 132 liver resections, with a median blood loss of 450 mL (2% blood transfusion rate) and a 5% rate of major morbidity (no operative deaths) in a patient cohort with a 50% rate of cirrhosis. Lesurtel et al [24] also found in an RCT that the clamp crushing technique was the most efficient method in terms of time, bleeding, and cost compared with instruments such as CUSA, water jet, and dissecting sealer. Hemorrhage is best controlled by performing hepatic transection along an avascular plane after selective devascu-

CHAPTER 16

Liver Resection of Primary Tumors

larization of an anatomic part of the liver. The various portal pedicles can be divided by ligature or with a vascular stapler. Bleeding on the raw surface is usually well controlled by stitching the bleeding site and coagulation with a cautery device. Other techniques for hemostasis include argon-beam coagulation and infrared contact, resulting in superficial tissue necrosis. Hemostasis can also be achieved with the use of biologic tissue components combined with collagen fleece or by the direct application of highly concentrated clotting factors. However, the surgical efficacy of using such materials on the hepatic raw surface has not been justified by an RCT [25].

Drainage Abdominal drainage has been practiced after liver resection. The tube is placed in the dead space near the resected surface. This serves to drain ascitic fluid and to detect postoperative bleeding or bile leakage. However, two RCTs [26, 27] showed that minor liver resection and major resection of a normal liver can be safely performed without drainage. Moreover, Liu et al [28] recommended that drainage is avoided even in patients with cirrhosis, because in their RCT the drainage group had a higher incidence of septic complications (33% versus 17%), possibly caused by ascending infection via the drainage tube. On multivariate analysis, drainage was found to be an independent risk factor for postoperative morbidity (relative risk 4.45; 95% CI 1.70–11.64; p = 0.002). In general, the prophylactic value of drainage in liver surgery remains controversial, but routine placement of a drainage tube in all patients may not be justified.

Figure 16.4 Left hemihepatectomy, exposing the middle hepatic vein (arrows).

results in excellent control of bleeding during hepatic transection. The other approach is to start with hepatic transection, ligating the vessels inside the liver in their order of appearance. This approach is quicker and makes it easier to monitor the amount of excised parenchyma; however, intraoperative bleeding may be greater. Anatomic resection of the hemiliver requires complete exposure of the middle hepatic vein running on the midplane of the liver (Figure 16.4). In practice, many surgeons employ a combination of techniques on a case-by-case basis. Belghiti et al [29] has recommended hanging the liver with a tape passed between the anterior surface of the vena cava and the liver before mobilization.

Anatomic resection Liver resections can be classified into two categories: (1) anatomic resections, which respect the segmental anatomy of the liver (two hemihepatectomies, four sectoriectomies, eight segmentectomies, and their extended or combined forms), and (2) nonanatomic resections, which are performed irrespective of anatomic structure (referred to as limited resection, wedge resection, or tumorectomy). The representative types of anatomic resection are outlined from a technical point of view.

Hemihepatectomy Two different approaches can be used for hemihepatectomy. One approach involves complete devascularization of the resected part of the liver before hepatic parenchymal transection. For instance, for right hemihepatectomy, the right hepatic artery, portal vein, and bile duct are individually ligated and divided, as are all caudate branches and the right hepatic vein. Thus, the right hemiliver is rendered ischemic, and the Rex–Cantlie line separating the left and right hemiliver becomes apparent. A similar approach is used for left hemihepatectomy, although the left hepatic vein is usually divided at the final stage of resection. This technique

Segmentectomy The minimum surgical unit of the liver is Couinaud’s segment, although segmental areas cannot be accurately delineated in situ because of the lack of landmarks on the hepatic surface. In 1985, the concept of systematic segmentectomy was realized through the introduction of intraoperative US to liver surgery, enabling segmental borders to be visualized by US-guided staining [4]. Systematic segmentectomy allows anatomic removal of tumor-bearing segments with full preservation of other segments and is thus suitable for patients with poor hepatic functional reserve. Makuuchi’s segmentectomy is performed in the following steps (Figure 16.5): (1) staining to identify the target segment to be resected; (2) marking the area with an electric cautery device; (3) tattooing to facilitate recognition of the relevant portal branch; (4) hemihepatic vascular occlusion to control inflow; (5) hepatic transection by clamp crushing; and (6) full exposure of landmarks on the raw surface.

Resection of segment 8 After cholecystectomy, the common bile duct, hepatic arteries, and the main branches of the portal vein are dissected

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Figure 16.5 Ultrasonically-guided systematic segmentectomy. (Reproduced from Makuuchi et al [4], with permission.)

(a)

(b)

Figure 16.6 Staining technique. (a) A hepatocellular carcinoma (broken circle) and portal pedicle of segment 8 (arrow). (b) Puncture needle (arrow) and dye-injection into the pedicle.

and taped at the hepatic hilum. Segment 8 usually has two major segmental branches (P8v and P8d, see Figure 16.2). Therefore, staining (5 mL of blue dye [indigocarmine] injected into the branch) is done twice to identify the entire area (Figure 16.6). During vascular occlusion of the left hemiliver, hepatic transection is started 1 cm to the left of the Rex–Cantlie line and is continued to expose the middle hepatic vein and its confluence with the IVC. Right-sided occlusion is then performed, and the parenchyma is divided between segments 8 and 5. Deep in the parenchyma, the roots of P8v and P8d can be exposed, ligated, and divided in accordance with their tattoos. The next step is exposure of

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the right hepatic vein, which is usually situated 2 cm dorsolateral to the P8 branches. Further divisions expose this vein from its caudal to its cranial aspect. The final division is directed toward the demarcation line on the cranial surface of the liver. Complete resection of segment 8 reveals the trunks of the middle and right hepatic veins and the stumps of the P8 branches on the raw surface (Figure 16.7).

Resection of segment 5 Segment 5 has more than three segmental branches, making the counterstaining technique preferable (i.e. P8v and P6v are punctured) [30]. Hepatic division starts on the Rex–

CHAPTER 16

Figure 16.7 Resection of segment 8, exposing its portal pedicle (arrowhead) and the middle and right hepatic veins (arrows).

Cantlie line, and the periphery of the middle hepatic vein is exposed. The cranial border is then transected, and the segmental branches are sequentially divided until the main trunk of the anterior sectorial branch is exposed to the hepatic hilum. Finally, the right lateral margin of this segment is divided.

Resection of segment 7 Segment 7 has one thick segmental branch (P7d), and one puncture suffices in most cases. First, the bare area should be dissected completely, thereby exposing the IVC. Extrahepatic taping of the right hepatic vein is then performed. Hepatic transection starts from the diaphragmatic surface between segment 7 and segment 6. Then, from the visceral surface, transection is extended to the line between segment 7 and segment 8. The bifurcation of P7 and P6 is exposed, and then P7 is divided. Transection should be performed along the right hepatic vein to the confluence into the IVC. Both the right hepatic vein and stump of P7 can be seen on the raw surface (Figure 16.8). Resection of segment 6 Segment 6 has one or two thick segmental branches (P6v and P6l). Hepatic transection is performed along the border between segment 6 and segment 5 and then along the border between segment 6 and segment 7, dividing P6 and exposing the periphery of the right hepatic vein. Resection of segments 4, 3, or 2 Segment 4, segment 3, or segment 3 plus 2 have been resected by conventional surgery, since their segmental branches can be divided extrahepatically without using USguided procedures. In cirrhosis, resection of segment 4 plus 3 (left paramedian sector) is indicated for tumors around the top of the umbilical portion, but resection of segment 2 is seldom indicated.

Liver Resection of Primary Tumors

Figure 16.8 Resection of segment 7, exposing its portal pedicle (arrowhead) and the right hepatic vein (arrow).

Resection of segment 1 Anatomic resection of segment 1 is challenging because it is located dorsally, behind the right and left hemilivers, and near the hepatic hilum and IVC. A tumor in Spiegel’s portion or a process portion of segment 1 can be removed by a routine limited resection. In contrast, tumors located in the caval portion of the liver (Couinaud’s segment 9) can be resected in combination with an adjacent segment or hemiliver in patients with adequate hepatic function. Such preparatory resection provides a wider operative field and improves access to the tumor, facilitating resection [31]. Isolated total resection of segment 1 (high dorsal resection) (Figure 16.9) is a challenging procedure and is feasible only in selected patients with moderate cirrhosis [6]. After the procedure, landmark veins such as the retrohepatic IVC and the right and middle hepatic veins are exposed on the raw surface (Figure 16.10). If allowed by hepatic function, we favor anatomic resection from an oncologic perspective because it is associated with better long-term survival than nonanatomic resection [32]. Because of the high likelihood of tumor cells spreading through the portal venous system [4], anatomic resection is theoretically more effective for tumor eradication. However, limited or wedge resection is still indicated for small tumors on the liver surface or for exophytic tumors. Limited resection rather than anatomic resection may also be indicated in patients with hepatic disease, such as severe steatosis and cirrhosis, to minimize the resected amount of liver tissue, or in elderly patients with multiple risk factors.

Hepatocellular carcinoma HCC is one of the most common malignancies in Asia and Africa, and its incidence is rising in Western countries [33].

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Figure 16.9 High dorsal resection of the liver (isolated total resection of segment 1). (a) Before and (b) after resection. The entire area of the dorsal sector comprises the Spiegel portion (SP), the process portion (PP), and the caval portion (CP). Hepatocellular carcinoma (HCC) is mainly located in the upper area of the CP. Arrowhead, the right margin of the dorsal sector, and the broken arrows, the transection sequence. Each inset demonstrates a horizontal plane through the tumor. 1, HCC; 2, inferior vena cava; 3, right hepatic vein; 4, middle hepatic vein; 5, left hepatic vein; 6, portal vein; 7, caudate branches; 8, Arantius’ ligament; 9, cut surface of segments 6 and 7; 10, cut surface of segments 5 and 8. (Reproduced from Takayama et al [6], with permission.)

Figure 16.10 Resection of segment 1, exposing the portal pedicle, the right hepatic veins (arrow), and the vena cava partially resected (arrowheads).

Chronic infection with hepatitis C virus (HCV) and hepatitis B virus (HBV) or alcoholism plays a major role in its etiology. The tumor is usually advanced when the patient presents with clinical symptoms. Screening for HCC in highrisk patients is thus justified. Early detection of HCC allows the application of potentially curative treatments, such as liver resection, percutaneous ablation, and transplantation. Liver resection is the treatment of choice mainly for a single HCC in noncirrhotic patients (about 5% in the West and 40% in Asia). Generally, liver resection is indicated for stage 1–3 HCCs in patients with Child–Pugh class A (or B) liver function. By experienced surgeons, various types of

184

liver resection can now be performed, with blood transfusion required in less than 10% of patients, a perioperative morbidity of lower than 30%, a postoperative hospital stay of less than 10 days, an operative mortality of less than 3%, and a 5-year survival rate of greater than 50% [34]. Common postoperative complications include bile leakage (10%), intra-abdominal abscess (2%), pleural effusion (10%), pneumonia (10%), hyperbilirubinemia (2%), and bleeding from the hepatic stump (1%) [35]. Most operative deaths are related to severe infection or liver failure. We have reviewed survival after resection for HCC in 15 series since 2000, each including more than 100 patients (Table 16.1) [32, 36–49]. Median survival rates were 80% (range 63–97%) at 1 year, 70% (34–78%) at 3 years, and 50% (17–69%) at 5 years. Such wide ranges of survival rates are attributed mainly to differences in HCC stage among different studies, but the survival rate is obviously much better for early-stage HCCs [50]. Today, liver resection is an established treatment for HCC owing to minimal surgical mortality and improved survival. The true value of liver resection for HCC remains controversial, because of the paucity of data from RCTs comparing resection with other modalities. In a nationwide Japanese survey including 12 888 patients with HCC, liver resection offered significantly better long-term survival than percutaneous ablation or arterial chemoembolization [36], a finding that has been confirmed in a new cohort of 17 149 patients [51]. Since these surveys were retrospective, there were biases associated with differences in baseline variables among patient subgroups. Recently, Chen et al’s RCT, including 180 patients with a single, small HCC who were assigned to

CHAPTER 16

Liver Resection of Primary Tumors

Table 16.1 Survival after resection of hepatocellular carcinoma. Authors [Ref.]

Arii et al [36] HCC < 2 cm, CP-A HCC < 2 cm, CP-B HCC, 2–5 cm, CP-A HCC, 2–5 cm, CP-B Zhou et al [37] Poon et al [38] Nagasue et al [39] Kanematsu et al [40] Belghiti et al [41] Chen et al [42] Wayne et al [43] Ercolani et al [44] Chen et al [45] Capussotti et al [46] Hasegawa et al [32] Anatomic resection Non-anatomic resection Sasaki et al [47] Hepatitis B positive Hepatitis C positive Nathan et al [48] Yang et al [49]

Year

Number of patients

Survival rate (%) at 1 year

3 years

5 years

96 92 95 95 83 82 97 84 81 80 83 83 NA NA

NA NA NA NA 61 62 61 67 57 54 NA 63 34 51

72 56 58 45 50 49 50 51 37 34 41 43 17 34

95 93

84 66

66 35

NA NA NA 87

80 78 NA 56

62 69 39 38

2000

2001 2001 2001 2002 2002 2002 2002 2003 2004 2005 2005

2006

2009 2009

1318 502 2722 1548 1366 241 100 303 300 252 249 224 525 216 210 156 54 417 66 351 788 260

NA, not assessed; CP, Child–Pugh classification.

receive liver resection or radiofrequency ablation, showed that ablation was not inferior to resection with respect to the endpoints of overall survival and disease-free survival, and treatment-related morbidity was higher after resection than after ablation [52]. However, the validity of their conclusions is questionable because of the small sample size and a high conversion rate (21%) from ablation to resection. Another well-designed RCT is needed to answer the important question of which treatment is superior, resection or ablation? Although early diagnosis and treatment improve survival, HCC is rarely cured and frequently recurs after regional therapy or even transplantation. The 5-year cumulative rate of recurrence is 77–100 % after liver resection, and median survival after recurrence is 7–28 months [53]. Micrometastases from HCC can be detected by molecular techniques in 88% of patients at the time of surgery and probably cause postsurgical recurrence. About 80% of recurrent tumors develop exclusively within the liver, and only 20% of such tumors are resectable. As a treatment option, repeat liver resection has played an important role in selected patients, yielding results similar to those after the primary resection, with a 5-year survival rate of about 50%. We have proposed

that repeat resection is indicated for the treatment of recurrence in patients with a single HCC at the first resection, a disease-free interval longer than 1 year, and recurrent HCC with no portal invasion. In patients who met these criteria, the 5-year survival rate was 86% after the second resection [54]. The prognostic factors for poor outcomes in HCC are common to all therapeutic approaches and include more than three tumors, a tumor size larger than 5 cm, portal vein invasion, intrahepatic metastases, absence of a tumor pseudocapsule, advanced TNM stage (III or IV), and a Child–Pugh class of C. The most important factors appear to be vascular invasion and liver function [55]. The ultimate option for an HCC considered to be unresectable owing to poor hepatic reserve is liver transplantation, which can remove the entire diseased liver with HCC (see Chapter 23). In patients who meet the Milan criteria (a single tumor smaller than 5 cm, or not more than three tumors smaller than 3 cm) [56], a 5-year survival rate of 60–80% has been reported repeatedly. However, patients with advanced HCC (stage III and IV) have a 0–20% 5-year survival rate because of the presence of extrahepatic metas-

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tases, and are therefore usually not candidates for liver transplantation [57]. Recently, treatments for HCC have been newly debated owing to the development of livingdonor liver transplantation, which circumvents the problem of a waiting list. Increased availability of donor organs may extend the indications for liver transplantation slightly beyond those for cadaveric organs, which are in very short supply. In a Japanese series, Todo et al [58] reported that the 3-year survival rate was significantly higher for patients with HCC within the Milan criteria than in those with HCC that did not meet the criteria (79% versus 60%) among 316 patients who underwent living-donor transplantation. However, the latter group may benefit from liver transplantation even if the long-term survival rate is about 20% lower than that in patients with small HCCs.

Cholangiocarcinoma Cholangiocarcinoma includes all cancers arising from the epithelial cells of the bile ducts regardless of location, and accounts for about 10% of all primary tumors of the liver and biliary tract. On the basis of location, cholangiocarcinoma can be classified into intrahepatic (6%), perihilar (67%), and distal (27%) types [59]. Intrahepatic tumors are further divided into three macroscopic subtypes: mass-forming, periductal infiltrating, and intraductal growing, each of which has different biologic and clinical behaviors [60]. Perihilar tumors are classified into four clinical categories accord-

ing to involvement of the primary and secondary intrahepatic bile ducts [61]. Intrahepatic and perihilar cholangiocarcinomas are focused on because liver resection is required in most cases. Surgical resection is the only potentially curative treatment for cholangiocarcinoma, but the disease is usually advanced at the time of diagnosis and treated by chemoradiotherapy or palliative therapy, including biliary drainage or stenting. In patients treated with curative intent, an extended hemihepatectomy is often needed to achieve negative margins. Preoperative jaundice and extended procedures are important risk factors for postoperative complications [62]. Preoperative placement of biliary catheters remains controversial, and some centers do not use catheters because of the increased risk of postoperative infections, whereas others routinely perform percutaneous drainage. Preoperative portal vein embolization also benefits patients undergoing extended hemihepatectomy [62]. Patients with lymph node metastases have an extremely poor prognosis and should be treated for unresectable disease. Even in high-volume centers, the resectability rate is about 30% of all patients with cholangiocarcinoma, with the operative mortality rate ranging from 0% to 15%. After curative resection, the 1-, 3-, and 5-year survival rates range from 50% to 70%, 30–40%, and 10–40%, respectively (Table 16.2) [63–77]. The 5-year survival rate in patients undergoing noncurative resection is below 10% [59]. Available data suggest that complete resection improves survival. Predictors of poor survival include positive resection margins, lymph

Table 16.2 Survival after resection of cholangiocarcinoma. Authors [Ref.]

Number of patients

Factors influencing survival

Intrahepatic cholangiocarcinoma Inoue et al [63] 2000 Ohtsuka et al [64] 2002 Kawarada et al [65] 2002 Nakagawa et al [66] 2005 Shimada et al [67] 2007 DeOliveira et al [68] 2007 Jonas et al [69] 2009 Lang et al [70] 2009

52 48 37 44 76 44 195 83

Margin, lymph nodes, vascular invasion Tumor number, CA19-9 Curative resection, lymph nodes, histologic type Tumor number, noncurable resection Metastases, macroscopic type Margin Curative resection, stage, lymph nodes Curative resection, stage, gender

Hilar cholangiocarcinoma Jarnagin et al [71] Seyama et al [72] Rea et al [73] Silva et al [74] Dinant et al [75] Witzigmann et al [76] DeOliveira et al [68] Baton et al [77]

80 58 46 45 99 60 281 59

Margin, hepatectomy, differentiation Lymph nodes Lymph nodes, tumor grade, bilirubin Tumor stage, margin Margin, resection period, lymph nodes Residual tumor status, grading Margin, lymph nodes Chemotherapy, margin, lymph nodes

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Year

2001 2003 2004 2005 2006 2006 2007 2007

Operative mortality rate %

5-year survival rate %

2 8 0 6 1 5 3 7

36 23 24 26 31 40 22 21

10 0 9 9 15 8 5 5

27 40 26 11 27 22 10 20

CHAPTER 16

node involvement, and poorly differentiated tumors. Liver transplantation is contraindicated because of disappointing long-term outcomes. However, a recent multi-institutional study in the United States, including 280 patients with earlier-stage tumors who received aggressive neoadjuvant chemoradiation, has reported that transplantation remarkably improves survival: the 1- and 5-year survival rates were 74% and 38%, respectively [78]. Liver transplantation is currently done only in the setting of clinical trials. Adjuvant therapy for cholangiocarcinoma has not been supported by clinical evidence. For intrahepatic cholangiocarcinoma, 5-flurouracil (5-FU) is the most extensively used chemotherapeutic drug, and 5-FU combined with cisplatin has yielded the best response. Recently, gemcitabine also has been shown to be active, with response rates of 8–60% and median survival of 6–16 months [60]. Therefore, further study of gemcitabine and of 5-FU plus cisplatin are warranted. For perihilar cholangiocarcinoma, Cheng et al [79] reported better survival for patients with Bismuth II/IV type tumors who received adjuvant radiotherapy after curative resection. Radiotherapy is potentially beneficial in patients with positive resection margins or unresectable tumors.

Gallbladder carcinoma Gallbladder carcinoma is the most common malignancy of the biliary tract. Women are more frequently affected than men, and the peak incidence is after the age of 40 years. Cholelithiasis is the most important risk factor, and up to 95% of all patients with gallbladder carcinoma have gallstones. Chronic cholecystitis, porcelain gallbladder, and anomalous pancreaticobiliary duct junctions may be associated with the development of cancer. The tumor stage is defined according to the TNM Classification of gallbladder tumors. Briefly, stage I tumors are

Liver Resection of Primary Tumors

limited to the muscularis, stage II tumors invade into the subserosa, stage III tumors penetrate the serosa or have lymph node involvement, and stage IV tumors infiltrate surrounding structures or have distant metastasis. From T2 to T4 tumors, nodal and distant metastases increase progressively from 16% to 79% and from 33% to 69%, respectively [80]. Lymph node metastasis is found in 54–64% of all gallbladder carcinomas and strongly correlates with the depth of invasion [81]. For T1 tumors, simple cholecystectomy is curative in about 90% of cases if negative margins are attained. For T1b tumors, because the 1-year survival rate after cholecystectomy alone is only 50%, a more radical procedure seems advisable. For T2 tumors, a radical cholecystectomy is required to achieve tumor clearance. An aggressive resection, including en bloc liver resection as well as regional lymphadenectomy, is needed. Several studies have shown that 5-year survival rates are higher than 80% after en bloc liver resection as compared with only 20–40% after simple cholecystectomy [82]. T3 tumors also require liver resection with regional lymphadenectomy. A major hepatectomy is indicated for extensive invasion into the liver or major vascular structures. Five-year survival rates of 30–50% can be achieved after complete resection of T3 tumors [80]. Nearly all T4 tumors are unresectable, and 5-year survival is exceptional. Resection is the only potentially curative treatment. Unfortunately, only 20–30% of all patients have resectable disease at the time of diagnosis. The 5-year survival rate after resection of T1 tumors ranges from 90% to 100%. Because of frequent lymph node involvement in T2 tumors, the 5-year survival rate is only 30%. Resection of T3 tumors results in a survival rate of only 10–25%, while long-term survival for T4 tumors is exceptional. Major predictors of poor outcomes include lymph node involvement and advanced tumor stage. The results of recent studies reporting survival outcomes according to tumor stage are summarized in Table 16.3 [83–90].

Table 16.3 Survival after resection of gallbladder cancer. Authors [Ref.]

Chijiiwa et al [83] Schauer et al [84] Kondo et al [85] Kokudo et al [86] Behari et al [87] Yagi et al [88] Kayahara et al [89] Jiang et al [90]

Year

2000 2001 2002 2003 2003 2006 2007 2008

Number of patients

52 127 80 152 42 63 4774 150

Operative mortality rate (%)

2 0 18 1 5 0 NA 2

5-year survival rate (%) Stage I

Stage II

100 NA NA 97 NA 100 77 94

70 65 (I and II) 80 (I and II) 78 80 (I and II) 17 60 22

Stage III 22 0 33 69 28 25 29 4

Stage IV NA 0 17 32 0 15 12 0

NA, not assessed.

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Adjuvant therapy for gallbladder cancer offers no benefit in most patients. An RCT showed that the rate of 5-year disease-free survival was 20.3% in 140 patients who received resection plus mitomycin and 5-FU, as compared with 11.6% in those who received resection alone [91]. Palliative chemotherapy has generally had poor results for unresectable tumors. However, gemcitabine with or without cisplatin in patients with stage IV tumors had a 64% response rate. Median time to progression was 28 weeks, and median overall survival was 42 weeks [92].

Self-assessment questions 1 Which of the following are exposed on the raw surface of the liver after anatomic resection of segment 8? (more than one answer is possible) A Trunk of left hepatic vein B Trunk of middle hepatic vein C Trunk of right hepatic vein D Stumps of P8 branches E Stumps of P7 branches 2 In which of the following situations is liver resection not recommended? (more than one answer is possible) A Child–Pugh A class B ICG clearance rate of 10% C Uncontrolled ascites D Serum bilirubin of 2.5 mg/dL E Platelet count of 150 000/mm3 3 Which of the following are frequent postoperative complications after liver resection for hepatocellular carcinoma? (more than one answer is possible) A Pleural effusion B Bile leakage C Abdominal infection D Atelectasia E Ileus 4 Which of the following vascular occlusion techniques are used during liver resection? (more than one answer is possible) A Total vascular exclusion B Heimlich’s maneuver C Pringle’s maneuver D Valsalva’s maneuver E Makuuchi’s maneuver 5 Which of the following techniques or devices are used for hepatic parenchymal transection? (more than one answer is possible. A Finger fracture method B Clamp crushing method

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C CUSA D Water jet dissector E Ultrasonically activated device 6 Which one of the following is exposed on the midplane of the liver after right hemihepatectomy? A Posterior branch of portal vein B Left hepatic vein C Middle hepatic vein D Anterior branch of portal vein E Right hepatic vein 7 Which of the following are included in macroscopic types of intrahepatic cholangiocarcinoma? (more than one answer is possible) A Simple nodular type B Mass-forming type C Periductal infiltrating type D Confluent multinodular type E Intraductal growth type 8 Which of the following are prognostic factors after surgery for cholangiocarcinoma? (more than one answer is possible) A Resection margin B Jaundice before surgery C Lymph node involvement D Albumin level before surgery E Differentiation of tumors 9 Which one of the following treatments is recommended for T1 gallbladder cancer? A Right hemihepatectomy B Liver resection of segment 5 C Simple cholecystectomy D Right hemihepatectomy with pancreatoduodenectomy E Pancreatoduodenectomy 10 Which one of the following treatments is associated with the best outcomes in patients with gallbladder cancer? A Surgical resection B 5-FU chemotherapy C Radiation D Chemoembolization E Cisplatin chemotherapy

References 1 Foster JH, Berman MM. Highlights in the history of liver tumors and their resection. In: Solid Liver Tumors. Major Problems in Clinical Surgery, vol XXIII. Philadelphia: WB Saunders, 1977:9–27.

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2 Couinaud C. Lobes et segments hepatiques. Note sur l’architecture anatomique et chirurgicale du foie. Presse Med 1954;62:709–11. 3 Kumon M. Anatomy of the caudate lobe with special reference to portal vein and bile duct. Acta Hepatol Jpn 1985;26:1193–9. 4 Makuuchi M, Hasegawa H, Yamazaki S. Ultrasonically guided subsegmentectomy. Surg Gynecol Obstet 1985;161:346–50. 5 Bismuth H. Surgical anatomy and anatomic surgery of the liver. World J Surg 1982;6:3–9. 6 Takayama T, Tanaka T, Higaki T, et al. High dorsal resection of the liver. J Am Coll Surg 1994;179:72–5. 7 Healey JE, Schroy PC. Anatomy of the biliary ducts within the human liver: analysis of the prevailing pattern of branching and the major variations of biliary ducts. Arch Surg 1953;66: 599–616. 8 Strasberg SM. Nomenclature of hepatic anatomy and resections: a review of the Brisbane 2000 system. J Hepatobiliary Pancreat Surg 2005;12:351–5. 9 Takayasu K, Moriyama N, Muramatsu Y, et al. Intrahepatic portal vein branches studied by percutaneous transhepatic portography. Radiology 1985;153:31–6. 10 Makuuchi M, Kosuge T, Takayama T, et al. Surgery for small liver cancers. Semin Surg Oncol 1993;9:298–304. 11 Cescon M, Cucchetti A, Grazi GL, et al. Indication of the extent of hepatectomy for hepatocellular carcinoma on cirrhosis by a simple algorithm based on operative variables. Arch Surg 2009;144:57–63. 12 Imamura H, Seyama Y, Kokudo N, et al. One thousand fifty-six hepatectomies without mortality in 8 years. Arch Surg 2003;138:1198–1206. 13 Takayama T, Makuuchi M. Intraoperative ultrasonography and other techniques for segmental resections. Surg Oncol Clin N Am 1996;5:261–9. 14 Man K, Fan ST, Ng IO, et al. Prospective evaluation of Pringle maneuver in hepatectomy for liver tumors by a randomized study. Ann Surg 1997;226:704–13. 15 Belghiti J, Noun R, Malafosse R, et al. Continous versus intermittent portal triad clamping for liver resection: a controlled study. Ann Surg 1999;229:369–75. 16 Clavien PA, Yadav S, Sindram D, Bently RC. Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans. Ann Surg 2000;232:155–62. 17 Beck-Schimmer B, Breitenstein S, Urech S, et al. A randomized controlled trial on pharmacological preconditioning in liver surgery using a volatile anesthetic. Ann Surg 2008;248: 909–18. 18 Imamura H, Takayama T, Sugawara Y, et al. Pringle’s manoeuvre in living donors. Lancet 2002;360:2049–50. 19 Ercolani G, Ravaioli M, Grazi GL, et al. Use of vascular clamping in hepatic surgery: lessons learned from 1260 liver resections. Arch Surg 2008;143:380–7. 20 Grazi GL, Mazziotti A, Jovine E, et al. Total vascular exclusion of the liver during hepatic surgery: selective use, extensive use, or abuse? Arch Surg 1997;132:1104–9. 21 Torzilli G, Makuuchi M, Midorikawa Y, et al. Liver resection without total vascular exclusion – hazardous or beneficial?: an analysis of our experience. Ann Surg 2001;233:167–81. 22 Takayama T, Makuuchi M, Kubota K, et al. Randomized comparison of ultrasonic vs clamp transection of the liver. Arch Surg 2001;136:922–8.

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23 Fan ST, Lai ECS, Lo CM, et al. Hepatectomy with an ultrasonic dissector for hepatocellular carcinoma. Br J Surg 1996;83: 117–20. 24 Lesurtel M, Selzner M, Petrowsky H, et al. How should transection of the liver be performed? a prospective randomized study in 100 consecutive patients: comparing four different transection strategies. Ann Surg 2005;242:814–23. 25 Figueras J, Llado L, Miro M, et al. Application of fibrin glue sealant after hepatectomy does not seem justified: results of a randomized study in 300 patients. Ann Surg 2007;245:536– 42. 26 Belghiti J, Kabbej M, Sauvanet A, et al. Drainage after elective hepatic resection: a randomized trial. Ann Surg 1993;218: 748–53. 27 Fong Y, Brennan MF, Brown K, et al. Drainage is unnecessary after elective liver resection. Am J Surg 1996;171:158–62. 28 Liu CL, Fan ST, Lo CM, et al. Abdominal drainage after hepatic resection is contraindicated in patients with chronic liver diseases. Ann Surg 2004;239:194–201. 29 Belghiti J, Guevara OA, Noun R, et al. Liver hanging maneuver: a safe approach to right hepatectomy without liver mobilization. J Am Coll Surg 2001;193:109–11. 30 Takayama T, Makuuchi M, Watanabe K, et al. A new method for mapping hepatic subsegment: counterstaining identification technique. Surgery 1991;109:226–9. 31 Takayama T, Makuuchi M. Segmental liver resection, present and future: caudate lobe resection for liver tumors. Hepatogastroenterology 1998;45:20–3. 32 Hasegawa K, Kokudo N, Imamura H, et al. Prognostic impact of anatomic resection for hepatocellular carcinoma. Ann Surg 2005;242:252–9. 33 Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907–17. 34 Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002;35:519– 24. 35 Midorikawa Y, Kubota K, Takayama T, et al. A comparative study of postoperative complications after hepatectomy in patients with and without chronic liver disease. Surgery 1999;126:484–91. 36 Arii S, Yamaoka Y, Futagawa S, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. Hepatology 2000;32:1244–29. 37 Zhou X, Tang Z, Yang B, et al. Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer 2001;91:1479–86. 38 Poon R, Fan ST, Lo C, et al. Improving survival rates after resection of hepatocellular carcinoma: a prospective study of 377 patients over 10 years. Ann Surg 2001;234:63–70. 39 Nagasue N, Ono T, Yamanoi A, et al. Prognostic factors and survival after hepatic resection for hepatocellular carcinoma without cirrhosis. Br J Surg 2001;88:515–22. 40 Kanematsu T, Furui J, Yanaga K, et al. A 16-year experience in performing hepatic resection in 303 patients with hepatocellular carcinoma: 1985–2000. Surgery 2002;131:153–8. 41 Belghiti J, Regimbeau JM, Durand F, et al. Resection of hepatocellular carcinoma: a European experience on 328 cases. Hepatogastroenterology 2002;49:41–6.

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42 Chen MF, Jeng LB, Lee WC. Surgical results in patients with hepatitis virus-related hepatocellular carcinoma in Taiwan. World J Surg 2002;26:742–7. 43 Wayne JD, Lauwers GY, Ikai I, et al. Preoperative predictors of survival after resection of small hepatocellular carcinomas. Ann Surg 2002;235:722–30. 44 Ercolani G, Grazi GL, Ravaioli M, et al. Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence. Ann Surg 2003;237:536–43. 45 Chen XP, Qiu FZ, Wu ZD, Zhang BX. Chinese experience with hepatectomy for huge hepatocellular carcinoma. Br J Surg 2004;91:322–6. 46 Capussotti L, Muratore A, Amisano M, et al. Liver resection for hepatocellular carcinoma on cirrhosis: analysis of mortality, morbidity and survival, a European single center experience. Eur J Surg Oncol 2005;31:986–93. 47 Sasaki Y, Yamada T, Tanaka H, et al. Risk of recurrence in a long-term follow-up after surgery in 417 patients with hepatitis B- or hepatitis C-related hepatocellular carcinoma. Ann Surg 2006;244: 771–80. 48 Nathan H, Schulick RD, Choti MA, et al. Predictors of survival after resection of early hepatocellular carcinoma. Ann Surg 2009;249:799–805. 49 Yang LY, Fang F, Ou DP, et al. Solitary large hepatocellular carcinoma: a specific subtype of hepatocellular carcinoma with good outcome after hepatic resection. Ann Surg 2009;249: 118–23. 50 Takayama T, Makuuchi M, Hirohashi S, et al. Early hepatocellular carcinoma as an entity with a high rate of surgical cure. Hepatology 1998;28:1241–6. 51 Hasegawa K, Makuuchi M, Takayama T, et al. Surgical resection vs. percutaneous ablation for hepatocellular carcinoma: a preliminary report of the Japanese nationwide survey. J Hepatol 2008;49:589–94. 52 Chen MS, Li JQ, Zheng Y, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 2006;243: 321–8. 53 Takayama T, Sekine T, Makuuchi M, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000;356:802–7. 54 Minagawa M, Makuuchi M, Takayama T, Kokudo N. Selection criteria for repeat hepatectomy in patients with recurrent hepatocellular carcinoma. Ann Surg 2003;238:703–10. 55 Poon RT, Ng IO, Fan ST, et al. Clinicopathologic features of longterm survivors and disease-free survivors after resection of hepatocellular carcinoma: a study of a prospective cohort. J Clin Oncol 2001;19:3037–44. 56 Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693–9. 57 Clavien PA. Orthotopic liver transplantation for stage III and stage IV hepatocellular carcinoma. Liver Transplant Surg 1997;3: S52–4. 58 Todo S, Furukawa H. Living donor liver transplantation for adult patients with hepatocellular carcinoma: experience in Japan. Ann Surg 2004;240:451–61.

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59 Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. Ann Surg 1996;224:463–75 60 Hammill CW, Wong LL. Intrahepatic cholangiocarcinoma: a malignancy of increasing importance. J Am Coll Surg 2008;207: 594–603. 61 Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg 1992;215: 31–8. 62 Nagino M, Kamiya J, Nishio H, et al. Two hundred forty consecutive portal vein embolizations before extended hepatectomy for biliary cancer: surgical outcome and long-term follow-up. Ann Surg 2006;243:364–72. 63 Inoue K, Makuuchi M, Takayama T, et al. Long-term survival and prognostic factors in the surgical treatment of mass-forming type cholangiocarcinoma. Surgery 2000;127:498–505. 64 Ohtsuka M, Ito H, Kimura F, et al. Results of surgical treatment for intrahepatic cholangiocarcinoma and clinicopathological factors influencing survival. Br J Surg 2002;89:1525–31. 65 Kawarada Y, Yamagiwa K, Das BC. Analysis of the relationships between clinicopathologic factors and survival time in intrahepatic cholangiocarcinoma. Am J Surg 2002;183:679–85. 66 Nakagawa T, Kamiyama T, Kurauchi N, et al. Number of lymph node metastases is a significant prognostic factor in intrahepatic cholangiocarcinoma. World J Surg 2005;29:728–33. 67 Shimada K, Sano T, Sakamoto Y, et al. Surgical outcomes of the mass-forming plus periductal infiltrating types of intrahepatic cholangiocarcinoma: a comparative study with the typical massforming type of intrahepatic cholangiocarcinoma. World J Surg 2007;31:2016–22. 68 DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 2007;245:755–62. 69 Jonas S, Thelen A, Benckert C, et al. Extended liver resection for intrahepatic cholangiocarcinoma: a comparison of the prognostic accuracy of the fifth and sixth editions of the TNM classification. Ann Surg 2009;249:303–9. 70 Lang H, Sotiropoul G, Sgourakis G, et al. Operations for intrahepatic cholangiocarcinoma: single-institution experience of 158 patients. J Am Coll Surg 2009;208:218–28. 71 Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 2001;234:507–17. 72 Seyama Y, Kubota K, Sano K, et al. Long-term outcome of extended hemihepatectomy for hilar bile duct cancer with no mortality and high survival rate. Ann Surg 2003;238:73–83. 73 Rea DJ, Munoz-Juarez M, Farnell MB, et al. Major hepatic resection for hilar cholangiocarcinoma: analysis of 46 patients. Arch Surg 2004;139:514–23. 74 Silva MA, Tekin K, Aytekin F, et al. Surgery for hilar cholangiocarcinoma: a 10 year experience of a tertiary referral centre in the UK. Eur J Surg Oncol 2005;31:533–9. 75 Dinant S, Gerhards MF, Rauws EA, et al. Improved outcome of resection of hilar cholangiocarcinoma (Klatskin tumor). Ann Surg Oncol 2006;13:872–80. 76 Witzigmann H, Berr F, Ringel U, et al. Surgical and palliative management and outcome in 184 patients with hilar cholangiocarcinoma: palliative photodynamic therapy plus stenting is comparable to r1/r2 resection. Ann Surg 2006;244:230–9.

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77 Baton O, Azoulay D, Adam DV, et al. Major hepatectomy for hilar cholangiocarcinoma type 3 and 4: prognostic factors and longterm outcomes. J Am Coll Surg 2007;204:250–60. 78 Becker NS, Rodriguez JA, Barshes NR, et al. Outcomes analysis for 280 patients with cholangiocarcinoma treated with liver transplantation over an 18-year period. J Gastrointest Surg 2008;12:117–22. 79 Cheng Q, Luo X, Zhang B, et al. Predictive factors for prognosis of hilar cholangiocarcinoma: postresection radiotherapy improves survival. Eur J Surg Oncol 2007;33:202–7. 80 Fong Y, Jarnagin W, Blumgart LH. Gallbladder cancer: comparison of patients presenting initially for definitive operation with those presenting after prior noncurative intervention. Ann Surg 2000;232:557–69. 81 Muratore A, Polastri R, Capussotti L. Radical surgery for gallbladder cancer: current options. Eur J Surg Oncol 2000;26: 438–43. 82 Bartlett DL, Fong Y, Fortner JG, et al. Longterm result after resection for gallbladder cancer: implications for staging and management. Ann Surg 1996;224:639–46. 83 Chijiiwa K, Noshiro H, Nakano K, et al. Role of surgery for gallbladder carcinoma with special reference to lymph node metastasis and stage using western and Japanese classification systems. World J Surg 2000;24:1271–6. 84 Schauer RJ, Meyer G, Baretton G, et al. Prognostic factors and long-term results after surgery for gallbladder carcinoma: a retrospective study of 127 patients. Langenbecks Arch Surg 2001;386:110–17. 85 Kondo S, Nimura Y, Hayakawa N, et al. Extensive surgery for carcinoma of the gallbladder. Br J Surg 2002;89:179–84. 86 Kokudo N, Makuuchi M, Natori T, et al. Strategies for surgical treatment of gallbladder carcinoma based on information available before resection. Arch Surg 2003;138:741–50. 87 Behari A, Sikora SS, Wagholikar GD, et al. Longterm survival after extended resections in patients with gallbladder cancer. J Am Coll Surg 2003;196:82–8. 88 Yagi H, Shimazu M, Kawachi S, et al. Retrospective analysis of outcome in 63 gallbladder carcinoma patients after radical resection. J Heparobiliary Panceat Surg 2006;13:530–6. 89 Kayahara M, Nagakawa T. Recent trends of gallbladder cancer in Japan: an analysis of 4,770 patients. Cancer 2007;110: 572–80. 90 Liang JW, Dong SX, Zhou ZX, et al. Surgical management for carcinoma of the gallbladder: a single-institution experience in 25 years. Chin Med J 2008;121:1900–5. 91 Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 2002;95: 1685–95. 92 Malik IA, Aziz Z, Zaidi SH, et al. Gemcitabine and cisplatin is a highly effective combination chemotherapy in patients with advanced cancer of the gallbladder. Am J Clin Oncol 2003;26:174–7.

Liver Resection of Primary Tumors

Self-assessment answers 1 B, C, D Complete resection of segment 8 reveals the trunks of the middle and right hepatic veins and the stumps of the P8 branches on the raw surface. 2 C, D Child–Pugh grading and Makuuchi’s criteria are useful evaluation systems for liver resection. In patients without ascites and with a normal bilirubin level (≤1 mg/dL), ICG clearance rate is the main determinant of the resection procedure. 3 A, B, C, D Ileus after hepatectomy is not a frequent complication of liver resection for hepatocellular carcinoma. 4 A, C, E Inflow occlusion (Pringle’s maneuver), hemihepatic inflow occlusion (Makuuchi’s maneuver), and total vascular exclusion are used to decrease bleeding during hepatic resection. 5 A, B, C, D, E Several techniques and devices have been used during hepatic resection to control blood loss, which is the important determinant of operative outcomes. 6 C Anatomic resection of the hemiliver requires complete exposure of the middle hepatic vein running along the midplane of the liver. 7 B, C, E Intrahepatic cholangiocarcinoma is divided into three macroscopic types. 8 A, C, E In patients with cholangiocarcinoma, prognostic factors associated with poor survival include positive resection margins, lymph node involvement, and poorly differentiated tumors. 9 C For T1 gallbladder cancer, simple cholecystectomy is curative in about 90% of cases if negative margins are attained. 10 A Surgical resection is the only potentially curative therapy for gallbladder cancer.

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Liver Resection of Colorectal Liver Metastases Daria Zorzi, Yun Shin Chun, and Jean-Nicolas Vauthey Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

In patients with colorectal liver metastases (CLM), hepatic resection is the treatment of choice, and the 5-year overall survival rate after surgery is now approaching 60% [1]. The multidisciplinary and multimodality approaches, including preoperative systemic chemotherapy and innovative surgical techniques, have enabled a larger proportion of patients to undergo potentially curative treatment. The definition of resectability has shifted from criteria based on morphologic characteristics of metastases (number, size) to new criteria based on whether both intrahepatic and extrahepatic disease can be completely resected and whether such an approach is appropriate from an oncologic standpoint [2].

Preoperative considerations and work-up After resection of their primary colorectal tumors, patients undergo follow-up with complete history and physical examination, colonoscopy, chest X-ray, abdominopelvic computed tomography (CT), and serum levels of carcinoembryonic antigen (CEA). More than 75% of colorectal tumors and metastases express CEA [3]. Following a curative resection of the colorectal primary, CEA levels fall to normal; thus, a secondary elevation indicates recurrent or metastatic disease and should be investigated with further imaging. Moreover, CEA represents one of the most important prognostic factors for long-term survival after resection of CLM. Adam et al [4] recently identified CA 19-9 as an important indicator of prognosis in patients undergoing hepatic resection; however, confirmatory studies are necessary to support this finding prior to widespread implementation (see also Chapter 8). The preferred imaging modality for detection of CLM is CT, since it is widely available and allows simultaneous imaging of the thorax, liver, abdomen, and pelvis. At the University of Texas M. D. Anderson Cancer Center (MDACC), we favor quadruple-phase (precontrast, arterial, portal, and

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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delayed) multislice CT with rapid intravenous contrast injection (3–5 mL/s) and 2- to 5-mm cuts of the liver. Fluorodeoxyglucose positron emission tomography (FDGPET) has recently been used in the preoperative work-up of patients with CLM and has been found to have a role in the selection of patients for hepatic resection. A recent metaanalysis [5] provided evidence that the sensitivity of FDGPET for the detection of CLM is higher than that of helical CT or magnetic resonance imaging (MRI) (sensitivity 94.6% for FDG-PET compared to 64.7% for CT and 75.8% for MRI). However, the anatomic resolution of FDG-PET remains inferior to that of CT or MRI, and the accuracy of FDG-PET is lower in patients who have received preoperative chemotherapy [6] (see also Chapter 9). Several groups have reported a benefit with the use of intraoperative staging laparoscopy to minimize noncurative or “open and close” laparotomy rates, which are reported to vary between 10% and 40% [7]. This wide range probably reflects differences in the quality of the preoperative imaging work-up and also center-to-center variation in patient referral patterns and extent of disease. We advocate laparoscopy in patients with advanced metastatic disease (multiple and bilateral metastases) and when hepatic injury from preoperative systemic chemotherapy is suspected. Once patients have been diagnosed and a decision made in a multidisciplinary setting that resection is appropriate, it is essential to ensure that patients undergo repeat high quality abdominopelvic CT (or MRI) within a month of the date of surgery. Chest CT should also be performed at this time. High quality imaging minimizes the risk of an “open and close” laparotomy. A full cardiopulmonary evaluation should be performed if past medical history and symptoms warrant. A baseline assessment of hepatic function is mandatory before any hepatic resection to exclude dysfunction from concomitant liver disease or chemotherapy-related toxicity, as impaired hepatic function will have a negative impact on postoperative outcomes and may also limit the extent of the resection. In addition, candidates for extended resection, namely the removal of more than four adjacent segments, should undergo estimation of the future liver remnant (FLR) volume using CT volumetry.

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Selection of surgical candidates As with any oncologic surgery, optimal outcomes after hepatic resection are contingent upon identifying appropriate candidates. Traditionally, contraindications to resection of CLM have been unresectable liver disease and extrahepatic disease. In the early 1990s, the best candidates for liver resection were patients with fewer than four liver metastases, each nodule less than 5 cm in diameter, and onset of metastasis more than 12 months after colorectal primary tumor resection [8]. While extrahepatic disease was once considered an absolute contraindication for surgery, currently, selected patients with extrahepatic disease may be offered potentially curative resection.

Number of metastases Previously, multiple hepatic metastases and the presence of bilobar disease were associated with a worse prognosis [9, 10], especially in patients with more than four hepatic metastases, which were associated with higher postoperative recurrence rates. It is now recommended that patients with more than four hepatic metastases undergo thorough preoperative staging and be considered for preoperative systemic chemotherapy, even if the disease is initially resectable [11]. The presence of multiple hepatic metastases should not be considered a contraindication to resection.

Extrahepatic disease Extrahepatic disease can be extra- or intra-abdominal. Studies have shown that long-term survival can be achieved after complete R0 resection of pulmonary colorectal metastases [12]. The most common forms of intra-abdominal extrahepatic disease are hepatic pedicle lymph node metastases and peritoneal carcinomatosis. In selected patients with hepatic colorectal metastases associated with limited, resectable extrahepatic disease, an aggressive surgical resection can offer hope for long-term survival. However, in such patients, surgery represents a cytoreductive procedure, and complete cure can only be obtained by means of a multidisciplinary approach including chemotherapy.

Hepatic pedicle lymph node involvement An area of controversy is the appropriateness of surgery in patients with metastases in perihepatic lymph nodes, as their presence predicts a poor outcome after surgery [13, 14]. The incidence of hepatic pedicle lymph node metastases ranges from 3% to 33% in patients with hepatic colorectal metastases. In patients with hepatic pedicle lymph node involvement, the reported 5-year survival rate after resection of CLM ranges from 5% to 42% [13, 14]. Metastases in hilar and perihepatic lymph nodes have been shown to have a stronger negative impact on prognosis than multiple liver metastases, elevated CEA, or even solitary resectable perito-

Liver Resection of Colorectal Liver Metastases

neal disease [15]. A prospective study on the benefit of hepatic pedicle lymph node dissection found that survival rates were significantly higher among patients with nodal involvement limited to area 1 (hepatoduodenal ligament area and retropancreatic nodes) than among patients with involvement of area 2 (common hepatic artery and celiac axis nodes) [13]. In addition, the study found that hepatic pedicle lymph node involvement was significantly more frequent in patients with more than three metastases, tumors located in segments 4 and 5, a solitary resectable peritoneal deposit, or with poorly differentiated primary tumors. The best strategy for patients presenting with hepatic colorectal metastases and hepatic pedicle lymph node involvement is not well defined, and the role of aggressive treatment of hepatic pedicle lymph node metastases, even when a curative resection can be achieved, remains a matter of discussion.

Peritoneal carcinomatosis Several authors have reported long-term survival in patients with resectable extrahepatic metastases [16, 17]. In a large series of patients, investigators from the Gustave Roussy Institute [17] evaluated whether resection of extrahepatic disease could improve the outcome of patients with resectable hepatic colorectal metastases. They showed that the survival rate was significantly lower for patients with extrahepatic disease than for those without extrahepatic disease. However, they found that 5-year survival rates ranging from 12% to 37% could be obtained in selected patients with extrahepatic disease, depending on the site of metastases. Among patients presenting with extrahepatic disease, the survival rate was significantly higher in patients who received neoadjuvant chemotherapy, had fewer than five liver metastases, and in whom a complete resection was performed. Therefore, in carefully selected patients, resection of intra-abdominal extrahepatic disease during hepatectomy for CLM may yield a survival benefit, provided that a margin-negative resection is achieved.

Definition of resectability The assessment of tumor extent is an essential step for determining resectability and the appropriate type of surgical resection. Along with tumor staging, meticulous preoperative evaluation of general medical fitness, underlying liver function, and size of the anticipated FLR are also critical in ensuring suitable patient selection. At the MDACC, resectability is defined as the ability to achieve complete resection while sparing two adjacent liver segments, preserving vascular inflow and outflow, and ensuring an adequate FLR volume (at least 20% of the total estimated liver volume) [18, 19]. Patient age alone should not be considered a contraindication for resection. However, in elderly patients, there is a high prevalence of comorbid illnesses, which have been

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reported to be an independent factor predictive of postoperative mortality after extended hepatectomy [20]. Patients with American Society of Anesthesiology (ASA) scores greater than 1 represent a population at higher risk for postoperative complications and death, particularly those with congestive heart failure, severe chronic obstructive pulmonary disease, or chronic renal failure.

Surgical techniques Anatomic and nonanatomic resection The current surgical technique for liver resection is based on the segmental hepatic anatomy described by Couinaud in 1954 [21]. Anatomic resection is performed for large, deeply situated, or multiple, clustered CLM located in one part of the liver, while wedge resection is performed for small, peripheral, isolated CLM. Anatomic resections include a segmentectomy, multisegmentectomy, sectionectomy, or segmentectomy plus sectionectomy, as defined by the Brisbane 2000 terminology of liver anatomy and resections [22] (Figure 17.1). A segmentectomy is resection of a Couinaud segment, and a sectionectomy is resection of one of Healey’s segments. Wedge resection is defined as a nonanatomic

resection of the CLM to include a rim of microscopically normal tissue (see also Chapter 2). Many authors have retrospectively studied the prognostic impact of the choice of surgical approach to CLM [23, 24]. Most studies found that the type of hepatic resection performed, whether major anatomic resection or a limited nonanatomic resection, had no impact on survival. In a recent multi-institutional study, we found an identical incidence of positive margins after both anatomic and wedge resections and a 5-year survival rate of approximately 60% in both groups [25]. The data demonstrated no inherent oncologic benefit to an anatomic resection, thereby validating the continued use of nonanatomic wedge resections when clinically appropriate. In summary, the resection strategy must be individualized for each patient based on the size, number, location, and distribution of the metastases. Extensive or multiple-clustered metastases in one lobe of the liver require a hemihepatectomy or extended hepatectomy; a single, large (>5 cm) metastasis, especially when located deep within the liver, is treated with an anatomic, segmented-oriented resection; and lastly, a small, superficial metastasis is best treated with a nonanatomic wedge resection.

Two-stage hepatectomy Extended right hepatectomy or right trisectionectomy

Right hepatectomy or right hemihepatectomy

VII

VIII

Bisegmentectomy II + III or left lateral sectionectomy

I IV

III VI

V

Left hepatectomy or left hemihepatectomy Extended left hepatectomy or left trisectionectomy Figure 17.1 Brisbane 2000 terminology of liver resection. (Reproduced from Abdalla et al. Surgery 2004;135:404–10, with permission.) (See also Chapter 2.)

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Patients with extensive, bilateral disease present a challenge to the goal of achieving margin-negative resection while preserving sufficient functional liver parenchyma to support normal postoperative hepatic function. Two-stage hepatectomy, with or without portal vein embolization (PVE), has been advocated for patients with extensive bilateral CLM that cannot be resected in a single procedure. At the first stage, a minor resection is performed to remove metastases from the FLR. The second major hepatectomy (more than three segments) is performed only if it is potentially curative in the absence of significant tumor progression and when adequate parenchymal hypertrophy has occurred to reduce the risk of postoperative liver failure. During the first-stage hepatectomy, a minimum amount of dissection is performed on the liver that will be dissected in the second stage. Postoperative chemotherapy (±PVE) is then given to control tumor growth. The timing of the second hepatectomy is determined as a function of liver regeneration, control of remnant liver tumor by chemotherapy, and the probability that the second hepatectomy can be curative. Two-stage hepatectomy was first described by Adam et al [26] who reported a 3-year survival rate of 35% in 13 patients who completed two-stage resection. Jaeck et al presented their series of 25 patients who completed two-stage hepatectomy with low perioperative morbidity and mortality rates, and 3-year overall and disease-free survival rates of 54% and 14%, respectively [27]. In a recent study, Chun et al [28] demonstrated that a stepwise approach to patients with multiple, bilateral CLM using preoperative systemic

CHAPTER 17

chemotherapy and two-stage hepatectomy is a safe and effective strategy to treat patients with extensive disease, who may otherwise not be eligible for surgery. This study compared one- versus two-stage hepatectomy after preoperative oxaliplatin- or irinotecan-based chemotherapy. The results demonstrated 3-year overall and disease-free survival rates of 86% and 51%, respectively, in patients who completed two-stage hepatectomy, which were similar to the survival rates of patients treated with one-stage hepatectomy. The morbidity and mortality rates were comparable between the one- and two-stage groups [28]. In summary, two-stage hepatectomy is part of a multidisciplinary approach that includes modern systemic chemotherapy, PVE, and careful patient selection to offer a chance of prolonged survival in patients who would otherwise have a grim outcome.

Anterior approach and liver hanging maneuver Surgical resection of a large right-lobe tumor presents a challenging situation. With the conventional technique for hepatectomy, mobilization of the right lobe from the retroperitoneum and anterior surface of the inferior vena cava (IVC) may be difficult because of tumor volume and adhesions to the diaphragm. To avoid these problems, the anterior approach has been advocated, in which the parenchyma is transected from the anterior surface of the liver down to the anterior surface of the IVC, without prior mobilization of the right lobe. After control of all venous tributaries to the IVC, including the right hepatic vein, is achieved, the right lobe is dissected away from the diaphragm. In a randomized study of 120 patients with large right-lobe tumors, the anterior approach resulted in less intraoperative blood loss, lower transfusion requirements, a lower inhospital death rate, and significantly better overall survival compared to the conventional approach [29]. The anterior approach to right or extended hepatectomy may hinder control of bleeding in the deeper parenchymal plane. Thus, the liver hanging maneuver has been proposed as a method to improve surgical exposure with the anterior approach [30]. Initially described in 2001 by Belghiti et al [30], the liver hanging maneuver involves creating a retrohepatic channel between the anterior surface of the IVC and the liver parenchyma without prior hepatic mobilization. A clamp is passed from the infra-hepatic cava to the suprahepatic cava in an avascular plane to join the previously dissected space between the right hepatic vein on the right and the common trunk of the middle and left hepatic veins on the left. Elastic tape is then passed along this avascular plane, enabling the surgeon to lift and hang the liver before liver transection. The parenchymal dissection is aided by upward traction on the tape, which allows the surgeon to follow a direct plane and facilitates exposure and hemostasis of the posterior parenchymal plane anterior to

Liver Resection of Colorectal Liver Metastases

the IVC. The liver hanging maneuver presents potential advantages in terms of shorter operative time, reduced dissemination of tumor cells, and improved surgical exposure for parenchymal transection, protection of the IVC, and hemostasis.

Prevention and control of bleeding: the two-surgeon technique Many studies have shown that intraoperative blood loss and transfusion requirements are independent predictors of major morbidity and mortality from hepatic surgery [31, 32]. Portal triad clamping with the Pringle maneuver is effective in reducing blood loss during hepatic transection. In patients with chronic liver disease, intermittent Pringle maneuver, i.e. 15 min of inflow occlusion followed by 5 min of liver revascularization, has been demonstrated to be safer than continuous inflow occlusion and should be considered the technique of choice [33]. However, the Pringle maneuver does not prevent back-bleeding from the hepatic veins. A direct association has been demonstrated between mean caval pressure and blood loss. As hepatic vein pressure directly reflects the caval pressure, we maintain a low central venous pressure (<5 mmHg) with minimal acceptable urine output (0.5 mg/kg/h) in patients until the parenchymal transection is completed. Several different parenchymal dissection techniques have been developed to minimize blood loss and expedite hepatic resection. Advances in instrumentation, such as development of the ultrasonic aspirator, the jet cutter, the argon beam coagulator, and saline-linked cautery, have all been purported to improve surgical technique. At the MDACC, we recently combined saline-linked cautery with ultrasonic dissection, which allows a clear delineation of the vascular and biliary anatomy within the transection plane (Figure 17.2) [34]. This technique resulted in a significant decrease in total operative time and blood loss [34]. The use of salinelinked cautery to coagulate small vessels minimized the need for suture control of intraparenchymal vessels and permitted rapid transection of the liver.

Margin status Formerly, the goal for minimum negative tumor margin after resection of CLM was 1 cm because of studies reporting that resection margin equal or greater than 1 cm was associated with better survival rates [35, 36]. Newer reports demonstrate that the width of negative surgical margin does not affect survival or risk of recurrence. In a multi-institutional study of over 500 patients, margin status was classified as a positive or negative margin, ranging from 1 mm to greater than 1 cm [1]. The 5-year survival rate of patients with a positive margin was 17%, compared to 64% for patients with a negative margin. No significant difference in survival was seen in patients with a negative surgical margin, regardless of the width of the margin (Figure 17.3). Although a

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Secondary surgeon

Primary surgeon

such patients achieved prolonged survival [37]. Recently, advances in chemotherapy have permitted resection in some patients with initially unresectable metastases.

1.0

Proportion surviving

.8

5–9 mm

Preoperative systemic chemotherapy

≥ 10 mm

.6

1–4 mm .4

.2

0.0

Positive

0

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40

60

80

100

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Time (months) Figure 17.3 Survival stratified by margin status. Results from an international multicenter study on hepatic resection for colorectal liver metastases. No significant difference in survival was seen in patients with a negative surgical margin, regardless of the width of the margin (all p > 0.5). (Reproduced from Pawlik et al [1], with permission.)

positive margin is predictive of a worse outcome, the width of tumor-free margin may not impact survival.

Methods to improve resectability Several strategies are available to render initially unresectable CLM resectable. The advances made by chemotherapy have been the major determinant of new therapeutic approaches for primarily unresectable patients. Previously, patients with unresectable hepatic colorectal metastases were treated with palliative chemotherapy, and almost no

196

Figure 17.2 Two-surgeon technique for hepatic parenchymal transection. Using the ultrasonic dissection device, the primary surgeon directs the dissection from the patient’s left side. Simultaneously, the secondary surgeon operates the saline-linked cautery device from the patient’s right side. Traction on 4-0 polypropylene stay sutures is used to expose the deepening transection plane. (Adapted from Aloia et al [34], with permission.)

Over a decade ago, 5-fluorouracil (5-FU) was the sole chemotherapy agent used for CLM and yielded response rates of 20% with no improvement in survival. However, advances in chemotherapeutic agents and delivery have changed the treatment of CLM dramatically. The introduction of oxaliplatin and irinotecan to the chemotherapeutic armamentarium has resulted in response rates of over 50% and the conversion of unresectable to resectable metastases in up to 38% of patients [4, 37]. Moreover, the advent of monoclonal antibodies has augmented response rates to upwards of 80% [38, 39]. Effective modern chemotherapy allows not only downsizing of liver disease but also treatment of systemic disease to reduce the chance of distant failure. Another benefit of preoperative systemic treatment is the identification of patients whose disease progresses on chemotherapy and who would not benefit from surgery. Finally, response to chemotherapy can guide postoperative treatment. Many groups, including our own, use preoperative chemotherapy for patients with resectable or unresectable liver metastases (Figure 17.4) [40]. Recently, Nordlinger et al [41] presented the results from a randomized study of perioperative oxaliplatin-based chemotherapy for patients with up to four resectable metastases: patients were randomly assigned to receive surgery alone or six cycles of chemotherapy given both before and after surgery. The authors showed that perioperative chemotherapy reduces the risk of progression-free survival events at 3 years. The absolute increase in 3-year progression-free survival rate with the addition of perioperative chemotherapy was 9% in patients who had resection, from 33% to

CHAPTER 17

Diagnosis of liver metastasis of colorectal cancer

Unresectable

Resectable Preoperative therapy 2–3 months

Resectable

First-line chemotherapy Re-evaluate 2–3 months

Hepatectomy (one or two-stage) ± PVE*

Second-line chemotherapy

Postoperative therapy 3–4 months

Third-line chemotherapy

Figure 17.4 Treatment recommendations for colorectal liver metastasis (see also Section 5). *Portal vein embolization (PVE) should be considered if the future liver remnant is ≤20% in normal liver, ≤30% after extensive chemotherapy, or ≤40% in cirrhosis. (Reproduced from Kopetz et al [40], with permission.)

42%, showing a significant (p = 0.025) benefit of administering chemotherapy. The extent of resection after downsizing with chemotherapy remains problematic. In a study by Benoist et al [42], 20 of 66 tumors that had complete radiographic response after neoadjuvant therapy demonstrated persistent macroscopic disease. In patients who have complete radiographic response to neoadjuvant therapy, outcome and patterns of recurrence are ill-defined. Until conclusive evidence is available, hepatic resection should be performed on the basis of prechemotherapy imaging to encompass the area initially involved by tumor. In general, hepatic resection should be performed as soon as CLM becomes resectable.

Safety of hepatectomy after chemotherapy The effect of perioperative chemotherapy on postoperative morbidity and mortality is controversial. Irinotecan and 5-FU are associated with hepatic steatosis, while oxaliplatin induces sinusoidal obstruction [43, 44]. Nonetheless, most series show that perioperative morbidity and mortality are not higher after hepatectomy following neoadjuvant chemotherapy than after de novo resection, provided the duration of chemotherapy is less than six cycles [45–47]. In a study from the MDACC of 248 patients who received neoadjuvant chemotherapy and 158 who did not, oxaliplatin was associated with sinusoidal dilation (19% versus 2%), which did not affect the postoperative complication rate [48]. On the other hand, irinotecan was associated with steatohepatitis (20% versus 4%), irrespective of body mass index (BMI), but more

Liver Resection of Colorectal Liver Metastases

pronounced in patients with a higher BMI. Patients with steatohepatitis had increased postoperative mortality, and the authors cautioned against using irinotecan-based therapies in patients with known steatosis or steatohepatitis. In patients with suspected steatosis on preoperative imaging, laparoscopy before laparotomy is advisable to directly evaluate the liver, with biopsies as indicated.

Biologic agents Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has resulted in increased response in patients with stage IV colorectal cancer and improved progression-free survival. However, the critical role of VEGF in liver regeneration has raised concerns regarding impaired liver regeneration after preoperative administration of bevacizumab. Recent studies show that bevacizumab can be administrated safely before hepatectomy. A study from the Memorial Sloan-Kettering Cancer Center compared 32 patients who underwent hepatectomy after bevacizumab with a matched set of controls and found no increase in morbidity [49]. The authors recommended 6–8 weeks after the last dose of bevacizumab as the optimal time interval between bevacizumab administration and hepatic resection. Another study from MDACC analyzed the addition of bevacizumab to oxaliplatin-based chemotherapy and found that bevacizumab improved the pathologic response to chemotherapy, demonstrated by a lower percentage of residual viable tumor cells in liver metastases [50]. Moreover, bevacizumab was found to have a protective effect against oxaliplatin-induced sinusoidal injury. Cetuximab, a chimeric monoclonal antibody against epidermal growth factor receptor, has been shown to have activity as a single agent and to exert synergistic activity in combination with cytotoxic chemotherapy. A recent French study [51] showed that combination therapy with cetuximab increased resectability rates without increasing operative mortality or liver injury. Specific cetuximab-associated pathologic features were not identified, and potential hepatotoxic effects of cetuximab remain unknown.

Evaluation of future liver remnant volume and portal vein embolization In patients selected for major hepatectomy, evaluation of the FLR volume is critical to avoid postoperative hepatic dysfunction and failure. Three-dimensional CT volumetry provides an accurate method for preoperatively measuring the FLR volume and is acquired by outlining hepatic segmental contours and calculating the volumes of surface measurements from each slice [52]. Although direct measurement of the total liver volume (TLV) is feasible by CT volumetry, it is not relevant for surgical planning, since subtracting the volumes of multiple tumors can lead to errors in CT measurement of the TLV. In addition, measurement of the TLV

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with CT may be an inaccurate estimation of the true volume of functional liver in patients with a hypertrophic or atrophic diseased liver, such as in steatosis or cirrhosis. A more accurate method uses the estimated TLV, which is calculated using a formula that relies on the linear correlation between TLV and body surface area (BSA): TLV (cm3) = −794.41 + 1267.28 × BSA (m2). The ratio of the CT-measured FLR volume to the calculated TLV is defined as the standardized FLR, or sFLR. This standardized method allows uniform comparison between patients and has been validated as an unbiased, precise method in a recent meta-analysis [53]. Using sFLR measurement, we have demonstrated a correlation between the anticipated liver remnant volume and operative outcome. In 48 patients without chronic liver disease undergoing extended hepatectomy with and without preoperative PVE, postoperative complication rates were significantly increased in patients with sFLR of 20% or less of the estimated TLV [18].

Portal vein embolization When the sFLR is inadequate, PVE can be safely used to induce hypertrophy of the FLR and offer potentially curative hepatectomy to a subset of patients not previously considered optimal surgical candidates. Under fluoroscopic guidance, PVE involves percutaneous cannulation of the portal vein, usually the ipsilateral branch, and embolization of the entire portal vein tree to be resected using microparticles and microcoils. The resultant redirection of portal flow to the FLR increases both volume and function of the nonembolized segments, as indicated by increased biliary excretion, increased technetium-99m-galactosyl human serum albumin uptake, and improvement in postoperative liver function tests [54]. The magnitude and rate of volume increase after PVE are higher in patients with normal underlying liver compared to those with chronic liver disease [55]. There is little agreement on the minimal FLR volume needed for safe hepatic resection. The surgical series published to date report different methods of liver volume measurement and include patients with considerably different degrees of underlying liver disease. In our experience, an sFLR of 20% or less is associated with a significant increase in postoperative morbidity [19]. In general, an sFLR of 20% appears to be the minimum volume needed following extended hepatic resection in patients with normal underlying liver, 30% for patients with chemotherapy-induced injury, and 40% in patients with chronic liver disease (Figure 17.5). Hypertrophy of the FLR is expected within the first month after PVE. After right PVE, a 30–80% absolute increase in volume of the nonembolized liver and 6–10% increase in FLR/TLV ratio occur within 3–4 weeks [56] (Figure 17.6). Ribero et al demonstrated that the greatest increase in FLR volume occurs within the first 3 weeks, after which regeneration reaches a plateau [19]. This is in agreement with

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Normal liver ≤ 20%

Extensive chemotherapy ≤ 30%

Cirrhosis ≤ 40%

Future liver remnant Figure 17.5 Indication for portal vein embolization. There is a consensus that, in patients treated with aggressive preoperative chemotherapy, the remnant liver volume should be at least 30% of the total liver volume to avoid a high risk of complications following hepatic resection. (Reproduced from Zorzi et al. Br J Surg 2007;94:274–86, with permission.)

recent data showing that hypertrophy of the nonembolized liver is regulated mainly by transforming growth factor-beta, whose serum level has been reported as peaking at day 20 after PVE and thereafter plateauing [57]. Thus, 3–4 weeks should be considered the optimum time interval to assess the hypertrophy response to PVE. In addition to the absolute value of the sFLR, the difference in sFLR before and after PVE, defined as the degree of hypertrophy, is predictive of outcome after major hepatectomy. A degree of hypertrophy of at least 5% has been associated with decreased risk of postoperative hepatic dysfunction after major hepatectomy (see also Chapter 29).

Conclusion Hepatobiliary surgeons, medical oncologists, and interventional radiologists should approach patients with CLM in a multidisciplinary fashion to individualize the treatment strategy and maximize the chances of long-term survival. The consensus statements from the Consensus Conference on CLM held in San Francisco, CA, in 2006 [58] were: 1 For patients with metastatic colorectal carcinoma isolated to the liver, hepatic resection is the only treatment associated with demonstrated long-term survival. All patients with resectable disease should be offered hepatic resection. 2 For patients with disease isolated to the liver that is deemed initially anatomically unresectable, preoperative chemotherapy permits complete resection in 15–30% of patients. 3 In patients with initially unresectable hepatic colorectal metastases who undergo resection, the survival rate at 5 years (30–35%) approaches the survival rate of patients who undergo upfront hepatic resection for initially resectable disease. 4 Preoperative chemotherapy results in damage to the liver that may increase morbidity and mortality after hepatic resection. Occasionally, preoperative chemotherapy results in a radiographic complete response (rarely histologically

CHAPTER 17

(a)

Liver Resection of Colorectal Liver Metastases

(b)

Figure 17.6 A patient with multiple, large metastases required extended right hepatectomy. (a) The measured volume of the future liver remnant (segments 2 and 3, outlined in white) was 291 cm3, and the standardized future liver remnant (sFLR) was calculated as 17% of the estimated total liver volume (TLV). To downsize metastases and induce hypertrophy of the FLR before hepatectomy, chemotherapy was administered followed by portal vein embolization. (b) This led to an increase in volume of the FLR to 510 cm3 and sFLR to 30% of the estimated TLV. (Reproduced from Chun et al [56], with permission.)

confirmed) that jeopardizes the performance of an adequate liver resection. For these reasons, the duration of neoadjuvant chemotherapy should be carefully considered, and resection should be performed as soon as hepatic metastases become technically resectable. 5 Radiological complete response is rarely associated with complete pathological response. Mapping and timing of resection are critical. Resection should encompass segments involved based on prechemotherapy imaging. Extended chemotherapy should be avoided and resection should be performed as soon as patients are “surgically” resectable.

Self-assessment questions

1 Hypertrophy of the future liver remnant after portal vein embolization is expected within how long? A 1 week B 1 month C 2 months D 3 months 2 The results of two-stage hepatectomy in the oxaliplatin- or irinotecan-based chemotherapy era indicate 3-year overall and disease-free survival, respectively, in excess of: A 50% and 20% B 60 % and 30% C 70% and 40% D 80% and 50%

3 The European randomized study comparing perioperative chemotherapy with FOLFOX-4 combined with surgery versus surgery alone indicated improvement in which one of the following? A Overall survival at 3 years in eligible patients B Overall survival at 3 years in resected patients C Progression-free survival at 3 years in resected patients D Progression-free survival at 3 years in all patients on an intend to treat 4 Which of the following are strategies to improve colorectal liver metastases resectability? (more than one answer is possible) A Liver hanging maneuver and anterior approach B Neoadjuvant chemotherapy C Portal vein embolization D Two-stage hepatectomy 5 Hepatic pedicle lymph node involvement in patient with colorectal liver metastases is more frequent in patients with which of the following? (more than one answer is possible) A More than three metastases B Tumors located in segments 4 and 5 C A solitary resectable peritoneal deposit D Poorly differentiated primary tumor E Lung metastases 6 Which of the following terms correctly define an anatomic liver resection according to the

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Brisbane 2000 Terminology? (more than one answer is possible) A Extended right hepatectomy B Bisegmentectomy 2 + 3 C Left lateral sectionectomy D Left lobectomy E Left hemihepatectomy 7 For the parenchymal transection techniques used for liver resection, the two-surgeon technique has been shown to be associated with which of the following? (more than one answer is possible) A Decreased total operative time B Reduced blood loss C Less need for suture control of intraparenchymal vessels D Reduction in perihepatic postoperative fluid collections E Low frequency of postoperative bile leaks 8 Preoperative systemic chemotherapy is associated with an increased risk of surgical complications in which of the following settings? (more than one answer is possible) A Duration of chemotherapy of more than 3 months (six cycles) B Body mass index of more than 25 kg/m2 C Use of biologic agents (bevacizumab or cetuximab) D Resection of a single peripherally located liver metastasis E Combination of multiple preoperative chemotherapy lines 9 Two-stage hepatectomy is indicated in patients with extensive bilateral colorectal liver metastases because the disease cannot be resected in a single procedure. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 10 The technique of liver hanging maneuver has been proposed because it allows better control of bleeding in the deeper parenchymal plane during hepatic resection than the anterior approach without the hanging maneuver A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect

200

E First part correct, second part correct, “because” correct 11 A future liver remnant of 20% is the minimum safe volume needed for an extended hepatic resection in normal liver because preoperative chemotherapy is associated with liver damage that may increase morbidity and mortality after hepatic resection. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct

References 1 Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 2005;5:715–24. 2 Vauthey JN, Zorzi D, Pawlik TM. Making unresectable hepatic colorectal metastases resectable – does it work? Semin Oncol 2005;6 (Suppl 9):S118–22. 3 Goldstein MJ, Mitchell EP. Carcinoembryonic antigen in the staging and follow-up of patients with colorectal cancer. Cancer Invest 2005;4:338–51. 4 Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004;4:644– 57. 5 Bipat S, van Leeuwen MS, Comans EF, et al. Colorectal liver metastases: CT, MR imaging, and PET for diagnosis – metaanalysis. Radiology 2005;1:123–31. 6 Akhurst T, Kates TJ, Mazumdar M, et al. Recent chemotherapy reduces the sensitivity of [18F]fluorodeoxyglucose positron emission tomography in the detection of colorectal metastases. J Clin Oncol 2005;34:8713–16. 7 Khan AZ, Karanjia ND. The impact of staging laparoscopy prior to hepatic resection for colorectal metastases. Eur J Surg Oncol 2007;8:1010–13. 8 Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;3:309–18. 9 Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 2002;6:759–66. 10 Minagawa M, Makuuchi M, Torzilli G, et al. Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer: long-term results. Ann Surg 2000;4:487–99. 11 Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC

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cellular carcinoma: a prospective randomized controlled study. Ann Surg 2006;2:194–203. Belghiti J, Guevara OA, Noun R, et al. Liver hanging maneuver: a safe approach to right hepatectomy without liver mobilization. J Am Coll Surg 2001;1:109–11. Kooby DA, Stockman J, Ben-Porat L, et al. Influence of transfusions on perioperative and long-term outcome in patients following hepatic resection for colorectal metastases. Ann Surg 2003;6:860–9. Rosen CB, Nagorney DM, Taswell HF, et al. Perioperative blood transfusion and determinants of survival after liver resection for metastatic colorectal carcinoma. Ann Surg 1992;4:493– 504. Ishizaki Y, Yoshimoto J, Miwa K, et al. Safety of prolonged intermittent pringle maneuver during hepatic resection. Arch Surg 2006;7:649–53. Aloia TA, Zorzi D, Abdalla EK, et al. Two-surgeon technique for hepatic parenchymal transection of the noncirrhotic liver using saline-linked cautery and ultrasonic dissection Ann Surg 2005;2:172–7. Cady B, Jenkins RL, Steele GD Jr, et al. Surgical margin in hepatic resection for colorectal metastasis: a critical and improvable determinant of outcome. Ann Surg 1998;4:566–71. Steele G Jr, Bleday R, Mayer RJ, et al. A prospective evaluation of hepatic resection for colorectal carcinoma metastases to the liver: Gastrointestinal Tumor Study Group Protocol 6584. J Clin Oncol 1991;7:1105–12. Giacchetti S, Itzhaki M, Gruia G, et al. Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 1999;6:663–9. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;23:2335–42. Wicherts DA, de Haas RJ, Adam R. Bringing unresectable liver disease to resection with curative intent. Eur J Surg Oncol 2007;33 (Suppl):S42–51. Kopetz S, Vauthey JN. Perioperative chemotherapy for resectable hepatic metastases Lancet 2008;371:963–65. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008;371:1007–16. Benoist S, Brouquet A, Penna C, et al. Complete response of colorectal liver metastases after chemotherapy: does it mean cure? J Clin Oncol 2006;24:3939–45. Peppercorn PD, Reznek RH, Wilson P, et al. Demonstration of hepatic steatosis by computerized tomography in patients receiving 5-fluorouracil-based therapy for advanced colorectal cancer. Br J Cancer 1998;11:2008–11. Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 2004;3:460–6. Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 2006;31:4983–90.

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46 Nordlinger B, Sorbye M, Debois M, et al. Feasibility and risks of pre-operative chemotherapy (CT) with FOLFOX 4 and surgery for resectable colorectal cancer liver metastases (LM). Interim results of the EORTC Intergroup randomized phase III study 40983. Proceedings of the American Society of Clinical Oncology, 2005:253s. 47 Karoui M, Penna C, Amin-Hashem M, et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg 2006;1:1–7. 48 Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006;13:2065–72. 49 D’Angelica M, Kornprat P, Gonen M, et al. (2007) Lack of evidence for increased operative morbidity after hepatectomy with perioperative use of bevacizumab: a matched case-control study. Ann Surg Oncol 2007;2:759–65. 50 Ribero D, Wang H, Donadon M, et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer 2007;12:2761–7. 51 Adam R, Aloia T, Levi F, et al. Hepatic resection after rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy. J Clin Oncol 2007;29:4593–602. 52 Zacharia TT. Assessment of future remnant liver regeneration after portal vein embolization using three-dimensional CT and MR volumetric analyses. Australas Radiol 2006;6:543–8. 53 Johnson TN, Tucker GT, Tanner MS, et al. Changes in liver volume from birth to adulthood: A meta-analysis. Liver Transpl 2005;12:1481–93. 54 Hirai I, Kimura W, Fuse A, et al. Evaluation of preoperative portal embolization for safe hepatectomy, with special reference

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to assessment of nonembolized lobe function with 99mTc-GSA SPECT scintigraphy. Surgery 2003;5:495–506. Farges O, Belghiti J, Kianmanesh R, et al. Portal vein embolization before right hepatectomy: prospective clinical trial. Ann Surg 2003;2:208–17. Chun YS, Vauthey JN. Extending the frontiers of resectability in advanced colorectal cancer. Eur J Surg Oncol 2007;33 (Suppl 2):52–8. Kusaka K, Imamura H, Tomiya T, et al. Expression of transforming growth factor-alpha and -beta in hepatic lobes after hemihepatic portal vein embolization. Dig Dis Sci 2006;8:1404–12. Abdalla EK, Adam R, Bilchik AJ, et al. Improving resectability of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol 2006;10:1271–80.

Self-assessment answers 1 2 3 4 5 6 7 8 9 10 11

B D C A, A, A, A, A, E E D

B, B, B, B, B,

C, D C, D C, E C E

18

Laparoscopic Liver Resection Luca Viganò1 and Daniel Cherqui2 1 2

Department of Hepatobiliary and Digestive Surgery, Ospedale Mauriziano “Umberto I”, Torino, Italy Department of Digestive and Hepatobiliary Surgery, Hôpital Henri Mondor-Université Paris, Créteil, France

Liver resection is one of the last surgical areas to lend itself to the laparoscopic approach. Fifteen years after the first reported laparoscopic liver resection [1], its application is still limited to a few centers and its results have yet to be clarified. The vast majority of hepatic resections are standalone procedures, without any need for reconstruction, which should make them good candidates for a laparoscopic approach. There are three reasons for the limited development of such an approach. First, technical problems are anticipated and, indeed, the elementary maneuvers of open hepatic surgery (including manual palpation, organ mobilization, vascular control, and parenchymal transection) are considered difficult to reproduce laparoscopically. Second, there are anticipated hazards; hemorrhage may be more difficult to control laparoscopically and the risk of gas embolism may be increased by the use of a pneumoperitoneum. Third, there is a fear of oncologic inadequacy and tumor spread. Some surgical teams, driven by past experience in hepatic and laparoscopic surgery and helped by technologic innovations, have explored the possibility of laparoscopic liver resection. However, at the present time, limited evaluation is available. Most reports include individual case series and retrospective comparisons with open resections, but there are no studies giving high levels of evidence. Most studies have focused on feasibility and safety, and there has been little published evaluation of oncologic results. In this chapter, we will review the various aspects of laparoscopic liver resection from our own experience and from the current literature.

hepatectomies have been reported in the literature, but only in about half of cases was the indication a malignant tumor (see Table 18.1) [2–10]. Despite the increasing number of reported series, in expert centers laparoscopic approach has been planned for only a small percentage of liver resections, ranging from 5% to 30%, except in one series where it reached 80% [3]. Over the past 10 years, of a total of 778 hepatectomies, we have performed 170 laparoscopic liver resections (21.9%). Focusing on malignant lesions, this percentage decreases to 15.6% (101 of 646).

Surgical technique State-of-the-art equipment is required. The use of two monitors is recommended. Although some groups use 0 °laparoscopes [4, 5], 30 °-laparoscopes are preferred by most authors.

Patient positioning We suggest two different positions according to the lesion site. For lesions located in segments 2–5 (the majority of cases), the patient is placed in the supine position, with the lower limbs apart (Figure 18.1). The surgeon stands between the patient’s legs with one assistant on either side. For patients with lesions of segment 6 scheduled for atypical resection or segmentectomy, the left lateral decubitus position may be used in order to expose the lateral and posterior aspect of the right liver lobe (Figure 18.2). In this case the surgeon is positioned on the ventral side of the patient. For laparoscopic right hepatectomy, the supine position with the patient’s lower limbs apart is preferred. Some authors prefer the supine position with the surgeon positioned on one side of the patient and the assistant on the opposite side [3].

Feasibility: technique and indications Pneumoperitoneum The feasibility of laparoscopic liver resection has been the main criterion studied to date. More than 1000 laparoscopic

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

A problem concerning laparoscopic liver surgery is the pneumoperitoneum itself. The risk of gas embolism due to hepatic veins lesions during parenchymal transection has been suggested. A transesophageal echocardiography study in animal models demonstrated gas embolism in almost all animals undergoing laparoscopic liver resection with cardiac arrhythmia in two-thirds of cases [11]. To avoid this, gasless

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laparoscopy has been proposed [12]. However, gas embolism in clinical practice is rare [13]. In 2002 Biertho et al reviewed published laparoscopic liver resections and reported only two cases of possible gas embolism among about 200 procedures [14]. In recent series [3, 4, 15] and in our experience, few cases of transient mild cardiovascular alteration due to embolism occurred and those that did were without clinical consequences. A carbon dioxide pneumoperitoneum minimizes the risk of gas embolism as compared to air, and a low pneumoperitoneum pressure further reduces its incidence [16]. Electronic monitoring of intra-abdominal pressure is required and should be maintained at less than 14 mmHg. Gas embolism occurrence has been also related to argon beam coagulation which increases endoabdominal pressure, leading to increased risk of gas embo-

lism [17]. To date a carbon dioxide pneumoperitoneum is considered safe and gasless laparoscopy is no longer practiced. A pneumoperitoneum can be created using a Veress needle or by the open technique. A previous laparotomy should not be considered a contraindication to laparoscopic resection.

Port site positioning and hand assistance The positioning of port sites differs according to tumor site (Figures 18.1 and 18.2). Many variants have been described. The trocar for the laparoscope can be positioned higher on the midline or more lateral on the right side in cases of right liver resection [4, 5]. Hand-assisted laparoscopy has been used by several authors [3, 18]. It consists of the placement through an 8-cm incision of a gas-tight port, permitting the introduction of a hand into the abdomen (Figure 18.3). The assisting hand allows tactile feedback while palpating the liver, and it may assist in abdominal exploration, mobilizing the liver, gentle retraction, and during parenchymal transection. In addition, in cases of bleeding, hand compression allows easier hemostasis. Its proponents argue that this technique may render laparoscopic liver resection safer and more accessible. Koffron et al recently proposed a wider use of hand assistance in order to increase the proportion of patients who can benefit from the laparoscopic-assisted approach [3]. In our experience, hand assistance has been used whenever needed to reduce the conversion rate in right hepatectomies and limited resections of the posterior right segments. In these cases liver mobilization and parenchymal transection can be difficult and hand assistance can reduce conversion rate.

Abdominal exploration and laparoscopic ultrasonography

Figure 18.1 Port placement for resection of lesions located in segments 2–5 and for right hepatectomy. The patient is in the supine position with the lower limbs apart and the surgeon between the legs. Numbers represent trocar sizes in mm.

Exploration of the liver and of the abdominal cavity is always the first stage. Inspection of the peritoneal cavity for ascites, carcinomatosis, hemoperitoneum, and signs of portal hypertension is always conducted. Frozen sections of encountered lesions can be performed. The liver volume, tumor characteristics, and presence of steatosis, cholestasis or cirrhosis can be evaluated. Superficial infracentimetric

Figure 18.2 Port placement for resection of lesions located in segment 6. The patient is in the left lateral decubitus for right lobe mobilization and posterior exposure. The table can be turned to the right to reapply the right lobe and gain anterior access. Numbers represent trocar sizes in mm.

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Figure 18.3 Hand-assisted laparoscopy. A gas-tight port allows the introduction of a hand into the abdomen through an 8-cm incision.

Laparoscopic Liver Resection

Figure 18.4 Laparoscopic left lateral sectionectomy. The transection plane is exposed through the traction of the round ligament and the left lobe parenchyma. Liver transection is performed using an harmonic scalpel (1).

tumors which otherwise are difficult to visualize upon imaging can be disclosed. Laparoscopic ultrasonography should be systematically performed. It reveals liver anatomy and its variations, locates known lesions, defines tumor connections with portal pedicles and hepatic veins, and screens the parenchyma for overlooked tumors. Several studies have shown the superiority of laparoscopic ultrasonography over preoperative staging [19–21]. Laparoscopic ultrasonography is also useful to check the adequacy of the surgical margin during parenchymal transection.

Pedicle clamping Once resection had been decided upon, the porta hepatis is encircled with an umbilical tape. The lesser omentum is checked for the left hepatic artery. Intermittent clamping (15 min clamping and 5 min release periods) can be performed whenever necessary. Our group demonstrated that in patients with normal cardiac function, laparoscopic pedicle clamping is safe and well tolerated [22, 23]. However, this technique is decreasingly used and the majority of recent resections have been performed without any clamping.

Liver mobilization and inflow/outflow control Several techniques have been described, but here only our usual technique is briefly described. In left lateral sectionectomy, the round, falciform, and left triangular ligaments, and the lesser omentum are divided. Dissection of the falciform ligament is continued to the level of the inferior vena cava and the insertions of the hepatic veins. Parenchymal transection is carried out until the level of the portal pedicles, which are then divided by linear sta-

Figure 18.5 Laparoscopic left lateral sectionectomy. Portal pedicles are identified and divided using a linear stapler (1) or after application of metallic clips (2).

plers. The left hepatic vein is divided at the end of parenchymal transection using a linear stapler [24] (Figures 18.4–18.6). In limited resections, parenchymal transection is carried out along the transection lines that have been decided upon. Portal pedicles and hepatic veins are controlled as they are encountered during transection. In limited right-sided resections, the right triangular ligament is divided, taking advantage of the lateral position of the patient. Parenchymal transection is then carried out. Laparoscopic right hepatectomy involves the dorsal decubitus position, initial division of the right portal pedicle, right liver mobilization, taping of the right hepatic vein if feasible,

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The ultrasonic aspirator The ultrasonic dissector selectively destroys liver parenchyma, and spares vessels and bile ducts, which can be selectively controlled. It does not have hemostatic properties. In our experience, the ultrasonic dissector is particularly useful in deep parenchymal transection, especially in right hepatectomy, to selectively identify and control vessels and bile ducts.

Figure 18.6 Laparoscopic left lateral sectionectomy. After division of segments 3 (1) and 2 (2) pedicles, the left hepatic vein (3) is isolated at the end of the parenchymal transection and divided using a linear stapler.

and transection. Hand assistance can be used. The assisting hand is introduced through a right iliac or flank transverse incision. The surgeon’s left hand or assistant’s right hand assists with mobilizing the liver and can provide compression if bleeding occurs.

Parenchymal transection The main technical challenge of laparoscopic liver resection remains intraoperative hemorrhage during parenchymal transection. In open procedures, the principle of transection is to progressively open the liver to expose and identify vascular and biliary structures, and to treat them according to their size. Most authors use cautery incision of the Glisson’s capsule followed by liver transection with a hemostat forceps (Kellyclasia) or an ultrasonic dissector. Hemostasis of vascular and biliary structures is then achieved within the liver as they were encountered along the transection plane. Minor structures are usually treated with bipolar coagulation and the application of clips or ties; larger structures are ligated with sutures. The main portal pedicles and hepatic veins can be divided extrahepatically or during liver transection. Several devices have been developed with the objective of allowing a more bloodless and accurate parenchymal transection to be performed. Most of these devices are “blind” instruments (i.e. blind parenchymal division without prior vessel identification) as opposed to the classic instruments, which require prior identification of the vascular and biliary structures. These latter devices have not proved to be indispensable during open resections. However, in laparoscopic surgery, the simple principles of transection are more difficult to apply and some of the newly designed technologies are required.

206

The ultrasonic scalpel Also called harmonic scalpel, the ultrasonic scalpel has the major advantage of cutting and coagulating at the same time. In laparoscopic procedures, easy handling and rapid action are major advantages of this device. It can be particularly recommended for the superficial parts of transection (2 cm in depth). However, it is a blind instrument which should be used with caution when deeper liver parts are reached because of the risk of vascular injuries to larger vessels, especially to the hepatic veins. The vessel sealing system The vessel sealing system uses low frequency bipolar current and seals vessels up to 7 mm in diameter. Its use is rather similar to that of the ultrasonic scalpel, and it includes a knife that cuts after sealing. Radiofrequency-assisted hepatic resection (Habib Laparoscopic Sealer 4XL®) The radiofrequency probe inserted along the transection line generates precoagulation. Subsequently, a cut along the coagulated line can be performed. It has been suggested to have many advantages: it allows easy and bloodless transection, mainly in atypical resections; it can be helpful in wedge resections, in which visualization of transection planes and bleeding control may be more difficult; it induces necrosis and may improve safe surgical margins. Further studies are needed to evaluate its role in laparoscopic liver surgery. Stapler hepatectomy Linear stapler devices are widely applied in laparoscopic liver surgery for portal pedicle and hepatic vein division. Recently, some authors have proposed their use for parenchymal transection [25]. After the transection line is marked and the liver capsule is incised with diathermy, the liver parenchyma can be divided with repeated applications of linear vascular staplers. These devices allow fast resection, but vascular and biliary injuries can occur during blind transection. Further studies are necessary to clarify the safety of stapler hepatectomy. This technique does not allow fine control of margins and requires that tumors are located remotely from the transection line. In addition, the cost of this method is high and increases with the number of applications required.

Laparoscopic Liver Resection

CHAPTER 18

Other devices Many other devices have been proposed in the last years, such as water jet dissection, microwave-based devices, curettage and aspiration devices, and monopolar irrigated coagulation devices, but available data do not allow any conclusive evaluation of them.

II VIII VII

Specimen extraction In all cases, the specimen is placed in a plastic bag and extracted through a separate incision, either along a previous appendectomy incision or a new suprapubic horizontal incision. An enlarged port site can also be utilized [3, 6]. Fragmentation should be avoided.

III

I

IV VI

V

Indications Indications for laparoscopic hepatectomy do not differ from those for open surgery. Technical feasibility is the only limiting factor. In the case of benign tumors, only symptomatic or doubtful lesions may justify resection and the laparoscopic approach should not expand the indications to include incidental asymptomatic benign lesions. In the case of malignant lesions, liver metastases and hepatocellular carcinoma (HCC) are the main indications, like in open surgery. Laparoscopic resection is contraindicated in cases of gallbladder cancer and hilar cholangiocarcinoma because of the risk of the peritoneal tumor spreading and the need for extensive resections, respectively. Patient selection for laparoscopic liver resection is related to tumor location and size.

Tumor location Laparoscopic limited resections, including wedges, segmentectomies, and left lateral sectionectomies, can be proposed for lesions located in anterolateral segments of the liver (segments 2–6, so-called “laparoscopic segments”) (Figure 18.7). Laparoscopic right hepatectomy can be planned for lesions located anywhere in the right lobe with the exception of those located close to the liver hilus or the hepatocaval junction, because of the risk of major vascular or biliary injury. The role of laparoscopy for lesions requiring resection of segments 7, 8 and 1 has not yet been standardized.

Tumor size Laparoscopy is usually not recommended for lesions exceeding 5 cm in diameter. Even if laparoscopic resection for larger lesions have been reported, it should be avoided because of the difficult tumor mobilization and risk of its rupture.

Evaluation of laparoscopic liver resection No randomized study on the efficacy of laparoscopic liver resection has so far been published. Studies on laparoscopy in other areas of abdominal surgery may provide a worth-

Figure 18.7 The “laparoscopic segments.” The gray areas are considered consistent with laparoscopic resection.

while analogy. There are few randomized trials even for common operations that compare open and laparoscopic approaches, and even fewer that have demonstrated any superiority of laparoscopy; conversely, none has demonstrated any superiority of laparotomy. For example, randomized studies comparing laparoscopy and minilaparotomy for cholecystectomy have failed to demonstrate the superiority of one approach over the other [26, 27]. However, few would dispute that laparoscopy is now the standard approach for elective cholecystectomy. This suggests that in the absence of a clear difference between laparotomy and laparoscopy, and provided that the same result can be achieved, surgeons favor laparoscopy. Another analogy can be drawn from the COST randomized trial of open versus laparoscopic colectomy for colon cancer [28]. This study was designed as a non-inferiority trial and enrolled 872 patients. It demonstrated similarity for recurrence and survival and a slight advantage to laparoscopy for hospital stay and analgesic requirements (1 day reduction for each item). The conclusion was that the laparoscopic approach is an acceptable alternative to open surgery for colon cancer. A randomized study of open versus laparoscopic liver resection is of course desirable, but it will be difficult to conduct because of the variability of the indications, types of resections, and types of techniques used. It will also require a large number of patients, which will be difficult to accrue. At present only retrospective and case-control comparisons are available. An increasing number of papers have reported outcomes of laparoscopic liver resections. The majority focus on shortterm outcomes, such as hospital stay and analgesic requirements. These are important but vary according to local

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Table 18.1 Series of laparoscopic liver resections including more than 50 patients. Authors

Year

n

Malignant lesions

Number of major hepatectomies (rate [%])

Mortality (rate [%])

Morbidity (rate [%])

Number of conversions (rate [%])

Descottes et al [9]* Mala et al [6] Kaneko [7] Vibert et al [5] Cai et al [10] Dagher et al [4] Koffron et al [3]** Chen et al [8] Authors’ series [57]***

2002 2005 2005 2006 2006 2007 2007 2008 2009

87 53 52 89 62 70 273 116 174

0% 89% NR 73% 32% 54% 37% 100% 63%

3 (3.4) 0 NR 38 (43) 2 (3.2) 19 (27) 96 (35) 4 (3.4) 35 (20)

– – – 1 (1.1) – 1 (1.4) – – –

4 (4.6) 8 (16) 5 (10) 31 (34.8) 2 (3.2) 11 (15.7) NR 7 (6) 25 (14.4)

9 3 1 12 2 7 – 6 17

(10%) (5.6) (2) (13) (3.2) (10) (5.2) (9.8)

*Multicenter study; **only pure laparoscopic and hand-assisted laparoscopic hepatectomies; ***updated data. NR, not reported.

practice. Other outcome measures, such as earlier access to chemotherapy, reoperations, incisional hernias, and bowel obstructions are potential advantages which remain to be demonstrated. Finally, there are very few oncologic results available.

Short-term outcomes Among more than 1000 laparoscopic liver resections described in the literature, only five postoperative deaths have been reported (<0.5%) [3–5, 29, 30]. Causes of death included liver failure in a cirrhotic patient (three cases), brain death after major intraoperative hemorrhage (one case), and acute respiratory distress (one case). Morbidity rates ranged from 3% to 35%. In our series of 170 laparoscopic resections, there were no deaths and the morbidity rate was 15%. Two complications are commonly feared in laparoscopic liver surgery: gas embolism and bleeding. As previously discussed, gas embolism is rarely reported and is usually without any clinical consequences, except for transient cardiovascular alterations. On the other hand, hemorrhagic complications can occur during parenchymal transection and lead to urgent conversion. In the literature some severe hemorrhagic complications have been reported, mainly related to hepatic veins injuries. They have been usually managed either laparoscopically or by conversion to laparotomy without major reported consequences for the patient, except for the one reported death mentioned above. No intraoperative death has been reported. In the literature, the reported conversion rate is up to 15% [4, 5, 31]. There are essentially two reasons for conversion. The first is a technical one, i.e. due to difficult exposure, an insufficient or poor quality view, a fragile tumor carrying

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the risk of rupture, or uncertainty about the distance between the tumor and the transection plane. The second reason is, of course, bleeding. In our series the conversion rate was 9.4%; two-thirds for technical reasons and onethird for bleeding. Massive bleeding requiring rapid conversion never occurred; rather it was situations that were difficult to control by laparoscopy and which, by their persistence, hampered the progress of the operation and were leading to a significant blood loss. Koffron et al recently reported a reduced conversion rate which they credited to the wide use of hand assistance: in their series of 241 laparoscopic liver resections, 6% required conversion to the handassisted procedure, with no conversion to laparotomy [3]. Outcomes of the largest published series of laparoscopic liver resections are detailed in Table 18.1. Surgical outcomes of laparoscopic surgery tend to improve with experience. Many series have described this phenomenon, with reduced operative times, blood losses, and conversion rates in last patients [4, 7, 24, 32]. In our center, the overall conversion rate was 9.4%, but this has decreased to 2.4% since 2004 and no conversion has been required in the past 2 years.

Comparison with open liver resections Up to December 2007, seven case-control studies comparing the results of laparoscopic and open liver resections have been published [13, 29, 33–37]. Six additional papers have compared outcomes of laparoscopic and open procedures without employing any matching criteria [38–43]. The results of these studies are reported in Table 18.2. A metaanalysis (including five case-control and three comparatives studies) has been recently published [31]. Laparoscopic liver resections were associated with significantly less blood loss; operative time, use of the Pringle maneuver, and blood

Table 18.2 Studies comparing laparoscopic versus open liver resection.

n

Operative time (min)

Blood loss (mL)

L

L

Year

L

Rau et al [33] Farges et al [13] Lesurtel et al [34] Morino et al [36] Laurent et al [35] Belli et al [29] Troisi et al [37]

1998 2002 2003 2003 2003 2007 2008

Case-control studies 17 17 184 ± 55 21 21 177 ± 57 18 20 202 ± 48 30 30 148 13 14 267 ± 79 23 23 148 ± 30 20 20 220 ± 122

128 156 145 142 182 125 242

Shimada et al [38] Mala et al [39] Buell et al [40] Kaneko et al [41] Soubrane et al [42] Cai et al [43]

2001 2002 2004 2005 2006 2007

Comparative studies 17 38 325 15 14 187 (80–334) 17 100 168 30 28 182 ± 38 16 14 320 ± 67 29 22 236 ± 135

280 185 270 210 244 220

O

± 37 ± 42 ± 31 ± 57 ± 17 ± 98

(100–335) ± 40 ± 55 ± 61

458 218 236 320 620 260 NR

O

± 344 ± 173 ± 155 (50–1500) ± 130 ± 127

400 600 (100–3300) 288 350 ± 210 18.7 ± 44 603 ± 525

556 285 429 479 720 377

800 500 485 505 199 655

± 386 ± 178 ± 286 (100–2100) ± 240 ± 114

(100–3700) ± 185 ± 185 ± 569

Hospital stay (days)

L

O

L

O

L

O

6 5 0 13 8 0 10

12 0 15 7 29 17 20

6 10 11 7 36 13 20

6 10 15 7 50 48 45

7.8 ± 8.2 5.1 ± 1.3 8±3 6.4 15.3 ± 8.6 8.2 ± 2.6 7.1 ± 4.4

11.6 ± 12.8 6.5 ± 1 10 ± 6 8.7 17.3 ± 18.9 12.0 ± 4.0 10.4 ± 3.9

6 NR NR NR 0 NR

11 13

6

11 29 NR 18 36 18

12 ± 5 4 (1–6) 2.9 14.9 ± 7.1 7.5 ± 2.3 8.8 ± 4.4

22 ± 8 8.5 (5–23) 6.5 21.6 ± 8.8 8.1 ± 3.0 13 ± 9.2

0

24 10 19 7

209

Laparoscopic Liver Resection

L, laparoscopic resections; O, open resections; NR, not reported. Bold typed data p < 0.05.

O

Morbidity (%)

CHAPTER 18

Authors

Blood transfusions (%)

SECTION 4

Resection, Ablation or Transplantation

transfusions were similar to those of open hepatectomies. However, in our experience, laparoscopic resections took longer that their open counterparts, except for left lateral sectionectomy. Postoperative stay and time to first oral intake were shorter in laparoscopic operations. Overall and liver-specific morbidity rates were similar. Reduced need for postoperative analgesia after laparoscopic hepatectomy has been reported in two studies [13, 39]. At laparoscopic liver resection, an incision is required to extract the specimen, but this is short (<8 cm) and in the lower abdomen; it is opened and closed immediately after the specimen has been removed, without application of retractors, and is extremely well tolerated. The exposure required for even a limited open liver resection demands a long (>15 cm) right subcostal incision with muscular division, often extended to the left or the upper midline or both. This leads to permanent cutaneous anesthesia below the incision and abdominal hypotonia; it can be a frequent cause of discomfort, often for many years. While such an approach is justified in the majority of cases, if the same operation can be performed laparoscopically with equal safety, the less invasive method may reasonably be considered.

Liver resection in cirrhotic patients In cirrhotic patients, liver resections, even minor ones, carry a high risk of complications, including ascites, jaundice, and encephalopathy. Specific benefits from the laparoscopic approach have been suggested. It might offer the advantage of preserving the abdominal wall and its collateral veins, resulting in less portal hypertension, less need for fluids, and improved reabsorption of ascites. Two case-control studies [29, 35] and two comparative analyses [38, 41] have compared outcomes of laparoscopic and open liver resections in cirrhotic patients. A trend towards reduced morbidity, especially little development of postoperative ascites, was observed in HCC patients operated on using a laparoscopic approach. In addition, hospital stay and postoperative quality of life were improved in the laparoscopic group. Based on theoretical advantages of the laparoscopic approach in cirrhotic patients, limited laparoscopic resections have been proposed in Child–Pugh class B–C [44]. We have used laparoscopic liver resection in Child B cirrhosis and patients with portal hypertension without major morbidity. We consider that laparoscopic liver resection may increase the indications in small HCC, even in presence of mild liver insufficiency. Further studies are necessary to validate these indications.

scopic left lateral sectionectomies reported no mortality and no liver-specific morbidity, low blood loss, and no transfusions [24]. Conversion occurred only in one early patient. In addition a clear learning curve effect was demonstrated: operating time, use of the Pringle maneuver, and hospital stay were significantly reduced in the last 18 patients. Laparoscopy can be recommended as the routine approach to left lateral sectionectomy.

Other minor resections Anterolateral liver segments (segments 2–6) are the so called “laparoscopic liver segments.” Their nonanatomic resections are commonly reported in the literature and can be considered safe and reproducible. In our opinion hand assistance can be useful in segment 6 atypical resections in selected cases because of difficulties in liver mobilization and parenchymal transection. Nonanatomic resections of segments 7 and 8 are usually excluded from the laparoscopic approach. Their location does not allow safe visualization of the surgical field by the traditional laparoscopic approach. Hand-assisted laparoscopy and thoracoscopy have been proposed in such a location [3, 8, 45, 46]. To date few cases have been reported. Further studies are necessary to validate these approaches. Atypical resections of segment 1 have been rarely reported. Right liver segmental anatomic resections still present many problems, mainly related to adequate exposure, the need for two transection planes, and the difficulties with checking margin adequacy.

Major hepatectomy About 200 major hepatectomies have been reported in the literature, but the majority of centers have performed few such procedures. Series reporting more than 10 laparoscopic major hepatectomies are summarized in Table 18.3. The majority of procedures are right hepatectomies. Laparoscopic left hepatectomy has been rarely reported, but it does not seem to represent a difficult procedure. Even if some authors suggest feasibility of right hepatectomy using a pure laparoscopic approach [4, 47, 48], the hand assistance can be useful in selected cases. It may help to mobilize the liver, to perform parenchymal transection, and to control accidental bleeding. To date laparoscopic major hepatectomy cannot be considered a standardized procedure. Further data and technical refinements are required.

Living donor liver procurement Left lateral sectionectomy Left lateral sectionectomy has a privileged place in laparoscopic resections. Our group demonstrated in a case-control study that, despite longer operating times, laparoscopy is associated with reduced blood loss and morbidity, especially in cirrhotic patients [34]. A further analysis of 36 laparo-

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Laparoscopy may have a role in living donor liver transplantation. In 2002 our group first reported the feasibility of laparoscopic left lateral section procurement in living donors [42]. A subsequent comparison with open left lateral section procurements confirmed the safety of the procedure and showed good recipient outcomes [49]. Koffron et al reported

CHAPTER 18

Laparoscopic Liver Resection

Table 18.3 Laparoscopic major hepatectomies in series including more than 10 patients. Authors

Year

n

Right Hx

Right Hx + Sg 4

Left Hx

Other

Hand assistance

Hüscher et al [30] O’Rourke et al [48] Dulucq et al [32] Dagher et al [4] Koffron et al [3]* Gayet et al [47] Authors’ series [57]**

1998 2004 2005 2007 2007 2007 2009

17 12 11 19 96 41 35

5 12 6 12 41 37 23

1 – – – 8 4 –

10 – 4 5 47 – 11

1 (Left Hx + Sg 5–8)

Y N N N Y N If needed

1 (Sg 1–3) 2 (Trisegmentectomy)

1 Central Hx

*Only pure laparoscopic and hand-assisted laparoscopic hepatectomies; **unpublished data. Right Hx, right hepatectomy; Sg, segment; Left Hx, left hepatectomy.

Table 18.4 Laparoscopic liver resections for hepatocellular carcinoma (HCC) in series including more than 10 patients. Authors

Year

n

Diameter (cm)

Shimada et al [38] Kaneko et al [41] Tang et al [15] Vibert et al [5] Santambrogio et al [58] Belli et al [29] Dagher et al [53] Chen et al [8]

2001 2005 2006 2006 2007 2007 2008 2008

17 40 17 16 12 23 32 116

Authors’ series [57]

2009

64

2.6 NR NR 6.5 3.2 3.1 3.8 2.1 3.2 4.4

± 0.9

± ± ± ± ± ±

1.5 0.7 2 0.8 * 1.9 ** 2.6

Surgical margin (mm)

Morbidity (%)

Overall survival (%)

Disease-free survival (%)

8±7 NR >1 cm in 70.6% NR >5 mm in 100% >1 cm in 91.4% 10.4 ± 9 >1 cm in 100%

5.9 10 20 NR 16.7 13 24.9 6

13 ± 12

20.6

NS vs open control group 5-year 61 5-year 31 2-year 59 NR 3-year 66 3-year 68 NR NS vs open control group 3-year 72 3-year 55 5-year 59* NR 5-year 62** 3-year 65 3-year 47

*Patients with resection of ≤2 segments; **patients with resection of >2 segments. NR, not reported; NS, not significant. In 2006 Cai et al[10] reported 18 laparoscopic hepatectomies for HCC. This study is not included because no specific data are available in the paper.

the feasibility of laparoscopic-assisted right liver procurement [3]. Further data are necessary to confirm outcomes of these procedures.

papers concerning laparoscopic liver resections. Available long-term results in colon cancer do not seem to be different from those of open liver surgery. Larger series and longer follow-up data are needed to confirm these outcomes.

Oncologic results Controversy about laparoscopy in cancer patients arose from unacceptable peritoneal and port site seeding in early patients with incidental gallbladder cancers or colon cancers [50, 51]. Proper use of oncologic surgical principles has reduced this problem to the point that there are no greater differences as compared to open surgery. It is very important that oncologic principles are strictly followed: “no touch,” no direct manipulation of the tumor, immediate conversion in case of locally advanced cancer, and protection for extraction. Few reports have focused specifically on neoplastic lesions. Some additional data can be extrapolated from

Hepatocellular carcinoma Up to December 2007, nine papers (two from our group) have focused on laparoscopic resection for HCC [8, 29, 35, 38, 41, 44, 45, 52, 53]. Considering all data available from published laparoscopic series, more than 350 laparoscopic liver resections for HCC have been reported in the literature. Results of published series that have included more than 10 patients are detailed in Table 18.4. Overall and disease-free survival rates were good and similar to those of open series [8, 38, 52, 53]. Surgical margin widths were not reduced in the laparoscopic series

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Table 18.5 Laparoscopic liver resections for colorectal liver metastases. Authors

Year

n

Diameter (cm)

Surgical margin

Overall survival (%)

Disease-free survival (%)

Mala et al [6, 39]

2002 2005 2004 2006 2009

15 42 22 41 22

8 (3.5–16) 3 (0.8–15) NR 3 (1–17) 3 (0.8–7)

≥1 cm 71% Infiltrated margin 6% >1 cm 54% 5 mm (median) 20 ± 17 mm

NR NR 2-year 75 3-year 87 2-year 89

2-year 67 3-year 51 2-year 83

O’Rourke et al [59] Vibert et al [5] Authors’ series [57] NR, not reported.

[38, 53]. No port site recurrences imputable to laparoscopy were noted. Laparoscopic liver resection of HCC can offer advantages if subsequent liver transplantation is required. Adam et al reported poor outcomes of salvage liver transplant after previous hepatectomy because of adhesions related to primary treatment and increased blood loss [54]. In our center, 12 patients underwent bridge or salvage transplantation after primary laparoscopic resection. When transplantation was performed, they benefitted from the absence of adhesions and, in comparison with 12 transplantations after laparotomic hepatectomies, they had lower operative time, blood loss, and transfusion rate [55]. These preliminary data could enhance the role of laparoscopic liver resection as first-line treatment of HCC.

Colorectal liver metastases Few data are available about laparoscopic liver resections of colorectal liver metastases. About 150 patients have been reported in the literature. Most relevant series are reported in Table 18.5. In 2002 Mala et al [39] compared outcomes of laparoscopic and open liver resections for colorectal liver metastases (15 versus 14). Short-term outcomes and margin width were similar in the two groups. No survival data were reported. The largest series was reported by Vibert et al [5] in 2006 (41 patients). The median margin width was 5 mm and overall and disease-free 3-year survival rates were 87% and 51%, respectively. In our series of 21 cases, the mean margin width was 2.0 cm. Two-year overall and disease-free survival rates were 89% and 83%, respectively. Further studies are needed to clarify outcomes of laparoscopic resection in colorectal liver metastases.

Reproducibility In comparison with open hepatectomy series, the number of published papers about laparoscopic liver surgery is

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extremely low and only few centers have reported their experience. As of March 2008, about 20 groups had reported more than 15 laparoscopic hepatectomies, but only nine of these reported 50 or more cases [3–10, 56] (see Table 18.1). Laparoscopic liver resections are long and difficult operations. They require considerable expertise in both hepatic and laparoscopic surgery, dedication, specific training, and the availability of appropriate technology. Some skilled surgeons have developed a special expertise in the laparoscopic approach, regardless of the organ and pathology being treated, a paradox at a time when there is a trend towards organ subspecialization, particularly in colorectal, pancreatic, and hepatic surgery. However, it seems unreasonable that even an experienced laparoscopist should perform laparoscopic liver resection outside of a regular practice of open liver surgery. Conversely, mastering simple laparoscopic procedures is insufficient training for an experienced liver surgeon to embark on laparoscopic liver resection. A few surgeons may acquire all the requisite skills but, in most cases, the collaboration of two surgeons, one expert in each field, seems desirable when initiating a laparoscopic liver resection program.

Conclusion For laparoscopic liver resection to be effective, specific training and access to adequate technology are required. Patient selection must be accurate, and the availability of laparoscopy should not change the indications for resection. The rules of oncologic surgery must be followed for minimally invasive operations, just as in their open counterparts. At present, good candidates for laparoscopic liver resection are patients with peripheral lesions requiring limited hepatectomy or left lateral sectionectomy. Further prospective evaluation is required to assess the results of laparoscopy in major liver resections and to define its long-term outcomes in cancer patients.

CHAPTER 18

Self-assessment questions 1 Currently, in which percentage of liver resections can the laparoscopic approach be planned? A <5% B 15–25% C >50% 2 In which percentage can the laparoscopic approach for left lateral sectionectomy be proposed? A <5% B 15–25% C >80% 3 Which of the following statements about laparoscopic liver surgery are true? (more than one answer is possible) A The use of two monitors is recommended B 0 °-laparoscopes are preferred by most authors C Different patient positions are recommended according to the lesion site D The specimen should be extracted in a plastic bag E Hand assistance is useful in left-sided resections 4 Which one of the following statements about the pneumoperitoneum is false? A Pneumoperitoneum should be maintained at less than 14 mmHg B Carbon dioxide pneumoperitoneum gas embolism is more severe than air embolism C Gas embolism occurrence is increased by argon beam coagulation D Gasless laparoscopy is no longer practiced 5 Is pedicle clamping feasible during laparoscopic liver surgery? A Yes, it should be systematically performed B No, it should be avoided C To date, no study has clarified its feasibility D Yes, it can be performed whenever necessary 6 Which of the following lesions can be scheduled for laparoscopic resection? (more than one answer is possible) A Peripheral lesion of segment 2 B Deep lesion of the right liver with a diameter of 3 cm far from portal pedicles C Peripheral lesion of segment 8 D Right liver lesion adjacent to the hepatocaval junction E Left liver tumor of 15 cm in diameter

Laparoscopic Liver Resection

7 Which of the following are not “laparoscopic segments”? (more than one answer is possible) A Segment 2 B Segment 5 C Segment 1 D Segment 6 E Segment 7 8 Laparoscopic liver resection for hepatocellular carcinoma is recommended because it reduces morbidity and facilitates subsequent reoperations A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 9 Which one of the following describes the reported advantages of laparoscopic resection? A Lower intraoperative blood loss B Shorter hospital stay C Earlier period of first oral intake D Reduced need for postoperative analgesia E All previous advantages 10 Which one of the following statements concerning laparoscopic liver resection for hepatocellular carcinoma on cirrhosis is false? A Overall and disease-free survival rates are similar to open series B It is preferred for small deep-located tumors C Reduced postoperative morbidity has been reported D It can offer advantages if subsequent liver transplantation is required E It preserves collateral veins of abdominal veins 11 Which of the following statements concerning laparoscopic major hepatectomies are true? (more than one answer is possible) A Laparoscopic left hepatectomy does not represent a difficult procedure B The majority of reported procedures are right hepatectomies C For laparoscopic right hepatectomy, a pure laparoscopic approach is recommended D For laparoscopic right hepatectomy, hand assistance can be useful E To date laparoscopic major hepatectomy can be considered a standardized procedure

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References 1 2

3

4

5 6

7 8

9 10

11

12

13

14 15

16

17

18

19

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20 Foroutani A, Garland AM, Berber E, et al. Laparoscopic ultrasound vs triphasic computed tomography for detecting liver tumors. Arch Surg 2000;135:933–8. 21 Callery MP, Strasberg SM, Doherty GM, Soper NJ, Newton JA. Staging laparoscopy with laparoscopic ultrasonography: optimizing resectability in hepatobiliary and pancreatic malignancy. J Am Coll Surg 1997;80:33–9. 22 Decailliot F, Cherqui D, Leroux B, et al. Effects of portal triad clamping on haemodynamic conditions during laparoscopic liver resection. Br J Anaesth 2001;87:493–6. 23 Decailliot F, Streich B, Heurtematte Y, Duvaldestin P, Cherqui D, Stéphan F. Hemodynamic effects of portal triad clamping with and without pneumoperitoneum: an echocardiographic study. Anesth Analg 2005;100:617–22. 24 Chang S, Laurent A, Tayar C, Karoui M, Cherqui D. Laparoscopy as a routine approach for left lateral sectionectomy. Br J Surg 2007;94:58–63. 25 Schemmer P, Friess H, Hinz U, et al. Stapler hepatectomy is a safe dissection technique: analysis of 300 patients. World J Surg 2006;30:419–30. 26 Ros A, Gustafsson L, Krook H, et al. Laparoscopic cholecystectomy versus mini-laparotomy cholecystectomy: a prospective, randomized, single-blind study. Ann Surg 2001;234: 741–9. 27 McMahon AJ, Russell IT, Baxter JN, et al. Laparoscopic versus minilaparotomy cholecystectomy: a randomised trial. Lancet 1994;343:135–8. 28 Fleshman J, Sargent DJ, Green E, et al. Laparoscopic colectomy for cancer is not inferior to open surgery based on 5-year data from the COST Study Group trial. Ann Surg 2007;246:655–62. 29 Belli G, Fantini C, D’Agostino A, et al. Laparoscopic versus open liver resection for hepatocellular carcinoma in patients with histologically proven cirrhosis: short- and middle-term results. Surg Endosc 2007;21:2004–11. 30 Huscher CG, Lirici MM, Chiodini S. Laparoscopic liver resections. Semin Laparosc Surg 1998;5:204–10. 31 Simillis C, Constantinides VA, Tekkis PP, et al. Laparoscopic versus open hepatic resections for benign and malignant neoplasms - a meta-analysis. Surgery 2007;141:203–11. 32 Dulucq JL, Wintringer P, Stabilini C, Berticelli J, Mahajna A. Laparoscopic liver resections: a single center experience. Surg Endosc 2005;19:886–91. 33 Rau HG, Buttler E, Meyer G, Schardey HM, Schildberg FW. Laparoscopic liver resection compared with conventional partial hepatectomy – a prospective analysis. Hepatogastroenterology 1998;45:2333–8. 34 Lesurtel M, Cherqui D, Laurent A, Tayar C, Fagniez PL. Laparoscopic versus open left lateral hepatic lobectomy: a case-control study. J Am Coll Surg 2003;196:236–42. 35 Laurent A, Cherqui D, Lesurtel M, Brunetti F, Tayar C, Fagniez PL. Laparoscopic liver resection for subcapsular hepatocellular carcinoma complicating chronic liver disease. Arch Surg 2003;138:763–9. 36 Morino M, Morra I, Rosso E, Miglietta C, Garrone C. Laparoscopic vs open hepatic resection: a comparative study. Surg Endosc 2003;17:1914–8. 37 Troisi R, Montalti R, Smeets P, et al. The value of laparoscopic liver surgery for solid benign hepatic tumors. Surg Endosc 2008;22:38–44.

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38 Shimada M, Hashizume M, Maehara S, et al. Laparoscopic hepatectomy for hepatocellular carcinoma. Surg Endosc 2001;15:541–4. 39 Mala T, Edwin B, Gladhaug I, et al. A comparative study of the short-term outcome following open and laparoscopic liver resection of colorectal metastases. Surg Endosc 2002;16:1059–63. 40 Buell JF, Thomas MJ, Doty TC, et al. An initial experience and evolution of laparoscopic hepatic resectional surgery. Surgery 2004;136:804–11. 41 Kaneko H, Takagi S, Otsuka Y, et al. Laparoscopic liver resection of hepatocellular carcinoma. Am J Surg 2005;189:190–4. 42 Soubrane O, Cherqui D, Scatton O, et al. Laparoscopic left lateral sectionectomy in living donors: safety and reproducibility of the technique in a single center. Ann Surg 2006;244:815–20. 43 Cai X, Wang Y, Yu H, Liang X, Peng S. Laparoscopic hepatectomy for hepatolithiasis: a feasibility and safety study in 29 patients. Surg Endosc 2007;21:1074–8. 44 Abdel-Atty MY, Farges O, Jagot P, Belghiti J. Laparoscopy extends the indications for liver resection in patients with cirrhosis. Br J Surg 1999;86:1397–400. 45 Teramoto K, Kawamura T, Takamatsu S, et al. Laparoscopic and thoracoscopic approaches for the treatment of hepatocellular carcinoma. Am J Surg 2005;189:474–8. 46 Huang MT, Lee WJ, Wang W, Wei PL, Chen RJ. Hand-assisted laparoscopic hepatectomy for solid tumor in the posterior portion of the right lobe: initial experience. Ann Surg 2003;238:674–9. 47 Gayet B, Cavaliere D, Vibert E, et al. Totally laparoscopic right hepatectomy. Am J Surg 2007;194:685–9. 48 O’Rourke N, Fielding G. Laparoscopic right hepatectomy: surgical technique. J Gastrointest Surg 2004;8:213–6. 49 Cherqui D, Soubrane O, Husson E, et al. Laparoscopic living donor hepatectomy for liver transplantation in children. Lancet 2002;359:392–6. 50 Fong Y, Brennan MF, Turnbull A, et al. Gallbladder cancer discovered during laparoscopic surgery–potential for iatrogenic dissemination. Arch Surg 1993;128:1054 –6. 51 Johnstone PA, Rohde DC, Swartz SE, Fetter JE, Wexner SD. Port site recurrences after laparoscopic and thoracoscopic procedures in malignancy. J Clin Oncol 1996;14:1950–6. 52 Cherqui D, Laurent A, Tayar C, et al. Laparoscopic liver resection for peripheral hepatocellular carcinoma in patients with chronic

53 54

55

56

57

58

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liver disease: midterm results and perspectives. Ann Surg 2006;243:499–506. Dagher I, Lainas P, Carloni A, et al. Laparoscopic liver resection for hepatocellular carcinoma. Surg Endosc 2008;22:372–8. Adam R, Azoulay D, Castaing D, et al. Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy? Ann Surg 2003;238:508–18. Laurent A, Tayar C, Andreoletti M, Lauzet JY, Merle JC, Cherqui D. Laparoscopic liver resection facilitates salvage liver transplantation for hepatocellular carcinoma. J Hepatobiliary Pancreat Surg 2009;16:310–4. Ardito F, Tayar C, Laurent A, Karoui M, Loriau J, Cherqui D. Laparoscopic liver resection for benign disease. Arch Surg 2007;142:1188–93. Bryant R, Laurent A, Tayar C, Cherqui D. Laparoscopic liver resection – understanding its role in current practice: the Henri Mondor Hospital experience. Ann Surg 2009;250:103–11. Santambrogio R, Opoche E, Ceretti AP, et al. Impact of intraoperative ultrasonography in laparoscopic liver surgery. Surg Endosc 2007;21:181–8. O’Rourke N, Shaw I, Nathanson L, Martin I, Fielding G. Laparoscopic resection of hepatic colorectal metastases. HPB 2004;6:230–5.

Self-assessment answers 1 2 3 4 5 6 7 8 9 10 11

B C A, C, D B D A, B C, E E E B A, B, D

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Repeat Resection for Liver Tumors Mickael Lesurtel1 and Henrik Petrowsky2 1 Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland 2 The Dumont-UCLA Transplant Center, Ronald Reagan Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Introduction Over the past 30 years, hepatic resection has evolved into the treatment of choice for a wide array of primary and metastatic hepatic malignancies. Historically, the first large series of first liver resections for secondary tumors was reported in 1978 [1]. Improvements in surgical technique, perioperative patient care, and management of postoperative complications have greatly reduced the morbidity and mortality associated with liver resection, resulting in a broadening of its application [2]. Metastatic colorectal cancer and hepatocellular carcinoma (HCC) remain the most common indications for liver resection. Although surgery is the only potentially curative treatment for these diseases, recurrence is common. The inefficacy of alternative nonsurgical therapies, as well as the recent advances in perioperative management and hepatic resection, have led to an increasing number of repeat hepatic resections. Historically, one of the first reports of repeat liver resections was reported by Tomas-de la Vega et al in 1984 [3] and consisted of four patients. Since then, larger experiences have been reported from several centers. This growing literature shows that, while repeat resection is possible in only a minority of patients, it can be done safely and with good long-term results. This chapter will summarize the reported experience to date, define patient selection, and discuss technical surgical issues. In addition, a brief discussion of the role for other locoregional treatment modalities, such as hepatic artery embolization, alcohol injection, cryoablation, and radiofrequency ablation (RFA) will be undertaken.

Technical considerations Repeat hepatic resection poses technical difficulties not commonly encountered at initial resection. First, adhesions at

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the previous line of parenchymal transection can make reexposure of the liver difficult. Mobilizing the liver off the vena cava and re-exposing the porta hepatis and hepatic veins can be extremely hazardous if there has been previous dissection in these areas. Second, liver parenchyma after liver regeneration and/or chemotherapy is more friable [4]. Especially certain chemotherapeutical drugs such as irinotecan and oxaliplatin can cause the development of friable liver parenchyma by steatohepatitis and severe sinusoidal obstruction [5, 6]. This further adds to the difficulties of reexposure and predisposes to tearing of Glisson’s capsule. Third, regeneration alters the normal anatomic configuration of the portal structures. For example, after an extended right hepatectomy, the porta hepatis is rotated posteriorly and to the right due to liver regeneration. The normal relationship among the portal structures may also be altered, with the bile duct displaced posteriorly and the portal vein displaced anteriorly. Therefore, repeat hepatic resections are generally more difficult and challenging. The fact that repeat hepatectomy is more difficult and more demanding is reflected by the findings of a recently published meta-analysis of outcome after first and second liver resection for colorectal liver metastases [7]. This analysis revealed a significant lower intraoperative blood loss and faster operating time by 30 min for the first liver resection compared with repeat hepatectomy. A major limiting factor at repeat hepatectomy is the extent of resection that can be performed. This is especially true if the initial resection was extensive. In a single-institution series of 615 patients with metastatic colorectal cancer, Adam et al [8] reported that major resections (three or more segments) accounted for 62% of initial hepatectomies, 59% of second hepatectomies, and 24% of third hepatectomies. Additionally, a multiinstitutional series from the French Surgical Association revealed that a second major resection (two or more adjacent segments) was possible in only 34% of patients previously subjected to a major resection [9]. Deterioration of hepatic function may also limit the extent of resection that can be safely performed, particularly in patients with HCC and underlying cirrhosis [10, 11]. Normally, for resection of liver tumors, we avoid wedge excisions. Evidence suggests

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Table 19.1 Selected series of repeat hepatic resection for metastatic colorectal cancer with more than 50 patients. First Authors (year)

Country

Number of patients (initial resection)

Number of patients (second resection)

Time interval, H1 to H2 (months)

Morbidity (%)

Mortality (%)

3-Year survival (%)

5-Year survival (%)

Median Survival (months)

Nordlinger et al (1994) [9] Fernandez-Trigo et al (1995) [12] Adam (1997) et al [4] Yamamoto et al (1999) [26] Petrowsky et al (2002) [28] Adam et al (2003) [8] Shaw et al (2006) [24] Yan, et al (2006) [27] Ishiguro et al (2006) [22] Thelen et al (2007) [25] Nishio et al (2007) [23]

France Worldwide

1818 –

116 (6%) 170

17 12

25 28

1 0

33 –

– 28

30 30

France Japan USA, Germany France Great Britain Australia Japan Germany Great Britain

243 362 1488 615 718 382 – 811 540

64 (26%) 75 (21%) 126 (8%) 199 (32%) 66 (9%) 55 (14%) 111 94 (12%) 54 (10%)

16 11 14 16 14 – 16 – –

20 – 19 23 18 29 14 23 19

0 0 2 4 0 0 0 3 6

60 48 51 54 68 – 74 55 53

41 31 34 35 44 49 41 38 46

46 30 37 – 56 53 43 – 50

H1 to H2 refers to the time interval between the first and second hepatectomies.

that wedge resections are more often associated with greater blood loss and tumor-involved margins than are anatomic resections, and survival after a wedge resection may be adversely affected [12, 13]. However, during a repeat liver resection, a wedge resection may be dictated by anatomic considerations of the regenerated liver. An analysis of 14 studies demonstrated that there were significantly fewer wedge resections performed in patients undergoing first liver resection (39%) compared to those having repeat hepatectomy (46%) [7]. In that case cryoassisted wedge excision, in which the tumor and a predetermined margin of noncancerous liver tissue are frozen and then excised, is an alternative strategy for achieving complete tumor clearance. This may be a better approach when anatomic resection is not feasible [13]. This approach is limited to tumors that can be adequately frozen and is generally not applicable to large tumors or those adjacent to major vascular structures.

Repeat hepatic resection for metastatic colorectal cancer Scope of the problem Each year approximately 150 000 new cases of colorectal carcinoma are diagnosed in the United States. Half of these patients (70 000–80 000) will present with metastatic disease in the liver. If patients with extrahepatic disease, those with extensive bilobar hepatic disease, and those unfit for surgery are discounted, approximately 10 000 patients are candidates for potentially curative liver resection annually [14].

Recurrence can be expected in roughly two-thirds of those resected, and the remnant liver is frequently involved. However, only 30–50% of these cases are isolated hepatic recurrences, of which 25–30% are resectable [9, 15]. Thus, of those patients submitted for initial hepatic resection, only 6–32% are candidates for potentially curative repeat hepatectomy (Table 19.1). This amounts to 1000–2000 patients a year.

Safety and efficacy There is no doubt that liver resections represent safe and effective therapy for patients with first presentation of hepatic metastases. Surgery is associated with a 5-year survival rate of 20–40% [16, 17]. Most major centers consistently report an operative mortality of less than 5%, which has been linked to the volume of cases performed [16, 17]. Surgery therefore remains the treatment of choice for all medically fit patients, provided that there is no or limited resectable extrahepatic disease and that all hepatic disease can be safely removed. The indications for hepatic resection have thus been expanded, and the number of patients presenting with recurrence after initial hepatectomy will likely increase until effective adjuvant therapies are developed. Recurrence after initial hepatectomy can be expected in the majority of patients. Repeat hepatectomy has emerged as a safe and effective intervention. The first report of repeat liver resection goes back to 1984 [3] and until the early 1990s, studies involved small numbers of patients, had a relatively short follow-up, and were almost anecdotal in nature [18–20]. Other than documenting feasibility in selected patients, these studies provided little

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meaningful information. Some authors suggested increased bleeding and other complications after repeat hepatectomy, but most reported acceptable morbidity and mortality figures [21]. As hepatic resections are done more frequently, the proportion of repeat resections performed is also increasing. Therefore, larger series of repeat hepatectomy for colorectal liver metastases can be analyzed (Table 19.1). More recently, the meta-analysis of several larger series has confirmed that morbidity and mortality rates after repeat hepatectomy are similar to those reported for initial hepatectomy [7]. Moreover, extended survival was also demonstrated, and in some cases survival rate was equivalent to or even better than that observed after initial hepatectomy (Table 19.1). In the two largest multicenter series, the operative morbidity rates were 25% and 28% and mortality rates were 1% and 0% [9, 12]. Median survival in both studies was 30 months. In the largest single-center series, similarly low morbidity and mortality rates and a 5-year survival rate of 31–49% were reported [4, 22–27]. The findings of the large bi-institutional experience of 126 second liver resections from an American and a European Surgical Oncology Center confirm the data of the previous large multi- and single-center studies in regard to morbidity, mortality, and survival [28] (Table 19.1). In another report of 96 patients who survived for 5 years after hepatic resection for metastatic colorectal cancer, half of the patients had been subjected to repeat resections [29]. Thus, these studies demonstrate that repeat hepatic resection is not only feasible, but can result in long-term survival. These data are the basis for the view that liver resection is the treatment of choice for recurrent resectable liver metastases from colorectal cancer since neither chemotherapy nor other nonsurgical therapies has been shown to achieve such favorable results. Comparison of resection results with historic data on untreated patients strongly suggests that repeat resection prolongs survival. This is probably the reason why no prospective comparison of repeat hepatic resection with supportive care has ever been performed. Median survival of untreated recurrence after liver resection is approximately 4 months, and 5-year survivors are extremely uncommon [9, 30]. The results of repeat resection also appear to be better than those achievable with systemic chemotherapy [30]. In most series, the response rates for chemotherapy are less than 40%, and the median response duration is less than 8 months [31]. By the time most patients present for repeat hepatectomy, they have received one or more courses of chemotherapy. In fact, some authors routinely treat all patients with chemotherapy after initial hepatectomy, despite the paucity of data to support such a policy [4]. Although it seemed unlikely in the past that these agents would be any more effective in treating hepatic recurrences than they are in preventing them, a recent large multicentric

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randomized controlled trial demonstrated that perioperative chemotherapy using the FOLFOX4 regimen was beneficial in terms of reducing recurrence after liver resection for colorectal liver metastases [32].

Patient selection Several authors have attempted to refine the indications for repeat hepatectomy by identifying risk factors associated with early treatment failure, a task made difficult by the small number of patients in each study. Early reports suggested that patients with more than one tumor and those with hepatic recurrence less than 1 year after initial hepatectomy were less likely to benefit from repeat hepatectomy [33]. Subsequent studies were unable to confirm these observations [12, 15, 34, 35]. The large series of the French Surgical Association study failed to identify any prognostic variables that would simplify patient selection [9]. This could be attributed to the heterogenous study population of this multicenter series since it is composed of 116 second liver resections from 85 centers. By contrast, the Repeat Hepatic Metastases Registry study found that, as with initial hepatic resection, extrahepatic disease and incomplete resection had a significant negative impact on survival [12]. However, this study did not demonstrate that these variables are independent predictors of outcome. More recently, larger series identified independent predictors of outcome (Table 19.2). In these studies, the curative nature of the resection [4, 23, 25, 26], size [23, 25, 28], and number [22, 26, 28] of hepatic lesions, bilobar involvement [25], time interval between first and second liver resections [4], regional lymph node metastases [26], extrahepatic disease [26], and elevated carcinoembryonic antigen (CEA) at time of repeat resection [23, 27] were independent outcome predictors in multivariate analysis. However, the curative nature of the resection, as well as the size and number of hepatic metastases, were the most frequently reported independent predictors associated with survival outcome after repeat hepatectomy (Table 19.2). Thus, in selecting patients for repeat resection, the ability to clear all disease (R0 resection) and a low tumor load (size and number of hepatic lesions) are the most important criteria for consideration. Although these prognostic variables provide rough indicators of prognosis, they should not be used as absolute contraindications to surgery. Long-term survival is possible despite the presence of poor prognostic variables [4], as is the case after initial hepatectomy [4]. Given the potential benefit of repeat hepatectomy, which is unavailable with other modalities, it is reasonable to use the same selection criteria as those applied for initial hepatectomy. Many centers have therefore adopted the policy of repeat resection in all medically fit patients with resectable hepatic disease [4, 26, 28, 36]. Complete resection must be possible, because the results of palliative repeat resection are poor [4, 23, 25, 26].

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Table 19.2 Independent predictors of outcome associated with repeat liver resection for recurrent colorectal liver metastases. Authors (year)

Period of H2

Curative

Time interval H1 to H2

Number

Size

Bilobar

Regional LN metastases

Extrahepatic disease

CEA at H2

Adam et al (1997) [4] Yamamoto et al (1999) [26] Petrowsky et al (2002) [28] Yan et al (2006) [27] Ishiguro et al (2006) [22] Thelen et al (2007) [25] Nishio et al (2007) [23]

– – – – – Y –

Y Y – – – Y Y

Y – – – – – –

– Y Y – Y – –

– – Y – – Y Y

– – – – – Y –

– Y – – – – –

– Y – – – – –

– – – Y – – Y

H1 to H2 refers to the time interval between the first and second hepatectomies; CEA, carcinoembryonic antigen; LN, lymph node.

The statement that the presence of extrahepatic disease generally precludes repeat hepatectomy, even if the extrahepatic disease is resectable, has been revised during the last decade. Especially, there is growing evidence that well-selected patients with hepatic and pulmonary metastases from colorectal cancer benefit from combined liver and lung surgery as long as the complete clearance of the disease can be achieved [37, 38]. Although Nordlinger et al [9] demonstrated that rapid recurrence occurred in those patients subjected to simultaneous removal of hepatic and extrahepatic metastases, limited and resectable extrahepatic disease is no longer an absolute contraindication for liver surgery. This fact is supported by Adam et al and Petrowsky et al [4, 28], who reported that the presence of extrahepatic disease was not an independent predictor of outcome after synchronous repeat hepatectomy and resection of resectable extrahepatic disease. Therefore, some authors have adopted a more aggressive posture with respect to such patients. They and others argue that resectable extrahepatic recurrence should not necessarily preclude repeat hepatectomy [4, 28, 39]. Close follow-up is mandatory after initial hepatectomy. Nordlinger et al [9] reported that resectability of hepatic recurrences after initial resection was closely related to tumor size, underscoring the need for early detection. CEA levels and abdominal/pelvic computed tomography (CT) scans should be performed every 4–6 months for the first 2 years after resection, within which time most recurrences are diagnosed [15, 34]. Some surgeons prefer abdominal ultrasound as a routine surveillance study [15]. During the past 5 years, positron emission tomography (PET)/CT has become a useful tool in preoperative staging and postoperative follow-up. There is also growing evidence that PET/CT is superior to conventional imaging modalities in terms of detecting extrahepatic disease [40]. Regular colonoscopic evaluation should also be practiced. Recurrences after 2 years are not uncommon, however. Continued surveillance is required, although the interval between investigations

may be extended to every 6 months [29]. Recurrent disease 5 years after initial hepatic resection is rare [29]. Some authors have recommended a brief period (4–8 weeks) of close observation before repeat hepatectomy [4, 15], but this is by no means a universally accepted recommendation. The rationale is to allow radiographically occult metastases to manifest themselves, thus allowing a change in the operative strategy or avoiding an unnecessary laparotomy. Although there is no proven benefit to this approach, it is not without some merit. A short interval between discovery of the disease and surgery is unlikely to affect the outcome.

Multiple repeat hepatic resections Recurrence after repeat hepatectomy has been reported in 60–80% of patients [34]. A select few have resectable disease limited to the liver and may be candidates for third or even fourth hepatic resections. Reports of large repeat hepatectomy series show that 9–30% of patients who underwent a second hepatectomy for colorectal liver metastases had a third resection [8, 9, 26, 28] and 4% a fourth liver resection [8, 26]. The safety of multiple repeat hepatic resections has been demonstrated in recent reports, and long-term survivors have been documented [8, 9, 26, 28]. Adam et al [8] published the largest series (n = 60) of third hepatectomies for recurrent colorectal liver metastases. Patients who underwent a third liver resection had zero mortality, and the morbidity rate (25%) and median hospital stay (14 days) were not significantly different from in those who had only one or two liver resections. In addition, patients with a third liver resection had a survival benefit of 32–38% at 5 years [8, 26]. Major hepatectomy is possible in the minority of these patients but patients likely to benefit represent a small and highly selected group [8, 9, 26].

Nonresectional approaches Cryoablation (Chapter 20), hepatic artery embolization, percutaneous ethanol injection (Chapter 22), and cryoablation

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and RFA (Chapter 21) are examples of nonresectional strategies that have shown some promise in the management of unresectable hepatic metastases. Most reports to date have included small numbers of patients with diverse tumors. Also, the majority of studies have focused on establishing safety and efficacy in patients who are not candidates for initial hepatic resection. Although these approaches are generally not considered curative, none has been compared directly with resection in a randomized trial. However, local ablation techniques, especially RFA, have been increasingly performed in patients with colorectal liver metastases during the last years, but the roles of these techniques in patients with recurrence after initial hepatic resection have to be defined. RFA has been used for the treatment of recurrent liver metastases from colorectal cancer following initial hepatectomy [41, 42]. Elias et al [41] demonstrated that percutaneous radiofrequency increases the number of patients with recurrent liver metastases amenable for curative treatment. Furthermore, the authors stated that repeat resection is only indicated when RFA is contraindicated. A more recently published series on colorectal hepatic recurrence after initial liver surgery suggested that RFA and repeat resection achieved similar results [42]. However, none of these studies compare the treatment groups in a randomized fashion and have therefore a lower level of evidence. This demonstrates the need for randomized studies to clarify the role of repeat resection and local ablation for recurrent colorectal liver metastases. Cryoablation involves placement of a specialized probe, designed for delivery of nitrogen or argon at its tip, directly into the tumor under ultrasound guidance. This has previously required laparotomy but is now adaptable to laparoscopy. Basically, cryoablation can be used as a therapeutic modality to treat unresectable liver tumors or to assist hepatic resection (edge or contralobe cryotherapy) [13, 43]. However, there are no reports that specifically address the use of cryoablation for treatment of hepatic recurrence after initial resection. Hepatic artery chemoembolization has shown some efficacy in treating HCC and its role is questionable in patients with metastatic colorectal cancer. Tellez et al reported a median survival of 8.6 months in patients with unresectable colorectal metastases treated with chemoembolization [44]. Percutaneous ethanol injection is limited to relatively soft tumors, such as HCC. Hard metastatic tumors such as metastatic colorectal cancer on the other hand, are not well ablated by this technique because the alcohol tends to diffuse into the relatively softer hepatic parenchyma rather than the dense tumor stroma [45]. Strategies aimed at preventing recurrence after first hepatic resection have been generally disappointing in the recent past. However, a recent randomized trial has shown that adjuvant chemotherapy with FOLFOX at the time of

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initial liver resection can reduce the rate of tumor recurrence after hepatectomy [32]. No study has addressed the role of adjuvant regional chemotherapy after repeat hepatectomy. Immunotherapy may also find a role in preventing recurrent disease, although this approach remains largely experimental.

Repeat hepatic resection for hepatocellular carcinoma Scope of the problem HCC is among the fifth most common fatal malignancies in the world, responsible for approximately one million deaths annually [46]. There are dramatic geographic variations in the incidence of HCC. The United States has one of the lowest incidence rates in the world at 1 per 100 000. On the other hand, incidence rates of 60–100 per 100 000 are common in Asia and sub-Saharan Africa, making HCC one of the most common adult malignancies in these areas [46]. HCC commonly arises in the setting of hepatic cirrhosis, although not all forms of cirrhosis carry the same risk. Worldwide, 70–80% of all patients with HCC have some degree of underlying chronic liver disease. As a result, extensive hepatic resection, or indeed any resection at all, is often not possible. Although screening programs in high-risk populations and improvements in imaging have resulted in earlier diagnosis, resectability at initial presentation remains low, approximately 20–30% in some estimates. Similarly, repeat hepatic resection is possible in a minority of patients that recur, perhaps as low as 10–20% (Table 19.3). The extent of tumor within the liver and underlying cirrhosis are the most common factors that preclude resection, both at initial presentation and at the time of recurrence [47, 48]. Despite its limitations, resection offers, beside liver transplantation, the best chance for long-term survival. The 5-year survival rate after initial resection is approximately 40–50% in most large series [49–52]. Recurrence is common, however, and may be as high as 70–80%. Unlike metastatic colorectal cancer, where extrahepatic recurrence is common, the overwhelming majority of cases of HCC recur in the remnant liver [49, 50, 52]. The reason for the large number of recurrences after initial hepatectomy is the subject of debate [48, 53–56]. The majority of cases recur within 2 years of initial hepatectomy, but recurrences after 2 years are not uncommon. Thus, as is speculated for metastatic colorectal cancer, undetected microscopic disease at the initial resection may be the principal underlying cause. Patients with HCC are at risk for multicentric tumors as well as intrahepatic spread of tumor by portal vein invasion and embolization. Both mechanisms put the remnant liver at risk for recurrent or persistent disease. Multicentric disease has been estimated to account for 25% of recurrences, but more recent studies suggest that

CHAPTER 19

Repeat Resection for Liver Tumors

Table 19.3 Selected series of repeat hepatic resections for hepatocellular carcinoma (number of patients >20). Study

Number of patients (initial resection)

Number of patients (second resection) (%)

Time interval H1 to H2 (months)

Morbidity (%)

Mortality (%)

3-Year survival (%)

5-Year survival (%)

Median Survival (months)

Lee et al (1995) [66] Neelemann and Andersson (1996) [11] Hu et al 1996 [64] Nagasue et al (1996) [10] Shimada et al (1996) [48] Shuto et al (1996) [69] Shimada et al (1998) [68] Sugimachi et al (2001) [70] Minagawa et al (2003) [47] Itamoto et al (2007) [65] Liang et al (2008) [67]

196 –

25 (13) 128

26 19

24 13

0 2

45 56

– 40

27 40

– 290 312 341 312 474 334 483 853

60 50 22 31 41 78 67 84 44

23 21 – – – – – – –

15 16 – – – – – 23 68

3 8 – – – 0 0 0 0

44 64 70 71 65 83 70 67 44

– 38 70 52 42 47 56 50 28

30 – – – – – – – –

(17) (7) (9) (13) (16) (20) (17) (5)

H1 to H2 refers to the time interval between the first and second hepatectomies.

it may be closer to 15% [55, 56]. Moreover, patients with significant cirrhosis or chronic hepatitis infection remain at high risk for new primary tumors (i.e. metachronous tumor growth) in the liver remnant. After initial resection, patients with HCC face not only the probability of recurrence but also the added burden of progressive hepatic dysfunction. The extent of repeat resection that can be safely performed may thus be limited, or surgery may not be possible at all [57]. In contrast to repeat resection of colorectal metastases where major procedures are performed in approximately 30%, only small numbers of patients, probably less than 15%, are candidates for major repeat resections in HCC (Table 19.3). Moreover, progressive deterioration in hepatic function also represents a major source of morbidity and mortality, irrespective of cancer status. Death from complications of portal hypertension has been reported [52, 58] and portal hypertension is today considered a contraindication for liver resection [2].

Safety and efficacy Although the majority of HCC cases recur after initial hepatectomy, surgery remains the most effective therapy. Earlier diagnosis and improvements in surgical technique have significantly lowered operative mortality [2]. Other interventions, such as hepatic artery embolization, percutaneous ethanol injection, and RFA have emerged as effective alternatives, but none has proven superior to resection [59–61]. Liver transplantation is appropriate only in patients with limited disease, and the critical shortage of donor organs markedly limits its applicability [62]. Repeat resection for

HCC has been performed with increasing frequency, although it has only recently gained acceptance as a safe and effective treatment. Initial reports were few and involved small numbers of patients, making it difficult to ascertain the true role of repeat resection [53, 63]. More recent reports, with larger numbers of patients (Table 19.3), have shown that repeat hepatectomy can be performed with morbidity and mortality comparable to those of initial hepatectomy, and it offers the possibility of extended survival [10, 11, 47, 48, 64–69]. Nagasue et al found no difference between initial and repeat hepatectomy in operative blood loss or operating time [10]. Morbidity after repeat hepatectomy is acceptable, ranging from 10% to 35%, and most of the recent series have not reported any mortality [47, 65, 67, 70]. A 5-year survival rate ranging from 28% to 70% has been reported and these results are comparable to those of initial hepatectomy for HCC. As previously discussed, underlying hepatic dysfunction is a significant problem for patients with recurrent HCC. The need to preserve hepatic parenchyma is reflected by the number of second major resections performed for HCC, which is dramatically lower than for metastatic colorectal cancer, and may partially explain the relatively low operative morbidity. In one study, lobar resections accounted for 33% of initial resections but only 5% of second resections [11].

Patient selection Several authors have identified variables associated with poor prognosis at the time of recurrence, including portal

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Table 19.4 Series of repeat hepatic resection for hepatocellular carcinoma (HCC) that identified independent predictors of outcome by multivariate analysis. Study

Year

Number of second resections (%)

Predictors of reduced outcome

Shimada et al [68]

1998

41 (13)

Minagawa et al [47]

2003

67 (20)

Itamoto et al [65]

2007

84 (17)

Portal vein invasion at first resection Portal vein invasion at second resection Several HCC at primary Disease-free interval <1 year after the first resection Microscopic vascular invasion at second resection

vein invasion, number of tumors, diameter of tumor, disease-free interval, type of recurrence (nodular versus diffuse), and type of treatment (resection versus palliative treatment) [47, 48, 53, 64, 65, 68]. The severity of hepatic dysfunction, while not usually identified as an independent risk factor for outcome, is clearly important because it critically influences treatment options. Portal vein invasion at initial resection has been identified as an important determinant of recurrence and outcome after repeat hepatectomy [68]. Interestingly, two recent studies identified portal vein invasion at the repeat hepatectomy as an independent predictor of outcome after repeat resection for recurrent HCC (Table 19.4) [47, 65]. Therefore, repeat resection should be considered carefully in patients with portal vein invasion, given the high risk of recurrence. Finally, Minagawa et al [47] identified single HCC at the primary hepatectomy and a disease-free interval of greater than 1 year as independent favorable factors following repeat resection for recurrent HCC. Similarly to metastatic colorectal cancer, prognostic variables for patients with recurrent HCC should be considered, but should not dictate therapy. Beside liver transplantation, repeat resection represents the most effective therapy for recurrent disease and should not be rejected without careful consideration. Patients with resectable hepatic disease, no evidence of extrahepatic metastases, and preserved hepatic function should be considered for repeat resection if they are not candidates for liver transplantation. While some patients with advanced cirrhosis (Child–Pugh B and C) have been successfully re-resected [10, 48], most authors recommend against surgery in such patients because of the associated morbidity and attenuated survival, and favor ablation therapy like RFA [57, 71, 72].

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In contrast, liver transplantation (LT) has been proposed to cure patients with recurrent HCC or decompensated liver cirrhosis after curative hepatectomy, a concept that has been called “salvage LT” [73–77]. Initial studies suggested that salvage LT offered poorer results [73]. Belghiti et al [74] reported that the survival after salvage LT was not significantly lower; indeed, the 5-year survival rate after salvage LT in their study was 61%. The Hong Kong group [76] showed that when recurrence occurs after resection of small HCC, up to 79% of patients are still considered transplantable using the same criteria of primary transplantation for HCC. Moreover, the Barcelona Clinic Liver Cancer Group [77] proposed salvage LT for patients in whom pathologic examination of a resected specimen indicated a high risk for recurrence even in the absence of proven residual disease. This approach may reduce the dropout rate on a waiting list and provides a strategy to select patients with HCC who are likely to benefit most from LT [75]. Patients should be followed closely after initial resection. Many groups in Asia recommend serum alpha-fetoprotein (AFP) levels and ultrasound examination of the liver every 2–3 months during the first 1–2 years after surgery [71]. Some investigators insist that such an intensive follow-up program has resulted in the discovery of much smaller recurrent tumors, and contributed to improved resectability [10].

Multiple repeat hepatic resections Multiple repeat hepatic resections for HCC are extremely uncommon. The overwhelming majority of patients who have recurrence after repeat hepatectomy are not candidates for further surgery, usually because progressive hepatic dysfunction and/or extensive recurrent hepatic disease preclude surgery in the majority. In the study by Itamoto et al [65], including 94 repeat hepatectomies in 84 patients, 84 patients underwent a second resection, eight a third and only two a fourth resection for recurrent HCC.

Resectional versus nonresectional approaches for recurrent hepatocellular carcinoma Because most patients with HCC are not candidates for resection or transplantation, effective alternative therapies are desperately needed. As discussed earlier, cryoablation, hepatic artery embolization, percutaneous ethanol injection, microwave hyperthermia, and RFA have all been used to treat patients with primary or secondary hepatic malignancies. For metastatic colorectal cancer, these modalities are generally reserved for patients with unresectable disease because they are not considered to be potentially curative. However, for HCC in cirrhotic patients, resection may not be possible because of underlying liver parenchymal dysfunction, even if disease is limited. Ablative therapies therefore have a wider role.

CHAPTER 19

Table 19.5 Studies comparing resectional and nonresectional therapies for recurrent hepatocellular carcinoma. Study

Lee et al (1995) [66] Shimada et al (1996) [48] Poon et al (1999) [54] Nakajiama et al (2001) [78] Liang et al (2008) [67]

Type of treatment

Repeat resection (n = 25) TACE (n = 12)§ Repeat resection (n = 22) Lipolidization (n = 106) Lipolidization + PEIT (n = 10) Repeat resection (n = 11) TACE (n = 71) Repeat resection (n = 12) Nonsurgical treatment (n = 45)# Repeat resection (n = 44) Radiofrequency ablation (n = 88)

Survival (%)* 3-Year

5-Year

45 48 70 38 76 69 38 72 51 57 49

65** 22** 70 20 0 69 21 NR NR 30 40

*Measured as 3- and 5-year survival rates after second liver resection or nonsurgical treatment for recurrent HCC. **5-year survival calculated from initial resection. §These 12 patients were resectable but refused repeat surgery and received TACE. #These 45 patients received mainly TACE and occasionally PEIT. TACE, transcatheter hepatic arterial chemoembolization; PEIT, percutaneous ethanol injection therapy; NR, not reported.

However, direct prospective randomized comparisons of repeat resection with nonresectional locoregional modalities for recurrent HCC have not been performed. There are only a few retrospective studies that compare resectional with nonresectional approaches for recurrent HCC [48, 54, 66, 67, 78] (Table 19.5). Shimada et al [48] have suggested that the combination of chemoembolization and percutaneous ethanol injection may be superior to either treatment alone. Survival at 3 years was similar to repeat resection using this combined approach, although in contrast to repeat resection no 5-year survivors were documented in this group. Another retrospective analysis has compared repeat resection with nonresectional therapies (transarterial chemoembolization, percutaneous ethanol injection, systemic chemotherapy) after initial hepatic resection. Despite the relatively small patient number in the re-resection group (n = 11), repeat resection had the best survival compared to all other nonresectional therapies [54]. Another Japanese study comparing repeat resection with nonresectional approaches (mainly hepatic arterial embolization) demonstrated a better 3-year survival for repeat resection; however, this difference was not statistically significant [78]. All of these studies [48, 54, 78] are obviously biased, because all patients subjected to resection usually have more limited disease and preserved

Repeat Resection for Liver Tumors

hepatic function. In the only study comparing repeat resection with hepatic artery embolization with comparable extent of disease, survival was equivalent at 3 years but significantly greater in the re-resected group at 5 years after initial resection [66]. Recently, RFA has been increasingly used to treat recurrent HCC after hepatectomy. Cohort studies reported the 5-year overall survival to range from 18% to 51.6%, and a high complete ablation rate of over 90% [79, 80]. Liang et al [67] compared the long-term survival outcomes of RFA (n = 88) and partial hepatectomy (n = 44) for recurrent HCC after resection (Table 19.5). The two groups were well balanced regarding demographic data and tumoral findings. They showed that there was no significant difference in the 5-year overall survival and in recurrence rates between the groups. RFA had the advantage over surgical resection of being less invasive and causing fewer complications. In conclusion, as far as nonresectional approaches are not curative and have not been proven their superiority to hepatic resection, hepatic resection remains the most accepted treatment for resectable recurrent HCC with preserved liver function.

Self-assessment questions 1 Which one of the following statements on repeat liver resection for colorectal liver metastases is false? A The rate of complications and mortality are comparable between first and repeat liver resection B There is recent evidence that perioperative chemotherapy with FOLFOX at the time of first resection is beneficial in reducing recurrence C A short interval between first and second liver resection is the strongest predictor for reduced survival after repeat hepatectomy D The primary goal of a repeat liver resection should be always a complete resection (R0) E The expected 5-year survival after repeat resection is approximately 30–45% 2 Which one of the following patients, who undergoes repeat liver resection for colorectal liver metastases, has the best prognosis? A Three metastases, largest size 6 cm, tumor-free margins (R0) B One metastasis, size 4 cm, microscopic disease in resection margin (R1) C Two metastases, both 3 cm, tumor-free margins (R0) D One metastases at the venous confluence, size 2.5 cm, incomplete resection (R2) E Six metastases, three tumors with size of 2.5 cm, tumor-free margins (R0)

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3 Which one of the following is an absolute contraindication for a repeat liver resection for recurrent colorectal cancer? A Synchronous pulmonary metastases B History of cardiac bypass operation C Bilobar tumor involvement D Portal hypertension E Extended right hepatectomy at first resection 4 In case of recurrence after a first hepatectomy for HCC, what is the percentage of patients qualifying for a repeat resection? A <5% B 10–20% C 30–40% D 50–60% E More than 60% 5 Which of the following factors have been identified as independent negative predictors of outcome after repeat resection for recurrent hepatocellular carcinoma? (more than one answer is possible) A Multifocal HCC at primary B Disease-free interval <1 year after the first resection C Diameter of tumors at repeat hepatectomy D Portal vein invasion at repeat hepatectomy E Severity of hepatic dysfunction

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64 Hu RH, Lee PH, Yu SC, et al. Surgical resection for recurrent hepatocellular carcinoma: prognosis and analysis of risk factors. Surgery 1996;120:23–9. 65 Itamoto T, Nakahara H, Amano H, et al. Repeat hepatectomy for recurrent hepatocellular carcinoma. Surgery 2007;141:589–97. 66 Lee PH, Lin WJ, Tsang YM, et al. Clinical management of recurrent hepatocellular carcinoma. Ann Surg 1995;222:670–6. 67 Liang HH, Chen MS, Peng ZW, et al. Percutaneous radiofrequency ablation versus repeat hepatectomy for recurrent hepatocellular carcinoma: a retrospective study. Ann Surg Oncol 2008;15:3484–93. 68 Shimada M, Takenaka K, Taguchi K, et al. Prognostic factors after repeat hepatectomy for recurrent hepatocellular carcinoma. Ann Surg 1998;227:80–5. 69 Shuto T, Kinoshita H, Hirohashi K, et al. Indications for, and effectiveness of, a second hepatic resection for recurrent hepatocellular carcinoma. Hepatogastroenterology 1996;43:932–7. 70 Sugimachi K, Maehara S, Tanaka S, Shimada M, Sugimachi K. Repeat hepatectomy is the most useful treatment for recurrent hepatocellular carcinoma. J HPB Surg 2001;8:410–6. 71 Kudo M, Okanoue T. Management of hepatocellular carcinoma in Japan: consensus-based clinical practice manual proposed by the Japan Society of Hepatology. Oncology 2007;72 (Suppl 1): 2–15. 72 Lau WY, Lai EC. The current role of radiofrequency ablation in the management of hepatocellular carcinoma: a systematic review. Ann Surg 2009;249:20–5. 73 Adam R, Azoulay D, Castaing D, et al. Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy? Ann Surg 2003;238:508–18. 74 Belghiti J, Cortes A, Abdalla EK, et al. Resection prior to liver transplantation for hepatocellular carcinoma. Ann Surg 2003;238:885–92.

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75 Majno PE, Sarasin FP, Mentha G, Hadengue A. Primary liver resection and salvage transplantation or primary liver transplantation in patients with single, small hepatocellular carcinoma and preserved liver function: an outcome-oriented decision analysis. Hepatology 2000;31:899–906. 76 Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg 2002;235: 373–82. 77 Sala M, Fuster J, Llovet JM, et al. High pathological risk of recurrence after surgical resection for hepatocellular carcinoma: an indication for salvage liver transplantation. Liver Transpl 2004;10:1294–300. 78 Nakajima Y, Ko S, Kanamura T, et al. Repeat liver resection for hepatocellular carcinoma. J Am Coll Surg 2001;192:339–44. 79 Choi D, Lim HK, Rhim H, et al. Percutaneous radiofrequency ablation for recurrent hepatocellular carcinoma after hepatectomy: long-term results and prognostic factors. Ann Surg Oncol 2007;14:2319–29. 80 Yang W, Chen MH, Yin SS, et al. Radiofrequency ablation of recurrent hepatocellular carcinoma after hepatectomy: therapeutic efficacy on early- and late-phase recurrence. AJR Am J Roentgenol 2006;186(5 Suppl):S275–83.

Self-assessment questions 1 2 3 4 5

C C D B A, B, D

20

Cryoablation of Liver Tumors Sivakumar Gananadha1 and David L. Morris2 1 Department of Surgery, The Canberra Hospital, Australian National University Medical School, Canberra, Australia 2 UNSW Department of Surgery, St George Hospital, Sydney, NSW, Australia

History The use of freezing temperatures for the treatment of cancers such as breast and uterine cervix was first introduced by James Arnott in the 1850s in London. He used iced saline solutions directly on ulcerating cancers and provided relief of pain, and reduction in the size of tumors, bleeding, and discharge. It was not until the development of cryosurgical systems capable of delivering liquid nitrogen through insulated probes that treatment of deep-seated cancers was possible using this approach. Dr Irving Cooper’s liquid nitrogen probes were initially designed for the treatment of patients with Parkinson disease but soon found applications in the treatment of cancer. Modern cryosurgical systems are capable of achieving probe temperatures of −196 °C and provide controlled delivery of freezing temperatures to tissues.

closest to the probe, will however result in crystallization of intracellular water, causing disruption of the cellular organelles and the cell membrane, and leading to a certain cell death. Crystallization of water in the vascular system causes stasis, endothelial damage, platelet aggregation, and thrombus formation. This is associated with a shutdown of microvascular perfusion and the loss of blood supply to the surviving cells, resulting in tissue necrosis. The main determinants of effective cryodestruction of tissues are described below.

Cooling rate Rapid cooling occurs primarily in those tissues closest to the probe and results in intracellular ice crystal formation, leading to cell death. As the distance from the probe increases, the cooling rate drops, resulting mainly in extracellular ice formation. Bischof et al showed that at slower cooling rates tumor cells were less susceptible to dehydration than normal liver tissue [2].

Mechanism of cryodestruction Tissue temperature The principle of cryodestruction involves rapid cooling, slow thawing, and a repetition of the freeze–thaw cycle. There are two main mechanisms of cryodestruction, one due to the direct cellular injury and the other due to a delayed post-thaw tissue ischemia due to vascular injury [1]. Tissues that are exposed to sub-zero temperature undergo crystallization of intracellular or extracellular water. Temperatures just below 0 °C will result in crystallization of water in the extracellular spaces including the vascular space. The resulting hyperosmotic milieu draws out water from the cells causing cellular dehydration, shrinkage, and cell death. Tissues that are exposed to colder temperatures (below −40 °C) or tissues exposed to rapid cooling, typically in those

There are wide ranging responses of various tissues, both normal and tumor cells, to the effects of cooling and a variety of temperatures have been reported as lethal to cells. However, a temperature of −40 °C has been found in most studies to be lethal to cells due to intracellular ice formation. This temperature is, however, hard to achieve in the entire tumor, especially in the periphery of the tumor.

Duration of freezing Duration of freezing is not considered to be important, especially in tissues held at temperatures below −40 °C. However, at warmer temperatures where cell death is due to extracellular crystallization and solute effects, greater destruction is achieved with longer duration of exposure [1].

Thaw rate Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

During thawing of the iceball, the ice crystals fuse to form larger crystals, causing mechanical disruption of the cells. This recrystallization occurs in the temperature range of −20

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to −25 °C. Another mechanism of injury during thawing is due to the melting ice causing a hypo-osmotic extracellular milieu. This results in water entering the cells, causing cell swelling and rupture of the cell membrane. Slow thawing was found to be more destructive than fast thawing, and thawing is most destructive if it is done completely [1, 2].

Repetition of the freeze–thaw cycle The repetition of the freeze–thaw cycle results in more extensive necrosis as the volume of the frozen tissue is larger due to increased thermal conductivity. This effect is greatest at the periphery of the iceball where the temperature of the tissue after the first cycle may not be as low as in the tissue close to the probe. A single freeze–thaw may be effective if the temperature of the entire tumor reaches below −40 °C, which is hard to achieve. Mala et al showed a median increase of 42% in the iceball volume as measured by magnetic resonance imaging (MRI) of percutaneous cryoablation with two freeze–thaw cycles compared to one [3]. There is still some controversy about the number of cycles needed to obtain effective cryoablation as studies have shown similar effectiveness of a single freeze–thaw cycle.

Indications Liver resection is the treatment of choice for malignant liver tumors with 5-year survival of up to 58%. However, less than 25% of patients are suitable for a curative resection. Local ablative therapies are indicated in patients with (1) limited hepatic reserve; (2) tumors involving both lobes where resection is not possible; (3) involved or inadequate margins following liver resection; and (4) in those who are not fit for a major resection due to other comorbidity. The tumor that is ideal for local ablative therapy is one that is small, ideally less than 3 cm, away from the capsule of the liver and adjacent structures, such as bowel and gallbladder, and away from the large central bile ducts and large blood vessels. Optimum lesion selection ensures complete ablation of the tumor with minimal complications and mortality. Cryoablation is the best established of the local ablative therapies for unresectable malignant tumors. It has been used in several different ways: alone, in combination with liver resection, with hepatic artery chemotherapy, or as an edge device. As cryoablation allows focal destruction of the tumor, patients with a limited hepatic reserve may be treated with preservation of maximum functional liver (Figure 20.1). Those with multiple bilobar disease beyond the reach of liver resection can be treated with cryoablation alone or in combination with resection, with no difference in the 5-year survival as compared to those having only resection [4–6].

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Figure 20.1 Cryoablation of a liver tumor in a patient with a poor liver reserve due to liver cirrhosis.

Those patients who after liver resection are found to have involved or inadequate surgical margins intraoperatively and in whom further liver resection is not possible due to either poor liver reserve, avoidance of a major resection or being unfit for further resection, can be treated by cryoablation to the resection edge. There has been concern about the use of cryoablation for tumors close to blood vessels as these vessels may act as a heat sink and result in inadequate cooling of the tumor, leading to high local recurrence rates. Blood vessels were found to be resistant to structural damage by direct cooling, probably due to the increased amount of fibrous tissues present [7]. Weber et al reported in normal pig liver parenchyma that cooling of the perivascular tissue resulted in complete necrosis of the tissue without damage to the vessels [8]. Hepatic inflow occlusion has been used to overcome the problem of the heat sink effect with increased volume and faster cooling of the tissue. The role of synchronous treatment of primary colorectal cancer resection and cryoablation of liver metastases is not very clear. Treatment of 13 patients with hepatic cryoablation at the time of colectomy for primary colorectal cancer was associated with a relatively higher risk of hepatic abscess formation [9]. However, a similar study on nine patients treated with hepatic radiofrequency ablation (RFA) and synchronous colectomy found no difference in either the complication rates or the short-term outcome [10]. The role of cryoablation as an alternative to liver resection is not yet well supported and will probably not receive much attention given the similar morbidity and mortality data and the less certain long-term results. Bageacu et al [11] reported on their experience with cryoablation in patients with resectable liver tumors. They treated 53 patients of whom 31 had resectable liver metastases with cryoablation. Though the survival was similar to the reported survival following liver resection only, the local recurrence and morbidity were

CHAPTER 20

higher than resection. Resection still remains the treatment of choice for patients with liver malignancy.

Which ablative therapy? There have been many new developments in local ablative therapies for the treatment of liver malignancies. The most popular of these emerging therapies is RFA. There has been an explosion in the use of this technology with numerous reports in the literature (see Chapter 21). The main advantages of RFA include the ability to treat liver lesions percutaneously as well as less severe complications compared to cryoablation. However, there are very few well-conducted studies comparing cryoablation and RFA for the treatment of liver malignancy. Where studies exist, they suffer from lack of randomization and potential selection bias. Comparisons have been made between open procedure cryoablation with percutaneous RFA, as well as comparison of RFA with historic cryoablation controls. There are five studies comparing RFA and cryoablation of liver lesions. The first study by Pearson et al compared 54 patients (88 tumors) treated by cryoablation with 92 patients (138 tumors) treated by RFA performed at open operation [12]. This study was nonrandomized with the method of ablation left to the preference and training of the surgeon. Fifty percent of patients who underwent cryoablation and 20% of patients who underwent RFA also had resection of tumor in the contralateral lobe of the liver. At a median follow-up of 15 months the tumor recurred in 13.6% of the cryoablated sites compared to 3.3% of the RFA sites (22.2% of patients in the cryoablation group versus 3.3% of patients in the RFA group). There was one death in the cryoablation group due to cracking of the iceball into the hepatic vein, and no deaths in the RFA group. The overall morbidity and mortality rate was 40.7% of the patients in the cryoablation group and 3.3% in the RFA group [12]. Bilchik et al reported on 308 patients undergoing either RFA or cryoablation [13]. They compared 68 patients undergoing RFA with historic controls of patients undergoing cryosurgery at open surgery. The median size of tumor was larger among the cryoablation group compared to the RFA group (5 cm versus 2 cm), and the follow-up was longer in the cryoablation group (16 months versus 9 months). The length of procedure, the duration of hospitalization, and morbidity were significantly less for the RFA group compared to the cryoablation group. However, this may be due to the fact that the cryoablation group had ablation during an open operation compared to the RFA group who were treated with a percutaneous or laparoscopic approach as well. Though the overall survival and local recurrence rates were comparable between the two groups, the cryoablation group had a longer median follow-up. Looking at patients with larger lesions (>3 cm), the RFA group had a higher local

Cryoablation of Liver Tumors

recurrence rate (38% versus 17%), as well as more complications [13]. Adam et al reported on 31 patients treated with percutaneous cryoablation and 33 patients treated by percutaneous RFA [14]. This was again a nonrandomized study with patients receiving either treatment by “random availability of probes.” This study showed no difference in the complication rates between the two groups as both were performed percutaneously. There was, however, one death in the cryoablation group due to variceal hemorrhage on day 30. The local recurrence rate was higher in the cryoablated patients compared to the RFA group (60% versus 16%) with a follow-up of 21.2 ± 13.8 versus 16.3 ± 8.7 months, respectively [14]. The local recurrence rate following cryoablation in this study seemed quite high compared to the local recurrence rates reported in the literature (see Table 20.5). Tait et al treated 38 patients with laparoscopic cryoablation, laparoscopic RFA or both, with or without resection [15]. Local recurrence at the ablation site was seen in 12 of 44 lesions following cryoablation, and in 20 of 102 lesions following RFA. The complication rate was higher after cryoablation than RFA. However, in this study patients were treated with cryoablation if the size of the lesion was greater than 5 cm and with RFA if the size was less than 5 cm [15]. Joosten et al compared, in a nonrandomized study, 30 patients who underwent open cryoablation with or without resection with 28 patients who underwent open RFA with or without resection for colorectal liver metastases [16]. The median follow-up in the RFA group was 25 months, and in the cryoablation group the data were limited to a follow-up of 26 months. The groups were comparable except for a higher percentage of patients in the cryoablation group having a combination of resection and ablation and a higher number of lesions ablated by cryoablation. There was one death in each group and the overall morbidity in the cryoablation group was 30%, whereas it was 11% in the RFA group. The 1- and 2-year survival following cryoablation was 76% and 61%, respectively, and in the RFA group, 93% and 75%, respectively. The difference in overall survival between the two groups was not statistically different [16]. It is clear from these studies that patients undergoing cryoablation and RFA are not comparable in order to draw any meaningful conclusions. Cryoablation is preferred for larger and multiple lesions and is employed during an open operation. Cryoablation has several advantages over RFA, including the ability to use multiple probes, better intraoperative monitoring of the ablation, and the lower ongoing cost of the probes. Adequate care and appropriate patient selection can eliminate deaths from complications from cryoshock and hemorrhage. The true difference between the two methods can only be ascertained from well-constructed randomized and adequately powered studies.

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Preoperative work-up Patients undergoing cryoablation are assessed preoperatively to accurately define the disease within the liver and to exclude extrahepatic disease. As this is a local ablative therapy, the presence of extrahepatic disease will contraindicate cryoablation except in those patients with symptomatic hepatic metastases from neuroendocrine tumors, as significant palliation can be achieved in these patients. The preoperative work-up includes an abdominal computed tomography (CT) with arterial and venous phase images. This helps in the preoperative planning of the surgery. A CT of the chest and a whole body bone scan is essential to exclude extrahepatic disease. Positron emission tomography (PET) probably is the best technique for the diagnosis of extrahepatic disease, as Strasberg et al reported a 3-year overall survival of 77% and a 3-year disease-free survival of 40% in patients evaluated with PET prior to liver resection [17]. Preoperative measurement of the serum tumor markers where appropriate, hematologic profile including coagulation studies, and serum biochemistry are done to confirm normal or near-normal parameters and as a baseline value to monitor for any postoperative complications.

Equipment There are various commercially available systems for cryoablation of the liver (Figure 20.2). These systems use either liquid nitrogen or other cryogens such as gaseous argon, carbon dioxide, or nitrous oxide most commonly. Liquid nitrogen is the coldest cryogen available; it can be supercooled to provide probe temperatures of −190 °C. The liquid nitrogen-based system achieves probe cooling by the change of liquid nitrogen from the liquid to the gaseous state. Another method of cooling is by the expansion of compressed gas after passage through a restricting orifice (Joule–Thompson effect). The cryogens used in this method include gases such as argon, nitrous oxide, and carbon dioxide. Argon systems can achieve probe temperatures of −150 °C. Liquid nitrogen is used commonly in cryoablation of liver tumors as, as stated above, it is the coldest cryogen available. Liquid nitrogen-based systems were able to achieve larger volumes of cryoablation compared to argonbased systems. Various sizes of trocar probes are available ranging from 3 to 9 mm. Paddle probes for surface application are also available. Larger probes achieve larger volumes of cryoablation due to their large freezing areas. Most of the cryosurgical systems now allow the simultaneous use of multiple probes. The liquid nitrogen must be filled prior to the pro-

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Figure 20.2 The Erbe cryo 6 cryosurgical systems (Tübingen, Germany).

cedure and as such, one of the limitations to the use of cryotherapy is that it cannot be used in unplanned situations. Most machines have a thaw system, which allows quicker probe detachment after freezing. One of the other major differences between the systems is whether or not the probes are reusable, and there is a large recurrent cost associated with single-use probes. There are currently five manufacturers of cryosurgical units: Erbe (Tubingen, Germany), Cryomedical Sciences (Rockville, USA), Galil Medical (Yokneam, Israel), Endocare (Irwin, CA, USA), and Spembly (Andover, UK).

Technique Cryoablation of liver malignancies by the open approach is performed initially with a right subcostal incision to assess the hepatic disease with intraoperative ultrasound. A staging laparoscopy can also be performed with laparoscopic ultrasound. Presence of extrahepatic disease is assessed by looking for enlarged lymph nodes and peritoneal disease, and confirmed with frozen section if appropriate. The use of intraoperative ultrasound is useful for the assessment of the extent of the liver malignancy, its relationship to critical structures, and its site as well as its size (Figure 20.3). The use of intraoperative ultrasound increases the identification of additional lesions compared to preoperative imaging [13]. Once the decision to proceed is made, the incision is extended. The

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Cryoablation of Liver Tumors

Figure 20.4 Most modern cryosurgical systems allow the simultaneous use of multiple cryoprobes.

Figure 20.3 The use of intraoperative ultrasound helps in the assessment of the tumor and its relationship to critical structures.

always allowed to completely thaw prior to the closure of the abdomen in order to identify and control any bleeding.

Minimally invasive approach liver is mobilized in order to fully assess the disease as well as to allow access to the liver in the event of hemorrhage, especially when treating a large posterior tumor. The number, diameter, and position of the probes are selected according to the size and the location of the tumor, and probes are usually placed under intraoperative ultrasound guidance. For deeper tumors that cannot be palpated, a spinal needle is initially placed under ultrasound guidance and the probe placed using the needle as a guide for angle and depth. A needle, wire, sheath approach is probably even better. Many commercially available cryosurgical systems now allow multiple probes to be used simultaneously, and the number and diameter of probes used will depend on the capability of the particular system used (Figure 20.4). The freezing is continued to include a 1-cm rim of normal liver parenchyma beyond the margin of the tumor on ultrasound. This practice was validated by the findings of Kuszyk et al who reported patent vessels extending as far as 6 mm into the cryolesion on histologic assessment [18]. The freeze–thaw cycle is repeated. We allow the edge of the iceball to thaw by approximately 1 cm prior to refreezing to increase the lethality of freezing, as complete thaw would considerably increase the operative time and, more importantly, complete thaw and refreezing is causally associated with the phenomenon of cryoshock [19–21]. Once the probe is removed, the tract is filled with gelfoam strips soaked in thrombin to prevent bleeding. The iceball is

Laparoscopic cryoablation has been investigated for the treatment of liver malignancy. Its safety has been established in animals and clinically [22–24]. An advantage over a percutaneous approach is the ability to use intraoperative ultrasound as more liver tumors are diagnosed with intraoperative ultrasound compared to preoperative imaging. The laparoscopic approach also helps in better assessment of extrahepatic disease in contrast to the percutaneous approach. The probes used in the laparoscopic approach vary between the narrow 2-mm cryo needles specifically designed for cryotherapy to the 3–8-mm probes. Laparoscopic cryoablation, though feasible and safe, has not been reported extensively in the literature. Percutaneous cryoablation was found to be safe in a pig model using CT-guided ablations and small 2.4–3-mm probes [25]. It has also been used in a clinical study of eight patients with unresectable liver tumors [26]. There were no pre- or post-operative complications with a mean hospital stay of 6 days. Adam et al compared percutaneous cryoablation and percutaneous RFA and showed no difference in the complication rates [14]. There was one death in the percutaneous cryoablation group that was not directly related to the procedure. The main disadvantages with the percutaneous approach are the inability to use intraoperative ultrasound and the potential damage to surrounding structures such as bowel, as these cannot be protected from inadvertent contact with the probe or the iceball.

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These studies show that minimally invasive cryotherapy can be safely performed, but in comparison with RFA, is probably less easily applied.

of the ice–tissue interface, but the considerably higher cost of the MR and the need for MR-compatible probes make it less appealing.

Monitoring

Postoperative course and follow-up

Early attempts at monitoring cryotherapy involved temperature thermocouples placed at positions that were thought critical to the monitoring of the extent of freezing. These were at 1 cm beyond the margin of the tumor. The placement of the thermocouples was also critical as there was as much as a 10–15 °C difference with a 1-mm variation in thermocouple placement. The use of intraoperative ultrasound was a major advance in the monitoring of cryotherapy. It provides a real-time three-dimensional image of the cryoablation. It also helps to define the relationship of the lesions to the biliary and vascular structures, and is essential in the probe placement for deep-seated tumors (Figure 20.3). The frozen tissue appears as a hypoechoic area with the edge of the frozen tissue appearing as a hyperechoic rim (Figure 20.5). The main limitation of intraoperative ultrasound is the posterior acoustic shadowing, which limits the view beyond the hyperechoic surface, and there is a distortion of the frozen tissue on the ultrasound images. This requires imaging from behind the liver and frequent alteration in probe position. The leading hyperechoic edge correlates with a temperature of 0 °C using thermocouples. Other modalities have been used in the imaging of cryotherapy such as CT and MRI. T1-weighted MR images were found to be superior to CT and ultrasound in visualization

We routinely monitor our postoperative patients either in the intensive care or the high-dependency unit for the first 24 h for postoperative bleeding and the maintenance of an adequate urine output. CT scan of the cryoablated area appears as a hypoattenuated area on nonenhanced CT images and as an avascular area on contrast CT (Figure 20.6). Early postoperative scans may show small amounts of air in the probe track. There is a considerable shrinkage of the zone of ablation over time. Joosten et al used 18-fluoro-2-deoxy-D-glucose (FDG)PET for the postoperative monitoring of the local ablative therapies. CT scan failed to identify all seven patients with local treatment failures at 3 months, whereas FDG-PET identified six of the seven patients at 3 weeks and all seven patients at 3 months. There was one false-positive result in one patient with infection [16]. These are similar to findings in studies using FDG-PET scan following RFA. Patients are followed-up with measurement of tumor markers. There is a fall in carcinoembryonic antigen (CEA) in almost all CEA secretors following hepatic cryotherapy and this is probably the best measure of the technical adequacy of the procedure. There is a highly significant correlation between the maximum percentage fall in CEA and survival.

(a)

(b)

Figure 20.5 Intraoperative ultrasound helps in (a) probe placement and (b) monitoring of the iceball.

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Cryoablation of Liver Tumors

(b)

Figure 20.6 (a) The preoperative CT scan of liver metastases and (b) appearance of the same lesions after cryotherapy.

Complications Cryotherapy has now been used in over 2000 patients worldwide and has been found to be safe with an overall mortality of 1.5% [27]. Significant intraoperative hypothermia has been reported during cryotherapy, but the use of warm intravenous fluids and warming devices, such as the Bair Hugger, prevents excessive hypothermia. Cracking of the treated lesions is common in hepatic cryotherapy, occurring in 19–40% of the patients in published series [28]. The majority of the bleeding from these cracks can be controlled by pressure or suturing. Rarely, major bleeding may occur and requires packing. A significant drop in the platelet count after hepatic cryotherapy occurs in the majority of patients. Thrombocytopenia correlates with the degree of hepatocellular injury, with a double freeze–thaw cycle associated with a greater fall in the platelet count [29]. This may be due to excessive platelet trapping and destruction within the cryolesion. The platelet count nadir occurs between days 2 and 3. The serum aspartate level on day 1 is a good predictor of impending thrombocytopenia. There is a transient increase in the transaminase levels, which normalizes within 7 days post operation. Myoglobinemia and myoglobinuria were reported in patients immediately after thawing of the frozen lesion and resolved by day 3. They were related to the volume of tissue frozen and did not depend on the duration of the operation [30, 31]. They were associated with acute tubular necrosis and renal impairment in some patients, but acute renal failure is a rare complication [32]. Atelectasis and pleural effusions are fairly common after cryotherapy. Few patients require thoracocentesis for symp-

tomatic large pleural effusions. Lung injury following cryotherapy has been recognized, especially after cryoablation of greater than 30–35% of the liver [33, 34]. This is associated with a transient increase in pulmonary artery pressure, systemic arterial pressures, and increased capillary permeability, probably due to the induction of a systemic inflammatory response with overproduction of NF-kB-dependent cytokines [33]. The cryoshock is a syndrome of multiorgan failure, severe coagulopathy, disseminated intravascular coagulation, hypotension, and shock (Table 20.1). This syndrome, though associated with a high mortality, is uncommon, occurring in 1% of patients after hepatic cryotherapy [27]. It is associated with the induction and the release of cytokines occurring commonly in patients who have undergone cryoablation of more than 30–35% of the liver parenchyma. Table 20.2 shows the morbidity and mortality associated with cryotherapy in published series. Sohn et al in a retrospective review of 94 patients showed that the extent of cryoablation is the predictor of complication rate and length of hospital stay [35]. Cryoablation of total estimated area of 30 cm2 or greater resulted in a significantly higher complication rate and significantly longer hospital stay compared to cryoablation of less than 30 cm2. Not surprisingly, patients undergoing other concurrent procedures also had a higher complication rate and longer hospital stay.

Clinical results Hepatocellular carcinoma Transplantation and resection remain the treatments of choice for patients with hepatocellular carcinoma (HCC)

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Table 20.1 Cryoshock phenomenon. Cryoshock is a syndrome of severe coagulopathy, disseminated intravascular coagulation (DIC), and multiorgan failure associated with hypotension and features of shock Incidence of about 1.0% in patients undergoing hepatic cryotherapy [28] Pathophysiology Unclear but probably related to cryoablation of >30−35% of liver volume. This is associated with activation of the transcription factor complex- nuclear factor kB ( (NF-kB) with increased production of the acute phase proteins such as interleukin-6 and tumor necrosis factor-α [21, 33] Double freeze−thaw cycle with complete interval thaw is also associated with greater hepatocellular injury [20] and may be a factor in this complication Clinical features • Thrombocytopenia • Acute renal failure • Adult respiratory distress syndrome • DIC • Liver failure • Hypotension/shock • Death Isolated features of cryoshock are more common than the full syndrome. Prevention Avoidance of high volume of cryodestruction (>35%) Partial thawing of the iceball to about 1 cm before refreezing Management Supportive management, including treatment of the DIC with fresh frozen plasma. Cryoprecipitate and platelets. Ventilatory support for those patients with acute respiratory distress syndrome, and dialysis for those with renal failure Prognosis Though cryoshock is uncommon, occurring in about 1% of those having cryotherapy, it accounted for 18% of the mortality following hepatic cryotherapy [28]

(see Chapter 26). Local ablative therapies have been used for the treatment of patients with unresectable liver tumors, poor liver reserve, and severe cirrhosis. There are limited reports on the use of cryoablation for the treatment of HCC, with many studies including a mixture of tumor types. Zhou et al reported on 235 patients with primary liver tumors treated with cryoablation for unresectable tumors [36]. They included 232 patients with HCC. The majority of patients had additional treatments such as hepatic artery ligation and/or perfusion or resection. There was no mortality and the only significant complication was an intra-abdominal abscess. The overall 1-, 3- and 5-year survival rates were 78.4%, 54.1%, and 39.8%, respectively [36]. The 5-year survival for patients with tumors of 5 cm or less was better than those with larger tumors.

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Experience with cryotherapy for HCC from other centers is limited to smaller series. Wren et al reported on 12 patients with unresectable HCC, five of the patients having had preoperative intra-arterial chemoembolization [37]. There was no mortality and a mean survival of 19 months. Seven of nine patients treated with a curative intent developed recurrence of the HCC. Adam et al treated nine patients with unresectable HCC with cryotherapy either alone or in combination with resection. The cumulative survival rate at 2 years was 63% [38]. Xu et al treated 65 patients with unresectable HCC by percutaneous cryoablation followed by ethanol injection [39]. With a mean follow-up of 14 months, 50.8% of the patients were alive without recurrence and 33.8% were alive with recurrence. There were only three patients with recurrence at the cryosite. These studies support the use of cryotherapy for the treatment of unresectable HCC. The results of published series using cryotherapy for the treatment of HCC are shown in Table 20.3. Long-term follow-up of patients treated by cryoablation was reported by Kerkar et al [40]. They treated 98 patients by cryoablation. In the 14 patients who had HCC, the 1-, 3- and 5-year survival rates were 77%, 57%, and 48%, respectively, with a median survival of 40 months. The use of preoperative transarterial chemoembolization followed by cryosurgery was reported by Clavien et al in 15 patients with HCC and cirrhosis [41]. The aim of this was to decrease the complication rate from hemorrhage and decrease the local recurrence rate. They treated mainly solitary tumors but with a median diameter of 6.5 cm (range 3.5–12 cm). At a median follow-up of 2.5 years, 79% of the patients were alive. They reported a local recurrence rate at the cryosite of 20%. Tumor marker response in patients following cryotherapy gives a good indication of the effectiveness of the cryoablation. Xu et al reported that tumor markers were lowered to normal or near-normal levels in 91.3% of patients in the 3–6-month postablative period [39]. Adam et al reported reduction in the tumor markers in 60% of patients with preoperatively elevated serum tumor marker [38].

Neuroendocrine metastases Malignant neuroendocrine tumors are a heterogeneous group of tumors which are generally slow growing with a potential for long-term survival albeit with disabling symptoms. In this group of patients, significant palliation from symptoms and improved survival can be achieved with tumor debulking (see Chapter 37). Resection of neuroendocrine liver metastases has been shown to offer symptomatic response in 90% of patients at a mean duration of 19.3 months [42]. Cryotherapy has been evaluated in unresectable tumors and as an alternative to liver resection. The

Table 20.2 Morbidity and mortality associated with cryoablation of liver tumors. Patients (n)

Mortality n (%)

Morbidity n (%)

Pleural effusion n (%)

Cracking of iceball n (%)

Biliary fistula bile leak n (%)

Myoglobinuria renal failure/ ATN n (%)

Hepatic/ abdominal abscess n (%)

Chest infection n (%)

Coagulopathy n (%)

Intraabdominal hemorrhage n (%)

Others n (%)

Weaver et al [31] Zhou et al [73] Morris et al [74] Shafir et al [62] Adam et al [38] Yeh et al [63] Wren et al [37] Korpan et al [44] Seifert et al [45]

1995

140

6 (4)

–

7 (5)

–

6 (4)

1 (1)

2 (1)

–

2 (1)

–

Cryoinjury colon 1

1995

145

0

–

–

–

0

–

0

–

–

0

–

1996

110

2 (2)

–

4 (4)

10 (9)

9(9)

1 (1)

2 (2)

28 (25)

–

10 (9)

–

1996

39

0

9%

–

–

0

1 (3)

0

0

1 (3)

1 (3)

1997

34

1 (3)

8%

–

–

1 (3)

0

0

0

–

–

Cryoinjury – lung 1, skin 1 Abdominal collection 1 (3)

1997

24

2 (8)

–

2 (8)

3 (13)

1 (4)

–

–

–

–

0

Cardiac 3, CVA 1, line sepsis 1

1997

12

0

1 (8)

–

–

1 (8)

–

0

1 (8)

–

–

–

1997

63

0

6 (10)

–

–

0

–

0

3 (5)

–

0

Wound infection 1

1998

116

1 (1)

28%

4 (3)

–

4 (3)

5 (4)

5 (4)

8 (7)

–

4 (4)

Haddad et al [64] Rivoire et al [65] Rehrig et al [46] Ruers et al [66] Bilchik et al [13] Bageacu et al [11]

1998

31

2 (6)

19 (59)

–

–

4 (13)

3 (10)

–

–

20 (63)

1 (3)

Liver failure 1, DIC 1, PE 1, wound infection 2, cardiac compl 2, UTI 1 Encephalopathy 1

2000

19

0

21%

1 (5)

5 (26)

1 (5)

–

–

–

–

–

Liver failure 2

2001

24

0

25%

–

–

–

–

–

–

4 (17)

1 (4)

–

2001

30

1 (3)

–

–

2 (7)

–

–

4 (13)

3 (10)

–

–

–

2000

159

5/159 (3)

–

80%

–

7/159 (4)

–

11/159 (7)

–

–

–

2007

53

2/53 (3.8)

66%

20/53 (37.7)

2/53 (3.8)

2/53 (3.8)

2/53 (3.8)

2/53 (3.8)

4/53 (7.5)

–

4/53 (7.5)

Colitis 1, cholecystitis 1, enterocutaneous fistula 1

235

PE, pulmonary embolus; ATN, acute tubular necrosis; cardiac, cardiac complications; UTI, urinary tract infection; DIC, disseminated intravascular coagulation; CVA, cerebrovascular accident; −, no data available.

Cryoablation of Liver Tumors

Year

CHAPTER 20

Study

SECTION 4

Resection, Ablation or Transplantation

Table 20.3 Cryoablation of hepatocellular carcinoma (HCC). Study

Zhou et al [36]

Patient number

235

Adam et al [38]

9

Wren et al [37]

12

Xu et al [39] Zhao et al [75]

65 12

Kerker et al [40]

98

Pathology

HCC 232 Cholan 1 Mixed 2 HCC HCC with cirrhosis HCC HCC CRC 56 N-CRC 28 HCC 14

Median age (range)

Follow-up median months (range)

Median survival (months)

Survival (%) 1

2

3

4

47 (26–72)

–

–

78.4

–

54.1

58.1* (44–66) 62.1* (43–74) 51* 64 (35–75) 60*

16* (2–27) –

–

77

63

19*

–

14 (5–21) 13

– 21

40

5

Marker response n (%)

Liver recurrence n (%)

Recurrence at cryosite n (%)

–

39.8

–

–

–

–

–

–

3/5 (60)

3(33)

0

–

–

–

–

8/8 (100)

7/9 (78)

–

– –

– –

– –

– –

– –

91.30% 5/7 (71)

24/65 (37) 4/12 (33)

3/65 (4.6) 1/12 (8)

77

67

57

–

48

–

–

–

54

*, mean value. Cholan, cholangiocarcinoma.

Table 20.4 Published trials on neuroendocrine liver metastases treated by cryotherapy. Study

Year

Number (n)

Median follow-up months (range)

Symptomatic response n (%)

Marker response reduction n (%)

Operative mortality

Survival

Cozzi et al [43] Johnson et al [67] Bilchik et al [68] Shapiro et al [76] Seifert et al [69]* Sheen et al [70]

1995 1996 1997 1998 1998 2002

6 1 19 5 13 7

24 (6–72) 6# 17 (3–49) 30 13.5 30

7/7 (100) 1/1 (100) 19/19 (100) 5/5 (100) 5.0/7 (71) 7/7 (100)

3/3 (100) 100% 17/18 (94) 4/4 (100) 3/3 (100) –

0% 0% 0% 0% 0% 0%

100% 100% 72% 20% 92% 100%

*Includes six patients previously reported. #Last follow-up.

initial report by Cozzi et al showed symptomatic response in all six patients with hepatic metastases from neuroendocrine tumors by cryotherapy with a median follow-up of 24 months [43]. Similar results were achieved with cryoablation of neuroendocrine liver metastases in other reports. The published reports on the treatment of neuroendocrine liver metastases (Table 20.4) show good palliation of symptoms with good marker response.

Colorectal liver metastases The published reports of cryotherapy for the treatment of hepatic metastases from colorectal cancer, either as the sole therapy or in combination with liver resection or hepatic artery chemotherapy, are shown in Tables 20.5 and 20.6.

236

There is only one report of a prospective randomized control study comparing cryotherapy with liver resection [44]. In this paper, 123 patients were randomized to cryotherapy or liver resection, with 5- and 10-year survival rates of 44% and 19%, respectively, for the cryotherapy group, and 36% and 8%, respectively, for liver resection. Seifert et al reported on the long-term outcome of 116 patients with unresectable liver metastases from colorectal cancer. The median survival was 26 months with a 5-year survival of 13.5% [45]. Rehrig et al reported on 24 patients, 16 of whom had colorectal liver metastases. The survival estimate was 48.5% for the patients with colorectal metastases at a median follow-up of 33.7 months. The lesion size in these patients, however, was 2.24 ± 0.29 cm [46].

Table 20.5 Cryoablation of colorectal liver metastases. Study

Year

n

Etiology and number

Median age

CRC 119 NE 6 HCC 1 Other 14 CRC

1995

140

Weaver et al [71] Shafir et al [62]

1995

47

1996

39

Adam et al 1997 [38] Morris 1996 et al [74] Yeh et al 1997 [63] Seifert et al 1998 [45] Ruers et al 2001 [66] Rehrig 2001 et al [46]

25

CRC 25 HCC 4 NE 7 Other 3 CRC

92

CRC

24

CRC

116

CRC

30

CRC

24

CRC 16 HCC 6 NE 2 CRC 41 Other 22

1997

63+

Joosten et al [16] Bageacu et al [11]

2005

60++ 30

CRC

2007

53

CRC

Median survival months (range) n (%)

Patients alive n (%)

Patients dead n (%)

Alive disease free n (%)

Liver recurr n (%)

Cryosite n (%)

62 (14–79)

3 (1–15)

27 (7–80)

22 (4–80)

65/140 (46)

75/140 (54)

–

–

63 (31–75) –

3 (1–12) 4.8 (1–30)

26 (24–57) 14 (1–34)

26 (5–57) –

–

–

–

31/39 (79)

–

58.2* (38–73) –

1.5* (1–4) –

16* (2–27) –

–

15/25 (60)

25

63* (34–84) 60 (31–85)

–

19

3.9* (1–12) –

Extra hepatic n (%)

Survival (%) 1

2

3

–

–

–

–

–

–

–

–

–

–

62

–

–

20/39 (51)

–

–

–

–

–

–

–

5 (20)

15/25 (60)

11/25 (44)

10/25 (40)

77

52

–

–

53 (58)

10/25 (40) 39 (42)

18 (20)

–

–

–

–

–

–

–

32.7

20 (83)

4 (17)

4/21 (19)

1/21 (5)

8/21 (38)

–

–

–

–

26

43(37)

73 (63)

–

–

–

82.4

56

32.3

13

32

16/30 (53)

18/25 (72)

6/25 (24)

14/25 (56)

76

61

–

–

–

46%

14/30 (47) –

7%#

3.8*

20.5 (0–64) 26 (9–73) 33.7

9/20 (45) –

–

–

–

–

–

71

–

–

42 ± 11.2*

–

6–120

–

–

–

–

54 (85)

–

–

60

44

40.6 ± 13* 62*

– 3 (1–10)

5–120 26

– –

– 16/30

– 14/30

–

57 (95)

–

–

51

36

61.8 * (42–77)

2.6* (1–6)

24.8

–

–

–

–

30.20%

–

62* (45–79) 53.8 ± 3.2*

*, mean. #, percentage alive at 2 years. CRC, colorectal cancer; HCC, hepatocellular carcinoma; NE, neuroendocrine liver metastases; +, cryosurgery group; ++, liver resection group; −, no data available.

86.1

33.8

4

27

5

–

237

Cryoablation of Liver Tumors

Korpan et al [44]

Follow-up months (range)

CHAPTER 20

Weaver et al [31]

No of lesions median (range)

238 Table 20.6 Cryoablation combined with liver resection (results of these patients treated by the contained method). Study

Hewitt et al [4] Wallace et al [58] Cha et al [72]

Year

Pt n

Resection + Pathology cryotherapy n (%)

Median age No of (range) lesions median (range)

Size median (range)

Follow-up Median median survival (range) (months)

Patients alive n (%)

Patients dead n (%)

Alive disease free n (%)

Liver recurr n (%)

CRC

65 (43–78)

3 (2–8)

–

15 (6–53)

32

14 (70)

6 (30)

7 (35)

11 (55) –

88

60

–

1999 137 52 (49)

CRC

65.2 (36–85)

–

–

14

20

–

–

–

–

–

80

38

2001

CRC 13 HCC 1 Other 4 CRC 14

61 ± 12*

2

6.5* (1–13)

28 (18–51) –

11 (66)

7 (38)

6 (33)

11%

2/18 (11)

83

52 (24–73)

7.4 (5–25)

3 (1–13.5)

28 (5–60)

26

3/19 (16) 16/19 (84)

3/19 (16) 11(57)

2 (10)

Others 5 CRC

61 (30–80)

2 (1–7)

–

20

33

–

–

–

–

CRC 24 HCC 2 Others 5 CRC

61 ± 15*

3 (1–13)

– 1–8.0

18*

–

–

–

–

–

61 ± 10*

4.1 ± 3.5* 3.9 ± 3.6*

–

–

–

1998

20 20 (100)

38 18 (47)

Rivoire 2000 19 13 (68) et al [65] Finlay 2000 107 75(70) et al [5] Haddad 1998 31 17 (54) et al [64] Niu et al [6]

2007 415 124

+, mean value. CRC, colorectal cancer; HCC, hepatocellular carcinoma; −, no data available.

25 (1–124) 29 (1–117)

Cryosite Survival recurr 1 2 3 n (%)

Compl

Mortality

8 (40)

0

24 –

–

–

71

–

22

1(6)

89

–

31 16

21

0

–

–

–

–

–

–

–

59

33

22 –

59

2(6)

71 (60) –

84

61

43 24

–

5 (4)

5

–

–

CHAPTER 20

Cryoablation of Liver Tumors

The serum tumor marker was a significant prognostic factor that indicated tumor response and outcome. The pattern of fall in the serum CEA level after cryotherapy was different from the fall following liver resection of isolated hepatic metastases. The fall was more gradual, occurring over a period of 6 weeks to 3 months [50]. A failure of complete tumor marker response following cryotherapy for hepatic metastases from colorectal cancer was associated with shorter liver-free and overall disease-free intervals, and may be either due to incomplete cryoablation or that the hepatic or extrahepatic disease was not detected before operation [48].

Noncolorectal liver metastases Figure 20.7 Inadequately treated hepatocellular carcinoma adjacent to the area of cryoablation shown here taking up lipiodal 131I.

We reported our long-term results in 224 patients with unresectable colorectal liver metastases treated with cryotherapy and regional chemotherapy with or without resection [47]. The mortality in this group was 0.4% with a morbidity of 21%. At a median follow-up of 26 months the overall median survival was 31 months, and the median survival in 200 patients with complete tumor eradication was 36 months. There was no significant difference in survival in patients with more than five metastases and bilobar disease compared to those with less extensive disease. Recurrence of the tumor after cryoablation has been reported either locally at the cryoablation site, at other sites in the liver or at extrahepatic sites. The local recurrence at the cryosite is particularly important as this indicates tumors that were inadequately treated (Figure 20.7). The recurrence at the cryosite varies between 5% and 44% (Tables 20.5 and 20.6). In the 224 patients who underwent cryotherapy and regional chemotherapy with or without liver resection, the cryosite recurrence was 39% [47]. In a retrospective review of 85 patients, recurrence at the cryosite was reported in 33% of patients after a median follow-up of 22 months. Multivariate analysis indicated that the size of the cryotreated metastases was the only independent factor associated with local recurrence [48]. A failure of complete postoperative CEA response was also associated with shorter disease-free interval and probably indicates a failure to detect other hepatic and extrahepatic disease before the operation [48]. PET scan may be useful to better stage these patients [17]. The recurrence of tumor at other sites in the liver has been reported in the majority of patients following cryotherapy (Tables 20.5 and 20.6). The use of adjuvant hepatic artery chemotherapy was associated with a significant increase in the survival of patients [49].

Local ablative therapy has been used for the treatment of unresectable liver metastases from noncolorectal liver metastases. Goering et al treated 23 patients with cryoablation with or without liver resection and 25 patients with liver resection only for noncolorectal liver metastases [51]. The tumors included metastases from neuroendocrine, genitourinary, soft tissue, gastrointestinal, and head and neck tumors. With a median follow-up of 48 months, the overall 1-, 3-, and 5-year survival rates were 82%, 55%, and 39%, respectively, and the median survival 45 months. The 1-, 3- and 5-year survival rates in the resection group were 79%, 49%, and 40%, respectively, and in the cryoablation with or without liver resection group, 86%, 62%, and 37%, respectively. There was no significant difference between these groups [51]. Kerkar et al reported the long-term results of 98 patients of whom 28 had noncolorectal liver metastases treated by cryoablation [40]. These included five patients with liver metastases from neuroendocrine tumors. The overall median follow-up was 54 months. The 1-, 3-, and 5-year survival rates for those patients with noncolorectal liver metastases were 70%, 44%, and 28%, respectively. The median survival in this subgroup was 24 months [40].

Prognostic factors after cryotherapy The prognostic factors have now been worked out for those patients treated with cryotherapy for liver metastases from colorectal cancer. The preoperative CEA level was prognostic in those patients with low or medium volume disease, but in those with high volume disease the preoperative CEA level had no impact on survival and in these patients the prognosis was poor [52]. Low preoperative and low postoperative CEA levels were associated with a favorable prognosis in multivariate analysis [53]. Postoperative CEA values reflect the completeness of cryoablation. The number of lesions and the total estimated area of cryoablation did not significantly affect overall and hepatic recurrence-free survival [40]. However, Yan et al found that

239

SECTION 4

Resection, Ablation or Transplantation

cryoablation and resection compared to cryoablation alone, cryoablation of seven or fewer tumors, and a tumor diameter of 3 cm or less were associated with improved cryosite disease-free survival [53]. The other favorable prognostic factors were the small (<3 cm) diameter of the cryoablated metastases, absence of any untreated extrahepatic disease at laparotomy and complete tumor eradication [48]. Absence of nodal involvement at primary resection, good or moderate differentiation of the primary tumor, and synchronous development of liver metastases were also associated with a favorable prognosis [48]. Intraoperative blood transfusion was found to be a negative prognostic factor for long-term survival [54]. Major complications occurring post cryotherapy were found to be an independent predictor of overall and hepatic recurrence-free survival [40]. Sohn et al found in a multivariate analysis that a total estimated area of cryoablation of 30 cm2 or greater to be the most significant predictor of increased complication rate and length of hospital stay [35].

cryoablation of the residual lesion [4]. In a larger series consisting of 107 patients who underwent liver resection alone or in combination with cryotherapy, we found no significant difference in the survival [5]. Wallace et al were able to extend the indications for a curative treatment with the use of cryotherapy in combination with liver resection, with good long-term outcome in those patients who would otherwise be unresectable [58]. Cryotherapy was combined with liver resection in most of the patients with four to eight tumors and in all patients with more than eight tumors. The median survival was 20 months compared to 34 months in the liver resection-only group. As seven or fewer metastases and metastases diameter of 3 cm or less were associated with better cryosite disease-free survival, cryoablation with resection should be used for larger lesion [53]. Joosten et al also found no significant difference between those treated with local ablative therapy alone and those treated with local ablative therapy and resection [16].

Resection edge cryotherapy

Combined modality therapies using cryoablation Cryotherapy has been used in combination with other modalities for the treatment of liver tumors to increase the cure rates.

Adjuvant hepatic artery chemotherapy after cryotherapy The current knowledge on this topic is imperfect: we know that following liver resection hepatic artery chemotherapy reduces the risk of tumor recurrence [55, 56]. We reported, in a nonrandomized study, a lower rate of CEA relapse after cryotherapy when hepatic artery chemotherapy was used [49]. 5-Fluorouracil has been used in these studies with good survival advantage, but it is associated with higher arterial complication rates. The use of floxuridine (FUDR) to avoid this complication is, however, associated with the complication of bilomas at the cryosite when given early after cryotherapy [57] and probably should be avoided for 4–6 weeks. Our experience with regional chemotherapy following cryoablation with or without resection showed a median survival of 31 months in patients with unresectable liver metastases [47].

Cryotherapy with liver resection The use of cryotherapy with liver resection has allowed more patients to undergo curative treatments. Those patients with bilobar disease who are beyond the reach of multiple liver resections can be treated with liver resection and cryotherapy of the residual disease (Table 20.6).We previously reported 1- and 2-year survival rates of 88% and 60%, respectively, in 20 patients treated with liver resection and

240

Resection edge or margin is perhaps the only technical aspect of liver surgery which influences long-term survival. Most but not all authors have reported recurrence in a large percentage of patients with a histologically involved resection margin [59, 60]. There are often reasons why further resection is not possible or hard to do whilst maintaining an adequate volume of residual liver. Cryotherapy has been used for the local treatment of the liver resection edge in those with close or involved margins. Edge cryotherapy was used in 120 patients with small or involved margins following liver resection for colorectal liver metastases. The cryosite recurrence rate was 10%. The median survival in 68 patients with involved margins and 54 patients with close margins treated with edge cryotherapy was 35 months and 43 months, respectively. This was not statistically significant [61].

Advantages and limitations Cryotherapy is the best established of the local ablative therapies and has several advantages over other ablative therapies such as RFA. The ability to use multiple probes and simultaneous cryoablation of different tumors allows shorter operative times. The monitoring of the treatment is much easier with cryotherapy, where the iceball is clearly seen on intraoperative ultrasound, than with RFA. The reusable probes may decrease the recurring cost involved with cryotherapy. The main disadvantage is the larger, more complex, and expensive equipment required. It cannot be used in unplanned situations as it needs to be filled with liquid nitrogen prior to use. Patients with large tumors may not be suitable for cryotherapy as it is associated with the complication of cryoshock.

CHAPTER 20

Cryoablation of Liver Tumors

Self-assessment questions

References

1 Which of the following are indications for cryoablation of liver tumors? (more than one answer is possible) A Liver tumor in a patient with limited liver reserve B Bilobar disease not amenable to liver resection alone C Large tumor involving more than 50% of the liver D Treatment of the liver resection edge E Patients with liver tumors with extrahepatic metastases

1 Gage AA, Baust J. Mechanisms of tissue injury in cryosurgery. Cryobiology 1998;37:171–86. 2 Bischof J, Christov K, Rubinsky B. A morphological study of cooling rate response in normal and neoplastic human liver tissue: cryosurgical implications. Cryobiology 1993;30:482–92. 3 Mala T, Edwin B, Tillung T, Kristian Hol P, Soreide O, Gladhaug I. Percutaneous cryoablation of colorectal liver metastases: potentiated by two consecutive freeze-thaw cycles. Cryobiology 2003;46:99–102. 4 Hewitt PM, Dwerryhouse SJ, Zhao J, Morris DL. Multiple bilobar liver metastases: cryotherapy for residual lesions after liver resection. J Surg Oncol 1998;67:112–6. 5 Finlay IG, Seifert JK, Stewart GJ, Morris DL. Resection with cryotherapy of colorectal hepatic metastases has the same survival as hepatic resection alone. Eur J Surg Oncol 2000; 26:199–202. 6 Niu R, Yan TD, Zhu JC, Black D, Chu F, Morris DL. Recurrence and survival outcomes after hepatic resection with or without cryotherapy for liver metastases from colorectal carcinoma. Ann Surg Oncol 2007;14:2078–87. 7 Gage A, Fazekas G, Riley E. Freezing injury to large blood vessels in dogs. With comments on the effect of experimental freezing of bile ducts. Surgery 1967;61:748–54. 8 Weber SM, Lee FT Jr, Chinn DO, Warner T, Chosy SG, Mahvi DM. Perivascular and intralesional tissue necrosis after hepatic cryoablation: results in a porcine model. Surgery 1997;122: 742–7. 9 Cheung D, Morris DL. Synchronous hepatic cryotherapy and resection of colonic primary is a high risk procedure. HPB Surg 2000;11:379–82. 10 Machi J, Oishi AJ, Morioka WK, et al. Radiofrequency thermal ablation of synchronous metastatic liver tumors can be performed safely in conjunction with colorectal cancer resection. Cancer 2000;6 (Suppl 4):S344–50. 11 Bageacu S, Kaczmarek D, Lacroix M, Dubois J, Forest J, Porcheron J. Cryosurgery for resectable and unresectable hepatic metastases from colorectal cancer. Eur J Surg Oncol 2007; 33:590–6. 12 Pearson AS, Izzo F, Fleming RY, et al. Intraoperative radiofrequency ablation or cryoablation for hepatic malignancies. Am J Surg 1999;178:592–9. 13 Bilchik AJ, Wood TF, Allegra D, et al. Cryosurgical ablation and radiofrequency ablation for unresectable hepatic malignant neoplasms: a proposed algorithm. Arch Surg 2000;135:657–62; discussion 662–64. 14 Adam R, Hagopian EJ, Linhares M, et al. A comparison of percutaneous cryosurgery and percutaneous radiofrequency for unresectable hepatic malignancies. Arch Surg 2002;137:1332–9; discussion 1340. 15 Tait IS, Yong SM, Cuschieri SA. Laparoscopic in situ ablation of liver cancer with cryotherapy and radiofrequency ablation. Br J Surg 2002;89:1613–19. 16 Joosten J, Jager G, Oyen W, Wobbes T, Ruers T. Cryosurgery and radiofrequency ablation for unresectable colorectal liver metastases. Eur J Surg Oncol 2005;31:1152–9.

2 Which of the following are true for the phenomenon of cryoshock? (more than one answer is possible) A Is very common after cryoablation of liver tumors B Is associated with high volume cryodestruction C Can be minimized by partial thaw instead of complete thaw before refreezing D Is a common cause of mortality following cryoablation E Is related to the cracking of the iceball 3 In which one of the following ways does cryoablation differ from radiofrequency ablation? A Intraoperative monitoring is difficult B Multiple probes can be used simultaneously C Probes are not reusable D There is effective treatment of tumors close to major blood vessels E Can be used only during open operation 4 With which one of the following is cryoablation of colorectal liver metastases associated? A Median survival of less than 12 months B Cryosite recurrence rate of 5–44% C Recurrence rate independent of the size of the tumor treated D Similar survival to supportive measures E Higher complications rate compared to cryoablation of primary liver tumors 5 Cryoablation of liver tumors should be abandoned because there is conclusive evidence that radiofrequency ablation achieves better results. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct

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17 Selzner M, Hany TF, Wildbrett P, McCormack L, Kadry Z, Clavien PA. Does the novel PET/CT imaging modality impact on the treatment of patients with metastatic colorectal cancer of the liver? Ann Surg 2004;240:1027–34; discussion 1035–6. 18 Kuszyk BS, Boitnott JK, Choti MA, et al. Local tumor recurrence following hepatic cryoablation: radiologic-histopathologic correlation in a rabbit model. Radiology 2000;217:477–86. 19 Ross WB, Horton M, Bertolino P, Morris DL. Cryotherapy of liver tumours – a practical guide. HPB Surg 1995;8:167–73. 20 Stewart GJ, Preketes A, Horton M, Ross WB, Morris DL. Hepatic cryotherapy: double-freeze cycles achieve greater hepatocellular injury in man. Cryobiology 1995;32:215–9. 21 Seifert JK, Stewart GJ, Hewitt PM, Bolton EJ, Junginger T, Morris DL. Interleukin-6 and tumor necrosis factor-alpha levels following hepatic cryotherapy: association with volume and duration of freezing. World J Surg 1999;23:1019–26. 22 Iannitti DA, Heniford T, Hale J, Grundfest-Broniatowski S, Gagner M. Laparoscopic cryoablation of hepatic metastases. Arch Surg 1998;133:1011–15. 23 Lezoche E, Paganini AM, Feliciotti F, Guerrieri M, Lugnani F, Tamburini A. Ultrasound-guided laparoscopic cryoablation of hepatic tumors: preliminary report. World J Surg 1998;22:829– 35; discussion 835–6. 24 Cuschieri A, Crosthwaite G, Shimi S, Pietrabissa A, Joypaul V, Tair I, Naziri W. Hepatic cryotherapy for liver tumors. Development and clinical evaluation of a high-efficiency insulated multineedle probe system for open and laparoscopic use. Surg Endosc 1995;9:483–9. 25 Lee FT Jr, Chosy SG, Littrup PJ, Warner TF, Kuhlman JE, Mahvi DM. CT-monitored percutaneous cryoablation in a pig liver model: pilot study. Radiology 1999;211:687–92. 26 Schuder G, Pistorius G, Schneider G, Feifel G. Preliminary experience with percutaneous cryotherapy of liver tumours. Br J Surg 1998;85:1210–11. 27 Seifert JK, Morris DL. World survey on the complications of hepatic and prostate cryotherapy. World J Surg 1999;23:109–13; discussion 113–14. 28 Seifert JK, Junginger T, Morris DL. A collective review of the world literature on hepatic cryotherapy. J R Coll Surg Edinb 1998;43:141–54. 29 Cozzi PJ, Stewart GJ, Morris DL. Thrombocytopenia after hepatic cryotherapy for colorectal metastases: correlates with hepatocellular injury. World J Surg 1994;18:774–6; discussion 777. 30 Onik G, Rubinsky B, Zemel R, Weaver L, Diamond D, Cobb C, Porterfield B. Ultrasound-guided hepatic cryosurgery in the treatment of metastatic colon carcinoma. Preliminary results. Cancer 1991;67:901–7. 31 Weaver ML, Atkinson D, Zemel R. Hepatic cryosurgery in the treatment of unresectable metastases. Surg Oncol 1995;4:231–6. 32 Bagia JS, Perera DS, Morris DL. Renal impairment in hepatic cryotherapy. Cryobiology 1998;36:263–7. 33 Chapman WC, Debelak JP, Blackwell TS, et al. Hepatic cryoablation-induced acute lung injury: pulmonary hemodynamic and permeability effects in a sheep model. Arch Surg 2000;135:667– 72; discussion 672–73. 34 Blackwell TS, Debelak JP, Venkatakrishnan A, et al. Acute lung injury after hepatic cryoablation: correlation with NF-kappa B activation and cytokine production. Surgery 1999;126:518–26.

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35 Sohn RL, Carlin AM, Steffes C, Tyburski JG, Wilson RF, Littrup PJ, Weaver DW. The extent of cryosurgery increases the complication rate after hepatic cryoablation. Am Surg 2003;69:317– 22; discussion 322–3. 36 Zhou XD, Tang ZY. Cryotherapy for primary liver cancer. Semin Surg Oncol 1998;14:171–4. 37 Wren SM, Coburn MM, Tan M, et al. Is cryosurgical ablation appropriate for treating hepatocellular cancer? Arch Surg 1997;132:599–603; discussion 603–4. 38 Adam R, Akpinar E, Johann M, Kunstlinger F, Majno P, Bismuth H. Place of cryosurgery in the treatment of malignant liver tumors. Ann Surg 1997;225:38–9; discussion 48–50. 39 Xu KC, Niu LZ, He WB, Guo ZQ, Hu YZ, Zuo JS. Percutaneous cryoablation in combination with ethanol injection for unresectable hepatocellular carcinoma. World J Gastroenterol 2003;9: 2686–9. 40 Kerkar S, Carlin AM, Sohn RL, et al. Long-term follow up and prognostic factors for cryotherapy of malignant liver tumors. Surgery 2004;136:770–9. 41 Clavien PA, Kang KJ, Selzner N, Morse MA, Suhocki PV. Cryosurgery after chemoembolization for hepatocellular carcinoma in patients with cirrhosis. J Gastrointest Surg 2002;6:95–101. 42 Que FG, Nagorney DM, Batts KP, Linz LJ, Kvols LK. Hepatic resection for metastatic neuroendocrine carcinomas. Am J Surg 1995;169:36–42; discussion 42–3. 43 Cozzi PJ, Englund R, Morris DL. Cryotherapy treatment of patients with hepatic metastases from neuroendocrine tumors. Cancer 1995;76:501–9. 44 Korpan NN. Hepatic cryosurgery for liver metastases. Long-term follow-up. Ann Surg 1997;225:193–201. 45 Seifert JK, Morris DL. Prognostic factors after cryotherapy for hepatic metastases from colorectal cancer. Ann Surg 1998; 228:201–8. 46 Rehrig S, Marshall S, Meghoo C, Peoples GE, Shriver CD. 5-year qualitative results of isolated cryosurgical ablation for hepatic malignancy at Walter Reed Army Medical Center. Curr Surg 2001;58:81–5. 47 Yan TD, Padang R, Morris DL. Longterm results and prognostic indicators after cryotherapy and hepatic arterial chemotherapy with or without resection for colorectal liver metastases in 224 patients: longterm survival can be achieved in patients with multiple bilateral liver metastases. J Am Coll Surg 2006; 202:100–11. 48 Seifert JK, Morris DL. Indicators of recurrence following cryotherapy for hepatic metastases from colorectal cancer. Br J Surg 1999;86:234–40. 49 Preketes AP, Caplehorn JR, King J, Clingan PR, Ross WB, Morris DL. Effect of hepatic artery chemotherapy on survival of patients with hepatic metastases from colorectal carcinoma treated with cryotherapy. World J Surg 1995;19:768–71. 50 Steele G Jr, Ravikumar TS, Benotti PN. New surgical treatments for recurrent colorectal cancer. Cancer 1990;65 (3 Suppl): 723–30. 51 Goering JD, Mahvi DM, Niederhuber JE, Chicks D, Rikkers LF. Cryoablation and liver resection for noncolorectal liver metastases. Am J Surg 2002;183:384–9. 52 Seifert JK, Morris DL. Low preoperative serum carcinoembryonic antigen concentration is a marker of good prognosis in

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patients undergoing cryotherapy for low volume hepatic metastases from colorectal cancer. Int J Surg Invest 2000;2:327–34. Yan TD, Nunn DR, Morris DL. Recurrence after complete cryoablation of colorectal liver metastases: analysis of prognostic features. Am Surg 2006;72:382–90. Seifert JK, Junginger T. Prognostic factors for cryotherapy of colorectal liver metastases. Eur J Surg Oncol 2004;30:34–40. Curley SA, Roh MS, Chase JL, Hohn DC. Adjuvant hepatic arterial infusion chemotherapy after curative resection of colorectal liver metastases. Am J Surg 1993;166:743–6; discussion 746–8. Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer [see comment]. N Engl J Med 1999;341: 2039–48. Soon PS, Glenn D, Jorgensen J, Morris DL. Fluorodeoxyuridine causes bilomas after hepatic cryotherapy. J Surg Oncol 1998; 69:45–50. Wallace JR, Christians KK, Pitt HA, Quebbeman EJ. Cryotherapy extends the indications for treatment of colorectal liver metastases. Surgery 1999;126:766–72; discussion 772–74. Elias D, Cavalcanti A, Sabourin JC, et al. Resection of liver metastases from colorectal cancer: the real impact of the surgical margin. Eur J Surg Oncol 1998;24:174–9. Cady B, Jenkins RL, Steele GD, et al. Surgical margin in hepatic resection for colorectal metastasis: a critical and improvable determinant of outcome. Ann Surg 1998;227:566–71. Yan TD, Padang R, Xia H, Zhao J, Li J, Morris DL. Management of involved or close resection margins in 120 patients with colorectal liver metastases: edge cryotherapy can achieve longterm survival. Am J Surg 2006;191:735–42. Shafir M, Shapiro R, Sung M, Warner R, Sicular A, Klipfel A. Cryoablation of unresectable malignant liver tumors. Am J Surg 1996;171:27–31. Yeh KA, Fortunato L, Hoffman JP, Eisenberg BL. Cryosurgical ablation of hepatic metastases from colorectal carcinomas. Am Surg 1997;63:63–8. Haddad FF, Chapman WC, Wright JK, Blair TK, Pinson CW. Clinical experience with cryosurgery for advanced hepatobiliary tumors. J Surg Res 1998;75:103–8. Rivoire M, De Cian F, Meeus P, Gignoux B, Frering B, Kaemmerlen P. Cryosurgery as a means to improve surgical treatment of patients with multiple unresectable liver metastases. Anticancer Res 2000;20:3785–90.

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66 Ruers TJ, Joosten J, Jager GJ, Wobbes T. Long-term results of treating hepatic colorectal metastases with cryosurgery. Br J Surg 2001;88:844–9. 67 Johnson LB, Krebs T, Wong-You-Cheong J, et al. Cryosurgical debulking of unresectable liver metastases for palliation of carcinoid syndrome. Surgery 1997;121:468–70. 68 Bilchik AJ, Sarantou T, Foshag LJ, Giuliano AE, Ramming KP. Cryosurgical palliation of metastatic neuroendocrine tumors resistant to conventional therapy. Surgery 1997;122:1040–7; discussion 1047–8. 69 Seifert JK, Cozzi PJ, Morris DL. Cryotherapy for neuroendocrine liver metastases. Semin Surg Oncol 1998;14:175–83. 70 Sheen AJ, Poston GJ, Sherlock DJ. Cryotherapeutic ablation of liver tumours. Br J Surg 2002;89:1396–1401. 71 Weaver ML, Atkinson D, Zemel R. Hepatic cryosurgery in treating colorectal metastases. Cancer 1995;76:210–14. 72 Cha C, Lee FT Jr, Rikkers LF, Niederhuber JE, Nguyen BT, Mahvi DM. Rationale for the combination of cryoablation with surgical resection of hepatic tumors. J Gastrointest Surg 2001;5:206–13. 73 Zhou X, Tang ZY, Yu YQ, Ma ZC. Cryosurgery for liver tumors. In: Lances AR (ed). Novel Regional Therapies for Liver Tumors. New York: Springer, 1995:187–96. 74 Morris D, Ross WB, Iqbal J, et al. Cryoablation of hepatic malignancy: An evaluation of tumor marker data and survival in 110 patients. GI Cancer 1996;1:247–51. 75 Zhao J, Dwerryhouse SJ, Ross WB, Morris DL. Cryotherapy for hepatocellular carcinoma. Asian J Surg 1997;20:140–5. 76 Shapiro RS, Shafir M, Sung M, Warner R, Glajchen N. Cryotherapy of metastatic carcinoid tumors. Abdom Imaging 1998; 23:314–17.

Self-assessment answers 1 2 3 4 5

A, B, D B, C, D B B A

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Thermal Ablation of Liver Tumors by Radiofrequency, Microwave, and Laser Therapy M. B. Majella Doyle and David C. Linehan Department of Surgery, Washington University School of Medicine, St Louis, MO, USA

The search for a minimally invasive technique for the treatment of primary and secondary malignant hepatic tumors has been underway for centuries. The concept of the use of heat to kill tumors is not new. It was described as early as 1700 BC in The Edwin Smith Surgical Papyrus [1]. Since then, two general techniques – whole-body hyperthermia and localized hyperthermia – have been tested extensively. Whole-body hyperthermia, although capable of producing tumoral damage, has proven to be clinically ineffective and is not in use. Localized hyperthermia, on the other hand, holds great promise as a minimally invasive method of tumor destruction. There are three primary methods used to produce localized hyperthermia: radiofrequency (RF), microwave (MW), and laser. These three techniques were introduced by Beer in 1910 [2], Denier in 1936 [3], and McGuff et al [4] in 1963, respectively. Although initial enthusiasm for each technique was great, the existing technology was not sufficiently advanced to allow the development of clinically useful therapies. However, in the last few years, significant advances in equipment design have led to renewed interest and increased success in the use of these techniques for the treatment of primary and secondary malignant hepatic tumors. This chapter presents the recent research and clinical experience for each of these techniques, focusing mainly on RF ablation (RFA) as this technique remains the dominant one.

Radiofrequency thermal ablation Background The use of RF alternating current to heat living tissue dates back to the work of d’Arsonval in the late 1800s [5]. He demonstrated that high frequencies (>10 kHz) could pass through living tissue without causing neuromuscular excitation. Shortly thereafter, Von Zeynek proved that the same

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frequencies could be used to heat living tissue [6]. These discoveries led to the development of medical diathermy and electrocautery. In 1943, a report by King et al, which described the occurrence of hepatic damage with wholebody hyperthermia, began efforts to develop a clinically useful mechanism for harnessing RF to produce focal hepatic thermal injury [7]. However, it was not until 1990 that available technology was adapted to allow minimally invasive treatment of malignant hepatic tumors. In the same year, both Rossi et al and McGahan et al published papers on ultrasound-guided RFA of hepatic tissue [8, 9]. Both groups suggested that RF could be used to create focal coagulative necrosis of hepatic tumors while sparing normal liver tissue.

Basics of radiofrequency ablation: how radiofrequency current destroys tumors Temperature and cell death RF current destroys tumors and surrounding tissue by the generation of heat. Cells have a limited capacity to survive temperatures above 43 °C. At this temperature, cells die after 30 min. As temperature is raised, the time to death decreases. At 50 °C, death occurs at 30 s; at 55 °C it occurs at 1 s, and above 60 °C cell death is instantaneous. Higher temperatures have other important biologic effects. At 100 °C intracellular and extracellular water will start to boil. If the temperature rises over 200 °C, hydrocarbons will begin to break down, leaving a deposit of carbon in the tissues.

How alternating current causes tissue heating Heating of tissues due to passage of RF current is the result of two processes. These are ionic friction and the dissipation of the heat from the site of friction. Ionic friction is caused by the to and fro movement of ions induced by an alternating current circuit. Such circuits, as opposed to direct current circuits, cause electrons to flow back and forth. The friction generates heat. In fact, in such a circuit all the electrical energy is dissipated as heat. This type of heating is called electrical or resistive heating. The rate at which current switches back and forth, i.e. the number of cycles per second, is the “frequency” of the circuit

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and is expressed in Hertz (Hz = cycles per second). In classic experiments it was determined that high frequency alternating current circuits were safe for passage through animals, i.e. would not cause muscle stimulation or potentially lifethreatening arrhythmias. The frequency range for medical RF is about 200 KHz–20 MHz. These frequencies overlap AM radiofrequencies and are just below the frequencies of FM radio, i.e. they are in the RF part of the electromagnetic spectrum.

Radiofrequency generators and electrodes To pass RF electrical current through animal tissues, an RF generator and two electrodes are required. The electrodes are connected to the patient and to the generator to create an electrical circuit. The generator uses oscillators to convert commercially supplied alternating electrical current (60 Hz) to a current of the appropriate RF. The generator also uses transformers to increase the voltage from the 100 V at which it is supplied. Generators may be set to produce alternating current of different voltages and waveforms, and these settings produce different tissue effects due to the type of heating that occurs (e.g. the cutting versus coagulation effects used by surgeons on standard cautery machines). Coagulating current, the type used for RFA, provides bursts of current. The interval between bursts allows time for conduction of heat into tissues so that the energy is dispersed. In this way small blood vessels are thrombosed and bleeding is arrested.

Effect of electrical resistance on the effectiveness of tissue heating In RFA, the active electrode(s) are placed within tissues. Such electrodes are referred to as interstitial electrodes as opposed to surface electrodes. To cause electrical heating, it is desirable to pass high levels of current through the active electrode, since it is the density of the current and the duration of application that determines the magnitude of the frictional movement and consequent heating (current density = current/area of electrode). As heating progresses, tissue changes occur, some of which are desirable and others that are not. The latter may undermine the effectiveness of the ablation. RF generators are constructed to maintain a fairly uniform current over a range of resistances by increasing voltage as resistance rises. However, when voltages approach dangerous levels, further increases are forbidden and increases in resistance past this point are accompanied by reductions in current. Stated otherwise, if electrical resistance at the active electrode goes too high, current will stop flowing and electrical heating will cease. Resistance in an alternating current circuit is given the special name “impedance” because, in addition to pure resistance, there are other factors that such as the capacitance of the tissues that determine the resistance to current in an alternating circuit.

As heating occurs and the temperature of instantaneous cell death is reached, i.e. 65 °C, coagulative necrosis occurs. At temperatures over 100 °C, boiling of tissue water begins, leading to drying or desiccation of the tissues. The more the temperature exceeds 100 °C, the faster the boiling and desiccation occurs. Once desiccation occurs there is a large and dramatic increase in impedance. Charring does not happen until temperatures reach about 200 °C. The impedance of desiccated tissue is so high that only a thin rim of tissue around the active electrode is needed to greatly reduce the flow of current and consequent heating of tissue. These issues are of critical practical importance.

Conductive heating Electrical heating is confined to the zone immediately adjacent to the active electrode where the current density and ionic agitation are high. In fact, electrical heating decreases as the fourth power of the distance from the electrode. In other words, heating due to pure electrical factors will be 625 times less at 5 mm from the electrode than at 1 mm from the electrode, and at 1 cm from the electrode that number rises to 10 000. However, heat is conducted through tissue by contact of hot, more energetic molecules with cooler, less energetic molecules. The effect is such that conductive heating spreads the heat generated by ionic agitation through the adjacent tissues. Heat conduction may be thought of as occurring in a series of rings around the electrode. As the distance from the electrode increases, the size of the rings increases and the volume of tissue in each successive ring that must be brought up to temperature rises sharply. For instance, to extend the distance of ablation from a single electrode from 4 to 5 mm from a single RF electrode requires that only half the volume of tissue be heated compared with that required when attempting to extend the ablation from 9 to 10 mm from the electrode. The effect is that there is a rapid drop-off of energy dispersal by conduction into tissue as the distance from the electrode increases. Practically this means that a single interstitial RF electrode will produce a zone of coagulative necrosis of about 1 cm in diameter [11]. The shape of the lesion will depend on the electrode length. An electrode of 1 cm in length will produce a spherical lesion, but as the electrode is lengthened the shape becomes more elongated.

Convective heating (convective heat loss) Convective heating or heating through movement of heated matter also occurs in tissues as a result of blood flow. However, since the blood moves rapidly out of the area, the heating of blood actually has a negative influence on the effectiveness of ablation. Hence the commonly observed phenomenon of a zone of spared tumor adjacent to a large blood vessel. This “heat sink” effect of blood flow actually protects large blood vessels and explains why bile ducts are much more susceptible to injury than blood vessels. The

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heat sink effect also applies to smaller blood vessels, but as flow in these vessels is less, the wall of the vessel becomes heated and thrombosis ensues. To avoid the effect of convection, inflow occlusion may be used. In an animal model, inflow occlusion increased the volume of necrosis and resulted in more nearly spherical lesions [10, 11].

Application of electrical and thermal principles to the creation of a spherical zone of radiofrequency ablation Most hepatic tumors are spheroids. Those that might be targets of RFA range in size from a few millimeters to many centimeters. Ideally, the technology should allow production of spherical ablations ranging from 1 to 10 cm or more in a single ablation. A single RF electrode of 1 cm in length will produce a spherical lesion of 1 cm in diameter. Multiple strategies have been applied to getting uniform heating of a large sphere of tissue to temperatures that will result in instantaneous cell death. To create a sphere, multiple active electrodes are used. These are deployed either as a single electrode with multiple deployable arms or tines, or as three-needle electrodes in a triangular pattern [12]. Probes spaced 1.5 cm or less apart act synergistically, producing a total volume tissue destruction that is greater than when the individual probes are operated sequentially. To be successful, the heating program must create a temperature immediately around the active electrode that does not result in charring and interruption of heating before the tissues between the electrodes have been heated to at least 65 °C. To some extent the heating program is empirical and therefore differs with type of generator and electrode, but all have this same goal – to heat all the tissues in the sphere of interest to at least 65 C. One approach used to retard development of high resistance at the active electrode has been to cool the electrode by flowing cold water through the interior during RFA [13]. This prevents boiling of tissue water immediately adjacent to the electrode and thereby prevents desiccation and charring. This has two beneficial effects. It allows continued electrical heating and provides time for heat to be conducted away from the area of electrical heating by conduction before tissue impedance rises to levels at which current flow stops. Another strategy is to enlarge the surface area of the active electrode. Since electrical heating occurs only immediately around the electrode and heating is dependent on current density, making the active electrode somewhat larger can increase the volume of tissue that has the maximum effective current density [12]. Enlarging the electrode beyond a certain point, however, would have negative effects on current density at the electrode at permitted powers. Infusion of saline at the active electrode also results in a greater zone of ablation [14]. This is probably due to effectively increasing the electrode area since saline is a conductor of

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electricity. Other effects of saline may be to maintain good contact between tissue and electrode. Recently, electrodes have been produced that are cooled internally and also emit saline [15]. Another strategy is to effectively have a moving electrode, opening the electrode array in stages or to redeploy the electrode in a new area. Sending current in pulses gives time for conduction of heat away from the active electrode, preventing heat build-up, desiccation, and unacceptable rises in impedance.

Commercially available radiofrequency generators for treatment of hepatic tumors There are currently three commercially available RF generator/electrode systems. Two use single electrodes with deployable tines (RITA, Radiotherapeutics) and the third (Radionics/ Valleylab) uses a triangular array. For each generator a program has been developed based on empirical experimental observations in animals. This is necessary to convert the theoretical considerations discussed above to a working system that will produce spherical ablations. The RITA generator/electrode system has both nonperfused and saline perfusion electrodes. For ablations of 5 cm or less, the standard (nonperfused) electrodes are used. These electrode can project nine tines, one of which is central and the other eight peripheral. The projection tends to be further forward from the shaft than the comparable electrode made by Radiotherapeutics, which is more like an umbrella with the tines turning to face 180 ° to the shaft. Several of the tines have temperature thermistors. The RITA equipment functions on a combined electrode/generator program. The “burn” is performed at various degrees of electrode deployment (moving electrode). The generator endpoints are tissue temperature and time. At each level of deployment, a mean temperature, e.g. 105 °C, is reached before beginning the countdown or deploying the tines further. At the fully deployed state, the countdown starts when the desired temperature is reached and is continued for a fixed time. This is followed by a 30 s “cool-down” period at which time the temperature at the ends of the tines is displayed. Temperatures above 65 °C are taken as evidence of a satisfactory ablation. The saline-perfused electrode injects hypertonic saline using a pump. This electrode permits 7-cm spherical ablations, the largest to date. This electrode has passive tines that measure tissue temperature between active tines. The RITA electrodes, because of their spatial deployment, tend to produce truly spherical lesions. The Radiotherapeutics system also uses a single electrode with deployable tines. Its tines are somewhat more closely spaced and curve more during deployment. As a result this system, in the authors’ experience, tends to produce a more cylindrical spheroid or compressed sphere or cylinder. The endpoint of this system is high impedance. Power is applied

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and impedance is measured. Impedance stays low throughout the program as power is increased and heating occurs. The end of the program is signaled by a sudden increase in impedance (“rolloff”). Temperature is not measured. The largest diameter of ablation is about 4 cm. The Radionics/Valleylab system uses both a single electrode and a cluster electrode in a triangular array. Each electrode is internally perfused with cold saline, maintaining the temperature immediately adjacent to the electrode below 100 °C. This prevents desiccation and its deleterious effects. The individual electrodes are thicker than the tines of the other products and up to three electrodes can be used simultaneously to ablate a larger lesion or used separately to ablate up to three smaller lesions in one ablation cycle. There are now four lengths and four tip exposures for custom ablation lesions between 4.5 cm and 6.5 cm (cool tip, Valley Lab). The heating program is timed and is based on laboratory data that have varied time, power, electrode length, and diameter, and other variables. When this system senses a rise in impedance, power is automatically reduced and then increased again as impedance rises. Real-time feedback includes impedance, current, power, and temperature. After the 12–25-min cycle (the ablation time is dependent on the lesion size) is complete, the true tissue temperature is displayed on the generator. This system tends to produce an elongated spheroid. The largest diameter of ablation is now 6.5 cm. The maximum power of this generator is 200 W. There are two European companies also producing electrodes. One is a bipolar electrode that creates lesions of 5–6 cm in diameter (Celon, Germany), and the other monopolar electrode is saline perfused, reducing tissue impedance and allowing larger ablation lesions (Berchtold, Germany).

Technique Method of delivery RFA can be accomplished by an open, laparoscopic, or percutaneous approach. Each has advantages and disadvantages. Open surgery optimizes the chances of detection of unknown intrahepatic and extrahepatic tumors. Tumors in most areas of the liver can be treated, particularly peripheral lesions that otherwise risk injury to adjacent organs, including those touching the diaphragm. Accurate placement of electrodes is facilitated by open surgery and inflow occlusion, to prevent dissipation of heat, is easily applied. Also, it is easier to treat multiple tumors. Open surgery also permits the surgeon to combine resection with RFA, although now many resections may also be accomplished laparoscopically. However, open surgery requires a general anesthetic and an upper abdominal incision. Both open and laparoscopic surgery allow complete inspection of the abdomen to rule out extrahepatic disease as well as performance of intraoperative ultrasound, which has greater sensitivity for detection of hepatic lesions. With percutaneous techniques, the

advantages of open surgery are lost but the advantages of minimal invasiveness are gained. Open surgery is still the gold standard for treatment of hepatic tumors, however circumstances that contraindicate open surgery or even a general anesthetic may exist. Under these conditions laparoscopic or percutaneous methods are often tolerated and are the procedures of choice. For example, an otherwise healthy patient with multiple colorectal metastasis, some of which may be touching the diaphragm, is probably best served by open surgery. In contrast, a less invasive technique would be favored in a patient with end-stage liver disease and a hepatocellular carcinoma (HCC). A multivariate analysis of data comparing open, laparoscopic, and percutaneous techniques, that included all tumor types, suggests that an open or laparoscopic approach may be associated with less local recurrence (3.6% recurrence) than percutaneous ablation (16% recurrence) [16]. However, increased morbidity and mortality can be associated with an open approach [17]. Complete ablation of all viable tumor cells is the goal of RFA and so imaging the tumor for appropriate needle placement is of paramount importance. Ultrasound (either intraoperative or transcutaneous) remains the standard imaging modality [18], but it has some shortcomings. Unlike with cryoablation in which the formation of the “iceball” can be visualized ultrasonographically in real time, no reliable visible signs of the ablation zone with respect to the tumor are readily apparent at the time of tissue heating. Preablation positioning of the array must be precise and measured in three dimensions in order to optimize margins of ablation. Figure 21.1 shows an example of intraoperative images and placement and deployment of the RFA probe. Percutaneous RF can also be guided by magnetic resonance imaging (MRI). Several small studies demonstrate the feasibility of this technique and confirm its safety and efficacy [19–22]. However, the studies are small and no randomized comparisons to computerized tomography (CT) or ultrasound are available to prove its superiority, and also this technique is obviously limited by access and cost as many facilities do not have the capacity or experience to use intraprocedural MRI. There are several potential advantages of MRI guidance, such as accurate electrode placement, particularly when overlapping ablations are required, real-time monitoring of necrosis, and accurate thermal monitoring, so ablative temperatures can be reached and surrounding structures are protected from unintentional damage [23]. MRI guidance can also be used for MW and laser ablation [23]. Patient positioning is dependent on the number and position of tumors to be ablated, as well as the approach (i.e. laparoscopic or open). Grounding pad positioning is critical as severe skin burns have been reported in patients with malpositioned pads [24]. Two grounding pads should be used on the lower extremities with the long axis of the pad

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(b)

(a)

(c) Figure 21.1 (a) Longitudinal and (b) transverse ultrasound views of deployment of tines of a “Starburst” electrode through a tumor prior to ablation. Note that the tines encompass the tumor. (c) “Outgassing” is visible around tines after commencement of ablation.

facing the liver to allow for optimal heat dispersion. Previous reports suggesting that the grounding pad be placed on the patient’s back are incorrect and increase the risk of serious pad burns. Deployment of the RFA probe differs according to the type of probe used. The needle electrodes with retractable curved prongs (e.g. RITA, Radiotherapeutics) are positioned so that the epicenter of the sphere of ablation matches the epicenter of the tumor. After checking the position in two dimensions at full deployment, sequential ablations are performed, sometimes (RITA) with stepwise prong advancement (starting at 2 cm) to full extension (usually 5 cm). Real-time temperature monitoring and/or impedance monitoring is used to assure spherical ablation. Inflow occlusion can be used especially if focal target temperatures are not being reached due to a heat sink effect from surrounding blood vessels [25]. At laparotomy or laparoscopy, a Pringle maneuver can be employed, but it is associated with a 0.2–0.4% incidence of portal vein thrombosis so it must be used with caution

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[26]. However, optimal technique in this regard needs to be defined as more studies correlate local recurrence with technical factors of deployment, ablation, and tumor size. On completion of the ablation, needle tracts can be cauterized to avoid bleeding and potentially prevent tumor cell implantation in the needle tract. Currently, the largest spherical diameter that can be ablated with a single deployment is 7 cm (as stated above). The ideal ablative margin is controversial and depends on the size and pathology of the tumor. For example, to obtain a 1-cm margin of ablation, the diameter of the ablation sphere must be 2 cm greater than the tumor sphere; therefore, if a 3-cm tumor exists, a 5-cm ablation should be performed. If a system is to be used that produces 5-cm ablations, for larger lesions multiple ablations are then usually needed. Mathematical models show that the number of overlapping deployments rises dramatically as lesion size increases (Table 21.1). This is critical to achieve a marginnegative ablation. However, as the number of needed

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Table 21.1 Number of overlapping ablations required assuming a 5-cm deployment. Size of spherical ablation (cm) Number of overlapping ablations required

5 1

6 6

8 12

9.5 30

ablations/lesions rises, so does the possibility of placement error. The difficulty of multiple accurate deployments is evidenced by the higher local recurrence rate in tumors larger than 5 cm. There are no studies currently comparing efficacy of different electrodes, and while technology is constantly changing we await a less complex method of ablation of larger lesions.

Clinical results RFA has become the most widely used modality for the thermal ablation of liver tumors, but the indications for its use remain controversial. For primary and certain secondary liver tumors, complete resection, when feasible, remains the only proven potentially curative treatment. However, many patients are not candidates for surgical resection of their hepatic neoplasm(s) and for this reason, there is increasing interest in ablative approaches. In addition, re-resection is not possible in many patients who recur after hepatic resection, and an ablative approach has much appeal. Improved equipment that allows larger spherical thermal ablation of tumors (and therefore higher likelihood of complete tumor destruction) has further kindled interest in this treatment modality. Clinical studies are ongoing and it is evident that liver lesions can be successfully ablated with low morbidity. The critical question that needs to be answered is whether RFA in unresectable patients impacts patient overall survival and/ or quality of life. The majority of patients treated to date have had HCC, metastatic colorectal cancer, or metastatic neuroendocrine tumors. Because many studies have heterogeneity of tumor origin, size, mode of delivery of ablation, and resectability, as well as a variety of definitions of resectability, interpretation of the data can be challenging. The principle of hepatic resection for colorectal metastasis are an important guide when considering patients for ablation. There are almost no 5-year survivors of untreated single or multiple hepatic metastasis, whereas approximately 30–60% of completely resected patients survive for 5 years [27] and this may be higher in patient screened by positron emission tomography (PET) [28]. Furthermore, no resected patients with positive microscopic margins survives 5 years, suggesting that survival benefit depends on a macroscopically and microscopically complete resection. This emphasizes the point that only with microscopically complete ablation are we likely to impact survival of metastatic liver

disease. Certainly, patient selection is critical, as those with extrahepatic disease or subclinical hepatic metastasis are unlikely to benefit from local ablative treatments. In our recent study, PET scans were more likely to be positive in patients with more advanced disease. Since patients with unresectable disease usually have more advanced disease, PET scanning prior to ablation to rule out extrahepatic disease should be advocated for every patient. There are three groups of patients who might be treated by RFA: those with unresectable lesions, those with resectable lesions who are ineligible for resection for reasons of general health, and those with resectable lesions who have no contraindication to open surgery. The appeal of a minimally invasive, ablative approach to liver tumors is obvious. Compared to resection, RFA is less morbid, spares more parenchyma, can be accomplished laparoscopically or percutaneously, and is less costly. However, resection remains the gold standard for primary and secondary liver tumors and until RFA is proven to be as effective in a randomized trial, resection should remain the standard therapy for eligible patients.

Colorectal metastases Efficacy of RFA can be measured in several ways and certain caveats are imperative in interpreting the available studies. Local recurrence rates are often emphasized, usually on a per lesion basis, but sometimes on a per patient basis (in patients who have multiple ablations). Emphasis on local recurrence is certainly warranted when attempting to identify technical or anatomic considerations that increase the risk of local failure. Nonetheless, overall survival and disease-free survival must be the true measure of the efficacy of RFA, just as they are for resection. Unfortunately, due to the short follow-up period of most published studies and the lack of trials comparing RFA to systemic or regional chemotherapy, no conclusions regarding improvement in survival or quality of life can be drawn. In addition, many published studies lump results for primary and secondary hepatic tumors together, or do not separately present results for colorectal metastasis and neuroendocrine tumors. This is an important distinction when considering local recurrence, because neuroendocrine tumors may be indolent. They may take many years to recur and long-term survivors are not uncommon even in untreated patients. As a result, lumping results of such patents with those of more aggressive tumors makes evaluation of efficacy problematic. There are some studies to date commenting on greater than 3-year survival after RFA for colorectal tumors (Table 21.2). None of the data is randomized and patients who received RFA were considered unresectable based on inability to tolerate surgery, refusal of surgery, or technical considerations. The largest clinical series of RFA of hepatic neoplasms are shown in Table 21.3. Based on the caveats outlined above,

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Resection, Ablation or Transplantation

Table 21.2 Colorectal cancer liver metastases: survival studies after radiofrequency ablation. Survival (years) Author

Year

Patients

Size (cm)

1 (%)

2 (%)

3 (%)

4 (%)

Solbiati et al [29] Iannitti et al [30] Oshowo et al [31] White et al [32] Abdalla et al [27] Gillams et al [33] Joosten et al [33]

2001 2002 2003 2004 2004 2005 2005

117 52 25 30 57 167 28

3.2 5.2 3.0 3.0 2.5 3.9 2.0

93 87 – 75 – 99 93

69 77 – 45 – – 75

46 50 53

– – – – – 30 –

37 58 46

Table 21.3 Results from the largest clinical series of radiofrequency ablation of hepatic neoplasms. Authors (year)

Patient

Tumor

Histology

Technique

Complications

LR*

Median follow-up (months)

Rossi et al (1996) [37] Curley et al (1999) [38]

39 123

41 169

H H, CRM, NEM, Misc

P O, P

None 3/123 (2.4%)

22.6 15

Bilchik et al (1999) [39]

50

231

H, CRM, NEM, Misc

O, P, L

7/84 (8.0%)

Siperstein et al (2000) [35]

43

181

H, CRM, NEM, Misc

L

Not reported

De Baere et al (2000) [40] Machi et al (2001) [41]

68 60

121 204

CRM, NEM, Misc H, CRM, NEM, Misc

O, P O, P, L

7/68 (10%) 4/60 (6.7%)

CRM

P

3/117 (2%)

NEM CRM, HCC

L O, P, L

Minimal 36/153 (23.5%)

CRM

P

1/25

2/41 (4.9%) 3/169 (1.8%) 15/231 (6.4%) 22/181 (12.2%) 9/121 (7%) 18/204 (8.8%) 70/179 (39%) 6/227 (3%) 52/447 (12%) Not reported 13/227 (5.7%) 39 9 Not reported 6

Solbiati et al (2001) [29]

117

Berber et al (2002) [42] Bleicher et al (2003) [43]

34 153

222 447

Oshowo et al (2003) [31]

25

25

Elias et al (2004) [44]

88

227

CRM, NEM, Misc

O

None

30 57 167 28

30 57 167 28

CRM CRM CRM CRM

P O P O

Minimal Not reported 14/354 (4%) (11%)

White et al (2004) [32] Abdalla et al (2004) [27] Gillams et al (2005) [33] Joosten et al (2005) [34]

9 13.9 13.7 20.5 6–53 (range) 1.6 11 37 (median survival) 27.6 17 21 38 (median survival) 26

*LR reported on a per lesion, not a per patient, basis. LR, local recurrence; H, hepatocellular carcinoma; CRM, colorectal metastasis; NEM, neuroendocrine metastasis; Misc, miscellaneous metastases (breast, gastric, ovarian, adrenal carcinoma, melanoma, leiomyosarcoma; O, open; P, percutaneous; L, laparoscopic.

the data deserve some scrutiny. For example, in the study published by Siperstein et al [35], local recurrence is reported at 12%. However, when the analysis is performed on a per patient (rather than a per lesion) basis, the recurrence rate goes up to 28%. Furthermore, if the analysis is restricted to patients with metastatic adenocarcinoma (the group most

250

likely to recur rapidly), 12 of 18 (66%) had definite or suspected local recurrence even with a relatively short median follow-up. Based on these recurrence rates, a benefit in disease-free or overall survival is unlikely. As expected, studies with longer follow-up have higher local recurrence rates [36].

CHAPTER 21

Thermal Ablation of Liver Tumors by Radiofrequency, Microwave, and Laser Therapy

Table 21.4 Comparison of partial hepatectomy and radiofrequency ablation for resectable hepatocellular carcinoma Authors

Patient no Abl vs Rx

Tumor size (mm) Abl vs Rx

Median follow-up (months)

Median DFS (months) Abl vs Rx

5-year survival Abl vs Rx

5-year DFS

Ueno et al (2009) [49] Guglielmi et al (2008) [50] Lupo et al (2007) [51] Chen et al (2006) [52] Lu et al (2006) [53]

110 vs 123 109 vs 91 60 vs 42 71 vs 90 51 vs 54

27 vs 20 <60 30–50 <50 Milan criteria**

24 27 31.3 (mean) 24 –

– 36 vs 16* – – 4.9 vs 9.6 (time to first recurrence

Cho et al (2005) [54]

99 vs 61

<50

23 vs 21.9

60% vs 80%* 20% vs 48%* 32% vs 43% 67.9% vs 64% 87.1% vs 86.4 % (3 years) 80% vs 77% (3 years)

20% vs 38%* 22% vs 27% 0% vs 14% 46.4% vs 51.6% 51% vs 82% (3 years) 30% vs 36% (3 years)

*Significantly different. **Milan criteria [45]: single tumor ≤50 mm or three tumors ≤30 mm. NS, not significant; DFS, disease-free survival; Abl, RF ablation; Rx, hepatic resection.

Elias et al performed a comparative study between RFA and hepatic resection, and found RFA to be as efficacious and safe as a wedge resection in terms of local control. Small (15 mm) central lesions were RF ablated (227 lesions in 88 patients), small (14 mm) peripheral lesions were wedge resected (99 lesions in 64 patients), and large (44.2 mm) lesions underwent anatomic resection (213 lesions in 40 patients). They reported no significant difference in local recurrence rates on a per lesion basis (5.7%, 7.1%, and 12.5% for RFA, wedge and anatomic resection, respectively). Although RFA local recurrence rates were low, the local recurrence for resection was particularly high compared to other reports [44]. Another comparison study of resection to RFA demonstrated comparable survival for 20 resected single colorectal metastases versus 25 RF ablated lesions, despite the presence of extrahepatic disease in seven patients receiving RFA: they demonstrated 3-year survival of 52.6% and 55.4% for RFA and resection, respectively. They failed to mention local recurrence rates for RFA but stated that three patients recurred post resection [31]. Because of the high likelihood of recurrence after RFA of patients with unresectable colorectal metastases, the use of adjuvant chemotherapy is very common.

Hepatocellular carcinoma The treatment of HCC is a little different because the majority of patients have cirrhosis. In many of these patients, resection is not an option and while in the United States a certain percentage will qualify for liver transplantation (i.e. patients who have a tumor within Milan criteria [45]; one tumor <5 cm or three tumors <3 cm), which is associated with a 5-year survival rate of 60–80%, there are countries where transplantation for early HCC is not an option and resection or ablation remain the only treatment. Also, there are a considerable number of patients who have unresect-

able/nontransplantable HCC either due to their underlying liver disease or tumor burden. Several randomized and nonrandomized studies comparing percutaneous ethanol injection (PEI) and RFA have been performed. Overall RFA has been shown to produce a larger ablation zone of necrosis, to need fewer treatments, and to give better local control and improved survival [46–48]. Since PEI is not an established treatment for liver tumors, it is probably a poor choice for comparison and since resection remains the standard treatment, comparing RFA to surgery is probably a more effective comparison. Comparisons of surgery versus ablation have now been performed in several studies (Table 21.4). Two of these are randomized controlled trials. One hundred and eighty patients were randomized to receive either percutaneous RFA or resection. Complications were greater after resection. The 4-year survival rates were 67.9% and 64%, respectively. Disease-free survival rates were 46.4% and 51.6%, respectively. There was no statistical difference between the two treatments and the authors concluded that RFA was as effective as surgical resection in the treatment of solitary and small HCC [48]. A second randomized controlled trial in which 54 patients had a partial hepatectomy versus 51 who had percutaneous RFA or MW ablation (MWA), showed similar outcomes between the two groups [49]. Two of the nonrandomized studies demonstrated superior results for resection compared to RFA [50, 51], although one demonstrated no difference if the tumors were less than 3 cm [50]. Based on the available data, it is probably reasonable to suggest that RFA could be an alternative treatment to resection for HCC less than 3 cm [52].

Radiofrequency ablation as a bridge to liver transplant As patients awaiting liver transplantation have a risk of progression of their disease and therefore drop-out on the

251

SECTION 4

Resection, Ablation or Transplantation

waiting list, many centers pretreat patients with local ablation or transarterial chemoembolization (TACE) to slow down tumor progression. Drop-out rates of 5.8% and 14% after 11–12 months have been reported in two separate studies [55, 56]. While there is no high level evidence to show that RFA decreases drop-out in centers where it is performed regularly, it is thought to be important in prolonging patient survival, but this is yet to be proven [57].

which shows increased 18-fluoro-2-deoxy-D-glucose (FDG) uptake in the same location, confirming the presence of functioning, hypermetabolic cancer cells at the margin of the ablation zone. The presence of a shrinking ablation zone on serial CT/MRI scans without evidence of peripheral contrast enhancement is indicative of successful local control of disease.

Complications Recurrence post hepatic resection hepatocellular carcinoma In the setting of cirrhosis the majority of patients will recur at some point. Occasionally salvage transplantation is possible. Repeat resection is often difficult to perform in the setting of previous resection and cirrhosis. Locally, ablative therapies would seem to be an ideal treatment in these patients. Yang et al reported on 41 patients with recurrent HCC, after hepatic resection, treated with RFA. Patients recurring within 1 year had a significantly shorter overall survival compared to those with disease recurring later (16.4 months and 42.9 months, respectively) [58]. Finally, recurrent HCC after liver transplant, fortunately, is uncommon. We have successfully used RFA for recurrence of HCC in the transplanted graft. Of course these cases are too infrequent to have anything other than anecdotal evidence.

Radiographic follow-up Radiographic follow-up of patients after RFA is important and a standard definition of local failure needs to be adopted. In our current practice we routinely perform imaging at 3, 6, 12, and 24 months post ablation. If not viewed by experienced radiologists, ablation zones are often misinterpreted as local recurrences. Figure 21.2 illustrates an example of a typical local recurrence characterized by peripheral contrast enhancement along the rim of ablation. This can be confirmed by PET scan in patients with colorectal metastases,

(a) (b)

252

Due to different techniques, the reported complications vary for RFA, especially when there are multiple tumors and/or multiple treatments required. Early complications typically seen are low grade fever, transient transaminase increase, right upper quadrant pain, and small pleural effusions. Biloma, abscess, hemorrhage, pneumothorax, and hemothorax are some of the more serious complications that are encountered. Burns from the ground pads were reported more frequently in the early days. Now, however, the pad size and placement has improved to lessen this risk. However, careful placement is important, as previously mentioned. RFA of surface tumors can cause injurious harm to organs in close proximity, such as colon, stomach, and diaphragm, and ablation of these tumors should be avoided [57]. Patients with cirrhosis, of course, have a risk of liver decompensation, although the majority of patients undergoing RFA, as with other ablative procedures for patients with cirrhosis, are usually Child class A and occasionally Child class B cirrhotics, and have relatively stable liver disease. Later complications such as biliary strictures may occur as a result of ablation of tumors in close proximity to major bile ducts, so tumors located close to the hilum should not be ablated. Tumor seeding after RFA was a concern when reported rates were as high as 12.5% [59]. However, tumor seeding is now thought to be associated with previous biopsy and less likely related to RFA. Minimal seeding rates of 0–1.4% have since been reported [60, 61].

Figure 21.2 (a) CT scan 6 months after an ablation of a single lesion in the right liver of an elderly female who was not fit for right hepatectomy. An abnormality is seen on the right upper edge of the zone of ablation (white arrow). (b) PET scan demonstrating uptake of FDG at site of suspected recurrence (black arrow).

CHAPTER 21

Thermal Ablation of Liver Tumors by Radiofrequency, Microwave, and Laser Therapy

Current indications As technology improves, larger spherical volumes of ablation will be achievable, which may help improve the high local recurrence rates, especially in patients with large lesions requiring overlapping ablations. Based on currently available data, we believe that RFA is probably the most effective and most studied ablative technique. It is indicated for use in the following patients with hepatoma or colorectal/neuroendocrine metastasis: (1) unresectable patients with tumors amenable to ablation; (2) as an adjunct to resection in patients with small volume residual disease after hepatic resection; (3) for HCC with cirrhosis in patients with small tumors who are unsuitable for transplantation or resection; (4) as a bridge to transplantation to prevent dropout on the waiting list; and (5) in selected patients who have isolated, liver-only recurrence after hepatic resection or transplantation.

increasing interest in this method of ablation in the United States.

Mechanism MWA refers to the use of all electromagnetic methods for introducing tumor destruction using devices with frequencies of at least 900 MHz [66, 67]. The frequencies most commonly used in medical therapy are 915 MHz and 2450 MHz. This type of radiation lies between infrared radiation and radiowaves. There are three basic mechanisms by which microwaves heat biologic tissue: (1) displacement of free electrons or ions by electric field oscillations; (2) polarization of atoms and molecules; and (3) polarization of permanently existing dipoles. The displacement of free electrons and ions, and the relaxation of electric dipoles, generate kinetic energy that causes an increase in temperature in the treated tissue. This rise in temperature produces predictable patterns of thermal coagulation.

Summary Recent technologic advances in equipment design have renewed enthusiasm for ablative approaches to hepatic neoplasms. Preclinical and clinical data have demonstrated that using the currently available RF probes, up to 5-cm spherical ablations can be reliably and reproducibly accomplished. Real-time imaging for accurate probe placement and deployment is critical in order to achieve complete ablation of all malignant tissue. Technical factors which diminish local recurrence need to be identified in carefully designed and monitored clinical trials. Furthermore, in patients with unresectable metastatic disease, further studies of RFA combined with regional and or systemic anticancer therapy are warranted.

Microwave thermal ablation Background In 1936, Denier reported the use of low-frequency MW therapy to treat a tumor [3]. Since then, there have been varying applications of this technique in the treatment of tumors. Szwanowski et al [62] developed implantable coaxial systems that were used to treat deep-seeded tumors without affecting the overlying tissue. In the early 1980s, MW ablation (MWA) was developed as a technique to obtain hemostasis along the hepatic resection plane [63]. In 1983, Coughlin et al were the first to report the use of interstitial MW therapy for the treatment of a brain tumor [64]. However, the electrode was prohibitively large, measuring 1 cm in diameter. This limitation was overcome in 1986 when Tabuse et al designed a small (2.8-mm diameter) coaxial interstitial MW system [65]. Much of the current research and clinical trials with this method and laser ablation have been going on in Japan and are focused on HCC. However, in the last decade there has been

Equipment There is one primary MW unit that has been used in many of the initial clinical studies. It consists of a 150-W, 2450MHz electrical generator (Microtaze; Heiwa, Osaka, Japan), 17-cm long, 14G access needles (Quickcut-C2; Hakko, Tokyo, Japan), and 25–30-cm long, 15G coaxial needle electrodes (percutaneous coagulation electrode; Heiwa). The needle electrodes are straight tipped with only the distal 1 cm representing the active element. A more powerful device was subsequently developed in China. This microwave system was designed by the Chinese PLA General Hospital and Institute 207 of the Aerospace Industry Company, Beijing, China. It uses an antenna with a diameter of 1.4 mm and an active tip of 27 mm. It operates at 2450 MHz. A 14G needle is used to facilitate antenna insertion and ablation is carried out for 300 s. A zone of 3.7 cm × 2.6 cm was achieved in porcine livers. The only downside of this device is that the antenna shaft temperature can rise too quickly, resulting in skin burn, so protective cooling of the skin was routinely used during ablation. More recently, cool shaft antennae have been developed and have been approved for the treatment of HCC. There are channels inside the shaft where cold saline is circulated to keep the shaft cool, allowing higher power output and longer treatment duration to be tolerated. This can deliver more energy into the tissues, and potentially increase the ablation zone size. A 2450-MHz, cooled shaft antenna at 80 W for 25 min produces a mean ablation zone of 3.6 cm × 5 cm [68]. All of the human studies from China are using this device. In 2003 an MWA system was developed in the United States (Vivant Medical, Mountain View, CA), which is capable of producing 60 W at 915 MHz [69], and this machine has been used in the clinical studies performed in this country.

253

SECTION 4

Resection, Ablation or Transplantation

Microwave generator A magnetron generates the microwaves and through a low loss flexible coaxial cable, which connects to a microwave antenna, the microwaves are transmitted into the tissue. A 3.6-cm active tip tunes into the dialectic properties of liver tumors, increasing the amount of energy deposited in the tissue. A 13G, 15-cm long antenna is used. Three antennae can be spaced apart by 1.5–2.5 cm, resulting in a maximum ablation area of 5.5 cm [70]. This triaxial antenna has been used in some studies and a loop-shaped antenna, recently developed, has also been tested in some animal and human studies (see below). The loop results in a more spherical ablation zone and the antennae never enter the tumor so there is less risk of seeding. Loop placement at laparotomy, because it requires cautery for its insertion, is however, a potential disadvantage.

Technique Local anesthesia is administered at the site of needle insertion. A 14G styletted access needle is inserted into the tumor under ultrasound guidance. The stylet of the access needle is removed and a 15G MW electrode is inserted through the access needle. The tip of the electrode is positioned within the tumor. The electrode is connected to an MW generator by means of a flexible coaxial cable. The generator is operated at 60 W, and the tumor is heated for 60–120 s. After the ablation process, the needle track is coagulated as the electrode and access needle are withdrawn. The ablation process creates multiple microbubbles, which can be visualized by real-time ultrasonography. A single ablation causes an increase in local temperature greater than 50 °C in an area 1.6–2.4 cm in diameter around the tip of the electrode. Thus, lesions less than 2 cm in diameter can be treated in one or two ablations; larger lesions require multiple overlapping ablations. The Californian microwave system is capable of producing 60 W of power at 915 MHz. With the triple antenna, lesions ranging from 5 cm to 6.5 cm can be ablated. As technology develops, new antennae will be further perfected. Approaches can be laparoscopic, open, or percutaneous under local anesthetic, usually with sedation. The MW antennae are inserted under image guidance. Ultrasound and more recently MRI are employed as the method of guidance. The size of the ablation zone can be roughly judged by the expanding hyperechoic area during ablation. Often for MWA, a thermal monitoring system is used. These systems are placed 0.5 cm outside of the tumor, and if the temperature does not reach 60 °C by the end of the treatment, and remains at 54 °C for at least 3 min, the treatment is prolonged until the desired temperature is achieved. Temperature monitoring also avoids overheating.

Current results Early clinical reports using MWA therapy appeared in the early 1990s from Asia. Seki et al in 1994 [71] evaluated the

254

efficacy of MWA percutaneously in 18 patients with single unresectable HCCs, all of which were 2 cm in diameter or smaller. Tumors measuring 1.5 cm or less were ablated one or two times; tumors measuring 1.5–2.0 cm were ablated three or four times. In all patients, CT and MRI showed complete response with no evidence of residual tumor. No recurrences were noted at the treated sites during 11–33 months of follow-up. Three patients developed new tumors in sites remote from the treated sites. No serious complications were encountered. Matsukawa et al in 1997 reported their further experience in 24 patients with 27 tumors of mixed origin [72]. From one to 12 ablations were performed per tumor; no more than four ablations were performed per session. The authors defined a positive response as disappearance of the tumor or a decrease in tumor size on followup CT scan. The authors reported better positive response rates for tumors less than or equal to 3 cm in diameter (70%) than for tumors greater than 3 cm (53%). Well-differentiated HCCs responded 85% of the time compared with moderately differentiated HCCs which responded 25% of the time, and poorly differentiated HCCs failed to respond. The overall survival rates for all treated patients were 83% at 1 year and 69% at 2 years. The authors reported no significant complications. Most reports continue to come from Japan and China and concern treatment of HCC primarily. One of the largest studies [73] included 288 patients (477 tumors), most of whom (82%) were not candidates for resection. The Chinese microwave system was used. Survival rates at 1, 3 and 5 years of 93%, 72% and 51%, respectively, were demonstrated. The tumor size averaged 4 cm or less. Local recurrence occurred in 8% (n = 24), new tumors in the same segment occurred in 9% (n = 25), elsewhere in the liver in 12% (n = 34), and extrahepatically in 6% (n = 17). The total recurrence or metastatic rate was 35%. Kawamoto et al laparoscopically treated 69 patients with solitary lesions up to 4 cm in diameter [74]. The 5-year survival rate was 63.9% for the entire group. Aramaki et al used MWA in 24 cirrhotic patients with HCC tumors ranging from 1 cm to 5 cm [75]. These were all unresectable and a range of one to seven tumors were ablated per patient. Two patients died postoperatively and the others recovered well. The 3-year cumulative survival rate was 83.9%. However, the disease-free survival rate was only 9.9%. Wang et al published a retrospective study comparing hepatic resection to MWA. Of 194 patients with biopsy proven HCCs of less than 5 cm (range 1.1–4.9 cm), 114 patients had MWA and 80 had hepatic resection [76]. MWA was performed under local anesthesia and sedation. For lesions of less than 1.7 cm, a single puncture technique was used and two electrodes were used for any tumors greater than 3 cm. Disease-free survival for MWA was 72%, 54%, and 33% at 1, 3, and 5 years, respectively, which was not significantly different from results for hepatic resection (1-, 3-, and 5-year

CHAPTER 21

Thermal Ablation of Liver Tumors by Radiofrequency, Microwave, and Laser Therapy

disease-free survival of 68%, 60%, and 25.6%, respectively). In the MWA group, 13.2% developed local recurrence compared with 10% resection margin recurrence in the hepatic resection group. The authors concluded that MWA may achieve a similar effect when compared to hepatic resection for HCC in cirrhotic livers without increased risk of recurrence, but this conclusion is drawn from a recent retrospective study without long-term follow up, so the recommendations are guarded. In an effort to increase ablation zone and prevent skin burn, Kuang et al experimented, both in in vivo animal models and human models, with a cooled microwave delivery system [68]. In 90 patients with 133 tumors, 0.8–8 cm in diameter (mean 2.7 cm), and either primary or metastatic cancers, treated with 80 W for 25 min, a coagulation diameter of up to 5.6 × 7.4 cm was achieved. A 14G antennae with a 16.5-cm long shaft was used. The shaft was cooled by a continuous steady flow pump of 4 °C saline solution circulating within the lumen of the antenna so that the shaft maintained a mean temperature of 10 °C during the ablation. To treat large tumors, between 5 cm and 8 cm, multiple overlapping ablations were performed, each ablation lasting 20 min with three or four inserted antennae. The needle tract was cauterized for 10 s and the antenna was withdrawn. No skin burns were encountered. Complete ablation was 94%, 91%, and 92% in small (<3 cm), medium (3–5 cm), and large (5–8 cm) tumors, respectively. The mean period of follow-up was 17.4 months. Five percent of patients had local recurrence. So, increasing the power to increase the ablation zone and reduce the ablation time is limited by overheating of the antennae, resulting in skin burns. This can be overcome by a cooled system such as the one described above. The studies to date from the United States are limited and most relate to safety and efficacy. One technique described using dual loop probes (Valley Laboratories, Boulder, Colorado, USA) in a phase I clinical trial [77], and previously tried in porcine models, resulted in the ability to encircle a tumor and deliver large amounts of precisely targeted MW energy to the tumor. The tumor is not entered and is heated from the outside, avoiding potential tumor tract seeding. The loops were placed using diathermy to cut through hepatic tissue and avoid loop distortion. Ablation took 5–7 min. Five patients with six tumors were ablated, mixed between HCC and colorectal cancer metastases. All patients were resected post ablation. Mean tumor ablation volume was 63.9 cm3 ± 8.7 cm3. The lesions were spherical in shape with no distortion from the presence of vessels. Pathologic examination confirmed complete necrosis. Another study to determine the effectiveness of MWA was followed by resection and pathologic correlation [70]. Ten patients with colorectal cancer metastases and HCC were treated. Three probes were arranged in a triangular cluster-like configuration, spaced between 1.5 and 2.5 cm

apart, using the Vivant Medical system with 60 W of power at 915 MHz. Median tumor diameter was 4.4 cm (range 2–5.7 cm) and the median ablation zone diameter was 5.5 cm (range 5–6.5 cm) with a volume of 50.8 cm3. Microscopic examination of the ablation areas afterwards demonstrated clear coagulation necrosis with no viable tissue seen, confirming the effectiveness of MWA. They concluded that ablations of 50.8 cm3 can be achieved in 10 min using the triple ablation system. Another trial of safety and efficacy treated 67 tumors in 20 patients with the Vivant Medical microwave system [78]. Tumors were amenable to complete ablation or ablation combined with resection. A bracketed technique of placing multiple (maximum of three) probes around the tumor was used. Smaller tumors, less than 1.5 cm, usually just needed a single straight probe. Median tumor size was 3 cm (range 1.5–4.5) and median ablation time was 10 min (range 5–40). Abdominal CT demonstrated 100% success post ablation, there were no perioperative deaths, and complications were minor. This was followed by a phase II study in which 84 patients had 94 ablations [79]. Local recurrence was 2.7% and complications were minor. Overall follow-up was 19 months. Tumor recurrence was determined by viable tumor on CT scan with confirmation on PET. The authors concluded that MWA represents a safe and efficient way to perform hepatic ablation with multiple antennae resulting in a more complete ablation. Yet another technique, described by Yu et al in the United States, looked at nine patients with resectable HCC [80]. Mean tumor diameter was 4.2 cm, ranging from 2.9 to 6 cm. Tumor ablation was followed by resection. They used a spherical triple loop antenna configuration which forms a “cage” around the tumor and compared this to a single standard straight antenna configuration. Ablation took 5 min, ultrasound monitoring was used to track the progress of the ablation. The single straight antenna configuration appeared to produce ablations that were slightly ellipsoid but the loop cage configuration produced a rounder ablation zone. The loop cage ensures that coagulation can proceed from the outside in. Uniform coagulation inside the cage was confirmed by pathologic analysis. Table 21.5 summarizes the studies performed with MWA.

Comparison of radiofrequency ablation to microwave ablation The zone of active tissue heating in RF is limited to a few millimeters surrounding the probe. Heat then radiates into the tissues by thermal conduction. RF energy cannot consistently heat the tissues above 100 °C during ablation and temperature decreases rapidly with increasing distances from the probe, likely due to increased impedance from tissue charring. Microwave, on the other hand, enables a zone of active heating up to 2 cm surrounding the antenna. Proponents agree that this allows for a more uniform tumor

255

SECTION 4

256 Authors

Number of patients

Number of nodules

Tumor type

Tumor size (mm)

Tumor ablation rates

Number of treatments

Major morbidity

Follow- up (months)

Overall survival (%)

Local recurrence (%)

HCC HCC (n = 20), CRM, Misc HCC

≤20 Mean 30

Complete 60%

2–4 1–12

0 0

11–33

17/18 alive 2 year – 69

0% 8%

≤40

64/69 patients

1 (up to 11 electrodes placed) –

0

54

5 year – 63.9

17.4%

–

31.4

8%

4.4

17.4

3 year – 72 5 year – 51 –

1.3% (1 death)

40

1 year – 94.9 5 year – 68.6

Cumulative recurrence 1 year – 20%, 5 year – 52.9 5

Seki et al (1994) [71] Matsukawa et al (1997) [72]

18 24

18 27

Kawamoto et al (2005) [74]

69

69

Liang et al (2005) [73]

288

477

HCC

≤40

–

Kuang et al (2007) [68]

90

133

HCC, CRM

≤80 (mean 27)

92–94%

Dong et al (2006) [81]

216

275

HCC

<50

95.6%

1 (cooled shaft, up to 4 electrodes) –

20

67

–

–

19

–

224

Median 30 (1.5–4.5) Mean 36

100% (per CT)

87

CRM, HCC, Misc CRM, HCC, Misc HCC

–

–

19

≤50

–

1 (up to 2 electrodes)

2.3% mortality 0

47% alive at 19 months 1, 3 ,5 year – 72, 54, amd 33 DFS

Martin et al (2007) [78] (USA) Iannitti et al (2007) [79] (USA) Wang et al (2008) [76]

114 (vs 80 having resection)

194

–

5%

2.7 13.2 vs 10 (resection)

HCC, hepatocellular carcinoma; CRM, colorectal metastasis; NEM, neuroendocrine metastasis; Misc, miscellaneous metastases (breast, gastric, ovarian, adrenal carcinoma, melanoma, leiomyosarcoma).

Resection, Ablation or Transplantation

Table 21.5 Studies using microwave ablation (MWA): the majority of experience with MWA in the United States is limited and the vast majority of studies have been performed in Asia, and on HCC in the setting of cirrhosis. There are no reports on efficacy of MWA in colorectal metastases alone.

CHAPTER 21

Thermal Ablation of Liver Tumors by Radiofrequency, Microwave, and Laser Therapy

kill, both within a targeted area and next to the vessels, and, unlike RF, does not appear to be limited by charring and tissue desecration; thus temperatures may be driven considerably higher than in RF systems. The loop may prove to be a better device since it creates a cage around the tumor which allows for accurate thermal destruction. The tumor is heated from the outside, rapidly truncating the blood supply to the tumor, minimizing the heat sink effect of tumor blood flow, and theoretically reducing the risk of seeding. However, placement of the loop antennae is difficult, requiring greater operator skill and ultrasound guidance, and it may not be easily implemented in the percutaneous approach.

Clinical studies (Table 21.6) Shibata et al studied 72 patients with 94 HCC nodules [84]. Forty-eight tumors treated with RF were compared to 46 tumors treated with MWA. Follow-up was 6–27 months, with local recurrence occurring in four RF and eight MWA patients. They concluded that there was no difference between the two procedures except that RF required fewer treatments. Another comparison of MWA to RF analyzed risk factors for distant recurrence as opposed to local recurrence in patients who have fewer than three tumors of less than 3 cm in diameter. More than two nodules of HCC, along with hepatitis C, were associated with a higher incidence of recurrence, but there was no difference between the two treatments. Lu et al also compared MWA and RFA for treatment of HCC using the Chinese device [83]. In 98 nodules in 49 patients, 72 nodules were treated with MWA and they found similar complete ablation (95% versus 93%) for both techniques and a similar local recurrence rate of 11.8% after MWA compared to 21% after RFA. They concluded that both techniques were effective.

Radiographic follow-up Similarly to RFA, the success of MW tumor ablation is judged by dynamic CT scans or MRI obtained a few days and/or months after the treatment. Complete tumor ablation is defined as disappearance of tumor vascularity and ultimate shrinkage of the tumor. Criteria for local recurrence are defined as recurrent hypervascularity or rim enhancement on the cross-sectional imaging and/or enlargement of the tumor. Some studies confirm the presence or absence of recurrence by PET. Outside of cross-sectional imaging, there are no recommendations. Many studies also base their level of response on the imaging studies without pathologic confirmation; however, evidence for the efficacy of this type of ablation is present in a recent review of all reports of MWA followed by resection and pathologic analysis, which reported necrosis rates of 93% in lesions up to 6 cm [85, 86].

Complications These are similar to RFA. However, there are conflicting reports of increased pain, nausea, and fever in some, and

fewer postprocedural complaints in others. As there are no grounding pads, the pad skin burns seen in RFA are avoided. As more studies are reported we may see some unique complications relative to MWA.

Current indications The indications for MW therapy are identical to those for RF therapy, although the efficacy in colorectal metastases is as yet unknown.

Summary MWA has several potential advantages over RFA: consistently higher intratumoral temperatures can be maintained, the ability to create larger tumor ablation volumes, with faster ablation times, and the ability to use multiple MW energy sources. There appears to be a smaller heat sink effect and MWA can be monitored in real time with ultrasound, insuring complete treatment. MWA has been most widely used in Japan and China, particularly for the treatment of smaller HCCs. It is relatively new in the rest of the world. Newer techniques, using multiple antennae, triangular configuration antenna, bracketed techniques and loop antenna, with or without cooling shafts, allow greater delivery of power and MW energy to produce larger volume tissue destruction in less time. This may result in a more effective and faster technique than RFA. However, this remains to be seen. Also, as in the other ablative techniques, major clinical trials comparing this MWA to the goal standard of resection are severely lacking. MW therapy continues to be promising but, due to the fact that most reports have small numbers of patients, it is currently not possible to truly evaluate its effectiveness.

Laser thermal ablation Background Interstitial hyperthermia of tumors induced by lightconducting quartz fibers attached to laser generators was first described by Bown in 1983 [86]. Experimental studies have shown that 1.6-cm thermal injuries can be produced in rat livers using neodymium : yttrium aluminum garnet (Nd : YAG) lasers operated at very low power. This technology has been used to treat a variety of surface tumors, including those of the esophagus, stomach, colon, and pulmonary bronchus [88–90]. Steger et al [91] was the first to use this technology to treat patients with hepatic metastases.

Mechanism Light of very high intensity can be used to heat or destroy tissue. When soft tissue absorbs a small amount of energy, its temperature increases. As the amount of energy increases, interstitial and intracellular water is vaporized and the tissue

257

SECTION 4

258 Authors

Number of patients MWA vs RFA

No. nodules MWA vs RFA

Tumor type

Tumor size (mm) MWA vs RFA

Tumor ablation rates MWA vs RFA (%)

Tumor area necrosis

Number of treatments MWA vs RFA

Morbidity MWA vs RFA (%)

Overall survival MWA vs RFA (%)

Local recurrence MWA vs RFA (%)

Result

Ohmoto et al (2009) [82]

49 vs 34

56 vs 37

HCC

18

–

2.7 vs 2.2*

2.6 vs 1.7*

> in MWA*

4 year – 39 vs 70*

4 year – 19 vs 9*

RFA > MWA

Lu et al (2005) [83]

49 vs 53

98 vs 72

HCC

25 vs 26

94.9 vs 93.1

–

2/nodule vs 1/nodule

8.2 vs 5.7

4 year – 36.8 vs 24.2

4 year – 11.8 vs 20.9

RFA = MWA

Shibata et al (2002) [84]

36 vs 36

46 vs 48

HCC

2.2 vs 2.3

89 vs 96

2.4 vs 1.1*

4 vs 1 patient

–

24 vs 12

RFA = MWA but fewer sessions for RFA

*Significant difference. HCC, hepatocellular carcinoma.

Resection, Ablation or Transplantation

Table 21.6 Microwave ablation (MWA) compared to radiofrequency ablation (RFA).

CHAPTER 21

Thermal Ablation of Liver Tumors by Radiofrequency, Microwave, and Laser Therapy

contracts. At higher energy levels, all cellular material is vaporized and a crater is created in the treated tissue. The ablated lesion size depends on total heat deposition, thermal conductivity, and heat loss by means of convection through blood flow. High vascularity or the presence of large vessels near the tumor can result in small or irregular lesions, leading to treatment failure or early recurrence. There are two types of lasers that have outputs suitable for thermal ablation of tissue: the Nd : YAG laser, which operates at a wavelength of 1060 nm; and the argon ion laser, which has settings at both 488 and 514 nm. These lasers are capable of producing coagulative necrosis. However, the Nd : YAG laser appears to be best suited for deep tumor ablation. An ellipsoid thermal injury measuring 2.5–3.0 cm in diameter can be created in the liver at a therapeutic setting of approximately 5 W of laser power administered for 20 min [87].

Equipment The Nd : YAG laser has been the laser most commonly used to ablate hepatic tumors. These generators cost about $120 000. The laser fibers have an external diameter of 800 tm and a quartz core measuring 400 tm. Some investigators use a bare optical fiber and others prefer to use a diffuser at the tip of the fiber. The diffuser is believed to increase the extent of the necrosis around the tip of the fiber. The bare fibers are reported to create a region of necrosis approximately 1.6 cm in diameter.

Technique The technique of laser thermal ablation is similar to that of MW therapy. An 18G access needle is inserted into the tumor to be treated. A laser fiber needle is inserted through the access needle. The access needle is withdrawn to avoid heating of the needle tract. Microthermocouple needles are placed around the margins of the tumor. The microthermocouple needles are connected to an electronic display and are used to monitor the temperature of the treated tissue. The Nd : YAG laser is turned on and the ablation is continued until the heated sites reach 60 °C or exceed 45 °C for 15 min. The laser is operated at 2–10 W. Each ablation takes from 5 to 45 min. The following mechanisms have been suggested to improve laser thermal ablation: (1) blood flow occlusion with a Pringle maneuver, which can be performed at open or laparoscopic surgery; and (2) the use of TACE prior to laser ablation or transarterial embolization without chemotherapy prior to ablation. Multiple fiber applications have shown improved ablation size with the use of newer more effective laser fibers, such as sapphire tipped fibers, cool tip applicators, and/or cylindrical quartz diffusers. Modern diffusing fibers, allowing more homogenous laser light emission, have replaced the traditional type of baretipped quartz fibers which were prone to tissue charring, reduced laser light penetration, and necrosis [92]. A single

diffusing fiber has a maximum ablation diameter of 4–6 cm. A multiple fiber system may produce lesions in the region of 4–7 cm. However, like others, these new technologies, which claim to be better than their predecessors, lack evidence for this from sufficient long-term follow-up. Most laser therapy is performed under ultrasound guidance, but it has been performed under MRI guidance as well [93, 94]. MRI guidance is reportedly the more accurate way of monitoring the extent of the ablation during the procedure [95]. The success of the thermal ablation can be assessed by dynamic contrast-enhanced CT scanning or MRI. Improvements in intraprocedural monitoring with MRI has shown potential advantages because: (1) there is better topographical assessment, (2) a temperature-sensitive thermo-turbo flash, plus flash two-dimensional sequence can be used with MRI to monitor the temperature elevation in the tumor and the surrounding tissues in real time; (3) accurate information on the degree of necrosis and the ablation size is obtained; and (4) MRI can confirm proximity of local important structures to avoid their injury and can detect early local complications such as hemorrhage. Unfortunately, however, as mentioned in the RFA section, few operating suites are equipped to perform MRI-monitored ablation.

Current results The least amount of literature exists on this type of ablation. Table 21.7 highlights the studies performed. In 1993 two publications concerned the use of interstitial laser therapy for ablation of metastatic hepatic tumors. Nolsoe et al published a study on the technical feasibility of using laser thermal ablation for the treatment of colorectal liver metastases [93]. They treated 16 hepatic metastases from colon carcinoma in 11 patients. The tumors ranged from 1 to 4 cm in diameter, with a mean of 2.6 cm. These investigators used a continuous wave Nd : YAG laser (Flexilase; Living Technology, Glasgow, Scotland) with a wavelength of 1064 nm, and diffuser-tipped optical fibers. Nine of the 11 patients were treated percutaneously, and all but one of these treatments was performed with general anesthesia. The laser output for each ablation was set at 4–8 W and continued for 5–45 min. Follow-up ultrasound and percutaneous biopsy showed apparent complete ablation in 12 of 16 metastases. The 12 completely ablated tumors had a mean diameter of 2.4 cm compared with 3.4 cm for the incompletely ablated tumors. Transient pain and/or fever were reported in five patients. Amin et al evaluated the efficacy of laser therapy in the treatment of 55 metastatic nodules in the livers of 21 patients [91]. The primary tumors were colorectal in 15 cases and gastric, esophageal, renal, breast, carcinoid, and pancreatic islet cell in one case each. The tumors measured from 1 to 15 cm in diameter. Of the 21 patients, 14 received chemotherapy before or after laser ablation, and intravenous sedation and antibiotics were administered before all ablations.

259

SECTION 4

Resection, Ablation or Transplantation

Table 21.7 Studies performed with laser ablation. Authors

Amin et al (1993) [94] Pacella et al (1996) [93] Mack et al (2001) [94] Christophi et al (2004) [95]

Number of patients

Number of nodules

Tumor type

Tumor size (mm)

Tumor ablation rates (%)

Major morbidity (%)

Overall survival

Local recurrence

21

55

CRM, Misc

10–150

38%

0

–

–

14

20

CRM, Misc

Mean 29

0

–

–

705

1981

<5 cm

1.3

60

180

CRM, HCC, Breast CRM

100% in lesions <30 mm 99.3% at 3 months 67% complete at 6 months

1 year − 93% 5 year – 30% 5 year – 3.8%

3% at 6 months DFS mean 24.6 months

<100

0

HCC, hepatocellular carcinoma; CRM, colorectal metastasis; NEM, neuroendocrine metastasis; Misc, miscellaneous metastases (breast, gastric, ovarian, adrenal carcinoma, melanoma, leiomyosarcoma); DFS, disease-free survival.

Each tumor was ablated using from two to eight simultaneously placed 19G access needles positioned 1.5 cm apart and two to four bare optical fibers fired simultaneously. The generator was a continuous wave Nd : YAG laser (Flexilase; Living Technology, Glasgow, Scotland). Each ablation was performed at a power of 2 W/fiber for approximately 8 min. Follow-up CT scans showed 100% necrosis in 38% of the tumors and at least 50% necrosis in an additional 44%. An insufficient number of patients had long-term follow-up to determine local recurrence or survival data. Transient abdominal pain, fever, and pleural effusions occurred in some patients. One patient had a marked but self-limited drop in hemoglobin. Pacella et al reported in 1996 their results on the use of this therapy for the treatment of 14 patients with 20 metastatic tumors (14 colon carcinomas, five breast cancers, and one lung cancer) [96]. The mean tumor diameter was 2.9 cm. All ablations were performed with an Nd : YAG laser and standard quartz optical fibers. The fibers were positioned through 18–21G access needles. Power was set at 5 W, and each ablation was continued for 5–6 min. CT was used to assess the completeness of the ablations. Average follow-up was 6 months. Complete necrosis was achieved in all lesions less than 3 cm in diameter, but in only 44% of lesions larger than 3 cm. Two larger reports from the same group were published in 2001, both using MR monitoring. Vogl et al [97] reported their experience in primary and metastatic tumors. In the period from June 1993 to April 2000 a collective of 600 patients with malignant liver tumors and liver metastases from different primary tumors were treated via MR-guided laser therapy. After ultrasound- or CT-guided puncture, MR-compatible laser catheters were positioned. Tumor destruction was visualized via MR thermometry. A local tumor control rate of 97.8% was achieved. The complication

260

rate was very low. The mean survival in the whole group was 47.7 months, and for liver metastases from a colorectal cancer a value of 46.8 months was achieved. Mack et al [98], in an updated study, demonstrated 2- and 5-year survival rates of 74% and 30%, respectively, in 705 patients with hepatic metastases. Between June 1993 and August 2000, 705 patients had 7148 laser applications performed on 1981 lesions in 1653 treatment sessions. Local control at 3 months was 99.3% and 97.9% at 6 months. 1-, 3- and 5-year survival was 93%, 74%, and 30%, respectively. Median survival in the colorectal cancer group was 41.8 months. Breast cancer patients with hepatic metastases had a mean survival of 4.3 years. The clinically relevant complication rate was 1.3%, with bile duct injury, hepatic abscess, pyemia, and pleural effusions being the most common. There were three deaths, but only one associated with the ablation. Christophi et al [99] treated 168 unresectable colorectal cancer metastases in 80 patients with laser ablation, using a bare-tipped quartz fiber connected to an Nd : YAG laser source (prior to availability of diffusing fibers). Ablation was monitored by ultrasound and treatment was continued until a hyperechoic rim extended 1 cm beyond the tumor margin. Liver lesions measured less than 10 cm and patients had no more than five lesions. Sixty-seven percent maintained complete ablation at 6 months. Median follow-up was 35 months, disease-free survival was 24.6 months and 5-year survival 3.8%. When the tumor was greater than 2 cm, multiple needles were inserted 1.5 cm apart. Fourteen patients had laser ablation to treat a recurrent metastases post prior resection. In this small group the 5-year survival was 17%. Complications were minor and included arrhythmias (6%), pneumothoraces (4%), and fever (4%). They concluded that laser ablation may be beneficial to unresectable patients, since patients with untreated colorectal cancer

CHAPTER 21

Thermal Ablation of Liver Tumors by Radiofrequency, Microwave, and Laser Therapy

liver metastases have a median survival of 6 months and a 2% 3-year survival. However, they did not compare the survival in their study with unresectable patients receiving modern systemic chemotherapy, which is clearly superior. There may also be a role for laser ablation in treating recurrent metastases as they believe their results to be comparable to repeat hepatectomy, but the numbers are small and the evidence is low.

Additional techniques to improve outcome with laser ablation Chang et al performed laser ablation at laparoscopy with hepatic vascular occlusion and demonstrated increased ablation lesion size [100]. Using TACE to downsize tumors prior to laser ablation was investigated by Vogl et al [101]. One hundred and sixty-two patients received TACE for unresectable metastases from colorectal cancer (62), breast cancer and other primary cancers (6). All lesions were less than 8 cm and each patient had no more than four tumors. Tumors downsized to 5 cm or smaller in 82 patients were eligible for laser ablation (Nd : YAG laser). Ablation was MR guided, with intraprocedural and temperature monitoring. All patients had either progressed on chemotherapy or were nonresponders. TACE was preformed with mitomycin-C and lipiodol followed by injection of microspheres. The mean decrease in tumor size after TACE was 35%. The laser lesion necrosis volume was 62 cm3. Five percent of patients recurred within 6 months. Median survival of patients who responded to combined therapy was 26 months; TACE-only survival was 12.8 months. The cumulative survival of 17 months for the overall group with the combined therapy was 24.9 months. TACE may be advantageous because it decreases the hypervascularity of the lesion, reducing the risk of bleeding, and it increases laser effectiveness because it reduces the cooling effect of blood flow through intratumoral vessels. Also, it is advantageous to obtain a more detailed insight about the biologic behavior of the tumor during the 3-month courses or therapy. Further studies are required to evaluate the types of tumor best treated, the types of pretreatment to be used, the number of lesions that correspond to a better response, and those patients who would benefit from a neoadjuvant protocol. TACE prior to laser treatment is probably only required in lesion greater than 5 cm, since tumors less than 5 cm can be treated with laser therapy primarily. Ritz et al performed laser ablation in a control group and compared them to laser ablation in groups treated with interrupted perfusion, either by transarterial embolization with microspheres (TAE) or hepatic inflow occlusion at laparotomy (Pringle) [102]. They used a cooled laser system (Somatex, Germany), with a diffuser-tip applicator with an active length of 25 mm (Huttinger Medizintechnik, Germany) and a Nd : YAG laser with a wavelength of 1064 nm (5100 fibertome, Dornier Medizinlaser, Germany). The laser power

varied between 24 and 30 W for 28–30 min. Fifty-six patients with 104 metastases were treated. There were 14 patients (25 metastases) in the control group versus 19 patients (37 metastases) who had TAE prior to ablation and 23 patients (42 metastases) who had a Pringle maneuver applied at laparotomy. Mean preoperative tumor volumes were 9.8 cm3, 9.5 cm3 and 12.9 cm3 in the three respective groups with a maximal diameter of 5.0 cm. Significantly increased tumor ablation volume size was seen with both types of vascular occlusion (TAE and Pringle maneuver, 65.4 cm3 and 76.5 cm3, respectively) compared with the control group (25.3 cm3). Two patients recurred locally in the control group at 6 months. No local recurrences occurred in either vascular occlusion groups. As the study was performed recently, long-term follow-up is not yet available, but using interrupted perfusion may add to the efficacy of this therapy.

Current indications The indications for laser ablation of hepatic tumors are identical to those for RF and MW therapy. However, there are far less studies available on this type of ablation and many are performed in multiple tumor types. It is difficult to make recommendations at this time. We await further studies to demonstrate the efficacy of laser ablation in both the treatment of HCC and colorectal metastases.

Radiographic follow-up The recommendations are the same as for RFA. Crosssectional imaging provides the best indicator of successful ablation.

Summary There seems little doubt that this therapy is safe, but evaluation of its effectiveness, like for the other interstitial therapies described, is limited by lack of good comparative trials and hampered by constantly changing technologies. Randomized data on the impact of laser ablation on survival, quality of life and cost-effectiveness are lacking for both primary and secondary liver tumors.

Self-assessment questions 1 Which one of the following is not a modality of therapy for hepatocellular carcinoma? A Radiofrequency ablation B Transarterial catheter embolization C Percutaneous acetic acid D Nd : YAG laser 2 Which one of the following is not an absolute contraindication to ablation? A Proximity to major bile duct B Significant extrahepatic disease

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C Child class C cirrhosis or active infection D HCC < 3 cm in Child class A cirrhosis 3 With which one of the following should patients post ablation for hepatocellular carcinoma be followed with? A Cross-sectional imaging B Contrast-enhanced cross-sectional imaging C Trans-abdominal ultrasound D FDG-PET scanning 4 In which one of the following situations is ablation not useful? A Unresectable patients with tumors amenable to ablation B As an adjunct to resection in patients with small volume residual disease after hepatic resection C For hepatocellular carcinoma with cirrhosis in patients with small tumors who are unsuitable for transplantation or resection D In patients with resectable colorectal metastases 5 Which method of ablation is the most efficacious? A RFA B MWA C Laser

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33 34

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48 Lin SM, Lin CJ, Lin CC, et al. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less. Gut 2005;54:1151–6. 49 Ueno S, Sakoda M, Kubo F, et al. Surgical resection versus radiofrequency ablation for small hepatocellular carcinomas within the Milan criteria. J Hepatobiliary Pancreat Surg 2009;16:359–66. 50 Guglielmi A, Ruzzenente A, Valdegamberi A, et al. Radiofrequency ablation versus surgical resection for the treatment of hepatocellular carcinoma in cirrhosis. J Gastrointest Surg 2008;12:192–8. 51 Lupo L, Panzera P, Giannelli G, et al. Single hepatocellular carcinoma ranging from 3 to 5 cm: radiofrequency ablation or resection? HPB (Oxf) 2007;9:429–34. 52 Chen MS, Li JQ, Zheng Y, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 2006;243:321–8. 53 Lu MD, Kuang M, Liang LJ, et al. [Surgical resection versus percutaneous thermal ablation for early-stage hepatocellular carcinoma: a randomized clinical trial]. Zhonghua Yi Xue Za Zhi 2006;86:801–5. 54 Cho CM, Tak WY, Kweon YO, et al. [The comparative results of radiofrequency ablation versus surgical resection for the treatment of hepatocellular carcinoma.]. Korean J Hepatol 2005;11:59–71. 55 Lu DS, Yu NC, Raman SS, et al. Percutaneous radiofrequency ablation of hepatocellular carcinoma as a bridge to liver transplantation. Hepatology 2005;41:1130–7. 56 Brillet PY, Paradis V, Brancatelli G, et al. Percutaneous radiofrequency ablation for hepatocellular carcinoma before liver transplantation: a prospective study with histopathologic comparison. AJR Am J Roentgenol 2006;186 (5 Suppl):S296–305. 57 Lau WY, Lai EC. The current role of radiofrequency ablation in the management of hepatocellular carcinoma: a systematic review. Ann Surg 2009;249:20–5. 58 Yang W, Chen MH, Yin SS, et al. Radiofrequency ablation of recurrent hepatocellular carcinoma after hepatectomy: therapeutic efficacy on early- and late-phase recurrence. AJR Am J Roentgenol 2006;186 (Suppl 5): S275–83. 59 Llovet JM, Vilana R, Bru C, et al. Increased risk of tumor seeding after percutaneous radiofrequency ablation for single hepatocellular carcinoma. Hepatology 2001;33:1124–9. 60 Stigliano R, Marelli L, Yu D, et al. Seeding following percutaneous diagnostic and therapeutic approaches for hepatocellular carcinoma. What is the risk and the outcome? Seeding risk for percutaneous approach of HCC. Cancer Treat Rev 2007;33:437–47. 61 Livraghi T, Lazzaroni S, Meloni F, Solbiati L. Risk of tumour seeding after percutaneous radiofrequency ablation for hepatocellular carcinoma. Br J Surg 2005;92:856–8. 62 Szwarnowski S, Sheppard RJ, Grant EH, Bleehen NM. A broad band microwave applicator for heating tumours. Br J Radiol 1980;53:31–3. 63 Tabuse K, Katsumi M, Kobayashi Y, et al. Microwave surgery: hepatectomy using a microwave tissue coagulator. World J Surg 1985;9:136–43.

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64 Coughlin CT, Douple EB, Strohbehn JW, et al. Interstitial hyperthermia in combination with brachytherapy. Radiology 1983;148:285–8. 65 Tabuse Y, Tabuse K, Mori K, et al. Percutaneous microwave tissue coagulation in liver biopsy: experimental and clinical studies. Nippon Geka Hokan 1986;55:381–92. 66 Simon CJ, Dupuy DE, Mayo-Smith WW. Microwave ablation: principles and applications. Radiographics 2005;25 (Suppl 1):S69–83. 67 Liang P, Wang Y. Microwave ablation of hepatocellular carcinoma. Oncology 2007;72 (Suppl 1):124–31. 68 Kuang M, Lu MD, Xie XY, et al. Liver cancer: increased microwave delivery to ablation zone with cooled-shaft antenna– experimental and clinical studies. Radiology 2007;242:914–24. 69 Wright AS, Lee FT Jr, Mahvi DM. Hepatic microwave ablation with multiple antennae results in synergistically larger zones of coagulation necrosis. Ann Surg Oncol 2003; 10:275–83. 70 Simon CJ, Dupuy DE, Iannitti DA, et al. Intraoperative triple antenna hepatic microwave ablation. AJR Am J Roentgenol 2006;187:W333–40. 71 Seki T, Wakabayashi M, Nakagawa T, et al. Ultrasonically guided percutaneous microwave coagulation therapy for small hepatocellular carcinoma. Cancer 1994;74:817–25. 72 Matsukawa T, Yamashita Y, Arakawa A, et al. Percutaneous microwave coagulation therapy in liver tumors. A 3-year experience. Acta Radiol 1997;38:410–5. 73 Liang P, Dong B, Yu X, et al. Prognostic factors for survival in patients with hepatocellular carcinoma after percutaneous microwave ablation. Radiology 2005;235:299–307. 74 Kawamoto C, Ido K, Isoda N, et al. Long-term outcomes for patients with solitary hepatocellular carcinoma treated by laparoscopic microwave coagulation. Cancer 2005;103:985–93. 75 Aramaki M, Kawano K, Ohno T, et al. Microwave coagulation therapy for unresectable hepatocellular carcinoma. Hepatogastroenterology 2004;51:1784–7. 76 Wang ZL, Liang P, Dong BW, et al. Prognostic factors and recurrence of small hepatocellular carcinoma after hepatic resection or microwave ablation: A retrospective study. J Gastrointest Surg 2008;12:327–37. 77 Meredith K, Lee F, Henry MB, et al. Microwave ablation of hepatic tumors using dual-loop probes: results of a phase I clinical trial. J Gastrointest Surg 2005;9:1354–60. 78 Martin RC, Scoggins CR, McMasters KM. Microwave hepatic ablation: initial experience of safety and efficacy. J Surg Oncol 2007;96:481–6. 79 Iannitti DA, Martin RC, Simon CJ, et al. Hepatic tumor ablation with clustered microwave antennae: the US Phase II Trial. HPB (Oxf) 2007;9:120–4. 80 Yu NC, Lu DS, Raman SS, et al. Hepatocellular carcinoma: microwave ablation with multiple straight and loop antenna clusters–pilot comparison with pathologic findings. Radiology 2006;239:269–75. 81 Dong BW, Liang P, Yu XL, et al. [Long-term results of percutaneous sonographically-guided microwave ablation therapy of early-stage hepatocellular carcinoma]. Zhonghua Yi Xue Za Zhi 2006;86:797–800. 82 Ohmoto K, Yoshioka N, Tomiyama Y, et al. Comparison of therapeutic effects between radiofrequency ablation

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100 Chang CK, Hendy MP, Smith JM, et al. Radiofrequency ablation of the porcine liver with complete hepatic vascular occlusion. Ann Surg Oncol 2002;9:594–8. 101 Vogl TJ, Mack MG, Balzer JO, et al. Liver metastases: neoadjuvant downsizing with transarterial chemoembolization before laser-induced thermotherapy. Radiology 2003;229:457– 64. 102 Ritz JP, Lehmann KS, Zurbuchen U, et al. Improving laserinduced thermotherapy of liver metastases – effects of arterial microembolization and complete blood flow occlusion. Eur J Surg Oncol 2007;33:608–15.

2 D Tumors of 5 cm and above can be treated with ablative techniques, however resection is still the gold standard and recommended procedure. 3 B PET is not useful in HCC. 4 D Resection is still the gold standard. 5 A RFA has the most evidence demonstrating its efficacy, however future studies may change this answer.

Self-assessment answers 1 C PEI has been shown to be worse than RFA in several studies.

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Ethanol and Other Percutaneous Injection Modalities in the Treatment of Liver Tumors Michael A. Heneghan and Andrew D. Yeoman Institute of Liver Studies, King’s College Hospital, London, UK

A dilemma facing clinicians in the management of liver tumors, both primary and secondary, is the array of techniques available to treat these lesions. An effective local ablative modality should be one that can induce a high degree of tumor necrosis, with a margin, yet remain nontoxic to surrounding liver parenchyma or structures. One approach has been the use of percutaneous injection of ethanol and other agents into small tumors. Percutaneous ethanol injection (PEI) emerged in the 1980s as a minimally invasive treatment modality for the ablation of small hepatocellular carcinomas (HCCs). The technique was described first in 1983 by Sugiura et al who originally limited its use to the treatment of unresectable HCCs [1]. This technique has since been modified, enhanced, and gained widespread use in clinical practice [2–4]. Currently, a number of agents are available for percutaneous injection, including acetic acid, hot saline, drugs with chemotherapeutic activity, and, more recently hydrochloric acid and sodium hydroxide solutions. The relative simplicity of the procedure coupled with its lack of systemic toxicity, makes this technique attractive for patients and practitioners alike. Current data suggest that patients with Child class A or B cirrhosis with single tumors less than 3 cm in diameter who undergo PEI have a long-term survival rate as high as 70%, which is equal to if not better than that for many of the traditional approaches to HCC. However, survival rates have been shown to decrease considerably in patients with more advanced disease, larger tumors, or multiple lesions. For that reason, PEI has been largely restricted to the treatment of single small lesions 3 cm or less in size. This limitation has been based on the fact that it is difficult in instil ethanol throughout the entirety of larger lesions. In response, novel approaches have been developed, including laparoscopicguided injection [5], higher dose therapy [6], or percutaneous injection in combination with transcatheter arterial

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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embolization (TAE) [4, 7–9]. The theoretical advantage of combined therapy is the ability to achieve more complete tumor necrosis than can be obtained with either modality alone. In this chapter, we will review the indications for and results of percutaneous therapy for HCC and other liver tumors. We will also establish the indications for this procedure.

Mechanism of action The success of PEI centers around the pathologic features of HCCs that render them susceptible to ablation. Compared to the normal hepatic parenchyma, HCCs have an abundant blood supply and are hence detectable as a tumor blush during the arterial phase of an arteriogram or as a hyperenhancing nodule during the arterial phase of contrastenhanced computerized tomography (CT) scanning. In addition, hypervascularity can be seen using power or color Doppler ultrasound. These tumors also tend to be softer and more supple than other tumors, including metastases, and are usually surrounded by a capsule or circumference of hard hepatic parenchyma as a result of scarring and fibrosis. The precise mechanism whereby ethanol causes cell necrosis remains speculative. One mechanism is the denaturation of proteins and dehydration of the cytoplasm caused by dissemination of alcohol within neoplastic cells. The consequence of this is coagulative necrosis. An alternative mechanism relates to ethanol gaining access to the vascular supply of the tumor, resulting in necrosis of the vascular endothelium, platelet aggregation, small vessel thrombosis, and tissue ischemia. As discussed previously, since HCCs tend to be softer than surrounding cirrhotic parenchyma, alcohol diffuses through them easily and uniformly. The fact that these lesions have a rich network of vessels contributes also to the distribution of ethanol. Moreover, the presence of a capsule tends to trap the ethanol within the lesion, contributing also to its effectiveness. A recent study assessed the elimination of labeled ethanol from tumors using

CHAPTER 22

Ethanol and Other Percutaneous Injection Modalities in the Treatment of Liver Tumors

dynamic positron emission tomography (PET) [10]. The majority of tumors demonstrated a high 11C uptake shortly after the end of the ethanol injection, followed by a constant 11 C-ethanol concentration during the study period of 45 min. No significant elimination of the 11C-ethanol from the tumor was observed and no accumulation was seen in the surrounding liver tissue. In one patient, puncture of a venous channel within the tumor resulted in a decrease of the intratumoral 11C-ethanol, suggesting a mechanism for treatment failure in some patients [10]. By histologic examination, treated lesions typically show coagulative necrosis with fibrosis and areas of hemorrhage [11]. Histopathologic studies have shown that PEI can induce complete tumor necrosis in approximately 70% of patients with HCC smaller than 3 cm. The extent of necrosis is related to tumor size with an almost 100% rate of necrosis seen in tumors smaller than 2 cm. When treatment fails, viable tumor persists in small satellite nodules along the edge of the tumor and in portions of the tumor isolated by septations. The tendency of tumors such as this towards local recurrence around the capsule of the tumor has led to some investigators injecting ethanol around the capsule. Consequently, in this area surrounding the treated nodule, a lymphocytic infiltrate is seen in addition to thrombosis of blood vessels around the treated tumor.

Patient selection Even though PEI is now a well-established technique, the selection criteria for these patients continue to evolve. However, available data suggest that patients with HCCs 3 cm or smaller in size and with three or fewer lesions are the best candidates for percutaneous injection therapy. However, many centers perform PEI for HCCs up to 5 cm. Rarely have lesions up to 10 cm in size been injected [15]. In general, selection of patients thereafter relates to the availability of other treatment modalities locally and the indication for treatment. For example, PEI may be appropriate for patients who are awaiting liver transplantation. This adjuvant therapy can provide tumor necrosis without significant systemic toxicity. Moreover, in patients in whom surgical resection is not an option due to their inability to tolerate laparotomy or inadequate synthetic reserve, ethanol or other percutaneous modalities may provide prolonged survival in comparison with no therapy. Lastly, patients with pain may be palliated. Since these injections may be repeated several times over a period of months to years, they are an attractive palliative option.

Contraindications Acetic acid injection An approach to the patient with septa within the tumor nodule is the injection of percutaneous acetic acid into the tumor nodule. Acetic acid has stronger necrotizing power than ethanol because of its ability to dissolve lipids and extract collagen. The observation that septum formation increases as the size of the tumor increases was critical in understanding the biologic activity of this agent [12, 13]. Septations occur in approximately 50% of tumors ranging in size from 1.5 cm to 2 cm and in 70% of tumors between 2 and 3 cm in size. These septa contain Type I and Type III collagen, whereas Type IV collagen is typically seen in the vessels of the fibrous capsule. To treat larger HCCs, many treatment sessions may be needed in order to treat individual nodules within a single tumor. Since ethanol is unable to penetrate the septum, an alternative approach has been acetic acid injection. Acetic acid injected into one nodule will penetrate through septa because of its low pH. This induces swelling of the fibers and promotes dissociation of intermolecular cross-links containing aldimine bonds of collagen within the septa [14]. Even with this instability however, small HCC cannot be treated successfully in one treatment session since it takes several hours or a day for acetic acid to solubilize interstitial and basement membrane collagens.

PEI is contraindicated in the presence of large ascites, severe thrombocytopenia, or coagulopathy. In addition, large infiltrating lesions greater than 5 cm in size are a contraindication to therapy in most centers. Tumors causing thrombosis of the main portal or hepatic veins are also considered contraindications. Despite this, some investigators have injected ethanol directly into clots within the portal system and used its irritant properties as a thrombolytic agent [16]. Following partial or complete clot lysis, PEI of the remaining HCC was undertaken [16]. Tumors on the surface of the liver are typically not ideal for PEI because of potential leakage from the tumor into the peritoneal cavity. In addition, there is a substantial risk of tumor seeding into the abdominal cavity. Finally, lesions that are situated near the bile ducts or near major blood vessels may result in arterial or venous thromboses. This can result in biliary ischemia, liver infarction, and secondary structuring.

Procedure A number of needles have been used for percutaneous therapies. A 20 or 22G (outer diameter) needle of 15–20 cm length is used. Examples of these include the Crown or Chiba needles. These needles are efficacious, inexpensive, and familiar to most physicians performing image-guided

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procedures. However, they have some drawbacks. Specifically, they have a single end hole that squirts the alcohol or other agent forcibly into a localized area of tumor. This method of deployment may result in uneven distribution of alcohol throughout the lesion. Other needles, particularly those with an angled bevel, may deflect the needle away from its intended target. In addition, these needles can be difficult to identify by ultrasound once placed within the liver. To overcome these disadvantages, other needles that have been created, including the Bernadino needle (Cook, Bloomington, IN, USA), that offer a theoretical advantage over standard single end hole needles. These needles have pointed rather than beveled tips, and therefore track in a straight line on insertion. A further advantage is the presence of multiple side holes that allow infusion of the injection agent throughout the nodule. These needles are also easier to visualize than some of the other needles due to enhanced echogenicity from multiple side holes.

Imaging modality The ability to perform percutaneous therapy is dependent on the physician’s skill in performing interventional procedures using either ultrasound or CT. If a lesion is identifiable by ultrasound, then this is the modality of choice. Its principle advantage is its “real-time” capability during both needle placement and ethanol injection. This ability allows the procedure to be short compared to either conventional or helical CT guidance. Another advantage of ultrasound is that needle guides may be attached to the transducer, facilitating accurate and efficient needle placement. CT may be used instead of ultrasound as long as the lesion can be seen on noncontrast-enhanced CT scan. With CT, the steps in needle placement are identical to those in ultrasound, although the procedure tends to take more time. CT is the modality of choice when a lesion cannot be seen and accessed safely using ultrasound. One study examined the outcomes of 51 patients who underwent PEI between 1994 and 2001 for difficult to access HCCs [17]. Fifty-one patients had 57 nodules undetectable with ultrasound and 71 percutaneous injection sessions were performed with CT guidance via the transthoracic route. Using this route, the rate of pneumothorax was 30%, moderate pleural effusion 6%, and hemoptysis 4%. Despite this, tumor necrosis was noted on CT in 51 nodules (89%). During follow-up, local recurrence was seen in 12%, and repeat treatment with transthoracic PEI was undertaken. Twenty-six patients survived, and 25 patients died of multiple tumors, hepatic failure, or rupture of esophageal varices [17].

Sedation Conscious sedation is routinely used during percutaneous therapies. Typically, a short-acting benzodiazepine such as midazolam is utilized. In addition, a narcotic agent such as

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fentanyl citrate is utilized to control pain. Sedation should not be undertaken without monitoring of vital signs and oxygen saturation. Although it has been suggested that percutaneous injection therapy be performed under general anesthesia, typically this is not required and should probably be reserved for treatment of larger tumors or for patients with greater than three detectable lesions on imaging [3].

Technique of percutaneous injection Slight variation in technique is found from center to center. However, using commercially available ultrasound or CT, the lesion is localized. Using sterile technique, and induction of local anesthesia, a skinny needle, 20 or 22G, is placed within the lesion. Ethanol (sterile ethyl alcohol, 95%) or acetic acid (50%) is drawn into a syringe with or without an attached plastic extension tube. Ethanol or acetic acid is slowly instilled throughout the lesion, which is monitored using CT or ultrasound. Typically, the needle is placed at the farthest edge of the lesion and ethanol is deposited milliliter by milliliter as the needle is withdrawn in a stepwise fashion (Figure 22.1). Under real-time ultrasound, ethanol may be seen to seep out of the lesion into hepatic vessels or spill out onto the capsule of the liver or peritoneal space. For small lesions, single needle placement is often sufficient. For larger lesions, it may be necessary to reposition the needle within the lesion three or four times to insure adequate deposition of alcohol. If using alcohol, the appropriate volume of ethanol required to treat a lesion can be calculated by using the formula for a sphere. V ( mL ) = 4 3 × 3.14 × ( r + 0.5)

3

where V is the total volume of injected ethanol and r is the radius of the tumor in centimeters. The addition of 0.5 cm is presumed to provide a safety margin on the principle that a certain amount of surrounding tissue at the margin of the lesion must be treated to ensure complete tumor necrosis. Based on this formula, the appropriate volume for ethanol for a 1-cm lesion is 4 mL; for a 2 cm lesion is 14 mL, etc. Some authors have suggested injecting individual doses of 10 mL or less during each session. However, this requires the performance of multiple sessions for treatment of small HCCs. Typically, the maximum dose of ethanol that is injected during a single session is 30 mL. Larger doses may be used with caution [13]. For injection of acetic acid, the assumption is made that 50% acetic acid is three times more likely to necrotize hepatocytes than ethanol. For that reason, a different equation is utilized to calculate the amount of acetic acid to be injected [13]. V ( mL ) = 4 3 × 3.14 × ( r + 0.5) × 1 3 3

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Ethanol and Other Percutaneous Injection Modalities in the Treatment of Liver Tumors

(a)

(b)

(c)

(d)

Figure 22.1 The selected injection agent (ethanol, acetic acid, etc) is drawn into a syringe and attached to the injection needle. (a) Using real-time imaging, the needle is directed into the tumor and the needle is placed at the distal edge of the lesion. (b) Ethanol is injected in 1–2 mL aliquots as the needle is withdrawn and until all the tumor is treated. (c) Ethanol diffuses throughout the treated lesion. (d) Tumor necrosis ensues.

After ethanol or acetic acid is instilled, it is routine to inject a small amount of saline through the needle, to avoid spillage of alcohol into the peritoneal space. Leaving the injection needle in place for a period of several minutes following the procedure may also decrease pain and spillage. When spillage occurs, the patient typically experiences significant pain, particularly when it seeps beyond the liver capsule into the peritoneum. To counteract this, some authors suggest mixing small amounts of lidocaine with the alcohol to reduce the pain resulting from extravasation. It is also possible to place gelfoam in the needle tract to prevent spillage of alcohol into the peritoneum. Typically, the procedure is well tolerated, but occasionally the patient must be admitted to hospital for pain management. Routinely, it is an outpatient procedure requiring 4 h of observation prior to discharge.

Laparoscopic ethanol therapy As discussed, general anesthesia may be administered to facilitate injection of larger volumes of ethanol into HCCs or for treatment of multifocal lesions [3]. Another approach to tumors located in an area where it is impossible or difficult to perform PEI is the use of laparoscopy. Nine patients with HCC underwent laparoscopic ethanol injection therapy (LEIT) in one report [5]. The tumors were located on the liver surface and could be visualized by laparoscopic examination. In the majority of patients, both tumor size and alpha-fetoprotein (AFP) levels decreased after LEIT. Three cases had transient abdominal pain or portal vein damage.

Interestingly, all cases required additional therapies, including transcatheter arterial chemoembolization (TACE) or further injections of ethanol to complete the tumor necrosis. Although, LEIT appears to be a safe and effective therapy for HCC, its role remains to be clearly defined.

Complications of therapy Since the majority of patients referred for PEI have cirrhosis, a number of complications can be anticipated. Almost all patients undergoing percutaneous injection experience some pain. This can be treated with acetaminophen or with oral opiate agents. Nonsteroidal anti-inflammatory drugs should be avoided. A low-grade fever may also be present for 1–3 days following the procedure due to tumor necrosis. Again, this can be treated symptomatically. Other reported complications include pleural effusion, pneumothorax, ascites, vasovagal reactions, and myoglobinuria. Since bleeding can occur in any patient, it is important to correct coagulopathy prior to inserting any needle within the hepatic parenchyma. Specifically, a platelet count of greater than 50 000 is recommended. In addition, the international normalized ratio should be less than 1.5 and the activated partial thromboplastin time no more than 5 s prolonged. The prevalence of major complications increases with the use of higher doses of ethanol. These include liver abscess, liver failure, jaundice, bleeding requiring transfusion, portal vein thrombosis, liver infarction, damage to bile ducts,

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tumor seeding, and acute cholecystitis [15, 17–22]. These occur in 3–5% of patients. A death rate for the procedure of 0.1% is frequently cited.

Follow-up imaging PEI changes the appearance of HCC on follow-up CT, ultrasound, or MRI. In order to accurately interpret follow-up imaging in patients who have undergone injection techniques, it is important to have an appreciation of expected findings in the imaging appearance. During injection or shortly thereafter, the ethanol appears to be of low attenuation on CT scan and can mimic gas

(a)

(Figure 22.2). On ultrasound, injected ethanol is echogenic and can cause acoustic shadow. This may obscure portions of the lesion beyond the tumor. After 2–3 weeks, the lesion will liquefy and appear as fluid attenuation. At that time, a necrotic tumor will be seen. On CT, these lesions are of low attenuation. On ultrasound, they have an anechoic mass enhanced through transmission. On MRI, necrotic lesions are bright on T2-weighted images. A hematoma may often be present and will create high attenuation nonenhancing areas on contrast-enhanced CT scan. Following treatment, the lesions may increase in size and this relates to necrosis of not only the tumor but also of the surrounding parenchyma. Many inexperienced radiologists may interpret that finding as a progressive HCC rather than

(b)

(c) Figure 22.2 CT images of a 52-year-old man with a 4.5-cm hepatocellular carcinoma in the right lobe of the liver treated by percutaneous ethanol injection. (a) Contrast-enhanced CT scan obtained prior to therapy. (b) CT scan obtained following ethanol injection. Part of the lesion is now of low attenuation (arrow), with an appearance similar to that of gas, suggesting tumor necrosis in that area. (c) CT scan obtained months after injection showing calcification.

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Ethanol and Other Percutaneous Injection Modalities in the Treatment of Liver Tumors

a treated tumor. Occasionally, the lesion may mimic a hepatic infarct or abscess. This is the case if gas is introduced during the injection therapy. Two to 4 months following treatment, the treated lesions can be expected to decrease in size progressively and to form a rounded or an oval fluid-filled cavity or scar. The parenchyma surrounding the tumor may also show atrophy and retraction of the tumor capsule. Identification of recurrent tumor following ethanol injection is difficult. An adequately treated tumor typically has no areas of persistent blood flow or enhancement. If follow-up imaging reveals persistent blood flow, recurrent or persistent tumor is likely. Using contrast-enhanced CT, areas of recurrence can be seen as nodular enhancement. On color Doppler, recurrence is manifested as areas of hypervascularity [23]. On MRI scans, areas of persistent tumor are enhanced during dynamic administration of contrast agent. If a patient has undergone TACE in conjunction with PEI, the embolization material is usually combined with an agent such as lipiodol, which is of high attenuation on CT scan [24, 25]. It is important to know whether lipiodol has been injected, because high attenuation material may be misinterpreted as higher enhancement during the arterial phase of CT scan. Obtaining a four-phase CT scan clarifies this issue. It is also important to recognize that recurrence may not occur in the individual lesion itself, but that new foci of tumor may arise in the surrounding cirrhotic parenchyma. These nodules take on the appearance of HCC.

Clinical results Percutaneous ethanol injection therapy Unfortunately, there are little randomized data comparing PEI to surgical resection in the treatment of HCC. Despite this, a number of centers have examined their results obtained in treating HCC by both surgical resection and percutaneous therapy. Table 22.1 summarizes the results of some of the larger series. In a retrospective review of 1108 consecutive patients with HCC, the outcomes of 391 patients with single, small

(≤5 cm) HCCs (260 Child class A; 131 Child class B) were examined [26]. One hundred and twenty patients were treated by surgical resection, and 155 by PEI. One hundred and sixteen patients were untreated. In Child class A patients, cumulative 3-year survival was 79% for surgery and 71% for PEI, whereas survival rates of 26% at 3 years were reported for no treatment (p < 0.001 for surgery versus no treatment; p < 0.001 for PEI versus no treatment). In patients with potentially operable disease who underwent percutaneous therapy or no treatment, survival was 80% for PEI and 30% for no treatment. For Child class B patients, 3-year survival was 40% for surgically treated patients and 41% for PEI. Survival rates at 3 years were 13% for patients who received no treatment (p < 0.01 for surgery versus no treatment; p < 0.001 for PEI versus no treatment) [26]. In another large retrospective study of 534 patients seen between 1981 and 1992, the outcomes of multidisciplinary therapy for treatment of HCC were reviewed [27]. Cumulative survival curves at 1 year, 3 years, and 5 years were 66%, 33%, and 18%, respectively. Predictors of survival were female sex, hepatitis B surface antigen (HBsAg) negativity, lower Child class, and smaller tumor burden. Other investigators have challenged these predictors; however, these studies have tended to have smaller numbers of patients [27]. Survival curves for hepatectomy, PEI, and TACE overlapped to a large degree. Interestingly, survival curves obtained for patients treated during the 6-year period from 1987 to 1992 were better than those of the earlier 6-year period from 1981 to 1986, suggesting that a learning curve existed for all of the procedures. In keeping with those results, a Japanese center reported almost identical survival between cohorts treated with PEI and surgical resection [28]. One-, 3-, and 5-year overall survival rates were 100%, 82.1%, and 59%, respectively in the PEI group, and 96.6%, 84.4%, and 61.5%, respectively, in the surgery group [28]. During follow-up, 33 of 39 (85%) and 41 of 58 (71%) patients developed tumor recurrence after PEI and surgery, respectively. Cumulative 1-, 3-, and 5-year tumor-free survival rates in the percutaneous ethanol group were 63.4%, 30.3%, and 9.7%, respectively, whereas those in the surgery group were 75.5%, 44.7%, and 25.7%,

Table 22.1 Survival in selected published series following percutaneous ethanol injection of hepatocellular carcinomas of typical size less than 3 cm. Study

Ito et al (1995) [2] Ebara et al 2005 (30) Sung et al 2006 (31) Sung et al 2006 [31]

Number of patients

534 270 39 25

Tumor size (cm)

Unspecified <3 <2 >2

Survival rate (%) 1 year

3 year

5 year

66 99 95 88

33 82 76 63

18 60 55 17

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respectively (p = 0.1) Interestingly, the patients who had PEI were those who were deemed to be nonsurgical candidates. A further large multicenter Japanese study examined the treatment outcomes of 3225 patients with HCC treated with resection, TACE, and PEI [29]. Consistent with other observations, predictors of positive outcomes included tumor diameter of less than 3 cm, tumor burden less than or equal to three lesions, and clinical stage I disease. In patients with stage I disease fulfilling these criteria, survival after resection and PEI did not differ, whereas survival following embolization was significantly worse. In patients with stage II disease, survival after PEI was significantly better than after either resection or embolization. In contrast, patients with stage I or II disease with tumors greater than 3 cm in diameter and with fewer than three lesions, had better survival with surgical resection. In view of the proven efficacy of PEI in small tumors (<3 cm), and its equivalence to surgical resection in terms of survival, recent studies have focused on its use as primary therapy for HCC. In a recent Japanese report, PEI was evaluated over a 20-year period in 270 patients with small HCCs [30]. There were no treatment-related deaths and only 2.2% developed severe complications, confirming its safety. PEI induced a complete response in all HCCs on CT imaging performed 1 month after the procedure, and the local recurrence rate at 3 years was 10%. Overall 3- and 5-year survival rates were 81.6% and 60.3%, respectively. Survival rates were higher in Child class A patients (87.3% and 78.3%). Interestingly, radiofrequency ablation (RFA) was not considered possible in a 25% of this cohort for various reasons. In another recent retrospective series, from Korea, 64 patients treated with PEI as first- line therapy had 3- and 5-year survival rates of 71% and 39%, respectively, with tumor-free survival being 22% and 15%, respectively [31]. Furthermore, the 5-year survival rate for tumors smaller than 2 cm was 55% versus 17% for those tumors greater than 2 cm (p = 0.014).

Percutaneous acetic acid injection In a prospective randomized controlled trial comparing percutaneous acetic acid injection (PAAI) and PEI for small HCC, 50% acetic acid or percutaneous ethanol was injected into two cohorts [13]. In this study, all original tumors were treated successfully by either therapy. However, 8% of 38 tumors treated with PAAI and 37% of 35 tumors treated with PEI developed local recurrence (p = <0.001) during the follow-up periods of 29 ± 8 months and 23 ± 10 months, respectively. One- and 2-year survival rates were 100% and 92% in the PAAI and 83% and 63% in the PEI group, respectively (p = 0.0017). Multivariate analysis revealed that treatment modality was an independent predictor of survival. The risk ratio for PAAI versus PEI was 0.120 [13].

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A more recent prospective, nonrandomized, study demonstrated no benefit in 1- and 3-year survival (84% and 51% for PAAI versus 81% and 46% for PEI; p = 0.651) or tumor recurrence rates during a follow-up period of 24 ± 9 months [32]. PAAI required fewer treatment sessions to ablate the tumor (3.9 ± 9 1.6 versus 6.2 ± 9 2.3; p = 0.008). A further report from the same group demonstrated that PAAI is as effective as TACE for small (<3 cm) HCCs, but for tumors measuring 3–6 cm in size, TACE significantly improved both overall and progression-free survival (p = 0.018 and 0.038, respectively) [33].

Hot saline injection Against the background of toxicity observed with PEI, some investigators have turned their attention to the effects of coagulation necrosis induced by boiled physiologic saline (hot water) and devised percutaneous hot water injection therapy (PHoT) as a new local treatment method [34]. In one study, PHoT was performed a total of 41 times in 13 patients (16 nodules) with HCCs measuring less than 3 cm [34]. Changes in alpha-fetoprotein (AFP) values, CT findings, angiographic findings before and after treatment, and histopathologic findings of needle biopsy or resected specimen were investigated. AFP values decreased in all of the seven patients who initially showed high values. On CT scans, all treated lesions became hypodense, with this change thought to indicate necrosis. Disappearance of the tumor blush was confirmed in four patients by arteriography. The apparent efficacy of PHoT at inducing tumor ablation has been corroborated by Araki et al in a small, nonrandomized study of 17 patients [35]. PHoT was performed in 24 tumors ranging in size from less than 2 cm to greater than 4 cm, all of which became hypodense on follow-up CT imaging. AFP levels fell in all patients in whom it was elevated prior to injection. In a separate study, hot saline injection therapy has been performed in the treatment of large HCCs (mean diameter 7 cm) [36]. Twenty-nine patients with 31 HCCs underwent treatment. Normal saline was mixed with contrast medium and lipiodol, and the mixture was boiled and injected into the tumor. Initial regression rate for all tumors after a 3-month interval was 42% (13 of 31 tumors) and the median survival was 10.0 months (range 3–36 months). As would be expected, encapsulated tumors, tumors less than 10 cm in diameter, tumors with even saline dispersion, tumors with initial regression at 3-month follow-up, and TNM stage II or III rather than IV were predictive of prolonged survival. To date, this local treatment method has not yet been performed widely in the treatment of HCCs. One suggestion is that it may be a feasible alternative treatment for large HCCs when TACE is not feasible or has failed. However, this technique should probably be reserved

CHAPTER 22

Ethanol and Other Percutaneous Injection Modalities in the Treatment of Liver Tumors

for protocol patients until further comparative data are available.

Comparison of percutaneous ethanol injection and radiofrequency ablation From 2001 onwards, the majority of reports surrounding percutaneous therapy of HCC has centred on the comparison of more established techniques such as PEI or PAAI with the newer modality of RFA. Subsequently, four randomized controlled trials and one prospective trial have been published comparing the efficacy of RFA to PEI and, in one instance, to PAAI [37–40]. All have utilized survival as the primary outcome measure, with varying lengths of followup reported. Secondary outcome measures include tumor recurrence, disease-free survival, hospital stay, and complication rates. At the same time, a systematic review published

by the Cochrane collaboration compared RFA with other interventions (PEI and microwave ablation) suggested a benefit in disease-free, but not overall, survival with RFA over PEI [41]. This review is flawed, however, since it was undertaken when only one RCT comparing RFA and PEI had been undertaken and it fails to include the three major studies described above [37–39]. All four randomized studies have shown a benefit of RFA over PEI or PAAI in terms of a reduced frequency of treatment sessions and rate of tumor ablation. These studies have also shown RFA to improve recurrence-free and/or overall survival at up to 4 years of follow-up (Table 22.2). The complication rates between the two techniques, despite early concerns regarding RFA, do not appear to be significantly different. Multivariate analysis undertaken in these randomized controlled trials has also shown that treatment allocation (to RFA) is independently associated with improved survival. However, subanalysis in two of the

Table 22.2 Randomized controlled trials comparing radiofrequency ablation (RFA) with percutaneous ethanol injection (PEI) and/or percutaneous acetic acid injection (PAAI). Study

Number of patients

Number of sessions

Ablation rate (%)

Survival (years) (%) 1

Lin et al (2004) [37] Tumors ≤ 4 cm RFAa,b HDPEI SDPEI Shiina et al (2005) [38] Tumors < 3 cm RFAc,d PEI Lin et al (2005) [39] Tumors < 3cm RFAe,f PEI PAAI Lencioni et al (2003) [40] Tumors < 3 cm RFAg PEI

90 88 85

Disease-free survival (years) (%)

2

3

4

1

2

3

4

82 63 61

74 55 50

– – –

78 63 61

59 45 42

37 20 17

– – –

– –

– –

74 57

– –

– –

– –

– –

52 53 52

1.6 2.7 6.5

96 92 88

118 114

2.1 6.4

– –

62 62 63

1.3 4.9 2.5

96 88 92

93 88 90

81 66 67

74 51 53

– – –

74 70 71

60 41 43

43 21 23

– – –

52 51

1.1 5.9

91 82

100 96

98 88

– –

– –

98 83

96 62

– –

– –

– –

a

Improved overall survival with RFA vs SDPEI (p = 0.014) and HDPEI (p = 0.023). Improved disease free survival RFA vs SDPEI (p = 0.019) and HDPEI (p = 0.024). c Improved overall survival with RFA vs PEI (p = 0.01). d Improved overall recurrence rates with RFA vs PEI (p = 0.0007). e Improved overall survival with RFA vs PEI (p = 0.012) and PAAI (p = 0.017). f Improved disease-free survival with RFA vs PEI (0.038) and PAAI (p = 0.041). g Improved disease-free survival with RFA (p = 0.012) HDPEI, high dose percutaneous ethanol injection; SDPEI, standard dose percutaneous ethanol injection. b

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randomized studies has shown that there is no significant difference in local recurrence [37] or overall/cancer-free survival at 3 years for lesions less than 2 cm in size [39]. Indeed, other authors have also demonstrated improved survival with tumors of less than 2 cm treated with PEI alone [31].

Combined transcatheter arterial embolization/radiofrequency ablation and percutaneous ethanol injection One response to the outcomes seen following treatment of larger HCCs using the percutaneous route alone has been the amalgamation of two and sometimes three treatment modalities. First reported by Tanaka et al in 1991, the theoretical advantage of combining TAE and PEI is the potential for more complete necrosis of tumor than can be obtained using either modality alone [7]. In this approach, TAE is performed 2 weeks prior to percutaneous injection. This allows the treated tumor time to undergo necrosis and soften. This softening augments the diffusion of ethanol throughout the tumor and facilitates enhanced tumor necrosis. In one report that compared the efficacy of TACE combined with PEI versus repeated TACE in the treatment of large HCCs (>3 cm), 53 patients were enrolled in a prospective, randomized study [9]. Twenty-six patients underwent a single TACE session followed by PEI (TACE–PEI group), whereas 27 patients underwent two to five TACE sessions. After followup of 8–39 months, tumor response rates and patient survival were higher in the TACE–PEI group. In a similar study, PEI therapy was performed in 24 cases of large unresectable HCCs that had previously been treated with TACE using doxorubicin or epirubicin [42]. In patients with a tumor greater than 3 cm in diameter, or with multiple tumors, the 1-year survival rate obtained with combination therapy was 87.0%, and the 2-year survival rate was 65.2%. These rates were greater than those obtained with TACE alone. In a retrospective series of 50 patients with large unresectable HCC, repeated and combined TACE and PEI were performed in 22 patients, and repeated TACE monotherapy in 28 patients [43]. The 6-, 12-, 24-, and 36-month survival rates were 61%, 21%, 4%, and 4% for TACE monotherapy, and 77%, 55%, 39%, and 22% for combined TACE and PEI (p = 0.002). Becker et al meanwhile described a series of 52 patients with unresectable HCCs who were randomized to receive TACE or TACE plus PEI [44]. Overall survival was not statistically different between the groups, although patients with Okuda stage I disease (50% of the cohort) had longer survival in the combination therapy arm (>24 months versus 18.4 months for TACE alone; p = 0.04). In a prospective study that analyzed the clinical factors determining the prognosis of 132 inoperable HCC patients,

274

the feasibility, therapeutic efficacy, and safety of PEI, TACE, and a combination thereof was assessed [45]. Ninety-five percent of patients had cirrhosis and 39% were Okuda stage I, 48% stage II, and 13% stage III. Fifteen patients were treated by PEI, 33 by TACE, 39 by TACE and PEI, and 45 received best supportive care. Median survival time for these groups was 18 months, 8 months, 25 months, and 2 months, respectively. Multivariate analysis revealed that patients treated with a combination of TACE and PEI have a significantly better survival than patients receiving either PEI or TACE only (p = 0.001) and that favorable outcome can be expected in patients with compensated cirrhosis, low Okuda stage, a baseline AFP less than 100 ng/mL, and absence of portal vein thrombosis [45]. A further, nonrandomized study using combination TACE and PEI reported complete tumor responses in 71 of 86 (82%) patients treated and partial response in 15 of 86 (18%) [46]. Again, survival of Child class A patients (75% at 3 years and 59% at 5 years) was significantly longer (p < 0.01) than that of Child class B patients (61% at 3 years and 35% at 5 years) [46]. Jang et al reported cumulative survival rates at 6, 12, 18, and 24 months with TACE followed by PEI every 4 weeks compared with TACE alone, and showed rates of 90%, 57%, 27%, and 17% in the combination therapy cohort and 73%, 37%, 7%, and 0% for TACE monotherapy with an associated improved median survival of 13.5 months versus 10.5 months (p = 0.026) [47]. The long-term efficacy of TACE combined with transportal ethanol injection (TPEI) in patients with HCC has also been reported [48]. Twenty-six patients with unresectable HCC (2–9 cm) underwent TPEI 2–6 weeks after TACE. Ethanol (10–65 mL) was injected via a percutaneous transhepatic approach into the portal vein, perfusing the segment to be treated. TACE was repeated after TPEI in 18 patients. Therapy was technically successful in all 26 cases. Irreversible hepatic failure developed in two (8%) patients, and recurrent disease occurred either from the treated lesion or apart from the treated liver segment in nine of 21 patients (43%) followed up for a mean of 34 months. Survival rates were 87%, 72%, 72%, 63%, 51%, and 51% at 1, 2, 3, 4, 5, and 6 years, respectively [48]. Recently, Seror et al retrospectively evaluated the effectiveness of percutaneous intra-arterial ethanol with or without standard PEI for advanced HCC [49]. Only four patients were treated with intra-arterial injection alone and 14 received combination therapy. Tumor necrosis was complete in 88% and 1- and 2-year survival was 76.6% and 44.5%, respectively. However two patients who received intra-arterial ethanol developed serious complications (one liver abscess and one fatal pancreatitis) [49]. The use of this modality in patients with advanced disease, therefore, must be tempered by the low numbers of patients in this study and the potentially high serious complication rate.

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Ethanol and Other Percutaneous Injection Modalities in the Treatment of Liver Tumors

Several investigators have coined the term “multiablation therapy” to describe the combination therapy comprising RFA, microwave coagulation therapy (MCT), and PEI [50]. In 20 patients with advanced HCC, including 10 patients with stage III and 10 patients with stage IV disease (mean tumor diameter 3.6 cm [max: 6.6 cm]; mean tumor number 3.6 [max: 11 cm]), RFA, MCT, and PEI were performed in 20, 14, and 9 cases, respectively. The response rate, calculated from the tumor necrosis effect, was 100%. The cumulative 2-year recurrence rate in the treated sites was 33% and the 2-year cumulative survival rate was 90% [50]. A single study has evaluated PEI and RFA in combination and results have been compared with RFA alone in 73 patients with biopsy-proven HCC [51]. Although no survival data are available, patients treated with the RFA–PEI combination demonstrated a significantly greater volume of coagulative necrosis by volume. Similarly, a recent Italian report evaluated 40 consecutive patients with HCC of greater than 4 cm undergoing combined PEI and RFA [52].

Percutaneous ethanol injection of metastatic disease A further potential role for percutaneous injection modalities is the treatment of metastatic disease to the liver. As would be expected, experience to date has been limited and disappointing. In animal models, it has been shown that alcohol injected into metastatic deposits tends to flow away from the tumor and tracks into the normal hepatic parenchyma and hepatic capsule. As discussed previously, metastatic disease tends to be harder than HCC or indeed the surrounding liver. In 1991, Livraghi et al reported the results of PEI of 21 metastases in 14 patients [53]. Primary cancers were colorectal, stomach, leiomyosarcoma, gastrinoma, bronchial carcinoid or of unknown origin (one patient). No complications occurred after a total of 175 treatment sessions with a complete response obtained in 11 lesions, particularly those less than 2 cm in diameter. All endocrine metastases responded well. Disease-free follow-up was 38 months. The authors concluded that single metachronous, nonoperable metastases of adenocarcinoma and endocrine origin seemed to be reasonable indications for PEI. In a separate Italian report, Giorgio et al described 33 patients with 62 large liver metastases who were ineligible for surgery or RFA and were treated over a 4-year period with PEI under general anesthesia [54]. The diameter of the nodules ranged from 35 to 92 mL (mean 39 mL). Twenty-five to 110 mL of ethanol were injected at each session. Complete necrosis of metastases was obtained in 30% of patients whilst the rate of necrosis ranged from 70% to 90% in 21 patients and 50% in two patients. Survival rates at 12, 24, and 36 months were 94%, 80%, and 80%, respectively. Survival at 44 months was 44%.

In light of the above data, other treatment modalities have been adopted to treat metastatic disease of the liver. Subsequently RFA has, in recent years, supplanted PEI as the primary percutaneous modality in the treatment of liver metastases not amenable to surgical resection. This practice has been based on the apparent greater ability of RFA to ablate tumors in cohort series, although there have been no head-to-head comparisons with PEI. In addition, long-term follow-up data are limited and surgical resection remains the therapeutic mainstay for metastatic tumors of the liver. The use of RFA in this setting is discussed in greater detail in Chapter 21.

Intralesional chemotherapy Direct injection of cytotoxic agents has not been practical in the past due to rapid drug dispersion into surrounding tissue and the systemic circulation shortly after injection into the tumor. To address this problem, a modified-release drugdelivery system that provides a high intratumoral concentration of cisplatin for extended periods, with significantly reduced system exposure tissue, has been developed (Matrix Pharmaceutical Inc, Fremont, CA, USA) and used in the treatment of both HCC and colorectal metastases [55]. The novel drug, cisplatin/epinephrine (CDDP/epi) injectable gel, combines cisplatin and epinephrine, a vasoconstrictive agent, in a biodegradable matrix made of purified, buffered, nonpyrogenic bovine collagen that acts as a gellant. The objective of phase II open-labeled studies was to examine the efficacy and safety of CDDP/epi gel in the treatment of patients with localized unresectable metastases or HCC. Drug was injected directly into the tumors using an analogous technique to that described for ethanol or acetic acid. In preliminary studies, selected patients with HCC were bridged to orthotopic liver transplant with intralesional chemotherapy used as an alternative to TACE [55]. Figure 22.3 shows the effect of CDDP/epi injectable gel on two HCCs in a patient who went on to obtain a liver graft. Other approaches have included percutaneous injection of boiling carboplatin, which was tested on 57 small HCCs in 32 patients [56]. A 93% ablation rate and a local recurrence rate at 12 months of 16.2% have been reported, without major complications observed.

Cost PEI, PAAI, or PHoT are relatively low-cost procedures. Most radiology departments have ultrasound machines. The treatment is performed on an outpatient basis and a single physician and nurse are required. Although general anesthesia has been suggested by some authors, this is not a require-

275

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Resection, Ablation or Transplantation

A

B

(a)

(b)

(c)

(d)

Figure 22.3 CT images of a 62-year-old woman with multifocal hepatocellular carcinoma (HCC) treated with intralesional collagen cisplatin gel. (a) Contrast-enhanced CT scan showing two HCCs (labeled A and B). (b) CT scan obtained during percutaneous injection of cisplatin gel. (c) Contrastenhanced CT scan showing hypoattenuation of the treated lesions following four injection sessions (labeled A and B). (d) CT scan obtained 6 months following cessation of treatment showing calcification within the treated tumor. This signifies complete tumor necrosis. This radiologic appearance was confirmed histologically on examination of the explanted liver following orthotopic liver transplantation.

ment. In addition, these procedures are significantly less invasive and cheaper than those performed under laparoscopic control. Moreover, when compared to the cost of liver transplantation or surgical resection, there is a significant cost differential. This has been confirmed by Gournay et al who evaluated the long-term survival of patients undergoing either PEI or surgical resection and the costs per month of survival [57]. They demonstrated no difference in survival for tumors less than 3 cm but confirmed a survival benefit in favor of resection for lesions greater than 3 cm. Costs per month of survival were higher in the resection than the PEI

276

group (Euro 3865 versus Euro 999 [US$3792 versus US$980], respectively; p = <0.001). Additionally, Seror et al retrospectively determined the cost of treatment of RFA versus PEI, utilizing factors such as hospital stay related to treatment or complications, procedural devices, and imaging during follow-up (US and CT until complete ablation) [57]. Costs per patient amounted to Euro 1534 (approximately US$1973) for PEI and Euro 1196 (US$1538) for RFA, with the benefit most likely derived from the lower number of treatment sessions required with RFA versus PEI (1.1 versus 4.3, respectively) [57].

CHAPTER 22

Ethanol and Other Percutaneous Injection Modalities in the Treatment of Liver Tumors

The future of percutaneous therapy In tandem with the development of intralesional chemotherapy, other investigators have developed a percutaneous low-concentration alkali injection therapy (PLAIT) (an alkaline solution of sodium hydroxide [NaOH]) targeting HCC [58]. In a murine model, the results are promising but to date there have been no human studies. Alternatively, an acidic solution (6 mol/ hydrochloric acid [HCl]) has recently been tested on pig liver to assess its necrotic effect in comparison to PEI and PAAI [59], and 30 human subjects with HCC have also been treated with percutaneous HCl. This solution in pigs demonstrated greater coagulative effects than either PEI or PAAI, whilst in patients treated with HCl, high levels of tumor ablation were seen. One-, 2-, and 3-year survival was 100%, 90%, and 85%, respectively. No major complications were noted. HCC remains a disease process with considerable heterogeneity and therefore treatment options will continue to be individualized. For percutaneous therapy the major unresolved issues with regard to curative intent appear to revolve around whether RFA is of greater efficacy than PEI or PAAI for small HCCs less than 2 cm in size, and whether the combination of TACE and PEI is superior to RFA [60]. Additionally, further study into approaches to downsize tumors with subsequent curative intent is warranted. For palliative therapy, larger, randomized studies of TACE plus PEI (or possibly RFA plus PEI) are required to assess whether preliminary data suggesting improved survival with combination therapy represent a true phenomenon. To date, however, the relevant studies addressing these issues have not been published.

Conclusion Twenty years of experience with percutaneous ablative therapies have given a clear understanding of the limitations and benefits of these procedures. PEI and PAAI are safe, well tolerated, relatively cheap, and, in selected patients, associated with improved survival. In the last decade, however, RFA has become increasingly popular as a first-line treatment modality for nonsurgically managed HCC. This popularity has been based on the observation of improved survival with fewer treatment sessions and, despite initial concerns, a comparable complication rate. The unresolved issue is whether the benefit for RFA over PEI exists only for tumors greater than 2 cm in size. In that context, current data suggest that PEI remains an excellent choice for curative or adjunctive treatment of small HCC (<2 cm). Such differences in survival with tumors larger than 2 cm likely reflect the mode of action of the two therapies and this must be borne in mind when choosing which treatment modality to utilize

for any given patient. Similarly, many patients are unsuitable for RFA due either to tumor location and/or comorbidity, and again, PEI is an attractive option in such patients.

Self-assessment questions 1 Which of the following statements are true regarding septa within hepatocellular carcinomas? (more than one answer is possible) A Are present in 10% of tumors less than 2 cm B Are present in 50% of tumors of 1.5–2 cm C Rarely interfere with the efficacy of intralesional injection D May require multiple treatments using ethanol injection E Are more likely to be penetrated by acetic acid due to its lower pH 2 Percutaneous ethanol injection is contraindicated in which of the following? (more than one answer is possible) A In the presence of large ascites B In tumors greater than 5 cm in most centers C Severe thrombocytopenia or coagulopathy D In the presence of portal vein thrombosis E In tumors less than 2 cm 3 Percutaneous ethanol injection should not be used routinely in which one of the following? A In the treatment of single small lesions 3 cm or less in size B In conjunction with laparoscopy C In combination with transcatheter arterial embolization D To treat focal metastatic disease E For lesions greater than 5 cm in size 4 Which of the following statements regarding the prevalence of major complications from percutaneous ethanol injection are true? (more than one answer is possible) A Increases with the use of higher doses of ethanol B Include liver abscess formation C Include liver failure D Include bleeding requiring transfusion and a death rate of 0.1% E Include portal vein thrombosis and liver infarction 5 Using the approach of combined PEI and TAE, PAE is performed 2 weeks prior to percutaneous injection to allow the treated tumor time to undergo necrosis and

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soften, because softening augments the diffusion of ethanol throughout the tumor necrosis. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct

References 1 Sugiura N, Takara T, Ohto M, et al. Percutaneous intratumoral injection of ethanol under ultrasound imaging for treatment of small hepatocellular carcinoma. Acta Hepatol Jpn 1983;24: 920. 2 Ito T, Urabe Y, Shiraga K, et al. Retrospective analysis of the multidisciplinary treatment for 534 hepatocellular carcinoma patients over a 12-year period. Intern Med 1995;34:623–7. 3 Giorgio A, Tarantino L, de Stefano G, et al. Ultrasound-guided percutaneous ethanol injection under general anesthesia for the treatment of hepatocellular carcinoma on cirrhosis: long-term results in 268 patients. Eur J Ultrasound 2000;12:145–54. 4 Koda M, Murawaki Y, Mitsuda A, et al. Combination therapy with transcatheter arterial chemoembolization and percutaneous ethanol injection compared with percutaneous ethanol injection alone for patients with small hepatocellular carcinoma: a randomized control study. Cancer 2001;92:1516–24. 5 Okano H, Shiraki K, Inoue H, et al. Laparoscopic ethanol injection therapy for hepatocellular carcinoma. Int J Oncol 2002; 20:267–71. 6 Meloni F, Lazzaroni S, Livraghi T. Percutaneous ethanol injection: single session treatment. Eur J Ultrasound 2001;13: 107–15. 7 Tanaka K, Okazaki H, Nakamura S, et al. Hepatocellular carcinoma: treatment with a combination therapy of transcatheter arterial embolization and percutaneous ethanol injection. Radiology 1991;179:713–7. 8 Okano H, Shiraki K, Inoue H, et al. Combining transcatheter arterial chemoembolization with percutaneous ethanol injection therapy for small size hepatocellular carcinoma. Int J Oncol 2001;19:909–12. 9 Bartolozzi C, Lencioni R, Caramella D, et al. Treatment of large HCC: transcatheter arterial chemoembolization combined with percutaneous ethanol injection versus repeated transcatheter arterial chemoembolization. Radiology 1995;197:812–8. 10 Dimitrakopoulou-Strauss A, Gutzler F, Strauss LG, et al. PET studies with C-11 ethanol in intratumoral therapy of hepatocellular carcinomas. Radiologe 1996;36:744–9. 11 Fujita T, Ito K, Choji T, et al. Hepatic parenchymal changes after ethanol injection in rabbits: correlation of conventional and dynamic MR imaging with pathologic findings. J Magn Reson Imaging 1996;6:156–61. 12 Ohnishi K. Comparison of percutaneous acetic acid injection and percutaneous ethanol injection for small hepatocellular carcinoma. Hepatogastroenterology 1998;45 (Suppl 3):1254–8.

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13 Ohnishi K, Yoshioka H, Ito S, Fujiwara K. Prospective randomized controlled trial comparing percutaneous acetic acid injection and percutaneous ethanol injection for small hepatocellular carcinoma. Hepatology 1998;27:67–72. 14 Timpl T, Wiedemann H, Delden VV, et al. A network model for the organization of type IV collagen molecules in basement membranes. Eur J Biochem 1981;120:203–11. 15 Livraghi T, Benedini V, Lazzaroni S, et al. Long term results of single session percutaneous ethanol injection in patients with large hepatocellular carcinoma. Cancer 1998;83:48–57. 16 Livraghi T, Grigioni W, Mazziotti A, et al. Percutaneous alcohol injection of portal thrombosis in hepatocellular carcinoma: a new possible treatment. Tumori 1990;76:394–7. 17 Shibata T, Iimuro Y, Yamamoto Y, et al. CT-guided Transthoracic Percutaneous Ethanol Injection for Hepatocellular Carcinoma Not Detectable with US. Radiology 2002;223:115–20. 18 Isobe H, Fukai T, Iwamoto H, et al. Liver abscess complicating intratumoral ethanol injection therapy for HCC. Am J Gastroenterol 1990;85:1646–8. 19 Matsushita E, Unoura M, Inagaki Y, et al. Portal perfusion defect after percutaneous ethanol injection therapy (PEIT) for hepatocellular carcinoma (HCC). Nippon Shokakibyo Gakkai Zasshi 1990;87:1537–43. 20 Koda M, Okamoto K, Miyoshi Y, et al. Hepatic vascular and bile duct injury after ethanol injection therapy for hepatocellular carcinoma. Gastrointest Radiol 1992;17:167–9. 21 Nakano H, Sasaki Y, Imaoka S, et al. A case of hepatocellular carcinoma implantation to chest wall by percutaneous ethanol injection therapy. Gan To Kagaku Ryoho 1994;21:2350–3. 22 Shimada M, Maeda T, Saitoh A, et al. Needle track seeding after percutaneous ethanol injection therapy for small hepatocellular carcinoma. J Surg Oncol 1995;58:278–81. 23 Sato S, Shiratori Y, Imamura M, et al. Power Doppler signals after percutaneous ethanol injection therapy for hepatocellular carcinoma predict local recurrence of tumors: a prospective study using 199 consecutive patients. J Hepatol 2001;35: 225–34. 24 Bartolozzi C, Lencioni R, Armillotta N. Combined treatment of hepatocarcinoma with chemoembolization and alcohol administration. Long-term results. Radiol Med (Torino) 1997;94:19–23. 25 Lencioni R, Caramella D, Vignali C, et al. Lipiodol-CT in the detection of tumor persistence in hepatocellular carcinoma treated with percutaneous ethanol injection. Acta Radiol 1994;35:323–8. 26 Livraghi T, Bolondi L, Buscarini L, et al. No treatment, resection and ethanol injection in hepatocellular carcinoma: a retrospective analysis of survival in 391 patients with cirrhosis. Italian Cooperative HCC Study Group. J Hepatol 1995;22:522–6. 27 Pompili M, Rapaccini GL, Covino M, et al. Prognostic factors for survival in patients with compensated cirrhosis and small hepatocellular carcinoma after percutaneous ethanol injection therapy. Cancer 2001;92:126–35. 28 Yamamoto J, Okada S, Shimada K, et al. Treatment strategy for small hepatocellular carcinoma: comparison of long-term results after percutaneous ethanol injection therapy and surgical resection. Hepatology 2001;34:707–13. 29 Ryu M, Shimamura Y, Kinoshita T, et al. Therapeutic results of resection, transcatheter arterial embolization and percutaneous transhepatic ethanol injection in 3225 patients with hepatocel-

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30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

Ethanol and Other Percutaneous Injection Modalities in the Treatment of Liver Tumors

lular carcinoma: a retrospective multicenter study. Jpn J Clin Oncol 1997;27:251–7. Ebara M, Okabe S, Kita K, et al. Percutaneous ethanol injection for small hepatocellular carcinoma: therapeutic efficacy based on 20-year observation. J Hepatol 2005;43:458–64. Sung YM, Choi D, Lim HK, et al. Long-term results of percutaneous ethanol injection for the treatment of hepatocellular carcinoma in Korea. Korean J Radiol 2006;7:187–92. Huo TI, Huang YH, Wu JC, et al. Comparison of percutaneous acetic acid injection and percutaneous ethanol injection for hepatocellular carcinoma in cirrhotic patients: a prospective study. Scand J Gastroenterol 2003;38:770–8. Huo T, Huang YH, Wu JC, et al. Comparison of transarterial chemoembolization and percutaneous acetic acid injection as the primary loco-regional therapy for unresectable hepatocellular carcinoma: a prospective survey. Aliment Pharmacol Ther 2004;19:1301–8. Honda N, Guo Q, Uchida H, et al. Percutaneous hot water injection therapy (PHoT) for hepatic tumors: a clinical study. Nippon Igaku Hoshasen Gakkai Zasshi 1993;53:781–9. Araki Y, Hukano M, Urabe M, et al. Hepatocellular carcinoma treated by percutaneous hot saline injection. Oncol Rep 2004;12:569–71. Yoon HK, Song HY, Sung KB, et al. Percutaneous hot saline injection therapy: effectiveness in large hepatocellular carcinoma. J Vasc Interv Radiol 1999;10:477–82. Lin SM, Lin CJ, Lin CC, et al. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or = 4 cm. Gastroenterology 2004;127: 1714–23. Shiina S, Teratani T, Obi S, et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 2005;129: 122–30. Lin SM, Lin CJ, Lin CC, et al. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less. Gut 2005;54:1151–6. Lencioni R, Allgaler H-P, Cioni D, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 2003;228:235–40. Galandi D, Antes G. Radiofrequency thermal ablation versus other interventions for hepatocellular carcinoma. Cochrane Database Syst Rev 2004(2):CD003046. Kato T, Saito Y, Niwa M, et al. Combination therapy of transcatheter chemoembolization and percutaneous ethanol injection therapy for unresectable hepatocellular carcinoma. Cancer Chemother Pharmacol 1994;33 (Suppl):S115–18. Lubienski A, Bitsch RG, Schemmer P, et al. Long-term results of interventional treatment of large unresectable hepatocellular carcinoma (HCC): significant survival benefit from combined transcatheter arterial chemoembolization (TACE) and percutaneous ethanol injection (PEI) compared to TACE monotherapy. Rofo 2004;176:1794–802. Becker G, Soezgen T, Olschewski M, et al. Combined TACE and PEI for palliative treatment of unresectable hepatocellular carcinoma. World J Gastroenterol 2005;11:6104–9.

45 Allgaier HP, Deibert P, Olschewski M, et al. Survival benefit of patients with inoperable hepatocellular carcinoma treated by a combination of transarterial chemoembolization and percutaneous ethanol injection–a single-center analysis including 132 patients. Int J Cancer 1998;79:601–5. 46 Lencioni R, Paolicchi A, Moretti M, et al. Combined transcatheter arterial chemoembolization and percutaneous ethanol injection for the treatment of large hepatocellular carcinoma: local therapeutic effect and long-term survival rate. Eur Radiol 1998;8:439–44. 47 Jang JW, Park YM, Bae SH, et al. Therapeutic efficacy of multimodal combination therapy using transcatheter arterial infusion of epirubicin and cisplatin, systemic infusion of 5-fluorouracil, and additional percutaneous ethanol injection for unresectable hepatocellular carcinoma. Cancer Chemother Pharmacol 2004;54: 415–20. 48 Yamakado K, Nakatsuka A, Tanaka N, et al. Long-term follow-up arterial chemoembolization combined with transportal ethanol injection used to treat hepatocellular carcinoma. J Vasc Interv Radiol 1999;10:641–7. 49 Seror O, N’Kontchou G, Haddar D, et al. Large infiltrative hepatocellular carcinomas: treatment with percutaneous intraarterial ethanol injection alone or in combination with conventional percutaneous ethanol injection. Radiology 2005;234:299–309. 50 Beppu T, Ishiko T, Doi K, et al. A promising new treatment strategy for advanced hepatocellular carcinoma – “multiablation therapy” consisting of radio-frequency ablation (RFA), microwave coagulation therapy (MCT) and ethanol injection therapy (EIT). Gan To Kagaku Ryoho 2001;28:1583–6. 51 Kurokohchi K, Watanabe S, Masaki T, et al. Combined use of percutaneous ethanol injection and radiofrequency ablation for the effective treatment of hepatocellular carcinoma. Int J Oncol 2002;21:841–6. 52 Vallone P, Catalano O, Izzo F, et al. Combined ethanol injection therapy and radiofrequency ablation therapy in percutaneous treatment of hepatocellular carcinoma larger than 4 cm. Cardiovasc Intervent Radiol 2006;29:544–51. 53 Livraghi T, Vettori C, Lazzaroni S. Liver metastases: results of percutaneous ethanol injection in 14 patients. Radiology 1991;179:709–12. 54 Giorgio A, Tarantino L, Mariniello N, et al. Ultrasonographyguided percutaneous ethanol injection in large an/or multiple liver metastasis. Radiol Med (Torino) 1998;96:238–42. 55 Thuluvath PJ, Geschwind JF, Johnson PJ, et al. Management of hepatoma using cisplatin/epinephrine gel in patients awaiting orthotopic liver transplantation. Transplant Proc 2001;33: 1359–60. 56 Yin XY, Shen Q, Lu MD, et al. Ultrasound-guided percutaneous boiling carboplatin injection (PBCI) for the treatment of small hepatocellular carcinoma: a preliminary study. Hepatogastroenterology 2004;51:1129–34. 57 Gournay J, Tchuenbou J, Richou C, et al. Percutaneous ethanol injection vs. resection in patients with small single hepatocellular carcinoma: a retrospective case-control study with cost analysis. Aliment Pharmacol Ther 2002;16:1529–38. 58 Seror O, N’Kontchou G, Tin Tin Htar M, et al. Ethanol versus radiofrequency ablation for the treatment of small hepatocellular carcinoma in patients with cirrhosis: a retrospective

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study of efficacy and cost. Gastroenterol Clin Biol 2006;30: 1265–73. 59 Tamai T, Seki T, Imamura M, et al. Percutaneous injection of a low-concentration alkaline solution targeting hepatocellular carcinoma. Oncol Rep 2000;7:719–23. 60 Weijian F, Zan L, Suhong H, et al. Destructive effect of percutaneous hydrochloric acid injection therapy for liver cancer – a preliminary experimental and clinical study. Gan To Kagaku Ryoho 2006;33:1852–6.

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Self-assessment answers 1 2 3 4 5

B, D, E A, B, C E A, B, C, D, E E

23

Transplantation for Liver Tumors François Durand1, Claire Francoz1, and Jacques Belghiti2 1 2

Hepatology and Liver Intensive Care, Hospital Beaujon, Clichy, France Department of Hepatobiliary Surgery, Hospital Beaujon, Clichy, France

Introduction The use of solid organ transplantation to treat malignancies is unique to the liver. Indeed, transplantation of other solid organs, such as lungs or kidneys, has not been validated as a treatment for tumors originating from these organs. In the 1980s and early 1990s, while the general results of transplantation had improved, it was felt that liver transplantation might be the only curative treatment for patients with unresectable primary liver tumors, in particular large unresectable hepatocellular carcinoma (HCC). Unfortunately, most series reported during this period showed dismal results with 3-year survival rates of 30% or less [1]. Even in patients who had no evidence of extrahepatic involvement on pretransplant imaging, the most frequent cause of death was tumor recurrence. Additionally, tumor growth was markedly accelerated by post-transplant immunosuppression. These poor results illustrated the inability of preoperative staging to detect established micrometastases as the source of early recurrence. In view of these poor results, the indications for transplantation had to be revisited. Due to organ shortage and limitations in resource utilization, transplantation was restricted to the subset of patients expected to have the best prognosis. It would not be acceptable to allocate an organ to a patient with a very limited life-expectancy when this organ could be allocated to another recipient with a better prognosis. Liver transplantation was almost abandoned in patients with secondary liver tumors and cholangiocarcinoma. In patients with HCC, selection criteria were established to identify those candidates who had the lowest risk of post-transplant recurrence (i.e. those with small tumors). Thereafter, in patients with small HCC, the results of transplantation proved to be nearly as good as those obtained in cirrhotic patients without malignancy.

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

The good results reported by the mid 1990s led to greater confidence in transplantation. We are now faced with a third period characterized by a trend to relax the selection criteria. This trend is supported by the fact that the net benefit from transplantation in patients who are not considered to be optimal candidates remains relatively high compared to medical therapy alone. Life-expectancy after transplantation in patients with relatively large tumors exceeds that of many patients receiving chemotherapy or radiotherapy for other types of malignancies. Nonetheless, the use of transplantation in patients with liver tumors must always be considered in the general context of organ shortage and limited resource utilization. The aims of this chapter are to review the practice and results of liver transplantation for liver tumors, to expose therapeutic interventions that may help improve the results, and to discuss future directions.

Liver transplantation for hepatocellular carcinoma Basic concepts The vast majority of patients who develop HCC have underlying cirrhosis. The characteristic parenchymal changes defining cirrhosis can be considered an oncogenic condition. It is very rare that patients without any degree of liver fibrosis develop HCC. HCC is present in 5–15% of patients at the time cirrhosis first manifests. In those who do not have malignancy at presentation, the annual incidence of “de novo” HCC is about 1–5% [2]. In Western countries, chronic hepatitis C has been an increasingly important cause of cirrhosis and HCC. Cirrhosis is not only a predisposing factor for HCC; it also limits the access to most radical therapeutic interventions. Indeed, in patients with cirrhosis, regeneration capacities and “hepatic reserve” are limited. As a consequence, extended liver resection would result in early postoperative liver failure. Only limited resection is safely applicable, provided cirrhosis is compensated.

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Table 23.1 Results of liver transplantation for hepatocellular carcinoma in patients with cirrhosis. Authors

Bismuth et al [6] Mazzaferro et al [7] Ojogho et al [9] Figueras et al [10] Hemming et al [11] Decaens et al [12] Yao et al [13]

Year

1993 1996 1996 1997 2001 2006 2007

Number of patients

60 48 26 38 112 479 168

Tumor outside Milan criteria (%)

25 0 − 11 − 40 77

Survival (%) 1 year

3 year

5 year

75 90 73 82 78 − 95

49 75 65 79 63 − −

− − − 75 57 60* 81

* In patients meeting the Milan criteria.

Due to the generalization of systematic screening by ultrasonography, an increasing number of tumors are detected at an early stage of compensated cirrhosis. Surgical resection and percutaneous radiofrequency ablation (RFA) represent first-line options for small tumors with excellent results at 3–5 years [3, 4]. However, in the long term, the efficacy of these treatments is limited by a high rate of recurrence since the patients are left with a cirrhotic liver [5]. In addition, even in the absence of recurrence, severe complications of cirrhosis may also occur. Over 5 years, transplantation offers survival and recurrence-free survival that are superior to those following resection or local ablation. As a consequence, liver transplantation represents the safest option in the long term as it cures both the tumor and the underlying liver disease. As indicated above, patients with large tumors are not suitable for transplantation, even in the absence of detectable extrahepatic involvement, due to a high rate of early recurrence and an especially poor prognosis. In contrast, as early as in the 1990s, the results of transplantation in selected patients with small tumors proved to be as good as those obtained in cirrhotic patients without malignancy [6]. Following these early reports, the good results of transplantation were confirmed by a number of series [7–13] (Table 23.1). In patients with decompensated cirrhosis and small HCC, liver transplantation is the only “curative” option since other aggressive treatments are generally contraindicated. Again, long-term results of transplantation in patients with decompensated cirrhosis and small HCC proved comparable to those obtained in patients without malignancy. In patients with compensated cirrhosis and small HCC, options other than transplantation can be proposed. However, on an individual basis, there is no clear justification for discounting patients with compensated cirrhosis and small HCC, since transplantation offers better results than resection or local ablation in the long term.

282

Selection criteria in patients with cirrhosis Diagnosis of HCC In patients with compensated cirrhosis, HCC should be definitely ascertained before making a decision about transplantation. Indeed, in this group, transplantation would not be justified in the absence of malignancy. Diagnostic guidelines have been proposed, based on imaging and serum alphafetoprotein (AFP) [2]. A diagnosis of HCC can be ascertained without the need for biopsy if the nodule has characteristic appearance on imaging, with hypervascularity in the arterial phase and washout (hypovascularity) in the early or delayed portal phase. Unfortunately, although current imaging techniques allow the detection of nodules less than 1 cm, they may miss very small nodules. Not all small hypervascular nodules within cirrhotic parenchyma correspond to HCC. In addition, not all HCC nodules have characteristic patterns on imaging and not all patients with HCC have a significant increase in serum AFP. Ultrasound (US)-guided biopsy is the gold standard for either ascertaining or ruling out HCC. It has been argued that biopsy carries a risk of needle tract seeding and, potentially, hematogenous dissemination. However, in most series, the risk of needle tract seeding was shown to be less than 2% [14, 15]. The risk of dissemination has not been clearly documented. Overall, there is no evidence that pretransplant biopsy increases the risk of post-transplant recurrence. When patients with compensated cirrhosis are found to have small hypervascular nodules which do not meet all diagnostic criteria for HCC, US-guided biopsy should be performed before considering transplantation. Patients with negative biopsy findings should be entered into an enhanced surveillance protocol [16].

Selection criteria according to tumor status The aim of the selection process is to identify those patients who are the most likely to benefit from transplantation. The

CHAPTER 23

main limitation of transplantation is the risk of early tumor recurrence. Post-transplantation, tumor growth is markedly accelerated by immunosuppression. Recurrence may either involve the transplanted liver or extrahepatic sites, pulmonary and bone metastases being the most frequent. In case of recurrence, there is no curative option and the prognosis is especially poor. Stopping immunosuppression would rapidly lead to graft loss and the patient’s death. In the context of organ shortage, it is widely accepted that only HCC patients who derive a benefit comparable to that of non-HCC patients should be considered for transplantation. It would be ethically questionable to use an allograft for transplanting a patient with a very high risk of early recurrence when this graft could be allocated to a patient with a better prognosis. Therefore, patients in whom a high risk of post-transplant recurrence can be anticipated should be excluded. The risk of recurrence is mainly affected by the following variables: vascular invasion, the size of the nodule(s), the number of nodules, and tumor differentiation. Vascular invasion, either macroscopic or microscopic, is probably the key factor. Indeed, even if there is no obvious extrahepatic involvement, vascular invasion implies that there are circulating tumor cells, with a potential for recurrence, even after total hepatectomy. Early recurrence is almost constant in patients with macroscopic portal vein invasion. Macroscopic vascular invasion can be detected by pretransplant imaging. It represents a definitive contraindication for transplantation. In contrast, microscopic vascular invasion can only be documented after the fact by explant pathology. Indirect markers have to be taken into account. The size and number of nodules are strongly correlated to vascular invasion. The larger the size of the nodule, the higher the risk of vascular invasion. Similarly, the higher the number of nodules, the higher the risk of vascular invasion. This explains why selection criteria are generally based on tumor size and number of nodules. The Milan criteria have been the most widely used for selecting candidates for transplantation [7] (Table 23.2).

Transplantation for Liver Tumors

These criteria have been empirically defined. The long-term results of transplantation in patients who meet the Milan criteria were close to those obtained in patients without malignancy, with a 4-year survival rate of 85%. In those who fall outside the criteria, 4-year survival rate was only 50% at best, tumor recurrence being the main cause of death. The Milan criteria have been validated by a number of studies. These criteria have proved to be a reliable tool, relying on simple and readily available variables. However, it has been argued that they may be too restrictive and that a sizeable proportion of patients outside the criteria could derive an acceptable benefit from transplantation. In recent years, efforts have been made to extend the selection criteria. The University of California, San Francisco (UCSF)expanded criteria have been proposed as a less restrictive alternative to the Milan criteria (Table 23.2) [17]. One- and 5-year survival rates in patients fulfilling the UCSF criteria were 90% and 75% post transplantation, respectively. In patients outside the UCSF criteria, the 1-year survival rate was only 50% due to a high rate of recurrence. The UCSF criteria have been validated prospectively with results comparable to those reported in the initial publication [13]. Indeed, the UCSF criteria were initially based on the assessment of tumor status on explant pathology, which obviously represents a serious drawback. It must be noted that the UCSF criteria only represent a modest expansion over the Milan criteria. Only about 10% of patients who meet the UCSF criteria do not meet the Milan criteria. Again, patients who fall outside the UCSF criteria have a high risk of recurrence after transplantation. On a practical basis, the selection criteria should be based on the results of pretransplant imaging (triphasic computed tomography [CT] and/or magnetic resonance imaging [MRI]). Pretransplant imaging frequently underestimates tumor status because very small nodules may be undetected by imaging [18]. In addition, tumor size may progress and vascular invasion may occur during the waiting time to transplantation.

Table 23.2 Conventional criteria currently used for selecting patients with hepatocellular carcinoma for liver transplantation. Criteria

Year

Study population

Definition

Post transplant survival (%) Within the criteria

Outside the criteria

Milan criteria [7]

1996

48

• Single nodule ≤5 cm or • 2−3 nodules each ≤3 cm

85*

50*

UCSF criteria [17]

2001

70

• Single nodule ≤6.5 cm or • 2−3 nodules each ≤4.5 cm and a total tumor diameter ≤8 cm

75.2†

50†

* At 4 years. † At 5 years.

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Besides the number and size of nodules, tumor differentiation, microvascular invasion, satellite nodules, and serum AFP were shown to have a significant impact on posttransplant survival [19, 20]. These variables are not routinely used for patient selection either because they are difficult to assess during evaluation or because their incorporation into current selection criteria has not added much. However, patients with poorly differentiated tumors were found to have post-transplant recurrence rates about twice as high as those of patients with well-differentiated tumors [21]. More recently, gene expression profiling was found to be a useful tool for identifying patients with different tumor aggressiveness [22]. This variable could help identify those patients who fall just slightly outside the current selection criteria but who could derive an acceptable benefit from transplantation due to the less aggressive behavior of their tumor. Overall the risk of post-transplant recurrence according to pretransplant number and size of nodules is a continuum [23]. Even if no clear-cut limit can identify “good” and “bad” candidates for transplantation, stringent selection criteria have to be applied as the risk of recurrence rapidly increases for large tumors. Macroscopic extrahepatic metastases are highly uncommon in patients who fall within the Milan and/or UCSF criteria. However, careful evaluation should be performed during pretransplant work-up.

Selection criteria for transplantation according to liver status and “hepatic reserve” As indicated above, the vast majority of patients who develop HCC also have underlying cirrhosis. Therapeutic options may be markedly different according to which cirrhosis is decompensated (Child class B or C) or compensated (Child class A). Patients with decompensated cirrhosis are not suitable for surgical resection, even if the tumor is small. Due to limited hepatic reserve and poor regeneration capacities, resection, even if limited, would carry high morbidity and mortality risks. It has been suggested that resection should only be considered in patients with a model for end-stage liver disease (MELD) score below 11 [24]. Most often, transarterial chemoembolization (TACE) and RFA are also contraindicated due to the risk of further deterioration of liver function and/or procedure-related complications. In this group, transplantation represents the only option, provided tumor status corresponds to the limits cited above. In this group, transplantation makes it possible both to remove the tumor and to cure the underlying chronic liver disease. The issue of patients with compensated cirrhosis and small HCC is more complex because, even though these patients are eligible for transplantation, they may also be candidates for less demanding therapeutic options with good results in terms of survival. On the one hand, excellent results can be expected from transplantation in the long term. On the

284

Table 23.3 Results of liver resection for hepatocellular carcinoma less than 5 cm in patients with cirrhosis. Authors

Franco et al [25] Bismuth et al [6] Kawasaki et al [26] Lee et al [27] Belghiti et al [5]

Year

1990 1993 1995 1996 1998

Number of patients

43 46 93 48 122

Survival (%) 1 year

3 year

5 year

66 − 73 − 82

42 39 54 68 55

− − 40 50 33

other hand, good results can also be expected with resection, RFA or even TACE, allowing organs to be saved for patients for whom no options other than transplantation exist (patients with decompensated cirrhosis in particular). Selection criteria for surgical resection in cirrhotic patients with small HCC are restrictive. In order to be eligible for resection, patients may have compensated cirrhosis, small (noncentral) tumors, and no prominent portal hypertension [2]. Patients outside these criteria are at risk of postoperative decompensation. As a result, not all patients with compensated (Child class A) cirrhosis are eligible for resection. RFA is an alternative to resection with less restrictive selection criteria and a lower risk of decompensation. In patients with small HCC, the results for RFA are close to those for surgical resection. However, both resection and RFA are associated with lower recurrence-free survival rates compared to transplantation in the long term [5, 6, 25–27] (Table 23.3). Indeed, it can be expected that only 30–50% of patients will be alive 5 years after resection and that less than 20% will be free of recurrence. Therefore, in patients who are potentially eligible for transplantation, resection and RFA should be considered as a way to delay transplantation or to bridge patients to transplantation rather than as a real alternative. Additionally, in contrast to patients who are transplanted, patients who undergo local therapies may experience decompensation of cirrhosis due to the progression of the underlying liver disease, independent of tumor recurrence. Decompensation also represents a source of mortality. Even if there is now general agreement that the results of transplantation are superior to those of resection, it has been argued that, due to organ shortage and prolonged waiting times, this difference tends to narrow when the results are interpreted on an intention-to-treat basis [28]. During the waiting time, the tumor is likely to progress, increasing the risk of recurrence after transplantation and, even more importantly, making drop-outs possible. Intention-to-treat analyses suggest that the global results of resection are in fact superior to those of transplantation when taking into account drop-outs and deaths while on the waiting list [28]. However, these findings should be revisited in the light

CHAPTER 23

of current allocation policies allowing a more rapid access to transplantation in cases of HCC.

Concept of downstaging Despite the generalization of systematic screening in patients with cirrhosis, a sizeable proportion of patients are found with tumors exceeding the conventional criteria for transplantation at presentation. Patients who present with HCC outside either the Milan or UCSF criteria are generally excluded from transplantation. Downstaging consists of reducing the size of the tumor using nontransplant options (RFA, TACE or even resection) so that tumor status returns to eligibility criteria and patients can be eventually considered for transplantation. When tumor status returns to within conventional criteria, the issue is whether the risk for tumor recurrence is comparable or significantly increased compared to those with tumor within conventional criteria from the outset. Early results suggest that effective downstaging can be achieved in about 70% of patients who initially exceed the conventional criteria and that about 50% can be eventually transplanted [29]. Importantly, these results also suggest that survival and disease-free survival are comparable in patients with effective downstaging compared to patients with tumors initially within the conventional criteria [29]. It is recommended to apply a follow-up of at least 3 months after downstaging in order to exclude patients with rapid tumor progression (aggressive natural history) and a poor outcome. Although these early results are encouraging, it is important to note that only patients with compensated cirrhosis can receive TACE and/or RFA. The goals of downstaging are much more difficult to achieve in patients with decompensated cirrhosis. Further studies with longer follow-up are needed to clearly assess the feasibility and results of downstaging.

Summary: indications and contraindications for transplantation In patients with decompensated cirrhosis and HCC, transplantation is the only radical option provided tumor size does not exceed the conventional criteria. The choice between Milan criteria and the more recent and relatively less stringent UCSF criteria still depends on the policy adopted in each center. In patients with compensated cirrhosis, the first step is to ascertain the diagnosis of HCC if malignancy is the only justification for transplantation. Obviously, it would be highly questionable to transplant patients with compensated cirrhosis and benign hypervascular nodules. If imaging is not definitely conclusive, biopsy is recommended. Once the diagnosis of HCC is established, transplantation is the best option in the long term. Again, the tumor must be within conventional criteria. However, other therapeutic options can provide excellent results in terms of survival for small tumors

Transplantation for Liver Tumors

(T1 in particular). The decision between transplantation on the one hand and RFA or surgical resection on the other hand must be balanced against the availability of allografts. In Western countries where deceased donor transplantation is routinely performed, there is a trend to propose transplantation as a first-line option. However, in some geographic areas where deceased donors are especially scarce, another alternative is to propose RFA or surgical resection first and to save allografts for patients for whom transplantation is the only life-saving option. Salvage transplantation can be proposed in cases of recurrence. However, a sizeable proportion of tumors may exceed the conventional criteria at the time of recurrence. This proportion seems to be especially high in cases of hepatitis C virus (HCV)-related cirrhosis. Salvage transplantation is not feasible in all cases and no predictive factors have been clearly identified. In Eastern countries where deceased donors are especially scarce or absent, transplantation is generally considered a second-line option. When the tumor exceeds the conventional criteria, downstaging can be an option. Encouraging results have been reported in patients transplanted after downstaging. A period of 3–6 months between downstaging and transplantation is strongly recommended in order to exclude patients with an especially rapid tumor progression.

Liver transplantation in noncirrhotic patients with hepatocellular carcinoma HCC is a highly uncommon malignancy in patients without any underlying chronic liver disease. Patients who do not have chronic liver disease are not subjected to systematic screening. Therefore, in these patients, liver tumors are usually recognized at an advanced stage, when they have become symptomatic. However, due to the absence of underlying liver lesions, tumors larger than 10 cm can be resected in most cases. Liver regeneration capacities are preserved, allowing extended resection. In addition, it seems that the rate of recurrence after resection is lower in those without cirrhosis [30]. Occasionally, HCC occurring in this context has specific characteristics, including eosinophilic hepatocytes separated into bands of fibrous lamellar septa. These features define the rare fibrolamellar variant of HCC. Comparative studies suggest that the results of resection are comparable to those of transplantation in patients with fibrolamellar HCC (Table 23.4) [1, 31–34]. Therefore, resection, when feasible, should be preferred to transplantation. A second resection can be considered in cases of intrahepatic recurrence. It is important to note that while recurrence of HCC is generally limited to the liver, recurrence of the fibrolamellar variant frequently involves extrahepatic sites, in particular lymph nodes [33]. As a result, liver transplantation for unresectable fibrolamellar HCC remains questionable. Patients with multiple liver adenomas or adenomatosis are at risk of malignant transformation. Again, resection

285

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Resection, Ablation or Transplantation

Table 23.4 Results of transplantation and resection for fibrolamellar hepatocellular carcinomas. Authors

O’Grady et al [32] Penn [1] Ringe et al [33] Pinna et al [34] El-Gazzaz et al [31]

Year

1988 1991 1992 1997 2000

Transplantation

Resection

Number of patients

5-year survival (%)

Number of patients

5-year survival (%)

7 33 6 13 9

50 55 40 36 76*

− − 14 28 11

− − 40 75 100*

*3-year survival (%).

should be preferred to transplantation as the underlying liver parenchyma is normal.

Incidental hepatocellular carcinoma Although current imaging techniques detect nodules of less than 1 cm, very small (microscopic) nodules may not be detected until transplantation. The tumors which are discovered on explant pathology are termed incidental HCCs. These are found in 10–20% of cirrhotic recipients [35]. The size of incidental HCCs is usually less than 1 cm but poor visibility may mean that occasionally tumors as large as 3 cm may not be recognized as such [35]. Importantly, incidental HCC does not seem to affect posttransplant outcome [1, 6]. The risk of recurrence in cases of incidental HCCs seems to approach zero.

Pretransplant adjuvant therapies to bridge patients to transplantation Due to organ shortage, waiting time frequently exceeds 6 months. During this period of time, significant tumor growth is likely to occur, increasing by turn the risk of posttransplant recurrence. In addition, excessive tumor growth, over the limits of conventional criteria, may result in dropout from the waiting list. In a large series, the rate of removal from the waiting list was 9%, 17%, and 32% at 90, 180, and 365 days, respectively [36]. Adjuvant therapies are routinely used to prevent drop-out and reduce the risk of posttransplant recurrence. The most frequently used options are RFA and TACE. However, in some cases, surgery can also be considered. In general, adjuvant therapies are considered when the expected waiting time exceeds 3–6 months.

Radiofrequency ablation It is generally accepted that RFA is more efficacious than TACE for achieving complete tumor necrosis, at least for tumors of less than 3 cm. Results for several series of patients receiving RFA as a bridge to transplantation have been published in recent years [37]. There are no controlled studies.

286

However, pretransplant RFA is associated with a high degree of tumor necrosis, with low morbidity and low drop-out rates. In these series, the rate of post-transplant recurrence was low and 5-year survival generally exceeded 80%. Initial series have suggested that RFA could carry a higher risk of needle tract seeding compared to biopsy, possibly due to the large size of the needle [38]. Such a trend has not been confirmed by recent series. The results of RFA in this setting are attractive. However, RFA is generally restricted to patients with a single nodule of less than 3 cm and compensated cirrhosis, namely, those who have the best prognosis after transplantation and the lowest risk of drop-out. RFA may not be applicable to patients with nodules over 5 cm, multiple nodules, and/or decompensated cirrhosis (see also Chapter 21).

Transarterial chemoembolization TACE is a more widely applicable option than RFA. Even though TACE is generally contraindicated in patients with decompensated cirrhosis due to the risk of further deterioration of liver function, it can treat relatively large and/or multiple tumors. Several studies have shown that pretransplant TACE can result in a significant reduction in tumor size, low drop-out rates, low rates of recurrence, and good survival, provided the tumor was initially within the conventional criteria [39, 40]. The capacity of TACE to induce major tumor necrosis has also been clearly documented, based upon explant pathology. Supraselective TACE seems to be superior to conventional TACE at inducing complete tumor necrosis [40]. However, several studies, including a large meta-analysis, have failed to demonstrate a survival benefit in patients receiving TACE prior to transplantation [40, 41]. As a result, the role of TACE in candidates for transplantation still needs to be clarified (see also Chapter 13).

Surgical resection Surgical resection is generally considered an alternative to transplantation rather than an adjuvant therapy. However,

CHAPTER 23

several arguments suggest that resection prior to transplantation can be an attractive option in selected patients [42]. First, in contrast to what could be expected, prior resection neither increases operative morbidity nor impairs survival following transplantation. Second, compared to RFA and TACE, resection can be considered the most efficient option to control tumor progression. Finally, resection helps refine the selection process. Indeed, only resection offers the possibility of detailed pathologic examination of the tumor. Patients slightly outside the conventional criteria but with histologic features of good prognosis (well-differentiated tumor, no microscopic vascular invasion) should be considered for transplantation. Conversely, patients apparently within conventional criteria but with histologic features of poor prognosis (poorly differentiated tumor, evidence of microscopic vascular invasion) should undergo careful evaluation. In the near future, detailed analysis of the explant, including gene expression profiling, may help refine the prognosis. These emerging prognostic tools need to be validated. Nonetheless, surgical resection does not prevent the occurrence and/or progression of distant malignant nodules during the waiting time.

Practical guidelines Adjuvant therapies are justified when waiting time is expected to exceed 6 months. The aims are to control tumor growth, to reduce the risk of drop-out, and to lower the risk of post-transplant recurrence. There is no agreement on which strategy should be used in a given patient. RFA is generally the preferred option in patients with a small nodule (<3 cm), provided cirrhosis is compensated. Even if there is no clear evidence that TACE reduces drop-out rates and improves survival, this technique continues to be used in many centers. The main justification for using TACE is the objective results in terms of reduction in tumor size and tumor necrosis. TACE is preferred in patients with tumors over 5 cm and/or multiple nodules. Supraselective TACE should be preferred to conventional TACE. Resection prior to transplantation is also an option in patients with Child class A cirrhosis, no prominent portal hypertension, and who are expected to be placed on the waiting list for more than 6 months. It may be especially useful in patients with a very high serum AFP level in order to stop the progression of the tumor and to optimize tumor staging with pathology.

Post-transplantation interventions to reduce the risk of tumor recurrence No clear correlation between different immunosuppressive regimens and the risk of tumor recurrence has been clearly documented. It is generally recommended to avoid overimmunosuppression (a goal which is not specific to patients with HCC). The advent of mTOR (mammalian target of rapamycin) inhibitors in liver transplantation has been of major interest. Indeed, mTOR inhibitors (sirolimus and

Transplantation for Liver Tumors

everolimus) have both immunosuppressive and antiangiogenic properties. These drugs have been developed in parallel in the fields of solid organ transplantation and oncology for treating various malignancies. It could be expected that mTOR inhibitors would be especially attractive in patients transplanted for HCC. Sirolimus and everolimus are still under development in liver transplantation. However, it has been shown that mTOR inhibitor-based immunosuppression regimens are highly effective at preventing acute and chronic rejection. Their use may be limited by more frequent side effects compared to calcineurin inhibitors. Nonetheless, there is growing evidence that the incidence of de novo malignancy is lower in patients receiving mTOR inhibitor-based immunosuppression compared to patients receiving anticalcineurinbased immunosuppression. The effectiveness of m-TOR inhibitors for reducing the incidence of tumor recurrence remains uncertain. Prospective studies are currently being conducted. In most cases, patients who experience post-transplant recurrence of HCC have multifocal tumors involving the liver allograft and/or extrahepatic sites. Again, tumor progression is markedly accelerated by immunosuppression. In almost all cases, only palliative options can be considered. Sorafenib, an agent that targets mitogen-activated protein kinase pathways and has antiangiogenic properties, has been approved in patients with unresectable HCC and has shown attractive results in these patients. Whether this agent and/or a switch from calcineurin-inhibitors to mTORinhibitors improve survival in patients with recurrence of HCC has not been documented. Further studies are needed in this field.

Liver transplantation for hepatocellular carcinoma in the setting of living donor liver transplantation Adult-to-adult living donor liver transplantation (LDLT) is now an accepted alternative to deceased donor transplantation, even though in Western countries there has been a stagnation or a relative decline of this technique due to the issue of donor safety. The generalization of LDLT has two major implications with respect to HCC. First, the availability of a living donor shortens waiting time and virtually avoids tumor progression prior to transplantation. LDLT makes it possible to schedule the procedure rapidly. Consequently, it makes pretransplantation adjuvant therapies obsolete. Since tumor progression during waiting time is a determinant limiting factor, LDLT is especially attractive in patients with HCC. Small HCC in patients with compensated cirrhosis seems to be one of the most attractive indications for LDLT. Indeed, it seems that patients with a good hepatic reserve are less likely to develop small for size syndrome when receiving a partial graft compared to those with decompensated cirrhosis and a poor hepatic reserve. As indicated above, the selection criteria for transplanta-

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tion with respect to HCC are relatively stringent. A number of patients with HCC are excluded because the tumor exceeds conventional criteria. Data from several series show that, on an individual basis, a sizeable proportion of these patients could derive a significant benefit from transplantation in terms of survival. LDLT has been considered a way to expand the selection criteria as it does not involve the use of a deceased donor allograft which could be allocated to a patient with a better prognosis [43]. In addition, the difference in criteria between low- and high-risk patients proved to be narrow, although recurrence rates increased sharply for patients above the current selection criteria. Therefore, it seems difficult to place a healthy donor at risk when the patient to be transplanted has a major risk of recurrence within a few months, even if the procedure is considered to be a “last chance” option. Adult-to-adult LDLT carries important morbidity risks for the donor. There is also a potential mortality risk. Most argue that these risks are only justified if the expected benefit for the recipient is comparable to that expected with deceased donor transplantation. Overall, there are strong arguments for expanding the selection criteria for patients undergoing LDLT. In Asian countries where deceased donors are extremely scarce, LDLT remains the only option. Excellent results have been reported from Asian series in patients who meet the conventional criteria [44, 45]. There is no evidence that prior surgical resection alters the results of LDLT [46].

Allocation policies and prioritization Historically, allocation policy for deceased donors was determined by waiting time and urgency. Patients with HCC did not have particular consideration for transplantation. When HCC was the driving indication, patients were generally classified as being of intermediate medical urgency. Accordingly, waiting time frequently exceeded 1 year. Prolonged waiting time resulted in a high rate of drop-out. It was considered that patients with HCC were disadvantaged compared to those with advanced cirrhosis, particularly considering the excellent results of transplantation for small HCC. These inequities, along with accumulating evidence that waiting time is poorly correlated to waiting list mortality, led to a reconsideration of allocation policies [47]. The MELD score, which was originally derived for assessing the prognosis of patients undergoing transjugular intrahepatic portosystemic shunt, has also proved to be an objective and reliable marker of early (3-month) mortality in transplant candidates [48]. In 2002, a MELD score-based allocation policy was adopted in the United States. It has been rapidly recognized that in patients with compensated cirrhosis and HCC as primary indication for transplantation, MELD score is poorly correlated to disease severity. Based on “physiologic” MELD score, these patients are unlikely to be timely transplanted. MELD score had to be adjusted to HCC. The aim was to equate the risk of tumor progression

288

over the Milan criteria to that of death without transplantation. It has been estimated that patients with stage 1 (one lesion <2 cm) or 2 (one lesion <5 cm or two to three nodules each <3 cm) tumors had a risk of drop-out of 15% and 30% at 3 months, respectively. Experts convened to give the corresponding MELD scores of 24 and 29 to patients with stage 1 and 2 tumors, respectively. Importantly, patients with stage 3 or 4 tumors did not receive an additional score, although they could be listed with their “physiologic” MELD score. The justification was that, given the poor results of transplantation, patients with stage 3 or 4 HCC might not justify prioritization. The implementation of this system resulted in a decrease in mean waiting time from more than 2 years to slightly more than 6 months in the United States. It also resulted in an increase in the percentage of patients being transplanted for HCC, from 7% to 22% [49]. Serial assessments showed that, initially, HCC patients were overprioritized. For a similar MELD score, the mortality rate of non-HCC patients on the waiting list far exceeded the drop-out rate of HCC patients from the waiting list. In addition, about 30% of patients transplanted with a diagnosis of stage 1 HCC had no evidence of malignancy on the explanted liver [50]. Adjustments were performed. Under the current policy, stage 1 HCC patients no longer receive exception points. Stage 2 HCC patients receive a MELD score of 22. These patients receive additional points for every 3 months spent on the waiting list as long as tumor size remains within the Milan criteria (Table 23.5). Recent assessments suggest that the current policy achieves equitable prioritization for HCC and non-HCC patients. Comparable allocation policies have been adopted in other Western countries. However, there is no general agreement on whether patients with stage 1 HCC should or should not receive extra score. Similarly, whether prioritizaTable 23.5 Current allocation policy for deceased donor liver transplantation in patients with hepatocellular carcinoma according to the MELD score-based allocation policy in the United States. Tumor status

MELD score

Stage 1 HCC • One nodule < 2 cm Stage 2 HCC • One nodule between 2 and 5 cm or • 2−3 nodules each less than 3 cm

• No exception MELD score*

Stage 3 and 4 HCC

• MELD score of 22 • Plus additional points corresponding to a 10% increase in mortality risk for each month spent on the waiting list as long as tumor size remains within Milan criteria • No exception MELD score*

* Unless they do not receive exception MELD score, these patients can be listed with their physiologic MELD score.

CHAPTER 23

tion should be expanded over the Milan criteria is still a matter of debate.

Liver transplantation for cholangiocarcinoma In contrast to HCC, cholangiocarcinoma usually develops in patients who do not have cirrhosis. However, although HCC is by far the most frequent liver malignancy in patients with cirrhosis, some cirrhotic patients may also develop cholangiocarcinoma during the course of the disease. Finally, primary sclerosing cholangitis is a predisposing condition, although the annual risk of cholangiocarcinoma is relatively low (<10% over 5 years). Overall, the incidence of cholangiocarcinoma has increased in recent years in Western countries. The tumor can originate from either extrahepatic (proximal or peripheral cholangiocarcinoma) or intrahepatic (distal or peripheral cholangiocarcinoma) bile ducts. Patients with peripheral cholangiocarcinoma generally present with large, symptomatic tumors, while those with hilar cholangiocarcinoma generally present with smaller tumors and rapidly progressive jaundice.

Intrahepatic cholangiocarcinoma Because of the absence of underlying cirrhosis, most patients with peripheral (intrahepatic) cholangiocarcinoma, even those with large tumors, can undergo extended surgical resection, since the capacity for the liver to regenerate is preserved. Unfortunately, 5-year survival rates range between 20% and 40% [51] due to a high rate of tumor recurrence. In addition, the tumor may be unresectable due to bilobar involvement, vascular encasement, and/or extensive bile duct invasion. Occasionally, the presence of extensive liver fibrosis may also represent a contraindication for extensive resection, especially in those with primary sclerosing cholangitis. The results of transplantation for unresectable cholangiocarcinoma have proven to be especially poor, with 5-year survival below 20% and a high rate of recurrence in the early post-transplant course [51]. As the results of resection are dismal, total hepatectomy and transplantation have been considered an alternative to resection.

Transplantation for Liver Tumors

However, transplantation has not proven to be superior to resection in this context [51]. Overall, transplantation is neither a first-line nor a second-line option for treating large peripheral cholangiocarcinoma. Whether transplantation could be superior to resection in patients with small intrahepatic cholangiocarcinoma is uncertain. Cirrhotic patients do not have systematic screening and it is highly uncommon that cholangiocarcinoma is recognized at an early stage. However, it seems that the risk of recurrence is high in cirrhotic patients transplanted with a diagnosis of HCC and who are eventually found to have cholangiocarcinoma on the explanted liver. Similarly, incidental cholangiocarcinoma found on the explant of patients transplanted for primary sclerosing cholangitis is associated with a poor prognosis.

Hilar and perihilar cholangiocarcinoma The results of surgical resection for hilar cholangiocarcinoma are as dismal as those of resection for large peripheral cholangiocarcinoma. In selected patients, 5-year survival ranges between 20% and 40% [52]. Even more importantly, bilateral liver involvement and/or vascular encasement frequently preclude resection. Transplantation appeared to be a promising option for either resectable or unresectable hilar cholangiocarcinoma and avoided the difficulties in achieving tumor-free margins within the liver. Unfortunately, early experiences gave poor results with less than 30% 5-year survival and a high rate of recurrence. Early recurrence may result from an almost constant perineural invasion and/or metastatic lymph node invasion. Recently, encouraging results have been reported by several groups in highly selected patients with unresectable hilar cholangiocarcinoma. Aggressive neoadjuvant radiochemotherapy followed by transplantation seems to be especially attractive [53–55] (Table 23.6). The protocol consists in the administration of external beam radiotherapy in association with sensitizing chemotherapy (fluorouracil). External beam radiotherapy is followed by a transluminal boost of radiation through a brachytherapy wire. Once neoadjuvant radiochemotherapy is achieved, a staging operation is systematically performed with careful inspection and multiple lymph node biopsies. Only patients with negative lymph nodes and no evidence of tumor extension to

Table 23.6 Results of liver transplantation with or without neoadjuvant radiochemotherapy for hilar cholangiocarcinoma. Authors

Year

Neoadjuvant radiochemotherapy

Number of patients entered in the protocol for neoadjuvant therapy

Number of patients eventually transplanted

5-Year survival (%)

Robles et al [69] Sudan et al [55] Heimbach et al [54]

2004 2002 2006

No Yes Yes

−

36 11 (65%) 65 (61%)

30 45 76

17 106

289

SECTION 4

Resection, Ablation or Transplantation

adjacent organs or tissues are eventually considered for transplantation. In patients who entered the protocol and were transplanted, survival and disease-free survival were superior to those reported for surgical resection alone. However, this concept raises several concerns. It must be kept in mind that only selected patients with unresectable hilar cholangiocarcinoma were eligible to enter the protocol. Among these selected patients, only about 60% were eventually transplanted. Indeed, in the remaining 40%, positive lymph nodes or any other local extension precluded transplantation. Therefore, it can be anticipated that the intention-totreat results are not as good as the post-transplant results. Another limitation is that a rapid access to an allograft after the staging operation is an absolute prerequisite. Unless bilirubin is markedly elevated, patients with hilar CC are unlikely to have a high MELD score. As with HCC, exception MELD score needs to be considered in patients with CC. Overall, hilar cholangiocarcinoma should no longer be considered a definitive contraindication to transplantation since, in selected patients receiving neoadjuvant radiochemotherapy, good results can be obtained in the long term with a low rate of tumor recurrence.

Transplantation for liver metastases of neuroendocrine tumors Neuroendocrine tumors (NET) include several subtypes of malignancies all characterized by their relatively slow progression. They usually originate from the pancreas or small intestine and are drained by the portal system. The tumor is often discovered at a metastatic stage. Multiple liver metastases are frequent. Besides their slow progression, liver metastases of NET have two principal characteristics. First, the large size and multiplicity of metastatic nodules frequently contrast with the small size of the primary tumor. Occasionally, it may be impossible to detect the primary tumor for several years. Second, NET metastases, even if

large and multiple, tend to remain limited to the liver for prolonged periods. Therapeutic options for liver metastases of NET include surgical resection, systemic chemotherapy, TACE, RFA, and 131 I-metaiodo-benzylguanidine therapy. In the large majority, these options are only palliative, even if the primary tumor has been resected. Tumor recurrence occurs in the majority within less than 5 years [56]. Resection of the primary tumor and liver transplantation is an alternative in patients with multiple, bilobar liver metastases, and no evidence of extrahepatic involvement other than the primary tumor. The results of transplantation for liver metastases of NET have been quite variable from series to series, depending largely on the selection criteria (Table 23.7) [56–62]. However, in selected patients, 5-year survival rates after transplantation may exceed 80% [56, 57, 63]. Indications for liver transplantation in patients with NET have not been clearly defined. However, selection criteria based on tumor histology and grade, location of the primary tumor, extension to the liver, and natural history have been proposed to identify optimal candidates for transplantation [56] (Table 23.8). According to these criteria, candidates for transplantation should have well-differentiated (low-grade) tumors with a proliferation index below 10%, a variable which can be assessed by Ki67 staining [63]. The primary tumor should be located in a territory drained by the portal system. Resection of the primary tumor prior to transplantation should be preferred to complex removal of the tumor during the transplant procedure. Metastatic diffusion may involve less than 50% of liver parenchyma. Extrahepatic metastases should be excluded. Finally, patients may have a good response to previous therapy or a relatively stable disease for at least 6 months before transplantation. These criteria, which are based on clinical practice, should be further validated. According to all series, survival rates are markedly higher than disease-free survival rates. The majority of patients have tumor recurrence involving the allograft or extra-

Table 23.7 Patients survival after transplantation for metastatic neuroendocrine tumors. Authors

Year

Number of patients

Extrahepatic resection

Alessiani et al [58]

1995

14

14 of 14

Routley et al [59] Curtiss et al [60] Anthuber et al [61]

1995 1995 1996

11 3 4

− 2 of 3 2 of 4

Le Treut et al [62] Lang et al [57] Rosenau et al [63] Mazzaferro et al [56]

1997 1997 2002 2007

31 12 19 24

14 of 31 3 of 12 16 of 19 −

290

1-year survival (%)

3-year survival (%)

5-year survival (%)

64

64

64

82 100 25

57 − 0

28 − 0

58 82 89

47 82 − −

36 82 80 90

−

CHAPTER 23

Table 23.8 Proposed “Milan” criteria for transplantation in patients with liver metastases of neuroendocrine tumors [56]. Inclusion criteria 1. Confirmed histology of well-differentiated neuroendocrine tumor 2. Primary tumor drained by the portal system and removed with a curative resection through a surgical procedure different from transplantation 3. Metastatic diffusion to liver parenchyma < 50% 4. Good response to previous therapy or stable disease during at least 6 months during the pretransplant period 5. Age < 55 years Exclusion criteria 1. Small cell carcinoma and high neuroendocrine tumor 2. Other medical/surgical conditions contraindicating liver transplantation, including previous tumors 3. No gastrointestinal carcinoids or tumors not drained by the portal system

hepatic sites (bones, peritoneum, lymph nodes, and lung, in particular) within the first years following transplantation. However, even though patients receive immunosuppression, the tumor recurrence is far less aggressive than that of HCC for instance. Adjuvant therapies, including resection, chemotherapy, radiotherapy or 131I-metaiodo-benzylguanidine therapy may control the progression of recurrent malignancy for prolonged periods. In summary, liver transplantation is unlikely to be curative in patients with multiple liver metastases of NET. However, accumulating evidence suggests that selected patients with low-grade tumors derive an important survival benefit from transplantation, and that this benefit compares favorably with that of other candidates for transplantation. Indeed, tumor progression remains relatively slow after transplantation. The optimal timing for transplantation with respect to other therapeutic options needs to be clarified. However, transplantation should be given greater consideration in patients who had a good response to previous therapies than in those who have refractory and rapidly growing tumors.

Liver transplantation for hepatic epithelioid hemangioendothelioma Hepatic epithelioid hemangioendothelioma (HEHE) is a rare tumor of vascular origin. HEHE is a low-grade tumor with a slow progression. However, disease progression is quite variable from patient to patient. Most patients have large, multifocal liver tumors at the time of diagnosis. About 20% die within 2 years after the diagnosis and about 20% survive

Transplantation for Liver Tumors

more than 5 years after the diagnosis [64]. Survival for more than 10 years without any specific treatment has been reported [64]. As most patients have large tumors involving both lobes, resection is only possible in a minority. In addition, 40–50% of patients have metastases at the time of diagnosis, involving lungs, bones, spleen, and peritoneum. Preoperative identification of peritoneal invasion is especially difficult. On the grounds that the progression of the tumor is slow and surgical resection is rarely possible, transplantation has been proposed. Only relatively small series have been reported [1, 65]. The largest series includes 59 European patients transplanted over a 15-year period [66]. This series indicates that the long-term results of transplantation are good, with 5- and 10-year survival rates of 83% and 72%, respectively. The recurrence rate was of 24%, but only 15% of patients died due to disease recurrence. Extrahepatic involvement, including the peritoneum, diaphragm, lungs, and bones, is frequent. Importantly, there is no evidence that survival is significantly different in patients with and without extrahepatic tumors. In contrast, microvascular and combined microvascular and macrovascular invasion seem to be associated with a poorer prognosis. Overall, liver transplantation probably represents the firstline option in patients with diffuse HEHE. Extrahepatic metastases should not be considered a contraindication for transplantation. Regarding the nature of HEHE, post-transplant immunosuppression based on the antiangiogenic agents rapamycin and sirolimus might be especially attractive. The impact of these agents on recurrence and survival needs to be further analyzed.

Liver transplantation for other liver malignancies Angiosarcoma only accounts for 0.5–2% of primary liver malignancies. An association with previous exposure to thorotrast (thorium dioxide), arsenicals, and vinyl chloride has been clearly identified. Angiosarcoma is a rapidly growing tumor with ill-defined limits that make surgical resection rarely possible. A worldwide multicenter series of 14 patients transplanted has been reported [1]. The median 2-year survival rate was 15%. In another small series from the European Liver Transplant Registry, all patients died with tumor recurrence less than 7 months post transplantation [67]. As a result, angiosarcoma represents a contraindication to transplantation. Acute liver failure is an uncommon mode of presentation of diffuse lymphoma. Liver failure results from a massive infiltration of the parenchyma by lymphoma cells. The diagnosis of lymphoma may be especially difficult to establish in an emergency. The prognosis with medical management is especially poor. Successful emergency liver transplantation

291

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Resection, Ablation or Transplantation

followed by chemotherapy has been reported [68]. Therefore, lymphoma may not be considered a definitive contraindication to transplantation in patients presenting with acute liver failure. Some patients with unresectable isolated liver metastases of non-neuroendocrine tumors occurring several years after primary resection were transplanted in the 1980s. The results were dismal because of recurrence. Two-year survival rate was less than 15% [1]. Accordingly, patients with liver metastases of non-neuroendocrine tumors (colorectal tumors in particular) should no longer be considered for transplantation.

Conclusions and perspectives Due to the relatively high incidence of chronic liver diseases resulting from viral hepatitis, alcohol abuse or nonalcoholic steatohepatitis, or any other conditions, the burden of HCC will continue to be of major concern in the next decades. In patients with large tumors, the poor results of transplantation do not justify its use given the scarcity of organs. LDLT, which does not affect the pool of deceased donors, does not seem to be an acceptable alternative as the risk for the donor must be balanced against the excellent results in the recipient. However, the generalization of systematic screening has led an increasing proportion of HCC patients being diagnosed at an early stage with small tumors. Transplantation is an especially attractive option in this population since it cures both tumor and the underlying chronic liver disease. Local therapies are limited by the fact that the patients are left with cirrhosis which is an oncogenic condition. Recurrence is likely to occur after local therapies. Transplantation is not only superior to local therapies in the long term, but it also offers an excellent quality of life in most cases. In addition, the results of transplantation are comparable to those obtained in patients without malignancy. Prospective evaluation of allocation policies should be conducted to guarantee appropriate prioritization of HCC patients. Nonetheless, transplantation for malignancy represents a paradox. On the one hand, as indicated above, only transplantation allows complete removal of the tumor and the cure of cirrhosis. On the other hand, long-term immunosuppression is needed after transplantation. Immunosuppression favors the growth of previously undetected micrometastases. At present, there are only indirect markers of circulating micrometastases and their potential to lead to overt tumor recurrence. Refinements in the assessment of tumor status are needed to improve the selection process. Similarly, targeted adjuvant interventions may help reduce the risk of recurrence. A number of patients are still excluded because it is felt that the risk of recurrence is too high. Expanding the selection criteria will continue to be a challenging issue. Again,

292

only refinements in tumor staging and adjuvant therapies can help better define the patients who can derive an acceptable benefit from transplantation. Cholangiocarcinoma is far less common than HCC. However, there is growing evidence that transplantation can lead to excellent results in highly selected patients with cholangiocarcinoma. Finally, apart from rare tumors, including NET and HEHE, transplantation should not be considered in patients with non-neuroendocrine metastases.

Self-assessment questions 1 Which one of the following tumors represents a definitive contraindication for transplantation? A Hepatocellular carcinoma B Fibrolamellar hepatocellular carcinoma C Hepatic angiosarcoma D Hepatic metastases of neuroendocrine tumor E Hepatic epithelioid hemangioendothelioma 2 Which one of the following tumor characteristics represents a contraindication for transplantation? A More than one nodule B A single nodule more than 3 cm C Poor differentiation on histology D Previous percutaneous biopsy E Macroscopic tumor extension to the left branch of the portal vein 3 Which of the following situations represent an acceptable indication for liver transplantation? (more than one answer is possible) A Compensated cirrhosis and a single 3-cm HCC nodule with characteristic features on imaging (CT and MRI) B Decompensated cirrhosis and a single HCC nodule of 3 cm with characteristic features on imaging (CT and MRI) C Compensated cirrhosis and a single nodule of 2 cm with no characteristic features on imaging (CT and MRI) and no biopsy D Decompensated cirrhosis and a single nodule of 2 cm with no characteristic features on imaging (CT and MRI) and no biopsy E Compensated cirrhosis with seven HCC nodules, the largest nodule being 6 cm 4 What is the expected 5-year survival after transplantation in patients with cirrhosis and HCC within conventional criteria? A 30% B 50% C 70%

CHAPTER 23

D 90% E 100% 5 Which one of the following adjuvant therapies cannot be used to bridge HCC patients to transplantation? A Percutaneous radiofrequency ablation B Transarterial chemoembolization C Surgical resection D Local radiation therapy E Percutaneous ultrasound-guided alcoholization 6 Which of the following statements concerning posttransplant recurrence of HCC are true? (more than one answer is possible) A In most cases, HCC recurrence occurs more than 5 years after transplantation B Recurrence never involves liver allograft because the allograft is not HLA identical to the primary tumor C In case of recurrence, tumor growth is markedly accelerated by post-transplant immunosuppression D Recurrence rate is not affected by tumor differentiation E The risk of recurrence is influenced by tumor size and number of nodules 7 Which of the following statements concerning cholangiocarcinoma are true? (more than one answer is possible) A Liver transplantation is the first-line option in patients with small peripheral cholangiocarcinoma B In patients with small hilar cholangiocarcinoma, the risk of post-transplant recurrence is high due to early perineural invasion and/or metastatic lymph node invasion C Selected patients with hilar cholangiocarcinoma receiving aggressive neoadjuvant therapy can derive an acceptable benefit from transplantation D Hilar cholangiocarcinoma is a definitive contraindication for transplantation E In patients with primary sclerosing cholangitis, transplantation is justified, independent of any complication due to the high rate of de novo cholangiocarcinoma 8 Which of the following statements concerning why living donor transplantation is superior to deceased donor transplantation in patients with HCC are true? A In cases of genetically related living donor, the rate of rejection is lower and the need for immunosuppression is lower post transplantation B Waiting time is shorter on average C The risk of biliary complications is lower D The risk of vascular complications is lower

Transplantation for Liver Tumors

E It is easier to schedule transplantation with respect to pretransplant adjuvant therapies 9 Which one of the following immunosuppressive agents has both immunosuppressive and antiangiogenic properties? A Cyclosporine B Tacrolimus C Steroids D Mycophenolate mofetil E Sirolimus 10 Which of the following statements concerning liver transplantation for liver metastases of neuroendocrine tumors are true? (more than one answer is possible) A Liver transplantation is indicated in patients with unilobar metastases B The primary tumor is often very small and resection prior to transplantation is not mandatory C Tumor recurrence is almost universal D Life-expectancy after recurrence is generally lower than 6 months E Post-transplantation survival is significantly affected by the proliferation index

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10 Figueras J, Jaurrieta E, Valls C, et al. Survival after liver transplantation in cirrhotic patients with and without hepatocellular carcinoma: a comparative study. Hepatology 1997;25: 1485–9. 11 Hemming AW, Cattral MS, Reed AI, Van Der Werf WJ, Greig PD, Howard RJ. Liver transplantation for hepatocellular carcinoma. Ann Surg 2001;233:652–9. 12 Decaens T, Roudot-Thoraval F, Hadni-Bresson S, et al. Impact of UCSF criteria according to pre- and post-OLT tumor features: analysis of 479 patients listed for HCC with a short waiting time. Liver Transpl 2006;12:1761–9. 13 Yao FY, Xiao L, Bass NM, Kerlan R, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging. Am J Transplant 2007;7:2587–96. 14 Durand F, Regimbeau JM, Belghiti J, et al. Assessment of the benefits and risks of percutaneous biopsy before surgical resection of hepatocellular carcinoma. J Hepatol 2001;35:254–8. 15 Livraghi T, Lazzaroni S, Meloni F, Solbiati L. Risk of tumour seeding after percutaneous radiofrequency ablation for hepatocellular carcinoma. Br J Surg 2005;92:856–8. 16 Durand F, Belghiti J, Paradis V. Liver transplantation for hepatocellular carcinoma: role of biopsy. Liver Transpl 2007;13:S17–23. 17 Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394–403. 18 Decaens T, Roudot-Thoraval F, Bresson-Hadni S, et al. Role of immunosuppression and tumor differentiation in predicting recurrence after liver transplantation for hepatocellular carcinoma: A multicenter study of 412 patients. World J Gastroenterol 2006;12:7319–25. 19 Plessier A, Codes L, Consigny Y, et al. Underestimation of the influence of satellite nodules as a risk factor for post-transplantation recurrence in patients with small hepatocellular carcinoma. Liver Transpl 2004;10:S86–90. 20 Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Difference in tumor invasiveness in cirrhotic patients with hepatocellular carcinoma fulfilling the Milan criteria treated by resection and transplantation: impact on long-term survival. Ann Surg 2007;245:51–8. 21 Jonas S, Bechstein WO, Steinmuller T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 2001;33:1080–6. 22 Llovet JM. Clinical and molecular classification of hepatocellular carcinoma. Liver Transpl 2007;13:S13–16. 23 Mazzaferro V. Results of liver transplantation: with or without Milan criteria? Liver Transpl 2007;13:S44–47. 24 Cucchetti A, Ercolani G, Vivarelli M, et al. Impact of model for end-stage liver disease (MELD) score on prognosis after hepatectomy for hepatocellular carcinoma on cirrhosis. Liver Transpl 2006;12:966–71. 25 Franco D, Capussotti L, Smadja C, et al. Resection of hepatocellular carcinomas. Results in 72 European patients with cirrhosis. Gastroenterology 1990;98:733–8. 26 Kawasaki S, Makuuchi M, Miyagawa S, Kakazu T, Hayashi K, Kasai H, et al. Results of hepatic resection for hepatocellular carcinoma. World J Surg 1995;19:31–4.

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27 Lee CS, Sheu JC, Wang M, Hsu HC. Long-term outcome after surgery for asymptomatic small hepatocellular carcinoma. Br J Surg 1996;83:330–3. 28 Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30:1434–40. 29 Yao FY, Hirose R, LaBerge JM, et al. A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation. Liver Transpl 2005;11:1505–14. 30 Iwatsuki S, Starzl TE, Sheahan DG, et al. Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg 1991; 214:221–8. 31 El-Gazzaz G, Wong W, El-Hadary MK, et al. Outcome of liver resection and transplantation for fibrolamellar hepatocellular carcinoma. Transpl Int 2000;13 (Suppl 1):S406–9. 32 O’Grady JG, Polson RJ, Rolles K, Calne RY, Williams R. Liver transplantation for malignant disease. Results in 93 consecutive patients. Ann Surg 1988;207:373–9. 33 Ringe B, Wittekind C, Weimann A, Tusch G, Pichlmayr R. Results of hepatic resection and transplantation for fibrolamellar carcinoma. Surg Gynecol Obstet 1992;175:299–305. 34 Pinna AD, Iwatsuki S, Lee RG, et al. Treatment of fibrolamellar hepatoma with subtotal hepatectomy or transplantation. Hepatology 1997;26:877–83. 35 Mion F, Grozel L, Boillot O, Paliard P, Berger F. Adult cirrhotic liver explants: precancerous lesions and undetected small hepatocellular carcinomas. Gastroenterology 1996;111:1587– 92. 36 Freeman RB, Edwards EB, Harper AM. Waiting list removal rates among patients with chronic and malignant liver diseases. Am J Transplant 2006;6:1416–21. 37 Mazzaferro V, Battiston C, Perrone S, et al. Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: a prospective study. Ann Surg 2004;240:900–9. 38 Llovet JM, Vilana R, Bru C, Bianchi L, Salmeron JM, Boix L, et al. Increased risk of tumor seeding after percutaneous radiofrequency ablation for single hepatocellular carcinoma. Hepatology 2001;33:1124–9. 39 Majno P, Giostra E, Mentha G. Management of hepatocellular carcinoma on the waiting list before liver transplantation: time for controlled trials? Liver Transpl 2007;13:S27–35. 40 Dharancy S, Boitard J, Decaens T, et al. Comparison of two techniques of transarterial chemoembolization before liver transplantation for hepatocellular carcinoma: a case-control study. Liver Transpl 2007;13:665–71. 41 Lesurtel M, Mullhaupt B, Pestalozzi BC, Pfammatter T, Clavien PA. Transarterial chemoembolization as a bridge to liver transplantation for hepatocellular carcinoma: an evidence-based analysis. Am J Transplant 2006;6:2644–50. 42 Belghiti J, Durand F. Hepatectomy vs. liver transplantation: a combination rather than an opposition. Liver Transpl 2007;13:636–8. 43 Jonas S, Mittler J, Pascher A, et al. Living donor liver transplantation of the right lobe for hepatocellular carcinoma in cirrhosis in a European center. Liver Transpl 2007;13:896–903. 44 Todo S, Furukawa H. Living donor liver transplantation for adult patients with hepatocellular carcinoma: experience in Japan. Ann Surg 2004;240:451–9; discussion 459–61.

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45 Takada Y, Ueda M, Ito T, et al. Living donor liver transplantation as a second-line therapeutic strategy for patients with hepatocellular carcinoma. Liver Transpl 2006;12:912–19. 46 Todo S, Furukawa H, Tada M. Extending indication: role of living donor liver transplantation for hepatocellular carcinoma. Liver Transpl 2007;13:S48–54. 47 Freeman RB, Jr., Edwards EB. Liver transplant waiting time does not correlate with waiting list mortality: implications for liver allocation policy. Liver Transpl 2000;6:543–52. 48 Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 2000;31:864–71. 49 Roayaie K, Feng S. Allocation policy for hepatocellular carcinoma in the MELD era: room for improvement? Liver Transpl 2007;13:S36–43. 50 Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91–6. 51 Casavilla FA, Marsh JW, Iwatsuki S, et al. Hepatic resection and transplantation for peripheral cholangiocarcinoma. J Am Coll Surg 1997;185:429–36. 52 Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 2005;242:451–8; discussion 458–61. 53 De Vreede I, Steers JL, Burch PA, et al. Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma. Liver Transpl 2000; 6:309–16. 54 Heimbach JK, Gores GJ, Haddock MG, et al. Predictors of disease recurrence following neoadjuvant chemoradiotherapy and liver transplantation for unresectable perihilar cholangiocarcinoma. Transplantation 2006;82:1703–7. 55 Sudan D, DeRoover A, Chinnakotla S, et al. Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. Am J Transplant 2002;2:774–9. 56 Mazzaferro V, Pulvirenti A, Coppa J. Neuroendocrine tumors metastatic to the liver: how to select patients for liver transplantation? J Hepatol 2007;47:460–6. 57 Lang H, Oldhafer KJ, Weimann A, et al. Liver transplantation for metastatic neuroendocrine tumors. Ann Surg 1997;225: 347–54. 58 Alessiani M, Tzakis A, Todo S, Demetris AJ, Fung JJ, Starzl TE. Assessment of five-year experience with abdominal organ cluster transplantation. J Am Coll Surg 1995;180:1–9. 59 Routley D, Ramage JK, McPeake J, Tan KC, Williams R. Orthotopic liver transplantation in the treatment of metastatic neuroendocrine tumors of the liver. Liver Transpl Surg 1995;1:118–21.

Transplantation for Liver Tumors

60 Curtiss SI, Mor E, Schwartz ME, et al. A rational approach to the use of hepatic transplantation in the treatment of metastatic neuroendocrine tumors. J Am Coll Surg 1995;180:184–7. 61 Anthuber M, Jauch KW, Briegel J, Groh J, Schildberg FW. Results of liver transplantation for gastroenteropancreatic tumor metastases. World J Surg 1996;20:73–6. 62 Le Treut YP, Delpero JR, Dousset B, et al. Results of liver transplantation in the treatment of metastatic neuroendocrine tumors. A 31-case French multicentric report. Ann Surg 1997;225:355–64. 63 Rosenau J, Bahr MJ, von Wasielewski R, et al. Ki67, E-cadherin, and p53 as prognostic indicators of long-term outcome after liver transplantation for metastatic neuroendocrine tumors. Transplantation 2002;73:386–94. 64 Lauffer JM, Zimmermann A, Krahenbuhl L, Triller J, Baer HU. Epithelioid hemangioendothelioma of the liver. A rare hepatic tumor. Cancer 1996;78:2318–27. 65 Madariaga JR, Marino IR, Karavias DD, et al. Long-term results after liver transplantation for primary hepatic epithelioid hemangioendothelioma. Ann Surg Oncol 1995;2:483–7. 66 Lerut JP, Orlando G, Adam R, Schiavo M, Klempnauer J, Mirza D, et al. The place of liver transplantation in the treatment of hepatic epitheloid hemangioendothelioma: report of the European liver transplant registry. Ann Surg 2007;246:949–57; discussion 957. 67 Lerut JP, Weber M, Orlando G, Dutkowski P. Vascular and rare liver tumors: a good indication for liver transplantation? J Hepatol 2007;47:466–75. 68 Cameron AM, Truty J, Truell J, et al. Fulminant hepatic failure from primary hepatic lymphoma: successful treatment with orthotopic liver transplantation and chemotherapy. Transplantation 2005;80:993–6. Robles R, Figueras J, Turrion VS, et al. Spanish experience in liver transplantation for hilar and peripheral cholangiocarcinoma. Ann Surg 2004;239:265–71.

Self-assessment answers 1 2 3 4 5 6 7 8 9 10

C E A, B, D C D C, E B, C B, E E C, E

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Preventing Recurrence of Hepatocellular Carcinoma after Curative Resection Stefan Breitenstein, Dimitris Dimitroulis, and Beat Müllhaupt Department of Visceral Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland

Introduction

Interferon

Hepatocellular carcinoma (HCC) occurs in the Western world in more than 90% of cases on the basis of cirrhosis, or advanced fibrosis of the liver [1]. Virus (hepatitis C [HCV] and B [HBV] viruses) and iron-overload associated cirrhosis carry a particularly high risk, with an estimated annual HCC incidence rate between 2% and 8% [2–5]. Liver transplantation can only be offered to a small proportion of patients due to the limited availability of liver grafts, selection criteria, and high costs. Therefore, liver resection or ablation in patients with well-preserved liver function remain the only curative treatment options for the majority of patients with HCC, with a 5-year survival rate of 40–60% [6–10]. Locoregional tumor recurrence occurs in more than half of patients with HCC within 5 years of surgery despite clear resection margins [11–15] and is, in combination with the underlying liver disease, the main cause of death. There are two categories of recurrences: early and late. Early recurrent HCCs are the result of residual hepatic tumors left behind, presumably after R0 resection, and become apparent within 2 years of surgery. In contrast, late (also called de novo) recurrences are new tumors, typically occurring more than 2 years after surgery as a result of the underlying carcinogenic liver disease or virus [9, 16]. Therefore, in principle, strategies to prevent tumor recurrence should protect against early, postoperative intrahepatic tumor spread, and should reduce the carcinogenic potential of the underlying liver disease in the long term. Interferon immunotherapy, irradiation with lipiodol-iodine-131, oral administration of acyclic retinoids, and systemic or local chemotherapies have emerged and been tested as neoadjuvant or adjuvant options after hepatic resection for HCC. Several approaches will be discussed in this chapter (Table 24.1).

Immunotherapy with interferon (IFN) has been examined in the adjuvant setting after liver resection or ablation for HCC [17]. IFNs are cytokines possessing a variety of biologic properties, including antiviral, immunomodulatory, antiproliferative, and antiangiogenic effects [18, 19]. IFNs are effective in suppressing the replication of HBV and HCV, and are widely used for the treatment of viral hepatitis, reducing hepatocyte damage and turnover. Due to the additional tumoricidal effect, IFN acts against a number of tumors, such as HCC, renal cell carcinoma, and melanoma. This double action of interferon is thought to be responsible for the prevention of recurrence of HCC after surgical resection in viral hepatitis patients. Several retrospective studies have explored the effect of IFN therapy on the occurrence of HCC in viral hepatitis associated cirrhotic patients, the majority of which suggest a risk reduction for developing HCC. However, only seven randomized controlled trials (RCT) have investigated the effects of IFN on patient survival and tumor recurrence after curative resection or ablation of HCC (Table 24.2). The results of the individual trials were inconclusive, either because effects were not statistically significant, or results were only considered for defined subpopulations (Table 24.2). The data from these RCTs were collated in a meta-analysis with a high statistical strength [20], and showed statistically significant beneficial results of the adjuvant application of IFN after curative resection of HCC. A total of 580 patients who underwent curative resection or ablation for HCC were included in this study. The outcome parameters were extracted after a 2-year follow-up. Regarding survival, the trials were consistently favorable for IFN, showing a pooled risk ratio of 0.65 (95% CI 0.52–0.80; p < 0.001) without statistical heterogeneity (Figure 24.1). Recurrences were significantly reduced by IFN treatment with a pooled risk ratio of 0.86 (Figure 24.2). Neither the impact of the type of concomitant hepatitis infection (B or C) nor the type of IFN (IFN-α or IFN-β) could be convincingly assessed. The trial of Sun et al [21] included

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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Table 24.1 Summary of evidence for clinical efficacy of agents/approaches in treating/preventing hepatocellular carcinoma (HCC). Setting

Evidence for clinical efficacy in treating (advanced) HCC

Evidence for clinical efficacy in preventing HCC recurrence after curative resection

Interferon 131 I-Lipiodol Retinoids

HCV- or HBV- associated HCC HCC HCC

No Yes No

Octreotide

HCC

Pravastatin

HCC

Genetherapy Other Immunotherapy

HCC HCC

Yes (one controlled study [n = 57], only) Yes (one controlled study [n = 91], only) No Unclear (small phase II studies only)

Yes No Yes (one controlled study [n = 89] only) No No No Unclear (one controlled study, adoptive transfer [n = 150] only)

HBV, hepatitis B virus; HCV, hepatitis C virus.

Risk ratio (95% CI)

Study

% Weight

Kubo et al (2002) [26]

0.80 (0.44,1.45)

7.5

Lin et al (2004) [52]

0.40 (0.14,1.17)

5.0

Shiratori et al (2003) [27]

0.75 (0.45,1.25)

12.9

Mazzaferro et al (2006) [23]

0.72 (0.42,1.23)

17.5

Sun et al (2006) [21]

0.63 (0.46,0.87)

45.0

Lo et al (2007) [22]

0.50 (0.24,1.03)

12.0

Overall (95% CI)

0.65 (0.52,0.80), I2 = 0%

0.25

0.5

1

2

Risk ratio Favors interferon

Favors control

Figure 24.1 Results of the analysis regarding survival following interferon treatment for hepatocellular carcinoma (From Breitenstein S, Dimitroulis D, Petrowsky H, et al. Br J Surg [20] with permission.).

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Table 24.2 Characteristics of the randomized controlled trials investigating the effect of interferon treatment after curative ablation or resection of hepatocellular carcinoma (HCC). Study

Population

Therapy

Ikeda et al (2000) [24]

20 patients (13 males, 7 females, mean age 61 years) with HCV infection and curative treatment of HCC (surgical resection or percutaneous ethanol injection). Primary endpoint was tumor recurrence. Median follow-up 25.0 months 30 male patients with HCV infection and curative surgical resection of a single HCC tumor. Endpoint was tumor recurrence. Median follow-up Group A, 5 years; Group B, 4 years 74 patients (52 males, 22 females) with compensated cirrhosis due to HCV after curative ablation of maximal three HCC lesions with percutaneous ethanol injection. Primary endpoint was tumor recurrence. Mean follow-up 7.1 years 30 patients (23 males, 7 females) after nonsurgical treatment (transarterial chemoembolization or percutaneous acetic acid injection) of HCV- or HBV-related HCC nodules. Primary endpoint was tumor recurrence. Median follow-up 27 months

Group A: 10 patients received natural IFN-β 6 million units twice a week for 36 months Group B: control group of 10 patients

Kubo et al (2002) [26]

Shiratori et al (2003) [27]

Lin et al (2004) [52]

Sun et al (2006)[21]

Mazzaferro et al (2006) [23]

Lo et al (2007) [22]

236 patients (208 males and 28 females, mean age 50 years) after curative resection of HBV-related HCC. Median observation time was 36.5 months. Primary endpoint was disease-free survival 150 patients (112 males and 38 females) after curative resection of HCV- (n = 80) or HCV- and HBV-related (n = 70) HCC. Median follow-up 45 months. Primary endpoint was recurrence-free survival 80 patients (65 males and 15 females) after curative resection of predominantly HBV-related HCC. Primary endpoint was tumor recurrence. Minimum follow-up 30 months

Group A: 15 patients (mean age 61.9 years) received 6 MIU IFN-α intramuscularly every day for 2 weeks, then 3 times weekly for 14 weeks, and finally twice weekly for 88 weeks Group B: control group of 15 patients (mean age 60.0 y) Group A: 49 patients (median age 61 years) received 6 MIU IFN-α intramuscularly 3 times weekly for 48 weeks Group B: control group of 25 patients (mean age 63 years)

Group A: 11 patients (median age 60 years) received intramuscularly 3 MU IFN-α2β three times a week for 24 months Group B: 9 patients (median age 63 years) received 3 MIU IFN-α2β daily for 10 days every month for 6 months followed by 3 MU daily for 10 days every 3 months for an additional 18 months Group C: control group of 10 patients. Group A: 118 patients (mean age 52.2 years) received 3 MIU IFN-α intramuscularly twice a week for 2 weeks and then 5 MIU three times a week for 18 months Group B: control group of 118 patients (mean age 50.4 years). Group A: 76 patients (mean age 65 years) received 3 MIU IFN-α2β 3 times every week for 48 weeks Group B: control group of 74 patients (mean age 67 years).

Group A: 40 patients (mean age 49 years) received 10 MIU/m2 IFNA-α2β subcutaneously three times a week for 16 weeks Group B: control group of 40 patients (mean age 54 years)

HBV, hepatitis B virus; HCV, hepatitis C virus.

only patients infected with HBV, and demonstrated a significant overall survival effect of IFN-α after 2 years. However, disease-free survival and recurrence rates were not statistically different. The trial of Lo et al [22], involving predominantly HBV patients, failed to show significant benefits. The study of Mazzaferro et al [23] demonstrated a significant survival effect exclusively for the HCV patients. Regarding the type of IFN, only the trial of Ikeda et al [24] was performed with IFN-β, and showed a significant positive effect on tumor recurrence with a wide confidence interval (risk ratio 0.14; p = 0.05). The remaining six trials used IFN-α, without showing significant beneficial effects. Side effects of IFN-α are dose-dependent and often serious. Lo et al reported that minor flu-like side effects would have

298

been so frequent that double blinding in their study was not possible [22]. Severe adverse effects of the adjuvant IFN treatment leading either to treatment disruption or dose reduction occurred in up to a quarter of the patients (between 7.5% and 25%). The dependency of adverse effects on the dosage of IFN was supported by Lo et al [22] and Llovet et al [25], where the high-dose arms (30 MIU, three times a week) had to be discontinued. Based on the tolerance of relatively higher IFN dosages in some Asian trials (22, 24–27], there might be a different perception of adverse events in the Asian population compared to the European [25]. In accordance with this, Lo et al [22] applied the highest IFN dosage (10 MIU three times per week) and showed the

CHAPTER 24

Preventing Recurrence of Hepatocellular Carcinoma after Curative Resection Risk ratio (95% CI)

Study

% Weight

Ikeda et al (2000) [24]

0.14 (0.02,0.96)

3.4

Kubo et al (2002) [26]

0.69 (0.44,1.09)

6.4

Lin et al (2004) [52]

0.44 (0.25,0.79)

5.9

Shiratori et al (2003) [27]

0.89 (0.74,1.06)

15.0

Mazzaferro et al (2006) [23]

0.91 (0.70,1.18)

23.5

Sun et al (2006) [21]

0.94 (0.76,1.17)

35.0

Lo et al (2007) [22]

0.95 (0.64,1.43)

10.8

Overall (95% CI)

0.86 (0.76,0.97), I2 = 44%

0.25

0.5

1

2

Risk ratio Favors interferon

Favors control

Figure 24.2 Results of the analysis regarding recurrence of hepatocellular carcinoma following interferon treatment. (From Breitenstein S, Dimitroulis D, Petrowsky H, et al. Br J Surg [20] with permission.)

lowest rate of treatment discontinuation (7.5%) among the seven RCTs. To conclude, the effect of adjuvant IFN treatment after curative resection or ablation demonstrates a statistically significant benefit regarding both survival and tumor recurrence. However, the high rate of severe side effects indicates the need for further studies in order to optimize the type and dosage of this treatment.

Iodine-131-labelled lipiodol Lipiodol, a stable fatty acid ester derived from poppy-seed oil, contains iodine and can be radiolabeled by an atom-toatom exchange reaction using 131I. Following intra-arterial injection, lipiodol is retained by HCC, and 131I-lipidol has been successfully used to treat inoperable HCC [28–31]. One prospective, RCT of adjuvant 131I-lipiodol therapy after curative resection of HCC has been reported [32]. In this trial, a dose of 1850 MBq 131I-lipiodol was selectively injected into the hepatic artery within 6–8 weeks after curative resection of HCC. After a planned interim analysis, the study was terminated early since after a median follow-up of 34.6 months, only 6 of 21 (28.5%) patients in the treatment

group, but 13 of 22 (59%) in the control group had presented with recurrence (p = 0.04). Median disease-free survival was 57.2 months in the treatment group compared to 13.6 months in the control group (p = 0.037), and 3-year overall survival was 86.4% compared to 46.3% (p = 0.039), respectively. An uncontrolled trial using a similar regimen in 28 patients seems to confirm these results [33]. While tolerability was good in both of the studies, it should be emphasized that the numbers of enrolled patients was small. Additionally, in the study from France, only 7 of 28 patients were cirrhotic and the proportion of cirrhotic patients in the previous study from Hong Kong is not mentioned. Thus, it is doubtful whether these results on efficacy and safety can be transferred to the vast majority of HCC patients. Therefore, adjuvant 131I-lipiodol treatment to prevent HCC recurrence after curative resection should not be used outside controlled clinical trials.

Retinoids It is known that cirrhotic patients, particularly in the setting of HCC, have lower vitamin A serum levels than noncirrhotic patients [34, 35]. Retinoids, i.e. vitamin A and its

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naturally occurring or synthetic analogs, are able to inhibit malignant transformation of cells in various in-vitro systems. Additionally, in animal models they impair carcinogenesis in a number of organs, including the liver [36]. Retinoids have been shown to induce apoptosis and to inhibit growth in human hepatoma cell lines in vitro [37–39]. Moreover, retinoid treatment suppressed tumor growth in vivo in rat and mouse models of transplantable HCC [40, 41]. Based on these studies, the efficacy of polyprenoic acid, an acyclic retinoid, in preventing HCC recurrence following curative resection or percutaneous ethanol injection, was explored in a clinical trial [42]. Eighty-nine patients were randomly assigned to receive either polyprenoic acid (600 mg daily po) or placebo for 12 months, starting 8 weeks or earlier following treatment of the primary tumor. The primary endpoint was a histologically confirmed recurrent primary tumor or development of a secondary HCC. After a median follow-up of 38 months, 12 of 44 (27%) of the polyprenoic acid and 22 of 45 (49%) of the placebo treated patients reached the primary endpoint (p = 0.04). Polyprenoic acid was especially effective in preventing secondary HCC (7 of 44 patients [15.9%] compared to 20 of 45 patients [44.4%] in the placebo group; p = 0.040). Thus, the relative risk of developing a second HCC with polyprenoic acid treatment averaged 0.31 (95% CI 0.12–0.78). Polyprenoic acid was well tolerated, with only one patient discontinuing therapy due to side effects. While the majority of patients included in this Japanese study suffered from HCV-associated liver disease, the proportion of patients with established cirrhosis was not clearly stated. Therefore, some uncertainty exists regarding the reproducibility of these results in a cirrhotic population with HCC. Moreover, polyprenoic acid is not licensed and marketed in several countries. In conclusion, polyprenoic acid looks promising for preventing recurrence of HCC after curative resection. However, safety and efficacy need to be confirmed in a large phase III trial in cirrhotic patients.

Other potential approaches for secondary prevention The somatostatin analog octreotide has been explored in RCTs for the treatment of advanced, inoperable HCC [43, 44]. Kouroumalis et al found that in 57 mostly cirrhotic patients, octreotide was safe and prolonged median survival from 4 months in controls, to 13 months in the active treatment group (p = 0.02). On the other hand, Becker et al concluded that HCC patients treated with long-acting octreotide had no survival benefit compared to patients treated with placebo. No data are available regarding the use of somatostatin in an adjuvant setting after resection of HCC. Similarly, the HMG-Co-A reductase inhibitor pravastatin has been recently reported in an RCT in 91 patients with unresectable HCC to double median survival time from 9 months in controls, to 18 months in the active treatment 300

group (p = 0.006) [45]. The proportion of patients with cirrhosis, however, is not clear from this report and the results need to be confirmed in a large phase III trial before studies are designed exploring pravastatin for preventing HCC recurrence following curative resection. The increasing understanding of the molecular pathogenesis of HCC, as well as the introduction of molecular targeted therapies in oncology, have improved the management of this malignancy. Sorafenib is an oral multikinase inhibitor with activity against several tyrosine kinases [46]. A randomized phase III double-blind placebo-controlled trial conducted in patients with advanced HCC treated with sorafenib has shown improvement in survival of 3 months, which was not statistically significant but was clinically meaningful. These results imply that sorafenib should be assessed in the adjuvant setting after potentially curative treatment [47]. Conventional chemotherapy or radiotherapy is ineffective in HCC. In the future, gene therapy and/or immunotherapy approaches may complement chemoprevention strategies. However, both options still need to overcome major obstacles before they are suitable even for small-scale clinical trials. For prevention of HCC recurrence after curative treatment with a gene therapy approach, it would seem especially important to be able to deliver the gene(s) of interest to small clusters of seeded tumor cells and/or dysplastic precursors remaining within the remnant liver with high specificity and efficiency. Moreover, the optimal strategy and target remains to be defined [48]. Adoptive transfer of autologous and in-vitro expanded effector cells has been used to prevent postoperative recurrence of HCC [49]. In this prospective RCT, 150 patients with curative resection of HCC were either repetitively infused over 6 months with autologous lymphocytes activated and expanded in vitro with interleukin (IL)-2 and anti-CD3 antibodies, or received no treatment. Primary endpoints were time to recurrence and recurrence-free survival. After a median follow-up of 4.4 years, 45% of patients in the treatment group compared with 57% in the control group had presented with recurrence, giving a risk reduction by adoptive transfer of 41% (95% CI 12–60%, p = 0.01). Time to first recurrence (p = 0.008) and recurrence-free survival (p = 0.01) were significantly prolonged by adoptive transfer, whereas overall survival was no different between the groups (p = 0.09). Adoptive transfer was acceptably tolerated, fever being the most frequent side effect, which occurred in 47% of patients. While these results look promising, only about 50% of the patients had established cirrhosis. Confirmation in larger phase III trials in cirrhotic patients with curatively resected HCC seems therefore mandatory. Other, more sophisticated immunotherapy approaches may include development of T-cell vaccines against epitopes present on the tumor [50, 51]. This is currently tested for treatment of melanoma, and seems especially attractive for prevention of HCC recurrence. However, it requires the identification of

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Preventing Recurrence of Hepatocellular Carcinoma after Curative Resection

tumor-specific antigens prevalent in the majority of HCCs (and in all cells within a single HCC). In conclusion, gene therapy and other immunotherapy approaches may provide new options for preventing HCC recurrence in the future. However, further larger scale clinical trials are required.

Conclusion The efficacy of neoadjuvant or adjuvant therapeutic modalities for operable HCC remains unclear. While some results, particularly those for adjuvant therapy with IFNs, may look promising, there is a strong need for large, well-designed, prospective RCTs.

Self-assessment questions 1 Locoregional tumor recurrence occurs within 5 years after curative resection in what percentage of patients with hepatocellular carcinoma? A 10% B 20% C 40% D >50% 2 Adjuvant treatment with interferon after curative resection or ablation for HCC is responsible for which one of the following? A Improving survival B Reducing recurrence rate C None of the above D A and B 3 The action of interferon is responsible for preventing which one of the following? A Early recurrence B Late recurrence C A and B D None of the above 4 Side effects of interferon are best described by which one of the following? A Minimal B Very serious C Often a cause for terminating treatment D B and C 5 Iodine-131 labeled lipiodol is given via which one of the following routes? A Per os for systemic chemotherapy B IV for systemic chemotherapy C In the portal vein for local chemotherapy D In the hepatic artery for local chemotherapy

References 1 Stroffolini T, Andreone P, Andriulli A, et al. Characteristics of hepatocellular carcinoma in Italy. J Hepatol 1998;29:944– 52. 2 Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. J Hepatol 2000;35:421–30. 3 Fracanzani AL, Conte D, Fraquelli M, et al. Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease. Hepatology 2001;33:647–51. 4 Llovet JM, Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol. 2008;48 (Suppl 1):S20–37. 5 Bruix J, Sherman M, Practice Guidelines Committee, AASLD. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–36. 6 Chen MS, Li JQ, Zheng Y, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 2006;243: 321–8. 7 Huang GT, Lee PH, Tsang YM, et al. Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular carcinoma: a prospective study. Ann Surg 2005;242: 36–42. 8 Bolondi L, Sofia S, Siringo S, et al. Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis. Gut 2001;48: 251–9. 9 Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30:1434–40. 10 Yuen MF, Cheng CC, Lauder IJ, Lam SK, Ooi CG, Lai CL. Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience. Hepatology 2000;31: 330–5. 11 Adachi E, Maeda T, Matsumata T, et al. Risk factors for intrahepatic recurrence in human small hepatocellular carcinoma Gastroenterology 1995;108:768–75. 12 Bismuth H, Chiche L, Adam R, Castaing D, Diamond T, Dennison A. Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg 1993;218: 145–51. 13 Bronowicki JP, Boudjema K, Chone L, et al. Comparison of resection, liver transplantation and transcatheter oily chemoembolization in the treatment of hepatocellular carcinoma. J Hepatol 1996;24:293–300. 14 Markovic S, Gadzijev E, Stabuc B, et al. Treatment options in Western hepatocellular carcinoma: a prospective study of 224 patients. J Hepatol 1998;29:650–9. 15 Okada S, Shimada K, Yamamoto J, et al. Predictive factors for postoperative recurrence of hepatocellular carcinoma. Gastroenterology 1994;106:1618–24. 16 Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907–17. 17 Colombo M, Donato MF. Prevention of hepatocellular carcinoma. Semin Liver Dis 2005;25:155–61.

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18 Dinney CP, Bielenberg DR, Perrotte P, et al. Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth of human bladder carcinoma in mice by systemic interferon-alpha administration. Cancer Res 1998;58:808–14. 19 von Marschall Z, Scholz A, Cramer T, et al. Effects of interferon alpha on vascular endothelial growth factor gene transcription and tumor angiogenesis. J Natl Cancer Inst 2003;95:437–48. 20 Breitenstein S, Dimitroulis D, Petrowsky H, et al. Interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis – a systemic review and meta-analysis. Br J Surg 2009;96:975–81. 21 Sun HC, Tang ZY, Wang L, et al. Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial. J Cancer Res Clin Oncol 2006;132:458–65. 22 Lo CM, Liu CL, Chan SC, et al. A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma. Ann Surg 2007;245:831–42. 23 Mazzaferro V, Romito R, Schiavo M, et al. Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis. Hepatology. 2006;44(6): 1543–1554. 24 Ikeda K, Arase Y, Saitoh S, et al. Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor-A prospective randomized study of hepatitis C virus-related liver cancer. Hepatology 2000;32:228–32. 25 Llovet JM, Sala M, Castells L, et al. Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma. Hepatology 2000;31:54–8. 26 Kubo S, Nishiguchi S, Hirohashi K, Tanaka H, Shuto T, Kinoshita H. Randomized clinical trial of long-term outcome after resection of hepatitis C virus-related hepatocellular carcinoma by postoperative interferon therapy. Br J Surg 2002;89:418–22. 27 Shiratori Y, Shiina S, Teratani T, et al. Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med 2003;138:299–306. 28 Leung WT, Lau WY, Ho S, et al. Selective internal radiation therapy with intra-arterial iodine-131-Lipiodol in inoperable hepatocellular carcinoma. J Nucl Med 1994;35: 1313–18. 29 Maini CL, Scelsa MG, Fiumara C, et al. Superselective intraarterial radiometabolic therapy with I-131 lipiodol in hepatocellular carcinoma. Clin Nucl Med 1996;21:221–6. 30 Raoul JL, Guyader D, Bretagne JF, et al. Prospective randomized trial of chemoembolization versus intra-arterial injection of 131I-labeled-iodized oil in the treatment of hepatocellular carcinoma. Hepatology 1997;26:1156–61. 31 Yoo HS, Park CH, Lee JT, et al. Small hepatocellular carcinoma: high dose internal radiation therapy with superselective intraarterial injection of I-131-labeled Lipiodol. Cancer Chemother Pharmacol 1994;33 (Suppl):S128–S133. 32 Lau WY, Leung TW, Ho SK, et al. Adjuvant intra-arterial iodine131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet. 1999;353(9155):797– 801.

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33 Partensky C, Sassolas G, Henry L, Paliard P, GJ M. Intra-arterial iodine 131-labeled lipiodol as adjuvant therapy after curative liver resection for hepatocellular carcinoma: a phase 2 clinical study. Arch Surg 2000;135(11). 34 Clemente C, Elba S, Buongiorno G, Berloco P, Guerra V, A DL. Serum retinol and risk of hepatocellular carcinoma in patients with child-Pugh class A cirrhosis. Cancer Lett 2002;178(2): 123–129. 35 Newsome PN, Beldon I, Moussa Y, et al. Low serum retinol levels are associated with hepatocellular carcinoma in patients with chronic liver disease. Aliment Pharmacol Ther 2000;14(10): 1295–1301. 36 Lotan R. Retinoids in cancer chemoprevention. FASEB J 1996;10(9):1031–1039. 37 Kim DG, Jo BH, You KR, DS A. Apoptosis induced by retinoic acid in Hep 3B cells in vitro. Cancer Let. 1996;107(1):149– 159. 38 Nakamura N, Shidoji Y, Moriwaki H, Y M. Apoptosis in human hepatoma cell line induced by 4,5-didehydro geranylgeranoic acid (acyclic retinoid) via down-regulation of transforming growth factor-alpha. Biochem Biophys Res Commun 1996;219(1): 100–104. 39 Nakamura N, Shidoji Y, Yamada Y, Hatakeyama H, Moriwaki H, Y M. Induction of apoptosis by acyclic retinoid in the human hepatoma-derived cell line, HuH-7. Biochem Biophys Res Commun 1995;207(1):382–388. 40 Hsu SL, Lin HM, CK C. Suppression of the tumorigenicity of human hepatoma hep3B cells by long-term retinoic acid treatment. Cancer Lett 1996;99(1):79–85. 41 Morré DM, Kloppel TM, Rosenthal AL, PC F. Chemoprevention of tumor development and metastasis of transplantable hepatocellular carcinomas in rats by vitamin A. J Nutr 1980;110(8):1629–1634. 42 Muto Y, Moriwaki H, Ninomiya M, et al. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med 1996;334(24):1561–1567. 43 Kouroumalis E, Skordilis P, Thermos K, Vasilaki A, Moschandrea J, ON M. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut 1998;42(3):442–447. 44 Becker G, Allgaier HP, Olschewski M, Zähringer A, Blum HE, Group HS. Long-acting octreotide versus placebo for treatment of advanced HCC: a randomized controlled double-blind study. Hepatology 2007;45(1):9–15. 45 Kawata S, Yamasaki E, Nagase T, et al. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br J Cancer 2001;84(7):886– 891. 46 Wilhelm S, Carter C, Lynch M, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 2006;5(10):835–844. 47 Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359(4):378– 390. 48 Qian C, Drozdzik M, Caselmann WH, J P. The potential of gene therapy in the treatment of hepatocellular carcinoma. J Hepatol 2000;32(2):344–351. 49 Takayama T, Sekine T, Makuuchi M, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular

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carcinoma: a randomised trial. Lancet 2000;356(9232):802– 7. 50 Butterfield LH, Meng WS, Koh A, et al. T cell responses to HLAA*0201-restricted peptides derived from human alpha fetoprotein. J Immunol 2001;166(8):5300–5308. 51 Meng WS, Butterfield LH, Ribas A, et al. alphaFetoprotein-specific tumor immunity induced by plasmid primeadenovirus boost genetic vaccination. Cancer Res 2001; 61:8782–6. 52 Lin SM, Lin CJ, Hsu CW, et al. Prospective randomized controlled study of interferon-alpha in preventing hepatocellular carcinoma recurrence after medical ablation therapy for primary tumors. Cancer 2004;100:376–82.

Self-assessment answers 1 2 3 4 5

D A, B A, B B, C D

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5

Guidelines for Liver Tumor Treatment

Introduction Stefan Breitenstein and Pierre-Alain Clavien Department of Surgery, Swiss Hepato-Pancreato-Biliary Center, University Hospital of Zurich, Zurich, Switzerland

Both previous editions comprehensively covered most aspects of liver tumors, and received many positive reviews in the medical and surgical literature, such as “the best book in the area” [1]. However, they failed to address the challenging task of presenting guidelines, as was underlined in a review published in the New England Journal of Medicine: “If I were a physician who was consulting this book for advice on how to treat my patient, I would be impressed by how many treatment options my patient had, but I would have no idea how to pick up the best one” [2]. Therefore, we have included an entire new section presenting guidelines and algorithms covering the most common liver malignancies: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), gallbladder cancer, and colorectal liver metastases. It is a real challenge to write guidelines or draw algorithms because consensus agreement on how to approach a specific condition is rarely available; rather, there are often conflicting opinions among different countries, societies or medical specialties on how to treat a patient with a specific condition. Our rationale for not including guidelines in the first two editions of this book was that this would carry the risk of presenting not universally accepted, or even controversial, guidelines, which could have been seen/considered by many as dogmatic. We believe the book has now matured to the point that we must include guidelines to best serve readers in their search for a treatment for a specific patient. To minimize biased and personal opinions, the guidelines presented in this section were prepared exclusively by the Asso-

ciate Editors and the Deputy Editor, taking into account other available guidelines prepared by national or international societies. Guidelines for each type of cancer were written by at least two Associate Editors from different areas of the world and different medical backgrounds. While surgery often remains the cornerstone of any curative approach in many patients with liver tumors [3], many other aspects are essential prior to or after surgery in treating these patients. In patients with HCC, the underlying liver cirrhosis and related viral hepatitis infection with consecutive portal hypertension are central when deciding about treatment. In patients with CC or gallbladder cancer, treatment strategies are primarily based on tumour staging (local infiltration and metastases). Regarding patients with cololorectal liver metastases, the field is evolving rapidly, and algorithms must increasingly consider neoadjuvant and adjuvant chemotherapies. We hope that this first attempt at presenting guidelines and algorithms will be useful to readers treating a particular patient with a specific condition.

References 1 Morris DL. Book review. Br J Surg 2000;87:1117. 2 Di Bisceglie AM. Book review. N Engl J Med 2004;350:203. 3 Clavien PA, Petrowsky H, DeOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 2007;356:1545–59.

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Strategies for Safer Liver Surgery Philipp Dutkowski, Olivier de Rougemont, and Pierre-Alain Clavien Department of Surgery, Swiss Hepato-Pancreato-Biliary Center, University Hospital Zurich, Zurich, Switzerland

Introduction There has been substantial progress in liver resection owing to improved preoperative diagnosis, intraoperative, and postoperative care. However, insufficient function of the liver remnant after major liver resection is still associated with high morbidity and mortality rates, and limits the achievements of curative tumor resection. Some protective techniques for liver surgery have been recognized for years, e.g. occlusion of the portal triad (Pringle maneuver), which is known to be effective for minimizing blood loss and the need for blood transfusions during liver surgery. However, in spite of many advances in preoperative imaging and surgical approaches, liver resection remains limited by two major concurrent concerns. First, a sufficient volume of liver must be preserved, and second, ischemic injury to these remnant liver cells should be limited as much as possible to minimize reperfusion injury. Hepatoprotective strategies consider therefore response to major tissue loss and reperfusion injury after prolonged hepatic ischemia. Both issues are of utmost importance because below a certain threshold, a liver remnant cannot sustain metabolic, synthetic, and detoxifying functions. In this situation the postoperative course evolves with signs of liver failure, primary jaundice, coagulopathy, encephalopathy, and ascites, as well as renal and pulmonary failure, all of which may become apparent only 3–5 days after surgery. However, the threshold for remnant liver failure appears to be dependent on various conditions. For example, in a young patient with normal hepatic parenchyma the removal of up to 75% of the total liver volume is feasible, while resection must be more conservative in the presence of underlying liver disease or in elderly patients (>70 years). Strategies for safer liver surgery are therefore based first on identification of risk factors for postoperative liver failure

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dependent on the underlying disease, and second, on careful evaluation of remnant liver volume and liver function. In cases of insufficient volume or functional restriction, techniques to increase liver volume should be considered preoperatively. Third, during surgery, pharmacologic and surgical approaches may be applied to reduce oxidative stress due to ischemic injury. This chapter will summarize the current knowledge of these topics in a systematic fashion.

Strategies to evaluate risk factors before surgery Liver cirrhosis The best-studied underlying liver disease in persons undergoing resection is cirrhosis, which is frequently associated with the development of hepatocellular carcinoma. The cirrhotic liver tolerates acute tissue loss poorly due to its impaired function and decreased ability to regenerate [1]. In addition, portal hypertension, if present, is associated with a poor outcome because of compromised portal flow and the risk of postoperative upper gastrointestinal bleeding [2]. These features are critical in selecting patients with cirrhosis for surgery [2]. For example, a right hemihepatectomy is associated with a low risk of liver failure or death in patients with cirrhosis who present with normal serum bilirubin and prothrombin times, and do not have any signs of portal hypertension (Figure 25.1). In contrast, even a limited wedge resection may result in liver failure and death in patients with poor liver function and portal hypertension (Figure 25.1).

Fatty liver Liver steatosis is a common condition and is usually related to obesity, the presence of metabolic disorders, or the intake of alcohol or drugs. Hepatic steatosis increases the risk of liver resection, according to most large studies [3–5]. Experimental data indicate that macrosteatosis (the presence of a single large droplet of fat in hepatocytes, displacing the nucleus) increases this risk more than microsteatosis (the

CHAPTER 25

Strategies for Safer Liver Surgery

(a) Normal liver Potential liver remnant > 30% volume

Yes

No Portal vein embolization Potential liver remnant > 30% volume No

Yes

Resection

No resection

(b) Cirrhotic liver

Child-Turcotte-Pugh class A

Child-Turcotte-Pugh class B or C

Portal hypertension

No

Yes

Potential liver remnant > 50% volume

Yes

No Retention of ICG at 15 min

< 14%

14–20%

> 20%

Portal vein embolization Potential liver remnant > 50% volume Resection

Yes

No

presence of small, multiple fat deposits in hepatocytes) [6]. How to adjust the extent of liver resection in patients with steatosis is unclear, but most experienced surgeons consider mild steatosis (up to 30% of hepatocytes containing fat) a minimal additional risk, or none. Patients with severe steatosis (>60% of hepatocytes containing fat) should undergo only limited resection. In patients with moderate steatosis (30–60% of hepatocytes containing fat), caution is necessary, particularly if macrosteatosis is present, and conserva-

No resection

Figure 25.1 Algorithm of major liver resection for (a) patients with a normal liver and (b) patients with cirrhosis. ICG, indocyanine green. (Reproduced from Clavien et al [31], with permission from the Massachusetts Medical Society.)

tive resection should be favored over major resection. Steatosis can often be treated successfully within a few weeks if the patient is placed on a strict low-fat, high protein diet [7]. Oral supplementation with omega-3 fatty acids has been shown to be protective in this context [8]. Liver biopsies should be performed in patients with suspected moderate-to-severe steatosis to document improvement with such a diet. The association between inflammation (marked leukocyte infiltration), hepatocellular ballooning, and steatosis,

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termed nonalcoholic steatohepatitis, constitutes an additional operative risk [9, 10].

Liver after chemotherapy An increasing number of patients with tumors undergo extensive chemotherapy with multiple drugs before surgery. Irinotecan and oxaliplatin have been associated with the development of steatohepatitis [9, 10]. Among patients receiving these drugs, the rates of complications and death after major liver resection are likely to be increased compared to patients not receiving chemotherapy. In addition, severe hepatic sinusoidal obstruction, occasionally associated with nodular regenerative hyperplasia, has been ascribed to oxaliplatin-based chemotherapy [11, 12]. These vascular obstructions results in a bluish appearance of the liver. Patients with this histologic feature are at higher risk for intraoperative blood loss and postoperative complications. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), in combination with cytotoxic chemotherapy appears to improve survival in patients with metastatic colorectal cancer [13]. Because VEGF influences liver regeneration through its regulation of angiogenesis and the release of growth factors, the effect of bevacizumab may be deleterious [14]. However, after a window of 6–8 weeks between the administration of bevacizumab and surgery, the risk of complications after liver resection may not be increased [15]. Although most clinicians favor wedge rather than major resection in patients exposed to extensive chemotherapy, there is currently no consensus and the optimal window between the completion of chemotherapy and surgery remains uncertain.

Old liver Chronologic age alone is not a contraindication to liver resection for malignancy [16]. However, patients older than 70 years appear to have higher mortality depending on their general health [17]. On the other hand, the mortality risk for these patients has been markedly reduced during the last years [17]. Several studies have shown that selected elderly patients benefit from liver surgery and that overall survival is similar to that for younger patients [16, 18].

Strategies to recognize liver capacity before surgery Routine liver biochemical tests A number of liver-related serum parameters (bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase), a coagulation profile, and a platelet count generally fulfill a routine assessment of a candidate with normal liver parenchyma before major liver surgery. However, blood parameters must be interpreted with caution if a liver disease is present and should be complemented by dynamic liver function tests.

Dynamic liver tests Metabolic tests target different aspects of hepatic physiology (Table 25.1). The most commonly used test is intravenous injection of indocyanine green (ICG), a dark bluish–green tricarboncyanine dye that rapidly binds to plasma βlipoprotein and is completely and exclusively removed by hepatocytes via biliary secretion. The rate of retention of ICG

Table 25.1 Preoperative liver function tests. (Reproduced from Clavien et al [31], with permission of the Massachusetts Medical Society.) Function measured

Test

Principle of test

Microsomal hepatic function

Breath tests (C-labeled aminopyrine, methacetin, caffeine) Clearance tests (antipyrine, caffeine, lidocaine)

Breath tests are used to probe hepatic microsomal P450 enzyme activity and investigate hepatocellular function by assessing liver oxidation. The exhaled labeled CO2 is measured

Cytosolic hepatic function

Elimination capacity test (galactose)

The capacity for elimination of galactose is estimated by serial measurements of serum galactose levels after administration of an intravenous bolus of galactose; galactose is metabolized by the cytosolic enzyme galactokinase

Liver perfusion and biliary excretion

Clearance test (indocyanine green)

Indocyanine green is distributed in the serum, removed by the liver, and excreted unchanged into bile without entering the extrahepatic circulation

Liver perfusion

Clearance tests (low-dose galactose, sorbitol)

The high rate of hepatic extraction of low-dose galactose and sorbitol by the sinusoidal membrane of hepatocytes implies a hepatic plasma flow-dependent mechanism

Hepatocyte mass

Uptake test (technetium99m-galactosyl human serum albumin labeling)

Technetium-99m-galactosyl human serum albumin accumulates only in the liver by ligand– receptor binding and is visualized on scintigraphy

310

Clearance tests probe the hepatic microsomal P450 enzyme activity and measure either the metabolic elimination of the test compound or the appearance of metabolites in the blood that are primarily dependent on the hepatic metabolic capacity

CHAPTER 25

Table 25.2 Critical remnant liver mass for liver resection. Data (median and range) from a worldwide survey of 100 liver centers (adapted from Breitenstein et al [20]).

Europe North America Asia Australia South America Overall

Normal liver (%)

Cirrhotic liver (%)

28 25 30 28 28 25

50 50 50 50 45 50

(15–40) (15–30) (20–40) (25–30) (25–40) (15–40)

(30–80) (25–90) (30–80) (40–50) (40–80) (25–90)

determined at 15 min after injection must be interpreted in the context of other factors. Patients with a favorable Child– Turcotte–Pugh class A and a retention rate of ICG at 15 min of less than 14% tolerate major hepatectomy well, whereas those with a retention rate greater than 20% should be excluded from major liver resection. Patients with retention rates between 14% and 20% should undergo surgery only if potential liver remnant volume exceeds 50%.

Assessment of remnant volume A proper assessment of the predicted volume of the liver remnant on computed tomography (CT) or magnetic resonance imaging (MRI) is mandatory for major liver resection. Excellent correlation between estimated and real weights (r = 0.997 for MRI; r = 0.997 for CT) have been reported in recent imaging studies [19]. Generally, it is accepted that approximately 25% of the total liver volume needs to be preserved following hepatectomy to minimize the risk of liver failure. For patients with cirrhosis or those who are heavily pretreated with systemic chemotherapy, some investigators advocate that 40% should be the safe threshold. This has also been shown in a recent worldwide survey evaluating the current practice regarding critical liver mass [20] (Table 25.2).

Liver regeneration Response to major tissue loss The human body responds to partial hepatectomy not by regenerating lost segments, but by inducing hyperplasia in the liver remnant. The process of restoration of liver volume in humans is initiated by the replication of various types of intrahepatic cells, followed by an increase in cell size. The onset and peak of hepatocyte replication vary among species. In humans, replication of hepatocytes generally starts within 1 day after major resection. Nonparenchymal cells, such as endothelial cells, Kupffer cells, and biliary duct cells replicate in a delayed fashion. After replication is completed, growth consisting of an increase in cell size occurs over several

Strategies for Safer Liver Surgery

additional days. The initiation and synchronization of replication in different types of hepatic cells depend on the extent of the resection, tissue damage, or both. Low-grade tissue damage or a relatively small resection reduces the replication rate [21]. After a massive resection (removal of 70% of the liver), up to 90% of the hepatocytes appear to replicate.

Molecular basis of liver regeneration The process of liver regeneration involves mediators similar to those found in acute inflammation. Normally, hepatocytes are in the quiescent G0 phase. After resection, the remaining hepatocytes enter the G1 phase. Cytokines derived predominantly from Kupffer cells prime hepatocytes. Tumor necrosis factor-α and interleukin-6 are released, contributing to the initiation of the cell cycle [22]. Mitogenic factors are required for the regeneration process to enter the S phase, primarily growth factors such as epidermal growth factor and transforming growth factor-α (TGF-α). Serotonin, a neurotransmitter transported within the peripheral circulation by platelets, appears to be a comitogen [23]. Bile acids also influence regeneration [24]. Integration of all these signals induces full and synchronized regeneration. Failure to activate this signal cascade can result in a delayed onset of regeneration, inadequate recovery of liver volume, and eventually clinical signs of liver failure [22]. Termination of the regenerative process appears to be controlled by the action of TGF-β and other members of the activin family [25].

Strategies to increase liver volume Experiments performed almost a century ago suggested that selective occlusion of the portal branch causes atrophy of the ipsilateral liver lobe and hypertrophy of the contralateral lobe. Induced atrophy of the occluded hemiliver is triggered by increased apoptotic activity, whereas hypertrophy of the nonoccluded lobe appears to be linked to increased cellular proliferation [26]. In the late 1980s, Makuuchi et al first used the selective occlusion strategy in patients to extend the limits of liver resection [27]. Selective interruption of the portal flow to a part of the liver can be achieved by portal vein embolization (PVE) or ligation. Although portal vein ligation requires a surgical (open or laparoscopic) approach, PVE can be performed percutaneously, usually by the transhepatic approach using embolic materials such as gelatin sponge, cyanoacrylate with ethiodized oil, alcohol, fibrin glue, particles, or coils. Both embolization and ligation of the portal vein are usually performed on the right portal vein in preparation for a right hemihepatectomy when the potential liver remnant would otherwise be too small. When an extended right hemihepatectomy is to be performed, the volume of the liver remnant can be optimized by additional

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occlusion of the left medial branch (segment IV). Currently, portal vein ligation is used only during an open procedure.

Indications for portal vein occlusion PVE is indicated only if the volume of the potential liver remnant would be below the threshold associated with a high risk of inadequate liver volume after surgery. Most surgeons consider a major resection 2–4 weeks after portal vein occlusion, when the maximal changes in volume have been reached. PVE is also increasingly used as a dynamic preoperative test to identify patients in whom liver regeneration will be impaired [28]. This approach is especially relevant for patients with chronic liver diseases, cholestasis, and a history of chemotherapy [29]. It is supported by a study in patients with cirrhosis in whom the failure of regeneration after PVE predicted poor outcome after surgery [30]. Two algorithms for the treatment of patients with normal livers or cirrhotic livers can be concluded before major liver resection by considering portal hypertension, predicted remnant liver volume, and liver function (ICG test) (Figure 25.1) [31].

Effect on tumor growth A legitimate concern is whether the stimulus for liver regeneration induced by portal vein occlusion might enhance tumor growth. Although there have been few reports of an influence of portal vein occlusion on tumor growth [32, 33], most other studies on colorectal liver metastasis failed to show any negative effect on tumor growth or reduced patient survival after surgery [34, 35]. One study reported a lower rate of recurrence of hepatic cancer after PVE that was followed by surgery, as compared with resection alone [35]. However, the intuitive concern that metastases in the nonembolized hemiliver might grow more rapidly after right PVE has led to the proposal of a two-stage procedure: in the first stage, all visible metastases in the left hemiliver are cleared in association with right PVE or ligation. In the second stage, about 4 weeks later, a right or extended right hemihepatectomy is performed (Figure 25.2). When concomitant chemotherapy is used, definitive liver resection is usually performed 3 or more months after the start of treatment.

Portal vein occlusion with chemotherapy New strategies have focused on combining selective portal vein obstruction with the concomitant administration of systemic [36] or selective intra-arterial hepatic [37] chemotherapy before liver resection, with the aim of achieving both a reduction in the tumor size and a change in liver volume. These strategies have been applied in patients with an unresectable, advanced tumor load and a liver remnant that was predicted to be too small for resection. The regimen and the timing of systemic chemotherapy and PVE have been variable, but fluorouracil-based chemotherapy with or without oxaliplatin, irinotecan, or bevacizumab is the

312

regimen most often used [34, 36]. In a pilot study, continuous delivery of selective intra-arterial chemotherapy with floxuridine and right portal vein ligation in patients with multiple unresectable metastases of colorectal origin were associated with a significant decrease in tumor volume and increase in the volume of the contralateral left hemiliver [37]. About one-third of the patients receiving this treatment underwent curative liver resection 3 months after the start of treatment. Impairment of the hypertrophy induced by portal vein obstruction that results from continuous chemotherapy has not been observed to date. When liver resection is not performed after PVE or ligation, the use of further systemic or regional chemotherapy remains possible. The main complication of selective hepatic delivery of floxuridine appears to be the development of intrahepatic and extrahepatic biliary strictures [28].

Portal vein embolization with chemoembolization Another strategy in patients with hepatocellular carcinoma is the sequential use of transarterial chemoembolization, PVE, and then major liver resection [38]. Transarterial chemoembolization is directed both to the tumor treatment and to embolization of arterioportal shunts, which are frequently present in cirrhosis. Transarterial chemoembolization may prevent tumor progression after PVE [39]. This approach, compared with PVE alone, has been associated with more efficient hypertrophy and improved tumor control before major hepatectomy [30].

Portal vein embolization with biliary drainage Patients with hilar cholangiocarcinomas often require complex liver resection. Since segment I is also removed during such a resection because of a high incidence of recurrence at this location, the liver remnant typically consists of segments II and III and the upper part of segment IV. These patients frequently present with severe cholestasis and impaired liver function due to obstruction of the bile duct. A preoperative strategy of biliary drainage of the potential liver remnant followed by PVE of the area of the planned resection has been reported to reverse cholestasis and increase the size of the liver remnant [40]. Although the optimal timing of these interventions has not been determined, many surgeons now perform PVE within 1–3 weeks after biliary drainage, and consider surgery after the cholestasis resolves and there is an adequate regeneration response. With the use of this strategy, several studies of extensive liver resections for hilar cholangiocarcinomas have been reported [40, 41].

Strategies to protect liver function The novel strategies and the extension of the criteria for liver surgery expose more organs to the risk of ischemic injuries.

CHAPTER 25

(a)

Strategies for Safer Liver Surgery

(b) Atrophy

VIII

II

IV

VIII

III

Hypertrophy

IV

II III

VII

VII

VI

Left medial branch V

V

Left portal vein Right portal vein

(c)

VI

Portal vein

(d)

Tumor

(e)

(f)

Figure 25.2 (a) Normal liver anatomy and (b–f) principle of portal vein occlusion with and without concomitant chemotherapy, the two-stage procedure. (b) Occlusion of right portal vein, (c) multiple liver tumors, (d) occlusion of right portal vein with tumorectomies in left hemiliver, (e) hypertrophy of the left hemiliver and tumor shrinkage after chemotherapy, and (f) right hemihepatectomy. (Reproduced from Clavien et al [31], with permission from the Massachusetts Medical Society.) 313

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Injury is accentuated in livers with underlying diseases (e.g. cirrhosis and steatosis). Different strategies have been developed to avoid or attenuate such injuries: the concept of preconditioning aimed at tolerance of the organ to ischemia and strategies aimed at direct protection. From a practicable perspective, there are two types of treatment strategy: surgical interventions and pharmacologic agents.

Surgical approach Many surgeons use an inflow occlusion, e.g. Pringle maneuver, on a routine basis during liver resection. While this prevents blood loss during resection, it causes ischemic injury to the liver. To induce tolerance against such injury, two surgical strategies have made the transition into clinical practice. One is the concept of preconditioning with a shortterm Pringle maneuver [42]; the other is intermittent clamping of the portal triad [43]. In the mid-1980s Murry et al observed that brief periods of coronary occlusion followed by short reperfusion before a prolonged ischemia reduced the size of myocardial infarction [44]. This observation was reproduced in rodent livers [45]. The organ’s tolerance to reperfusion injury after prolonged periods of ischemia is increased by this manipulation. A common ischemic preconditioning protocol consists of 10 min of ischemia followed by 15 min of reperfusion before the prolonged inflow exclusion for resection. A two-fold reduction in postoperative serum transaminases has been reported [42]. The serum transaminases, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), are the most sensitive markers of ischemic injury to the liver. The effect has further been shown on one hand to be increased in patients with mildto-moderate steatosis, and on the other hand to be lost in patients older than 60 years old. An inhibition of apoptotic cells has been reported, too [46]. The other strategy which has found its way into clinical practice is intermittent clamping. This consists of an inflow occlusion followed by short periods of reperfusion, and results in repeated ischemia reperfusion injuries. This strategy also shows a better parenchymal tolerance [47].

Pharmacologic approach An attractive alternative to a surgical approach is a pharmacologic one. There is abundant literature on possible pharmacologic approaches to protect the liver against liver injury and enhance liver regeneration. Only a few have reached clinical practice; some are in the pipeline and are being tested in prospective randomized trials in humans. For example, cardiotrophin-1, a member of the interleukin-6 (IL-6) cytokine family, showed hepatoprotective potential in rescuing regeneration after 90% hepatectomy in rats [48]. Pentoxifylline, a TNF-α synthesis inhibitor and inductor of the IL-6 pathway, showed prevention of lethal outcome and full restoration of regeneration in a small for size murine

314

liver transplantation [22]. Their usefulness in humans remains to be demonstrated. Pharmacologic preconditioning as a hepatoprotective strategy in humans has only been described once in a prospective randomized human trial [49]. Patients undergoing an inflow occlusion for resection were randomized to sevoflurane preconditioning. Sevoflurane, a volatile anesthetic, has been shown to attenuate mechanical cardiac dysfunction on reperfusion after ischemia in the myocyte [50]. In terms of liver resection, lower serum levels of transaminases and significant improvement of the clinical outcome were shown with this pharmacologic preconditioning [49].

Conclusion Many hepatic tumors previously considered to be unresectable are now amenable to complete resection through innovative strategies that increase remnant liver volume. PVE or ligation cause atrophy of the ipsilateral hemiliver and hypertrophy of the contralateral side. PVE appears to be particularly valuable in patients who present with underlying liver disease. The concomitant administration of chemotherapy may further decrease both the tumor load and postoperative recurrences. In the future, the use of new drugs based on innovative experimental models, together with a better understanding of the pathways leading to liver regeneration, may permit a very small liver remnant to regenerate, resulting in safer surgery for patients with large hepatic tumors.

Self-assessment questions 1 The cirrhotic liver tolerates acute tissue loss poorly. Which of the following is a contraindication for major liver resection? A Potential liver remnant volume of 55% B Portal venous pressure of 20 mmHg C Retention of ICG (indocyanine green) of 12% at 15 min D Presence of a hepatocellular carcinoma 2 Which one of the following manipulative strategies has not resulted from the ability of the liver to regenerate? A Portal vein embolization B Portal vein ligation C Ligation of the hepatic artery D Biliary drainage 3 Which one of the following mediator does not trigger liver regeneration? A Transforming growth factor-β (TGF-β) B Tumor necrosis factor-α (TNF-α)

CHAPTER 25

C Interleukin-6 (IL-6) D Hepatic growth factor (HGF) E Serotonin 4 What is the minimal volume of a liver remnant after major liver resection in a young and healthy patient? A 60% B 10% C 25% D 35% E 40%

10

11

12

13

5 Major hepatic resection in selected cirrhotic patients can be performed with low risk because portal hypertension does not affect surgery. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct

16

References

17

1 Nagasue N, Yukaya H, Ogawa Y, Kohno H, Nakamura T. Human liver regeneration after major hepatic resection. A study of normal liver and livers with chronic hepatitis and cirrhosis. Ann Surg 1987;206:30–39. 2 Bruix J, Castells A, Bosch J, et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 1996;111:1018–22. 3 Belghiti J, Hiramatsu K, Benoist S, Massault P, Sauvanet A, Farges O. Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J Am Coll Surg 2000;191:38–46. 4 Kooby DA, Fong Y, Suriawinata A, et al. Impact of steatosis on perioperative outcome following hepatic resection. J Gastrointest Surg 2003;7:1034–44. 5 McCormack L, Petrowsky H, Jochum W, Mullhaupt B, Weber M, Clavien PA. Use of severely steatotic grafts in liver transplantation: a matched case-control study. Ann Surg 2007;246:940–6; discussion 946–8. 6 Selzner N, Selzner M, Jochum W, Amann-Vesti B, Graf R, Clavien PA. Mouse livers with macrosteatosis are more susceptible to normothermic ischemic injury than those with microsteatosis. J Hepatol 2006;44:694–701. 7 Nakamuta M, Morizono S, Soejima Y, et al. Short-term intensive treatment for donors with hepatic steatosis in living-donor liver transplantation. Transplantation 2005;80:608–12. 8 El-Badry AM, Moritz W, Contaldo C, Tian Y, Graf R, Clavien PA. Prevention of reperfusion injury and microcirculatory failure in macrosteatotic mouse liver by omega-3 fatty acids. Hepatology 2007;45:855–63. 9 Fernandez FG, Ritter J, Goodwin JW, Linehan DC, Hawkins WG, Strasberg SM. Effect of steatohepatitis associated with

14

15

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21

22

23 24

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irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg 2005;200:845–53. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006; 24:2065–72. Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 2006;24:4983–90. Bilchik AJ, Poston G, Curley SA, et al. Neoadjuvant chemotherapy for metastatic colon cancer: a cautionary note. J Clin Oncol 2005;23:9073–8. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–42. Ellis LM, Curley SA, Grothey A. Surgical resection after downsizing of colorectal liver metastasis in the era of bevacizumab. J Clin Oncol 2005;23:4853–5. D’Angelica M, Kornprat P, Gonen M, et al. Lack of evidence for increased operative morbidity after hepatectomy with perioperative use of bevacizumab: a matched case-control study. Ann Surg Oncol 2007;14:759–65. Fong Y, Blumgart LH, Fortner JG, Brennan MF. Pancreatic or liver resection for malignancy is safe and effective for the elderly. Ann Surg 1995;222:426–34; discussion 434–27. Figueras J, Ramos E, Lopez-Ben S, et al. Surgical treatment of liver metastases from colorectal carcinoma in elderly patients. When is it worthwhile? Clin Transl Oncol 2007;9:392–400. Petrowsky H, Clavien PA. Should we deny surgery for malignant hepato-pancreatico-biliary tumors to elderly patients? World J Surg 2005;29:1093–100. Jackowski C, Thali MJ, Buck U, et al. Noninvasive estimation of organ weights by postmortem magnetic resonance imaging and multislice computed tomography. Invest Radiol 2006;41: 572–8. Breitenstein S, Apestegui C, Petrowsky H, Clavien PA. “State of the art” in liver resection and living donor liver transplantation. A worldwide survey of 100 liver centers. World J Surg 2008;33:797–803. Nocito A, Georgiev P, Dahm F, et al. Platelets and plateletderived serotonin promote tissue repair after normothermic hepatic ischemia in mice. Hepatology 2007;45:369–76. Tian Y, Jochum W, Georgiev P, Moritz W, Graf R, Clavien PA. Kupffer cell-dependent TNF-alpha signaling mediates injury in the arterialized small-for-size liver transplantation in the mouse. Proc Natl Acad Sci U S A 2006;103:4598–603. Lesurtel M, Graf R, Aleil B, et al. Platelet-derived serotonin mediates liver regeneration. Science 2006;312:104–7. Huang W, Ma K, Zhang J, et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 2006;312:233–6. Strain AJ, Frazer A, Hill DJ, Milner RD. Transforming growth factor beta inhibits DNA synthesis in hepatocytes isolated from normal and regenerating rat liver. Biochem Biophys Res Commun 1987;145:436–42. Harada H, Imamura H, Miyagawa S, Kawasaki S. Fate of the human liver after hemihepatic portal vein embolization: cell kinetic and morphometric study. Hepatology 1997;26:1162–70.

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27 Makuuchi M, Thai BL, Takayasu K, et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 1990;107: 521–7. 28 Farges O, Belghiti J, Kianmanesh R, et al. Portal vein embolization before right hepatectomy: prospective clinical trial. Ann Surg 2003;237:208–17. 29 Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004;240:644–57; discussion 657–48. 30 Ogata S, Belghiti J, Farges O, Varma D, Sibert A, Vilgrain V. Sequential arterial and portal vein embolizations before right hepatectomy in patients with cirrhosis and hepatocellular carcinoma. Br J Surg 2006;93:1091–8. 31 Clavien PA, Petrowsky H, DeOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 2007;356:1545–59. 32 Elias D, Ouellet JF, De Baere T, Lasser P, Roche A. Preoperative selective portal vein embolization before hepatectomy for liver metastases: long-term results and impact on survival. Surgery 2002;131:294–9. 33 Heinrich S, Jochum W, Graf R, Clavien PA. Portal vein ligation and partial hepatectomy differentially influence growth of intrahepatic metastasis and liver regeneration in mice. J Hepatol 2006;45:35–42. 34 Azoulay D, Castaing D, Smail A, et al. Resection of nonresectable liver metastases from colorectal cancer after percutaneous portal vein embolization. Ann Surg 2000;231:480–6. 35 Oussoultzoglou E, Bachellier P, Rosso E, et al. Right portal vein embolization before right hepatectomy for unilobar colorectal liver metastases reduces the intrahepatic recurrence rate. Ann Surg 2006;244:71–9. 36 Jaeck D, Oussoultzoglou E, Rosso E, Greget M, Weber JC, Bachellier P. A two-stage hepatectomy procedure combined with portal vein embolization to achieve curative resection for initially unresectable multiple and bilobar colorectal liver metastases. Ann Surg 2004;240:1037–49; discussion 1049–51. 37 Selzner N, Pestalozzi BC, Kadry Z, Selzner M, Wildermuth S, Clavien PA. Downstaging colorectal liver metastases by concomitant unilateral portal vein ligation and selective intraarterial chemotherapy. Br J Surg 2006;93:587–92. 38 Aoki T, Imamura H, Hasegawa K, et al. Sequential preoperative arterial and portal venous embolizations in patients with hepatocellular carcinoma. Arch Surg 2004;139:766–74. 39 Kokudo N, Makuuchi M. Current role of portal vein embolization/hepatic artery chemoembolization. Surg Clin North Am 2004;84:643–57.

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40 Kawasaki S, Imamura H, Kobayashi A, Noike T, Miwa S, Miyagawa S. Results of surgical resection for patients with hilar bile duct cancer: application of extended hepatectomy after biliary drainage and hemihepatic portal vein embolization. Ann Surg 2003;238:84–92. 41 Nagino M, Kamiya J, Nishio H, Ebata T, Arai T, Nimura Y. Two hundred forty consecutive portal vein embolizations before extended hepatectomy for biliary cancer: surgical outcome and long-term follow-up. Ann Surg 2006;243:364–72. 42 Clavien PA, Selzner M, Rudiger HA, et al. A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning. Ann Surg 2003;238:843–50; discussion 851–2. 43 Makuuchi M, Mori T, Gunven P, Yamazaki S, Hasegawa H. Safety of hemihepatic vascular occlusion during resection of the liver. Surg Gynecol Obstet 1987;164:155–8. 44 Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124–36. 45 Lloris-Carsi JM, Cejalvo D, Toledo-Pereyra LH, Calvo MA, Suzuki S. Preconditioning: effect upon lesion modulation in warm liver ischemia. Transplant Proc 1993;25:3303–4. 46 Yadav SS, Sindram D, Perry DK, Clavien PA. Ischemic preconditioning protects the mouse liver by inhibition of apoptosis through a caspase-dependent pathway. Hepatology 1999;30: 1223–31. 47 Belghiti J, Noun R, Malafosse R, et al. Continuous versus intermittent portal triad clamping for liver resection: a controlled study. Ann Surg 1999;229:369–75. 48 Bustos M, Beraza N, Lasarte JJ, et al. Protection against liver damage by cardiotrophin-1: a hepatocyte survival factor upregulated in the regenerating liver in rats. Gastroenterology 2003;125:192–201. 49 Beck-Schimmer B, Breitenstein S, Urech S, et al. A randomized controlled trial on pharmacological preconditioning in liver surgery using a volatile anesthetic. Ann Surg 2008;248:909–18. 50 Mullenheim J, Ebel D, Frassdorf J, Preckel B, Thamer V, Schlack W. Isoflurane preconditions myocardium against infarction via release of free radicals. Anesthesiology 2002;96:934–40.

Self-assessment answers 1 2 3 4 5

B C A C B

26

Hepatocellular Carcinoma Tadatoshi Takayama Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan

Introduction Hepatocellular carcinoma (HCC) is unique in that both the tumor stage and the degree of liver damage must be simultaneously considered when selecting an optimal treatment strategy [1]. The best-suited therapeutic option for an individual patient needs to be selected from multiple approaches, including liver resection, percutaneous ablation, transarterial chemoembolization (TACE), and transplantation, but evidence-based guidelines for the decision-making are scarce [2–7]. There is no universal therapeutic strategy for HCC across the world because of geographic or etiologic differences. However, it would serve both doctors and patients if treatment guidelines were based on the accumulated evidence and objective interpretation. This chapter outlines the representative treatment guidelines for HCC from the West and the East where the clinical contexts differ.

Staging systems The staging systems for cancer are designed to stratify patients according to prognostic variables, to provide guidance for making therapeutic decisions, and to predict the prognosis. The system for HCCs can be more complex than for other cancers, because their prognosis depends not only on the tumor status but also on the underlying liver disease [8]. In 2001, the European Association for the Study of the Liver (EASL) recommended that appropriate staging systems for HCC should include four related categories: tumor stage, hepatic functional reserve, patients’ general condition, and treatment efficacy [3]. Recently, conventional systems addressing only one of these categories (TNM, Child–Pugh class, and performance status) have not been used in clinical practice.

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

Up to now, several staging systems for HCC have been proposed. The five representative systems (Table 26.1) integrate tumor status and liver function with or without health status, and are used in different regions of the world. The Okuda stage [9] is a prototype and is seldom used because of difficulty in distinguishing early and advanced HCC. The Barcelona Clinic Liver Cancer (BCLC) staging [10] stratifies patients into four major categories, which link the stages to treatment recommendation. The Cancer of the Liver Italian Program (CLIP) score [11] recognizes the contribution of tumor biology by including tumor morphology and alphafetoprotein (AFP), and has been validated by the authors and other groups [12, 13]. The Chinese University Prognostic Index (CUPI) [14] considers six predictive variables, and divides patients into three stages. The Japan Integrated Staging (JIS) score [15] is a score system that includes two previous classifications: the Liver Cancer Study Group of Japan TNM and Child–Pugh classifications. All systems include vascular invasion, which has a strong impact on prognosis, and the Child–Pugh class is used as a part of the BCLC, CLIP, and JIS systems. In the West, BCLC staging or the CLIP score are used as the staging systems for HCC, and the JIS score is used in the East. It is noted that these systems have different characteristics: BCLC staging is designed to facilitate treatment selection, but not outcome prediction, while the CLIP and JIS scores are systems for predicting prognosis [16]. In countries where HCC is usually diagnosed at an advanced stage, the CLIP score will provide a firm basis for stratification. The JIS score is most useful in countries like Japan, where many small HCCs are detected. Currently, there is no staging system for HCC that can be routinely used worldwide.

Treatment guidelines Treatment strategy for HCC varies throughout the world. Several guidelines have been proposed in the West and the East. Generally, the treatment guidelines should not be rigid protocols, but rather should represent a basis on which clinicians can consider the options available more clearly. The

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Table 26.1 Staging systems for hepatocellular carcinoma. Classification [Ref.]

Year

Background

Variables Tumor status

Liver function

Health status

Ascites, bilirubin, albumin Child–Pugh, bilirubin, portal hypertension Child–Pugh

– Performance status

Bilirubin, albumin, alkaline phosphatase Child–Pugh

Presence of symptoms

Okuda stage [9] BCLC staging [10]

1985 1999

850 Japanese patients Selected papers

CLIP score [11]

2000

435 Italian patients

CUPI [14]

2002

926 Chinese patients

50% liver involvement Size, number, vascular invasion, Okuda stage 50% liver involvement, vascular invasion, AFP TNM, AFP

JIS score [15]

2003

334 Japanese patients

TNM (Japanese)

–

–

BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program; CUPI, Chinese University Prognostic Index; JIS, Japan Integrated Staging; AFP, alpha-fetoprotein.

British guidelines for HCC, compiled by the British Society of Gastroenterology, may be the first evidence-based guidelines [5]. The strengths of the evidence levels and recommendations were defined by a systematic review of the relevant literature. These guidelines cover two areas of clinical practice: diagnosis, including surveillance of high-risk subjects; and treatment of patients.

Western guidelines The treatment guidelines for HCC in Europe were published in 2001 as the EASL Consensus [3], and in the USA in 2004 as The American Association for the Study of Liver Diseases (AASLD) Clinical Practice Guidelines [17]. Both were based on the BCLC staging system, but the latter included Stage 0 HCC (carcinoma in situ) as a new entity [18]. The BCLC guideline links the stage of HCC to a treatment algorithm (Figure 26.1), and aims to incorporate an estimation of prognosis and potential treatment advancements in a single unified proposal [2, 19]. Each stage contains the relevant prognostic variables of the tumor and the liver functional status independently related to a patient’s survival. The BCLC staging classification for HCC consists of five stages (Stage 0, A, B, C, and D). Patients with very early stage (Stage 0) disease and those with early stage (Stage A) disease are optimal candidates for a radical treatment for a possible cure. Liver resection is the best option for patients with a single tumor when serum bilirubin levels and portal pressure are normal (Stage A1). Single tumors associated with portal hypertension (Stage A2) are resected at the time of liver transplantation. Transplantation is the first choice for patients with a single tumor when both serum bilirubin levels and portal pressure are abnormal (Stage A3), and for those with up to three tumors smaller than 3 cm, irrespective of liver impairment (Stage A4). Percutaneous ablation,

318

either by ethanol injection or radiofrequency, is used to treat small nonsurgical HCC when the associated diseases may be complicated. Patients with intermediate stage (Stage B) disease who have four or more tumors and no portal invasion, are the best candidates for TACE, particularly those with Child–Pugh class A cirrhosis. Patients with advanced stage (Stage C) disease complicated by portal invasion, extrahepatic metastasis, or physical impairment are candidates for new antitumor agents. Patients with terminal stage (Stage D) disease who have massive tumor burden (Okuda Stage III) or heavily impaired physical status (performance status test [PST] > 2) may receive symptomatic treatment. A systematic review has reported the survival rates in patients with HCC who received radical therapies and those who were not treated [2]. The mean 1-, 3-, and 5-year survival rates of patients allocated to liver resection were 85%, 62%, and 51%, while those of patients allocated to ethanol injection were 87%, 50%, and 27%, respectively. Liver transplantation was the most effective intervention for cirrhotic patients: the 5-year survival rate was 74% and the recurrence rate was 15% in patients with HCC who met the Milan criteria. Mean survival rates at 1, 3, and 5 years were, respectively, 80%, 50%, and 16% in patients with intermediate-stage disease, falling to 29%, 8%, and 0% in patients with advanced-stage disease, and 10%, 10%, and 0% in those with end-stage disease. Independently of both the European and American guidelines, the National Comprehensive Cancer Network (NCCN) Guidelines Panel for HCC addresses cancer detection, prevention, diagnosis, treatment, and supportive care (http:// www.nccn.org/). Regarding treatment, patients with HCC, as confirmed by rising AFP values or by biopsy, are assessed for surgical treatment by resection alone or resection plus

CHAPTER 26

Hepatocellular Carcinoma

HCC

Stage 0

Stage A–C

Stage D

PST 0, Child–Pugh A, Okuda 1

Okuda 1–2, PST 0–2, Child–Pugh A, B

Okuda 3, PST > 2, Child–Pugh C

Early stage (A) Single or 3 nodules < 3 cm, PST 0

Very early stage (0) Single < 2 cm Carcinoma in situ

Single

Intermediate stage (B) Multinodular, PST 0

Advanced stage (C) Portal invasion, N1, M1, PST 1–2

Terminal stage (D)

3 nodules < 3 cm

Portal pressure/ bilirubin Increased

Associated diseases

No

Normal

Resection

Transplantation

Yes

PEI/RFA

Curative treatments

Portal invasion, N1, M1

No

Chemoembolization

Randomized controlled trials

Yes

New agents Symptomatic treatment

Figure 26.1 Barcelona Clinic Liver Cancer staging classification. Stage 0, Patients with very early hepatocellular carcinoma (HCC) are optimal candidates for resection; Stage A, patients with early HCC are candidate for radical therapies (resection, transplantation, or percutaneous ablation); Stage B, patients with intermediate HCC may benefit from chemoembolization; Stage C, patients with advanced HCC may receive new agents in the setting of randomized controlled trials; Stage D, patients with end-stage disease will receive symptomatic treatment. PST, performance status test; PEI/RFA; percutaneous ethanol injection/ radiofrequency thermal ablation. (Reproduced from Llovet et al [1], with permission.)

ablation, based on the tumor status and performance status. Patients with unresectable tumors are potential candidates for transplantation, while unfavorable candidates may choose other treatment options, such as sorafenib [20], TACE, chemotherapy, or radiation. The NCCN evidencebased approach allows the user to understand how the algorithm recommendations are derived and how evidence from important studies, as well as expert clinical experience, is incorporated into the algorithm. However, this guideline is not linked to clinical tumor staging.

Eastern guidelines In 2005, the Liver Cancer Study Group of Japan compiled the Clinical Practice Guidelines for HCC (the Japanese guidelines) based on an evidence-based methodology, which covered six fields, including prevention, diagnosis, surgery,

chemotherapy, TACE, and percutaneous ablation. A systematic review of the English-language medical literature was performed: a total of 7192 articles on HCC were extracted mainly from MEDLINE (1966–2002), and 334 were selected based on their evidence level to form 58 pairs of clinical questions and recommendations [6, 7]. To facilitate clinical use, two types of algorithms for the surveillance and treatment of HCC were created. After in-depth evaluation in accordance with the Appraisal of Guidelines for Research and Evaluation, the Shaneyfelt method, and the Conference on Guidelines Standardization, the external review board awarded the Japanese guidelines high marks (>80%) for clarity of subject, aim, formation, and recommendation [7]. A full English version was uploaded onto the website of The Japanese Society of Hepatology (http://www.jsh.or.jp/) in 2006.

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HCC

Tumor number

Single

2 or 3

≤ 3 cm

Tumor diameter

Treatment

C

A, B

Liver damage

Resection ablation†

Resection ablation

4 or more

4 or more

≤ 3 cm‡

> 3 cm

Resection embolization

1–3

Embolization HAIC

Transplantation

Palliative care

Figure 26.2 Japanese treatment algorithm for hepatocellular carcinoma (HCC). (Reproduced from Makuuchi et al [7], with permission.) HAIC, hepatic arterial infusion chemotherapy. † Selected when the severity of liver damage is class B and tumor size is 2 cm or less. ‡ Tumor size is 5 cm or less when there is only one tumor.

The treatment algorithm for HCC was based on three independent factors: degree of liver damage, tumor number, and tumor size (Figure 26.2). For the six patient subgroups, the first- or second-line treatment option was recommended as objectively as possible. “Degree of liver damage” is a modified system of Child–Pugh classification: “encephalopathy” was replaced by “indocyanine green retention rate at 15 min (ICG-R15),” allowing an accurate evaluation of liver functional reserve, especially in surgical candidates. The following recommendations apply to patients with mild (class A) or moderate (class B) liver damage: (1) in patients with a single tumor, liver resection is recommended, irrespective of the tumor size. Percutaneous ablation may be selected if liver damage is class B and the tumor size is not more than 2 cm; (2) for two or three tumors 3 cm or less in diameter, resection or ablation is equally recommended; (3) for two or three tumors larger than 3 cm, resection or TACE is recommended; and (4) for four or more tumors, TACE or hepatic arterial infusion chemotherapy is recommended. The recommendations for patients with severe (class C) liver damage are as follows: (5) in patients with tumor(s) meeting the Milan criteria, liver transplantation is recommended; and (6) for four or more tumors, palliative treatment is recommended. For patients with extrahepatic metastasis, chemotherapy may be selected. The selection criteria for resection or ablation in patients with class A or B liver damage are based on the outcome of a large multicenter study involving 12 888 patients with HCC in Japan [21]. The recommendation for TACE is sup-

320

ported by the results of two randomized controlled trials showing a significant improvement in the survival of patients with multiple tumors and Child–Pugh class A or B liver function [22, 23]. The indication for liver transplantation is derived from a prospective cohort study, which proposed the Milan criteria [24], and a nationwide Japanese survey justifying the criteria for living donor liver transplantation in Japan [25]. The Japanese guidelines are clinically useful for decisionmaking at every practical step. By sharing the information in the treatment algorithm chart, the doctor can recommend treatment options to the patient, and the patient can then choose one based on preference.

Discrepancies between the Western and the Eastern guidelines A major difference between the Western and Eastern guidelines (Table 26.2) is that the BCLC classification links stage stratification to a treatment strategy and recommends standard care for a given patient, whereas the Japanese guidelines are not directly associated with clinical tumor stage, such as the JIS score. There is agreement between BCLC and Japanese guidelines in the surgical recommendation that liver resection is the best option for a single HCC in patients with well-preserved liver function (Child–Pugh A or liver damage A). The BCLC guidelines have a more restricted policy than the Japanese guidelines with respect to the indications for resection. In the BCLC guidelines, in patients who have two or

CHAPTER 26

Hepatocellular Carcinoma

Table 26.2 Treatment options for hepatocellular carcinoma in the Western and Eastern guidelines. Tumor number

Single

2 or 3 nodules

4 or more nodules

Tumor size (cm)

Child-Pugh class

Treatment options Western guideline

Eastern guideline (1) Resection (2) Ablation Resection

2

A, B

Resection

2.1−3

A, B

3.1−5

A, B

3

A, B

(1) Resection (2) Transplantation or ablation (1) Resection (2) Transplantation Transplantation or ablation

>3

C A, B

Palliative care Chemoembolization

A, B C

Chemoembolization Palliative care

three tumors or portal hypertension, resection is contraindicated, because of supporting evidence that resection in these patients leads to a high incidence (73%) of postoperative liver decompensation with a poor 5-year survival rate (45%) [26]. In a similar Japanese cohort, however, resection was associated with better 5-year survival rates in patients with multiple tumors (58%) or portal hypertension (56%), with only minimal morbidity rates (15% and 9%, respectively) [27]. Similarly, a prospective Italian study showed that resection provides a survival benefit for some patients with HCC of BCLC Stage B and Stage C [28]. The BCLC guidelines recommend only liver transplantation as surgery for multiple tumors. Since graft shortages are a crucial problem worldwide, the indication of liver resection needs to be expanded to include multiple tumors as the secondbest treatment. The results of future clinical trials will hopefully justify this surgical indication for HCC with multiple tumors or portal hypertension, as recommended in the Japanese guidelines. Liver transplantation is recommended for patients with HCC meeting the Milan criteria in both Western and Eastern guidelines. These strict criteria have produced 5-year survival rates of around 80% and recurrence rates of less than 10% [24, 29]. Both sets of guidelines agree that transplantation is the best option for small multicentric tumors in decompensated cirrhosis. According to the Japanese guidelines, liver transplantation is indicated in patients with class C liver damage, i.e. HCC meeting the Milan criteria. This narrow indication is dependent on the fact that in Japan the majority of transplantations are performed using living donors, and the Japanese National Health Insurance system does not cover the costs for transplantation for patients with HCC not meeting the Milan criteria [7]. One study has reported that living donor liver transplantation is consistently more cost-

Resection (1) Resection (2) Ablation Transplantation (1) Resection (2) Chemoembolization Chemoembolization Palliative care

effective than cadaveric transplantation when the waiting time for the latter exceeds 7 months [30]. Percutaneous ablation is classified as a curative treatment under the BCLC guidelines, because it results in good 5-year survival rates (40–50%) but has lower rates of local control and survival than liver resection [21]. The Japanese guidelines recommend ablation as the second-best option for HCC with up to three tumors of 3 cm or less in diameter in patients with class A or B liver damage. Thus, ablation is applied only to patients in whom resection is precluded. Radiofrequency has been claimed to require significantly fewer sessions than ethanol injection to obtain a similar response, and may provide better local control. In fact, a meta-analysis of four randomized controlled trials showed a significant improvement in 3-year survival for radiofrequency compared to ethanol injection (odds ratio 0.48; 95% CI 0.34–0.67; p = 0.001) [31]. Although attempts to compare resection with ablation prospectively have failed [32], a recent randomized controlled trial in patients with a solitary HCC smaller than 5 cm demonstrated no significant betweengroup difference in the overall and recurrence-free survivals [33]. However, the latter study was not well-designed because of a small sample size, a high conversion rate, and no reported p values [34]. Therefore, firm evidence is still lacking to establish the optimum first-line treatment for patients who have a single small HCC and well-preserved liver function.

Conclusion Treatment guidelines for HCC facilitate decision-making by patients and doctors at every clinical step. By sharing the precise information in the algorithm charts, the physician

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can recommend treatment options and the patient can choose one based on preference. In due time, the guidelines should be carefully revised in line with the evidence provided by prospective trials, especially with respect to recommendations currently not supported by sufficient evidence.

6 Which of the following are prognostic factors after liver transplantation for hepatocellular carcinoma? (more than one answer is possible) A Tumor differentiation B Tumor diameter C Platelet count D Number of tumors E Vascular invasion

Self-assessment questions 1 Which of the following are included in the Child– Pugh scoring system? (more than one answer is possible) A Serum bilirubin B Serum albumin C Platelet count D Prothrombin activity E Serum creatinine 2 Which of the following are significant prognostic factors in hepatocellular carcinoma? (more than one answer is possible) A Stage of the cancer B Tumor location C Vascular invasion D Number of tumors E Liver function 3 Which of the following are effective treatments for small hepatocellular carcinoma? (more than one answer is possible) A Surgical resection B Ethanol injection C Radiation D Chemotherapy E Radiofrequency ablation 4 Which of the following are appropriate measures of liver function prior to liver resection? (more than one answer is possible) A Serum bilirubin B Serum albumin C Platelet count D Prothrombin activity E Serum creatinine 5 Which one of the following is the best therapy for a single, 4-cm hepatocellular carcinoma with uncontrollable ascites? A Liver resection B Ethanol injection C Liver transplantation D Chemotherapy E Radiofrequency ablation

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7 Which one of the following is the first treatment option for asymptomatic patients with five unresectable hepatocellular carcinomas? A Chemoembolization B Symptomatic treatment C Ethanol injection D Liver transplantation E Radiofrequency ablation 8 Which of the following patients are suitable candidates for transhepatic arterial chemoembolization? (more than one answer is possible) A Decompensated cirrhosis B Unresectable tumor in good liver function C Performance status 3 D Tumor thrombus in the main portal vein E Ruptured tumor without hyperbilirubinemia 9 Preoperative adjuvant therapy is recommended for hepatocellular carcinoma, because it improves the prognosis after hepatic resection. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part wrong, second part wrong, “because” incorrect E First part wrong, second part wrong, “because” correct 10 Which one of the following is an effective therapeutic drug for hepatocellular carcinoma? A 5-FU B Sorafenib C Cisplatin D Gemcitabine E Irinotecan

References 1 Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907–17. 2 Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999;19:332–8.

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3 Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona 2000 EASL conference. J Hepatol 2001;35:421–30. 4 Poon RT, Fan ST, Tsang FH, et al. Locoregional therapies for hepatocellular carcinoma: a critical review from the surgeon’s perspective. Ann Surg 2002;235:466–86. 5 Ryder SD. Guideline for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults. Gut 2003;52 (Suppl III):iii1–8. 6 Makuuchi M, Kokudo N. Clinical practice guidelines for hepatocellular carcinoma: the first evidence based guidelines from Japan. World J Gastroenterol 2006;12:828–9. 7 Makuuchi M, Kokudo N, Arii S, et al. Development of evidencebased clinical guidelines for the diagnosis and treatment of hepatocellular carcinoma in Japan. Hepatol Res 2008;38:37–51. 8 Helton WS, Strasberg SM. AHPBA/AJCC consensus conference on staging of hepatocellular carcinoma: rationale and overview of the conference. HPB Surg 2003;5:238–42. 9 Okuda K, Ohtsuki T, Obata H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Cancer 1985;56:918–28. 10 Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002;35:519–24. 11 CLIP. Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. Hepatology 2000;31:840–5. 12 Ueno S, Tanabe G, Sako K, et al. Discrimination value of the new western prognostic system (CLIP score) for hepatocellular carcinoma in 662 Japanese patients. Hepatology 2001;34:529–34. 13 Levy I, Sherman M. Staging of hepatocellular carcinoma: assessment of the CLIP, Okuda and Child-Pugh staging systems in a cohort of 257 patients in Toronto. Gut 2002;50:881– 5. 14 Leung TW, Tang AM, Zee B, et al. Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: a study based on 926 patients. Cancer 2002; 94:1760–69. 15 Kudo M, Chung H, Osaki Y. Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score). J Gastroenterol 2003;38:207–15. 16 Kudo M. Hepatocellular carcinoma 2009 and beyond: from the surveillance to molecular targeted therapy. Oncology 2008;75 (Suppl 1):1–12. 17 Bruix J, Sherman M. AASLD practice guideline:management of hepatocellular carcinoma. Hepatology 2005;42:1208–36. 18 Takayama T, Makuuchi S, Hirohashi S, et al. Early hepatocellular carcinoma as an entity with high rate of surgical cure. Hepatology 1998;28:1241–6. 19 Llovet JM. Updated treatment approach to hepatocellular carcinoma. J Gastroenterol 2005;40:225–35. 20 Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–90. 21 Arii S, Yamaoka Y, Futagawa S, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. Hepatology 2000;32:1224–9.

Hepatocellular Carcinoma

22 Llovet JM, Real MI, Montaña X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002;359:1734–9. 23 Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002;35:1164–71. 24 Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693–9. 25 Todo S, Furukawa H, Tada M. Extending indication: role of living donor liver transplantation for hepatocellular carcinoma. Liver Transpl 2007;11 (Suppl 2):S48–54. 26 Bruix J, Castells A, Bosch J, et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 1996;111:1018– 22. 27 Ishizawa T, Hasegawa K, Aoki T, et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 2008;134:1908–16. 28 Torzilli G, Donadon M, Marconi M, et al. Hepatectomy for stage B and stage C hepatocellular carcinoma in the Barcelona Clinic Liver Cancer Classification: results of a prospective analysis. Arch Surg 2008;143:1082–90. 29 Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1993;30:1434–40. 30 Sarasin F, Majno P, Llovet JM, et al. Live donor liver transplantation for early hepatocellular carcinoma: a cost-effectiveness perspective. Hepatology 2001;33:1073–9. 31 Cho YK, Kim JK, Kim MY, et al. Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies. Hepatology 2009;49:453–9. 32 Takayama T, Makuuchi M. Ablation of hepatocellular carcinoma. Jpn J Clin Oncol 2001;31:297–8. 33 Chen MS, Li JQ, Zheng Y, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 2006;243:321–8. 34 Hasegawa K, Kokudo N, Makuuchi M. Surgery or ablation for hepatocellular carcinoma? Ann Surg 2008;247:557–8.

Self-assessment answers 1 2 3 4 5 6 7 8 9 10

A, B, A, C, A, B, A, B, C A, B, A B, E A B

D D, E E C, D D, E

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27

Cholangiocarcinoma Jacques Belghiti1 and Charles B. Rosen2 1 2

Department of Hepatobiliary Surgery, Hospital Beaujon, Clichy. University of Paris, France Division of Transplantation Surgery, Mayo Clinic, Rochester, MN, USA

Introduction Cholangiocarcinoma (CC) is a primary malignant tumor arising from the biliary ductal epithelium. CC is the second most common primary liver cancer worldwide and accounts for 3% of all gastrointestinal cancers [1]. The incidence of CC is 2–6 per 100 000 and appears to be increasing, especially the intrahepatic type [2]. Primary sclerosing cholangitis (PSC) is a common predisposing condition in the West [3]. Other conditions associated with the development of CC include chronic biliary inflammation, biliary papillomatosis, and pancreaticobiliary maljunction [3]. The clinical features, treatment, and prognosis of CC depend on its location and pattern of growth. Intrahepatic CC arises within the parenchyma of the liver. Periductular CC arises along the major bile ducts. The most common location is at or near the common hepatic duct bifurcation. These tumors are called hilar CC or Klatskin tumors and present the greatest challenge to diagnosis and surgical treatment. Tumors involving the common hepatic and bile ducts below the bifurcation are called distal CC. Cancers of the gallbladder and ampulla are usually not included with CC due to their different clinical courses and prognoses. The Liver Cancer Study Group of Japan [4] classified CC based on macroscopic appearance of the cut surface of the tumor: mass forming (nodular), which is most common; periductal-infiltrating (sclerosing); and intraductal type (with papillary growth or formation of a tumor “thrombus” within the duct) [5]. This latter type, also called biliary papillomatosis or intraductal papillary mucinous neoplasm of the bile ducts, carries a better prognosis than the other two types [6]. Microscopic ductal spread of adenocarcinoma is usually far more extensive than the macroscopic boundaries of the tumor. Papillary tumors have a high risk of mucosal extension. Extraductal spread of CC is by perineural infiltration, lymphatic permeation, and vascular invasion. All these fea-

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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tures are associated with increasing depth of tumor invasion [7] and are independent prognostic parameters. Lymph node metastases are common and represent a significant adverse prognostic survival factor. Surgical resection is the best treatment for all CC regardless of location or type, and a negative margin (R0) at resection is the most important prognostic factor [8].

Intrahepatic cholangiocarcinoma The majority of patients with intrahepatic CC have normal livers. Nevertheless, some patients have an underlying liver disease that predisposes them to CC, such as Caroli disease, PSC, thorotrast deposition, parasitic infestation, hepatolithiasis [9], and viral hepatitis C infection [10]. Intrahepatic CC rarely produces early symptoms and is usually discovered at an advanced stage [11]. The presentation of intrahepatic CC is similar to that of other intrahepatic malignancies. Abdominal pain and weight loss develop with advanced tumors. Jaundice is rare and only occurs at a late stage with invasion of the hepatic confluence by tumor. Mass-forming intrahepatic CC presents as a large fibrous nonencapsulated heterogeneous tumor, which is often difficult to differentiate from metastatic tumors on preoperative imaging studies. Pathologic examination of biopsies shows a mucosecreting adenocarcinoma with a great density of fibrosis. Biopsy is highly reliable with histochemistry (especially for differentiation between CC and liver metastasis). Immunochemistry can be very helpful. Tumor cells typically express cytokeratins 7 and 19, epithelial membrane antigen, and BER-EP4, and display a cytoplasmic positivity for carcinoembryonic antigen (CEA) [12]. Periductalinfiltrating intrahepatic CC grows rapidly and may cause obstructive jaundice. It is often difficult to differentiate preoperatively from a Klatskin tumor. Periductal-infiltrating intrahepatic CC is a relative large mass with hilar invasion. The tumor grows into the hepatic hilus from an intrahepatic segmental duct, whereas a hilar CC is usually smaller and arises in the hilus. Both mass-forming and periductal-

CHAPTER 27

infiltrating types of intrahepatic CC may be associated with satellite nodules, focal liver atrophy, localized dilatation of intrahepatic bile ducts, encasement of adjacent vessels, and retraction of the liver capsule [13]. Intrahepatic CC is generally discovered at an advanced stage and only 40–60% of these patients have resectable tumors [14, 15]. Guidelines for evaluation and treatment are depicted in Figure 27.1. Resection is not considered in the presence of peritoneal carcinomatosis, extrahepatic metastases (mainly lung and bones), retroperitoneal lymph node involvement, tumor involving the three hepatic veins or hilar bifurcation, and bilobar tumors. Laparoscopic exploration is recommended to rule out peritoneal carcinomatosis and extensive lymph node metastases [16]. Due to large tumor size (6–10 cm) and frequent central location [8], most resectable tumors require a major hepatectomy, including portal vein resection and reconstruction [6]. In order to achieve a tumor-free margin with an adequate residual volume, portal vein embolization (PVE) may be necessary

Cholangiocarcinoma

prior to operative intervention. The high likelihood of hilar lymph node involvement warrants an extensive hepatoduodenal lymphadenectomy. The postoperative mortality rate ranges between 1.3% and 12% [6]. Five-year patient survival after potentially curative resection ranges between 10% and 40% (Table 27.1) [8, 17–22]. The best prognosis is with intraductal intrahepatic CC, followed by the mass-forming type. The worst prognosis is with periductular tumors [23, 24]. The presence of satellite nodules, metastatic lymph node involvement, large tumor size, and vascular invasion are the predominant adverse prognostic factors [6, 21]. Intrahepatic recurrence is the most common cause of death. Repeat liver resection for intrahepatic recurrence can be beneficial for highly selected cases [25]. Patients with a good performance status benefit from combination chemotherapy with gemcitabine, 5flurouracil (5-FU)/folinic acid (FA) (or capecitabine) or a platinum analog [26]. Liver transplantation is not an effective therapy for intrahepatic CC [27].

Intrahepatic mass Primary liver tumor? (biopsy if necessary)

Hepatocellular carcinoma, metastatic disease, or other – proceed accordingly

Primary liver tumor Probably CC

Assess for resection Metastatic work-up

Unresectable or metastatic disease – palliative therapy

Potentially resectable

Adequate future remnant liver

Inadequate future remnant liver

Laparoscopy

Laparoscopy followed by portal vein embolization

Resection Figure 27.1 Intrahepatic cholangiocarcinoma treatment guideline. CC, cholangiocarcinoma.

Adequate future remnant liver

Inadequate future remnant liver

Resection

Palliative therapy

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Table 27.1 Results of surgery for peripheral cholangiocarcinoma. Authors

Year

Population (n)

Hepatectomy (n)

Resectability rate (%)

5-Yearsurvival(%)

Ohtsuka et al [19] Lang et al [20] Harrison et al [18] Casavilla et al [21]

1998 2003 2004 2009

64 60 32 54

50 27 32 54

74 54 – –

23 –

Hilar cholangiocarcinoma Hilar CC is characterized by slow growth and infrequent distant metastases. The most common presentation is with the onset of jaundice. The majority of hilar CC are small infiltrating tumors. Approximately 90% of malignantappearing hilar strictures prove to be hilar CC [28]. Other lesions mimicking hilar CC are gallbladder cancer involving the liver pedicle, Mirizzi syndrome, PSC, autoimmune pancreatitis and portal biliopathy. Endoscopic biopsy is notoriously inaccurate [28]. Percutaneous biopsy is prone to seeding and should not be done for any patients with potentially resectable or transplantable disease. Hilar CC is best treated by resection, and evaluation guidelines are shown in Figure 27.2. Surgical management is difficult due to the propensity of these tumors to involve the portal and arterial vasculature, extend along the intrahepatic ducts, and grow into the surrounding hepatic parenchyma, especially the caudate (segment I). These characteristics make surgical resection often difficult and challenging. Although excellent results have been published after liver transplantation in highly selected cases, surgical resection remains the best treatment for hilar CC because it increases the length and the quality of survival. Most of the controversy is about the extent of the resection in order to achieve complete removal of the tumor [29]. Resection is not effective for patients with intrahepatic metastases, underlying cirrhosis or extensive fibrosis (mainly secondary to PSC), and/or bilateral secondary biliary ductular involvement. Bilateral vascular involvement is no longer an absolute contraindication to resection if it is possible to perform reconstruction of the artery and/or portal vein supplying the residual liver. Unresectable patients may now be evaluated for neoadjuvant therapy and liver transplantation. Otherwise, palliation is best achieved by percutaneous or endoscopic intubation, including use of large diameter metal stents [30]. Photodynamic therapy is another option that can prolong patient survival [31]. Evaluation for resectability includes an extensive morphologic assessment using multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI). MDCT

326

26

accurately predicts resectability in more than two-thirds of cases [32, 33]. MRI may help assess vascular invasion and is very helpful in predicting the extent of ductal involvement [34]. The advantages of MRI over direct cholangiography are that it is a noninvasive procedure which does not pose a risk of infection, and it affords better delineation of biliary anatomy and tumor extension [34]. Endoscopic ultrasound has not been shown to have high accuracy for staging of hilar CC [35], but it is an important component in the evaluation of unresectable hilar CC for liver transplantation. Imaging is done to assess resectability. Established criteria of nonresectability are: (1) bilateral intrahepatic secondary bile duct involvement; (2) bilateral involvement of hepatic arterial or portal venous branches; (3) a combination of unilateral hepatic arterial involvement with contralateral biliary spread; and inadequate future remnant liver volume. The Bismuth classification is commonly used to describe the extent and location of duct involvement [36]. It does not consider vascular involvement or hepatic atrophy which may preclude resection [37, 38]. Regional lymph node involvement is not a contraindication for resection. The goal of surgical therapy for patients with hilar CC is to achieve complete removal of the tumor with tumor-free surgical margins [39]. Tumors below the confluence of the hepatic ducts can be treated by local resection with subsequent biliary reconstruction. Perioperative mortality is less than 5% and 5-year survival is 20% for patients with negative microscopic margins [39]. Tumors involving the confluence should be treated by hepatic resection, including resection of the caudate lobe [40]. Left, right or central hepatectomies can be performed depending on the locations of the intrahepatic bile ducts and vascular involvement [40]. This aggressive strategy, initiated by Nimura, resulted in a dramatic increase in resectability rates to nearly 80% [41]. Five-year survival for patients treated with hepatic resection ranges from 25% to 40% [25, 27, 36, 40, 42, 44] (Table 27.2). Mesohepatectomy may be an oncologically adequate procedure for selected patients with compromised liver function [43]. Left-sided hilar CC with involvement of the secondary left biliary confluence or with atrophy of the left liver due

CHAPTER 27

Cholangiocarcinoma

Malignant stricture

Confirm diagnosis

De novo hilar CC

Hilar CC arising in PSC

Assess for resection Metastatic work-up

Evaluate for neoadjuvant therapy and liver transplantation

Potentially resectable with or without vascular reconstruction

Unresectable due to inadequate future remnant liver

Unresectable due to vascular or ductular involvement

Metastatic disease

Biliary drainage (if not already done)

Biliary drainage (if not already done) and laparoscopy

Evaluate for neoadjuvant therapy and liver transplantation

Palliative therapy

Laparoscopy

Portal vein embolization

Resection with or without vascular reconstruction

Adequate future remnant liver

Inadequate future remnant liver

Resection with or without vascular reconstruction

Evaluate for neoadjuvant therapy and liver transplantation

Figure 27.2 Hilar cholangiocarcinoma treatment guideline. CC, cholangiocarcinoma; PSC, primary sclerosing cholangitis.

Table 27.2 Results of surgery for hilar cholangiocarcinoma. Authors

Year

Resectability rate (%)

Major hepatectomy (n)

Mortality rate (%)

5-Year Survival (%)

Median survival (months)

Bismuth et al [36] Pichlmayr et al [27] Miyazaki et al [44] Nimura et al [40] Seyama et al [42] Konstadoulakis et al [25]

1992 1995 1999 1990 2003 2008

19 45 63 80 66 80

13 111 53 109 78 51

0 9.9 15 9.7 0 6.8

– 28.4 26 25.8 40 35

24 24 – – – 28

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to ipsilateral portal involvement is best treated by left hemihepatectomy [40, 44]. Right-sided hilar CC is best treated by right hepatic trisectionectomy [45, 46]. Neuhaus et al introduced a new approach using a “no touch technique,” avoiding tumor dissection and achieving a wide tumor-free margin by directly approaching the left secondary bile ducts and by performing “en-bloc” resection of the portal vein [45]. Hepatopancreatoduodenectomy may be indicated for patients with locally extensive CC in order to obtain negative surgical margins [4, 47]. Liver resection in patients with obstructive jaundice and cholangitis is associated with more severe complications, including intraoperative bleeding, bile leaks, and liver failure [48]. Preoperative biliary drainage has been shown to be helpful, with increased tolerance to hepatectomy [49, 50]. Unilateral biliary drainage of the future remnant liver is the best approach, and it can be done by either the endoscopic or percutaneous approach. Additional drainage is often necessary for patients with cholangitis to drain the obstructed septic ducts [4]. Although preoperative biliary drainage (PTBD) may increase infection rates and cause tumor seeding, this procedure allows hypertrophy of the future remnant liver, especially when done in conjunction with PVE [4]. Resolution of jaundice typically requires at least 4 weeks in patients with satisfactory liver and kidney function. Patients with early jaundice and adequate future remnant liver volume can undergo resection without preoperative biliary drainage. PVE increases resectability for patients with inadequate future remnant liver. PVE initiates compensatory hypertrophy of the future remnant liver, which minimizes postoperative liver dysfunction and the risk of liver failure. Some surgeons favor PVE for all patients needing right hepatectomy [47]. Efficient hypertrophy of the future remnant liver requires biliary drainage with a decrease in bilirubin below 50 μmol/L. Sufficient hypertrophy of the future remnant liver usually requires 6 weeks. PVE is not indicated for patients with portal venous involvement or those requiring a central hepatectomy. Preoperative staging laparoscopy is indicated before resection and/or extensive preoperative preparation to identify peritoneal carcinomatosis and/or small intrahepatic metastases not detectable with conventional preoperative imaging [16]. These findings occur in up to 20% of apparently resectable patients, and laparoscopy avoids the morbidity of exploration and/or extensive preparation such as PVE for these unfortunate patients. Orthotopic liver transplantation was once thought to be a promising option for patients with unresectable hilar CC since it easily achieves a negative margin, accomplishes a radical resection, is not limited by vascular involvement or future remnant liver volume, and treats underlying liver disease such as PSC. Unfortunately, actual experiences with liver transplantation as a single treatment modality have

328

been very poor, even for incidentally detected lesions [51– 54]. The University of Pittsburgh attempted a very aggressive approach with cluster abdominal transplantation, but results were equally poor with 20% 3-year survival [7]. As a result, CC became a widely recognized contraindication to liver transplantation. Based on the known efficacy of palliative radiotherapy and the knowledge that resection failures are usually due to locoregional recurrence rather than distant metastases, the transplant teams at the University of Nebraska and at the Mayo Clinic pioneered a strategy of high-dose radiotherapy, chemosensitization, and liver transplantation for highly selected patients with early-stage disease. The Mayo Clinic protocol, shown in Figure 27.3, utilizes high-dose external beam therapy, brachytherapy, chemosensitization with 5-FU, and maintenance therapy with capecitabine while patients await transplantation. All patients undergo operative staging to rule out extrahepatic disease, intrahepatic metastases, and regional lymph node involvement prior to transplantation. All patients must have early-stage hilar CC which is deemed unresectable by an experienced hepatobiliary surgeon or arising in the setting of underlying PSC. Vascular encasement of the hilar vessels is not a contraindication to transplantation. The upper limit of tumor size is 3 cm in radial diameter, and there must be no evidence for metastatic disease. The Mayo Clinic has treated over 171 patients with this protocol [55]. One hundred forty-nine patients have undergone operative staging, and 29 had findings precluding subsequent transplantation. One hundred and fifteen patients have undergone transplantation. Patient survival is 57% for all 171 patients 5 years after the start of neoadjuvant therapy and 73% for 115 patients 5 years after transplantation. Factors that adversely affect prognosis are: older patient age, prior cholecystectomy, CA 19.9 greater than 100 at the time of transplantation, visible mass on cross-sectional imaging, and prolongation of waiting time. Explanted livers with residual cancer greater than 2 cm, high tumor grade, and/or perineural invasion are also associated with tumor recurrence. Unlike with resection, endoscopic ultrasound-directed aspiration of the regional hepatic lymph nodes helps to avoid the morbidity of neoadjuvant therapy for patients destined to fall out at staging. Aspiration of the primary tumor has resulted in seeding and should not be done.

Distal cholangiocarcinoma CC arising in the common bile duct is usually subdivided into middle (pedicular) and distal (intrapancreatic) subgroups. Middle lesions frequently have regional lymph node involvement and perineural invasion requiring pancrea-

Cholangiocarcinoma

CHAPTER 27

Unresectable hilar CC or hilar CC arising in PSC

Satisfactory candidate for liver transplantation No clinical evidence of extrahepatic disease

Endoscopic ultrasound with aspiration of regional lymph nodes

No evidence for extrahepatic disease

Regional lymph node metastases – palliative therapy

Neoadjuvant therapy

Staging operation Figure 27.3 Hilar cholangiocarcinoma liver transplantation guideline. CC, cholangiocarcinoma; PSC, primary sclerosing cholangitis.

No extrahepatic disease – liver transplantation

toduodenectomy [56]. Thus, CC arising in both locations can be grouped together. Distal CC usually presents with jaundice. Other symptoms include weight loss, abdominal pain, pruritus, and fever. Diagnostic investigations suggest the correct final diagnosis in less than 50% of cases [57]. Benign strictures of the pedicular portion of the common bile duct can mimic distal CC. These strictures include benign tumors such as papilloma, adenomyoma, fibroma, and granular cell tumor. Other benign strictures include localized sclerosing cholangitis and nontraumatic inflammatory lesions [58]. Intrapancreatic distal CC may be detected as a mass lesion by US and CT, and can be confused with other periampullary tumors such as pancreatic cancer. A rare but useful finding can be the thickening of the bile duct wall [50]. Endoscopic ultrasound has a high accuracy in the detection of distal CC [59]. Bile duct brush cytology via endoscopic retrograde cholangiopancreatography (ERCP) has a high sensitivity for hilar CC [35, 60]. As with CC arising in other locations, distal CC is best treated by resection. Guidelines for evaluation and treat-

Extrahepatic disease – palliative therapy

Malignant stricture in common bile duct

Assess for resection Metastatic work-up

Potentially resectable disease

Unresectable disease

Laparoscopy

Palliative therapy

Resection with regional lymphadenectomy and with or without pancreatoduodenectomy Figure 27.4 Distal cholangiocarcinoma treatment guideline.

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ment are shown in Figure 27.4. Approximately half of distal CC located in the pedicular portion of the common bile duct can be resected by extrahepatic bile duct resection. Distal CC located in the intrapancreatic portion requires pancreatoduodenectomy. Involvement of the regional lymph nodes occurs in approximately two-thirds of cases. Microscopic involvement of resection margins is encountered in approximately 30% of cases, and perineural invasion is seen in 80% of cases [56–61]. Therefore, there are strong arguments favoring pancreatoduodenectomy for all distal CC, including those arising above the intrapancreatic portion of the bile duct. The prognosis of patients with distal CC is significantly associated with pancreatic invasion, lymph node involvement, and perineural and vascular invasion [62]. Five-year survival after potentially curative resection ranges from 28% to 53% [63–67]. Survival of patients with pancreatic invasion is similar to that for patients with adenocarcinoma of the pancreas [68, 69].

Conclusion Resection is the only potentially curative treatment for CC regardless of tumor type and location. Improvements in imaging and preoperative management have led to an increase in resectability. Survival exceeds 30% for patients with CC amenable to complete resection. Percutaneous or endoscopic stenting techniques are now preferred over palliative surgical procedures. The extent of resection remains controversial for CC arising in the hilus and common bile duct. Vascular reconstruction has enabled more patients with hilar CC to undergo resection. Neoadjuvant therapy and liver transplantation has emerged as an effective treatment for patients with unresectable hilar CC or hilar CC arising in the setting of PSC.

Self-assessment questions 1 Which of the following statements are true? (more than one answer is possible) A Hilar cholangiocarcinoma can be resected without major hepatectomy B Regional lymph node involvement does not affect the prognosis for cholangiocarcinoma provided all disease is removed during a potentially curative resection C Percutaneous biopsy of cholangiocarcinoma is not associated with tumor seeding D Laparoscopy should almost always be performed prior to attempted resection of cholangiocarcinoma E Preoperative biliary drainage is helpful prior to resection of hilar cholangiocarcinoma

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2 Which one of the following statements is true? A Liver transplantation without neoadjuvant therapy is appropriate for patients with early-stage hilar cholangiocarcinoma B Laparoscopy should be performed prior to portal vein embolization C Endoscopic ultrasound with regional lymph node aspiration is adequate for staging prior to liver transplantation D Resection of distal cholangiocarcinoma rarely requires pancreatoduodenectomy E Liver transplantation is an excellent option for the treatment of intrahepatic cholangiocarcinoma confined to the liver 3 Which one of the following is an indication for liver transplantation following neoadjuvant therapy? A Unresectable intrahepatic cholangiocarcinoma B Unresectable hilar cholangiocarcinoma C Unresectable distal cholangiocarcinoma D Resectable intrahepatic cholangiocarcinoma E Resectable distal cholangiocarcinoma 4 Biliary drainage of the future remnant liver should be done prior to portal vein embolization because it increases the likelihood of a satisfactory response. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 5 Which of the following preclude resection of hilar cholangiocarcinoma? (more than one answer is possible) A Bilateral intrahepatic secondary bile duct involvement B Bilateral involvement of hepatic arterial or portal branches C Unilateral hepatic arterial and contralateral biliary involvement D Inadequate future liver remnant following portal venous embolization E Underlying parenchymal disease due to primary sclerosing cholangitis

References 1 Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004;24:115–25.

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2 Nathan H, Pawlik TM, Wolfgang CL, Choti MA, Cameron JL, Schulick RD. Trends in survival after surgery for cholangiocarcinoma: a 30-year population-based SEER database analysis. J Gastrointest Surg 2007;11:1488–96 3 de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. N Engl J Med 1999;341: 1368–78. 4 Nimura Y, Kamiya J, Kondo S, et al. Aggressive preoperative management and extended surgery for hilar cholangiocarcinoma: Nagoya experience. J Hepatobiliary Pancreat Surg 2000;7:155–62. 5 Liver Cancer Study Group of Japan. The 14th report, surveillance of primary liver cancer patients in National Registry. Kyoto: LCSGJ, Kyoto, 2000:25. 6 Yeh CN, Jan YY, Yeh TS, Hwang TL, Chen MF. Hepatic resection of the intraductal papillary type of peripheral cholangiocarcinoma. Ann Surg Oncol 2004;11:606–11. 7 Bhuiya MR, Nimura Y, Kamiya J, Kondo S, Nagino M, Hayakawa N. Clinicopathologic factors influencing survival of patients with bile duct carcinoma: multivariate statistical analysis. World J Surg 1993;17:653–7. 8 DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 2007;245:755–62. 9 Endo I, Gonen M, Yopp AC, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg 2008;248:84–96. 10 El-Serag HB, Engels EA, Landgren O, et al. Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection: A population-based study of U.S. veterans. Hepatology 2009;49:116– 23. 11 Valverde A, Bonhomme N, Farges O, Sauvanet A, Fléjou JF, Belghiti J. Resection of intrahepatic cholangiocarcinoma. A Western experience. J Hepatobiliary Pancreat Surg 1999;6: 122–7. 12 Iguchi T, Yamashita N, Aishima S, et al. A comprehensive analysis of immunohistochemical studies in intrahepatic cholangiocarcinoma using the survival tree model. Oncology 2009;76:293–300. 13 Vilgrain V, Van Beers BE, Fléjou JF, et al. Intrahepatic cholangiocarcinoma : MRI and pathologic correlation in 14 patients. J Comput Assist Tomogr 1997;21:59–65. 14 Paik KY, Jung JC, Heo JS, Choi SH, Choi DW, Kim YI. What prognostic factors are important for resected intrahepatic cholangiocarcinoma? J Gastroenterol Hepatol 2008;23:766–0. 15 Kawarada Y, Yamagiwa K, Das BC. Analysis of the relationships between clinicopathologic factors and survival time in intrahepatic cholangiocarcinoma. Am J Surg 2002;183:679–85. 16 Goere D, Wagholikar GD, Pessaux P, et al. Utility of staging laparoscopy in subsets of biliary cancers : laparoscopy is a powerful diagnostic tool in patients with intrahepatic and gallbladder carcinoma. Surg Endosc 2006;20:721–5. 17 Shimada K, Sano T, Sakamoto Y, Esaki M, Kosuge T, Ojima H. Surgical outcomes of the mass-forming plus periductal infiltrating types of intrahepatic cholangiocarcinoma: a comparative study with the typical mass-forming type of intrahepatic cholangiocarcinoma. World J Surg 2007;31:2016–22. 18 Tajima Y, Kuroki T, Fukuda K, Tsuneoka N, Furui J, Kanematsu T. An intraductal papillary component is associated with pro-

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longed survival after hepatic resection for intrahepatic cholangiocarcinoma. Br J Surg 2004;91:99–104, Harrison LE, Fong Y, Klimstra DS, Zee SY, Blumgart LH. Surgical treatment of 32 patients with peripheral intrahepatic cholangiocarcinoma. Br J Surg 1998;85:1068–70. Ohtsuka M, Ito H, Kimura F, et al. Extended hepatic resection and outcomes in intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg 2003;10:259–64. Lang H, Sotiropoulos GC, Sgourakis G, et al. Operations for intrahepatic cholangiocarcinoma: single-institution experience of 158 patients. J Am Coll Surg 2009;208:218– 28. Casavilla FA, Marsh JW, Iwatsuki S, et al. Hepatic resection and transplantation for peripheral cholangiocarcinoma. J Am Coll Surg 1997;185:429–36. Chen MF, Jan YY, Chen TC. Clinical studies of mucin-producing cholangiocellular carcinoma: a study of 22 histopathology proven cases. Ann Surg 1998;227:63–9. Sasaki A, Aramaki M, Kawano K, et al. Intrahepatic peripheral cholangiocarcinoma: mode of spread and choice of surgical treatment. Br J Surg 1998;85:1206–9. Konstadoulakis MM, Roayaie S, Gomatos IP, et al. Fifteen-year, single-center experience with the surgical management of intrahepatic cholangiocarcinoma: operative results and long-term outcome. Surgery 2008;143:366–74. Kim MJ, Oh DY, Lee SH, et al. Gemcitabine-based versus fluoropyrimidine-based chemotherapy with or without platinum in unresectable biliary tract cancer: a retrospective study. BMC Cancer 2008;8:374. Pichlmayr R, Lamesch P, Weimann A, Tusch G, Ringe B. Surgical treatment of cholangiocellular carcinoma. World J Surg 1995;19:83–8. Buc E, Lesurtel M, Belghiti J. Is preoperative histological diagnosis necessary before referral to major surgery for cholangiocarcinoma? HPB (Oxf) 2008;10:98–105. Ogura Y, Kawarada Y. Surgical strategies for carcinoma of the hepatic duct confluence. Br J Surg 1998;85:20–4. Davids PH, Groen AK, Rauws EAJ, Tytgat GN, Huibregtse K. Randomised trial of self-expanding metal stents versus polyethylene stents for distal malignant biliary obstruction. Lancet 1992;340:1488–92. Ortner ME, Caca K, Berr F, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology 2003;125:1355–63. Aloia TA, Charnsangavej C, Faria S, et al. High-resolution computed tomography accurately predicts resectability in hilar cholangiocarcinoma. Am J Surg 2007;193:702–6. Lee HY, Kim SH, Lee JM, et al. Preoperative assessment of resectability of hepatic hilar cholangiocarcinoma: combined CT and cholangiography with revised criteria. Radiology 2006;239:113–21. Vogl TJ, Schwarz WO, Heller M, et al. Staging of Klatskin tumours (hilar cholangiocarcinomas): comparison of MR cholangiography, MR imaging, and endoscopic retrograde cholangiography. Eur Radiol 2006;16:2317–25. DeWitt J, Misra VL, Leblanc JK, McHenry L, Sherman S. EUS-guided FNA of proximal biliary strictures after negative ERCP brush cytology results. Gastrointest Endosc 2006;64:325– 33.

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36 Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg 1992;215:31–8. 37 Dinant S, Gerhards MF, Rauws EA, Busch OR, Gouma DJ, Van Gulik TM. Improved outcome of resection of hilar cholangiocarcinoma (Klatskin tumor). Ann Surg Oncol 2006;13:872–80. 38 Liu CL, Fan ST, Lo CM, Tso WK, Lam CM, Wong J. Improved operative and survival outcomes of surgical treatment for hilar cholangiocarcinoma. Br J Surg 2006;93:1488–94. 39 Ito F, Agni R, Rettammel RJ, et al. Resection of hilar cholangiocarcinoma: concomitant liver resection decreases hepatic recurrence. Ann Surg 2008;248:273–9. 40 Nimura Y, Hayakawa N, Kamiya J. Hepatic segmentectomy with caudate lobe resection for bile duct carcinoma of the hepatic hilus. World J Surg 1990;14:535–44. 41 Launois B, Terblanche J, Lakehal M, et al. Proximal bile duct cancer: high resectability rate and 5-year survival. Ann Surg 1999;230:266–75 42 Seyama Y, Kubota K, Sano K, et al. Long-term outcome of extended hemihepatectomy for hilar bile duct cancer with no mortality and high survival rate. Ann Surg 2003;238:73–83. 43 Kawarada Y, Isaji S, Taoka H, Tabata M, Das BC, Yokoi H. S4a + S5 with caudate lobe (S1) resection using the Taj Mahal liver parenchymal resection for carcinoma of the biliary tract. J Gastrointest Surg 1999;3:369–73. 44 Miyazaki M, Ito H, Nakagawa K, et al. Parenchyma-preserving hepatectomy in the surgical treatment of hilar cholangiocarcinoma. J Am Coll Surg 1999;189:575–83. 45 Neuhaus P, Jonas S, Bechstein WO, et al. Extended resections for hilar cholangiocarcinoma. Ann Surg 1999;230:808–18. 46 Tsukada K, Yoshida K, Aono T, et al. Major hepatectomy and pancreatoduodenectomy for advanced carcinoma of the biliary tract. Br J Surg 1994;81:108–10. 47 Yokoyama Y, Nagino M, Nishio H, Ebata T, Igami T, Nimura Y. Recent advances in the treatment of hilar cholangiocarcinoma: portal vein embolization. J Hepatobiliary Pancreat Surg 2007; 14:447–54. 48 Blumgart LH, Fong Y. Surgery of the Liver and Biliary Tract, 3rd edn. Philadelphia: W. B. Saunders, 2000:953. 49 Sherlock S, Dooley J. Diseases of the Liver and Biliary System, 9th edn. Oxford: Blackwell Scientific Publications, 1993. 50 Belghiti J, Ogata S. Preoperative optimization of the liver for resection in patients with hilar cholangiocarcinoma. HPB (Oxf) 2005;7:252–3. 51 Rea DJ, Munoz-Juarez M, Farnell MB, et al. Major hepatic resection for hilar cholangiocarcinoma: analysis of 46 patients. Arch Surg 2004;139:514–23, discussion 523–5. 52 Hemming AW, Reed AI, Fujita S, et al. Surgical management of hilar cholangiocarcinoma. Ann Surg 2005;241:693–9, discussion 699–702. 53 Rosen CB, Nagorney DM, Wiesner RH, et al. Cholangiocarcinoma complicating primary sclerosing cholangitis. Ann Surg 1991;213:21–5. 54 Rosen CB, Nagorney DM. Cholangiocarcinoma complicating primary sclerosing cholangitis. Semin Liver Dis 1991;11:26–30. 55 Rea DJ, Rosen CB, Nagorney DM, Heimbach JK, Gores GJ. Transplantation for cholangiocarcinoma: When and for whom? Surg Oncol Clin N Am 2009;18:325–37.

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56 Kayahara M, Nagakawa T, Ohta T, Kitagawa H, Tajima H, Miwa K. Role of nodal involvement and the periductal soft-tissue margin in middle and distal bile duct cancer. Ann Surg 1999;229:76–83. 57 Zerbi A, Balzano G, Leone BE, Angeli E, Veronesi P, Di Carlo V. Clinical presentation, diagnosis and survival of resected distal bile duct cancer. Dig Surg 1998;15:410–16. 58 Standfield NJ, Salisbury JR, Howard ER. Benign non-traumatic inflammatory strictures of the extrahepatic biliary system. Br J Surg 1989;76:849–52. 59 Rosch T, Breig C, Gain T. Staging of pancreatic and ampullary carcinoma by endoscopic ultrasonography. Gastroenterology 1992;102:188–99. 60 Foutch PG, Kerr DM, Harlen JR, Manne RK, Kummet TD, Sanowski RA. Endoscopic retrograde wire-guided brush cytology for diagnosis of patients with malignant obstruction of the bile duct. Am J Gastroenterol 1990;85:791–5. 61 Kurosaki I, Tsukada K, Watanabe H, Hatakeyama K. Prognostic determinations in extrahepatic bile duct cancer. HepatoGastroenterology 1998;45:905–9. 62 Bhuiya MR, Nimura Y, Kamiya J, Kondo S, Nagino M, Hayakawa N. Clinicopathologic factors influencing survival of patients with bile duct carcinoma: multivariate statistical analysis. World J Surg 1993;17:653–7. 63 Alden ME, Waterman FM, Topham BA, Barbot DJ, Shapiro MJ, Muhiuddin M. Cholangiocarcinoma: Clinical significance of tumor location along the extrahepatic bile duct. Radiology 1995;197:511–16. 64 Allen PJ, Reiner AS, Gonen M, et al. Extrahepatic cholangiocarcinoma: a comparison of patients with resected proximal and distal lesions. HPB (Oxf) 2008;10:341–6. 65 Hernandez J, Cowgill SM, Al-Saadi S, et al. An aggressive approach to extrahepatic cholangiocarcinomas is warranted: margin status does not impact survival after resection. Ann Surg Oncol 2008;15:807–14. 66 Murakami Y, Uemura K, Hayashidani Y, et al. Prognostic significance of lymph node metastasis and surgical margin status for distal cholangiocarcinoma. J Surg Oncol 2007;95:207–12 67 Yoshida T, Matsumoto T, Sasaki A, Morii Y, Aramaki M, Kitano S. Prognostic factors after pancreatoduodenectomy with extended lymphadenectomy for distal bile duct cancer. Arch Surg 2002;137:69–73. 68 Andersen HB, Baden H, Brahe NE, Burchart F. Pancreaticoduodenectomy for periampullary adenocarcinoma. J Am Coll Surg 1994;179:545–52. 69 Chan C, Herrera MF, De La Garza L, et al. Clinical behavior and prognostic factors of periampullary adenocarcinoma. Ann Surg 1995;222:632–7.

Self-assessment answers 1 2 3 4 5

D, E B B E A, B, C, D, E

28

Gallbladder Cancer Juan Hepp1 and Chung-Mau Lo2 1 2

Clínica Alemana – Universidad del Desarrollo School of Medicine, Department of Surgery, Santiago, Chile Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Introduction Gallbladder cancer (GBC) is an infrequent disease; as a result, even large surgical centers have only small series accumulated over long periods of time, with the inevitable variations that occur over time. It is difficult to conduct studies of evidence grades 1 or 2 that can answer the clinical questions associated with this condition. Few publications have offered evidence-based recommendations and most of the current knowledge on GBC is based on case series and expert opinions. When searching for gallbladder neoplasm in Medline [1], using the MeSH terminology that includes the diverse forms used to cite GBC, 5373 publications are obtained; 711 of these appear in core clinical journals. When systematic reviews are searched for, only two publications are found. There are nine randomized clinical trials (RCTs) and 722 references to clinical trials. In the Trip database [2], 424 records of gallbladder neoplasm are found. The design of the published studies does not focus solely on GBC, especially those concerning chemotherapy and radiotherapy, where patients with GBC are mixed with those with extrahepatic cholangiocarcinoma. Multicenter prospective studies are needed to obtain the necessary information to understand more about the etiology, diagnosis, therapy, and prognosis of GBC. There are two updated GBC guidelines [3, 4] in which current knowledge is described only schematically and briefly. The proposal for GBC guidelines outlined here, framed within a textbook of surgery, is more flexible than the traditional guideline. It represents the experience of the authors and their teams. References are limited but duplication of ideas raised in previous chapters is avoided. Its purpose is to orient the physician to treatment strategies. Since this is not a rigid protocol, it may change with time

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

and with new data. However, clinical judgment and the differences that may exist in the varied centers where these patients are cared for must always be the most important considerations.

Summary of evidence and recommendations The categories of evidence and grading of recommendations suggested by the Agency for Health Policy Research 1992 are used [5].

Etiology The strongest risk factors for GBC include cholelithiasis, obesity, anomalous pancreatobiliary junction, focal mucosal microcalcification, and gallbladder polyps [6–11]: • The risk of GBC is 1.5–6 times higher in patients with gallstones than in acalculous individuals. (Category of evidence IIb; strength of recommendation B) • The mechanism by which cholelithiasis predisposes to GBC has yet to be established. Time probably is the most relevant factor in the pathogenesis of GBC. Chronic inflammation of the gallbladder mucosa by gallstones may predispose to malignant transformation via a sequence evolving from atypia to dysplasia, carcinoma in situ, and finally, invasive carcinoma [9]. (Category of evidence IIb; strength of recommendation C) • Despite the association with cholelithiasis, only 1–3% of patients with gallstones develop GBC. Ransohoff and Gracie’s study [10] estimated the incidence of GBC for symptomatic gallstone patients to be 0.00078 per year after analyzing patients in 11 cohorts comprising 32 134 person-years of follow-up. (Category of evidence I; strength of recommendation B) • Compared with individuals of normal weight, GBC risk is higher in obese patients and in women. (Category of evidence IIa; strengths of recommendation B) • An anomalous junction of the pancreatobiliary duct increases the risk of GBC. This anatomic variant allows pancreatic secretions to reflux into the biliary tree and induce

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chronic inflammation and metaplastic changes. (Category of evidence IV; strength of recommendation C) • Most small gallbladder polyps are asymptomatic benign lesions that do not progress to cancer. The characteristics of the polyps associated with an increased risk of malignancy include polyp diameter greater than 10 mm, patient age over 50 years, presence of gallstones, solitary polyps, and symptomatic polyps. (Category of evidence IV; strength of recommendation C) • The incidence of GBC is increased in the presence of focal mucosal calcification (7%) when compared to those with intramural calcifications. The pattern of calcification is more important than the mere presence of calcifications, with focal mucosal calcifications posing the greatest risk over diffuse intramural calcifications [11]. (Category of evidence IV; strength of recommendation C) • Other conditions associated with an increased risk of GBC are xanthogranulomatous cholecystitis, chronic typhoid infection, adenomyomatosis, and inflammatory bowel disease. However, these associations are not strong enough to establish a definitive recommendation.

Diagnosis The laboratory diagnosis and the role of imaging in GBC have been studied in different publications [12–16]: • In early GBC with intramural invasion up to the muscular layer, accurate preoperative diagnosis of the depth of mural invasion is difficult, even with full use of ultrasonography (US), computed axial tomography (CT), and endoscopic ultrasonography (EUS). (Category of evidence IV; strength of recommendation C) • The sensitivity of US to recognize GBC is around 40%. If, however, there is tumor infiltration of the liver or lymph node metastasis, the yield from US is higher. (Category of evidence IIIb; strength of recommendation B) • Multidetector CT (MDCT) provided 84% accuracy in the diagnosis of the local GBC, thereby showing acceptable sensitivity and specificity. (Category of evidence IV; strength of recommendation C) • Endoscopic US is most useful as a preoperative staging modality. This improves the sensitivity of GBC diagnosis from 74% to 90% when compared to diagnosis with transabdominal ultrasonography alone. Endosonography can be used to obtain samples of the primary tumor, enlarged lymph nodes, or liver masses for cytology via fine needle aspiration. (Category of evidence IV; strength of recommendation C) • An overall accuracy of 71% has been reported with preoperative CT imaging in GBC. However, the accuracy of CT is variable, depending on the morphology of the neoplasm. A T1 carcinoma with only a thickened wall is often missed on CT (sensitivity of 54%). If, however, there is an intraluminal mass, then a sensitivity of up to 89% has been reported. (Category of evidence IIIb; strength of recommendation B)

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• Magnetic resonance imaging (MRI) detection rate of lymph node GBC metastasis remains poor (57%). However, when standard MRI is combined with MR cholangiography (MRC) and three-dimensional MR angiography (MRA), the sensitivity and specificity for vascular invasion can approach 100% and 87%, respectively. When compared to CT, the sensitivity for MRI in GBC improved from 50% to 67–100% with a specificity for MRA of 89–100%. (Category of evidence IV; strength of recommendation C) • The sensitivity of positron emission tomography (PET) for identifying the primary tumor is 86% for GBC. Several benign conditions such as adenomyomatosis can be positive on PET scan, leading to a significant number of false-positive results. In patients with potentially resectable GBC based on conventional imaging, PET–CT is able to identify occult metastatic disease, and changes the management in nearly onequarter of all patients. PET also helps to confirm recurrent cancer after resection. (Category of evidence IV; strength of recommendation C)

Therapy As is frequent in surgery, therapeutic recommendations are based on lessons learned when reviewing the outcomes obtained and establishing the prognosis of a therapeutic action [4, 17–33]: • In appropriate patients with GBC, surgery offers the best chance for survival and should remain the treatment of choice. (Category of evidence IIb; strength of recommendation B) • For patients with suspected GBC, laparoscopic cholecystectomy is not recommended, and open cholecystectomy should be performed. (Category of evidence IV; strength of recommendation C) • Although open surgery is the best treatment for GBC, recently a role for laparoscopy has been described for staging and treatment of early tumors [34, 35]. (Category of evidence IIIb; strength of recommendation C) • When laparoscopic cholecystectomy was carried out in unsuspected GBC and spilling bile as a consequence of gallbladder injury, port site and peritoneal recurrence developed in 43% of patients. The survival rate will be significantly lower. (Category of evidence IV; strength of recommendation C) • In patients in whom the diagnosis of Tis and T1 GBC has been made by pathologic examination of the entire gallbladder, an additional resection is not necessary as a rule if the cystic stump is negative. (Category of evidence IV; strength of recommendation C) • An additional resection should be considered after a simple cholecystectomy if GBC is found to have invaded the subserosal layer (T2) or deeper (T3). (Category of evidence IV; strength of recommendation C) • There is no RCT concerning additional resection in patients with GBC T2. There are many retrospective reports that

CHAPTER 28

point out that the prognosis is significantly better in the group for whom additional resection has been performed, compared with the group who received simple cholecystectomy alone. (Category of evidence IV; strength of recommendation C) • In advanced GBC, anatomic liver resection including common bile duct could be recommended in order to achieve tumor clearance (R0) [36]. (Category of evidence IIIb; strength of recommendation C) • For GBC patients not considered candidates for surgery, but willing and able to tolerate chemotherapy, 5-fluorouracil (5-FU), capecitabine or gemcitabine alone or in combination appear to be a better alternative to best supportive care, although this conclusion has not been confirmed by a RCT. (Category of evidence I; strength of recommendation C) • No controlled trials have compared the use of stents versus surgical bypass in advanced GBC. Given the high morbidity associated with surgery, it is best for patients who have locally advanced unresectable disease found on abdominal exploration to undergo an endoscopic minimally invasive procedure when possible. (Category of evidence IV; strength of recommendation D)

Prognosis The outcomes of therapies used in GBC have been assessed based on survival and prognosis [24–28, 37, 38]: • Survival of GBC patients is directly related to the penetration of the lesion in the gallbladder wall (T), the presence of regional lymph node involvement (N), and the presence of metastasis (M). (Category of evidence IIb) • Of the T and N factors in GBC, the most important prognostic factor is lymph node metastasis. (Category of evidence IIb) • The median survival for GBC stages I, II, III, and IV is 27, 8, 4, and 2 months respectively [37]. (Category of evidence IIb) • The 5-year survival for patients of stages 0, IA, IB, IIA, IIB, III, and IV is 81%, 50%, 29%, 7%, 9%, 3%, and 2%, respectively [37]. (Category of evidence IIb) • Nonresidual disease surgery (R0) is considered an important prognostic factor, even for advanced GBC. Long-term survival is not expected after incomplete R1 (microscopic residual tumor) or R2 (macroscopic residual tumor) resections. (Category of evidence IIb)

Diagnosis and treatment Diagnosis and work-up The absence of specific symptoms and signs of GBC, and the lack of known specific tumor markers, usually results in a late diagnosis. The presence of jaundice or the finding of a tumor in the gallbladder usually indicates advanced disease

Gallbladder Cancer

when the tumor is already unresectable. Other patients may present with a clinical condition resembling acute cholecystitis, or with abdominal pain, weight loss or unspecific symptoms. There is a subgroup of patients in whom the diagnosis of GBC is made during surgery, or in whom GBC becomes evident in the pathology review of the removed gallbladder. These patients have a better prognosis since they have an earlier stage of disease and pose special therapeutic challenges [20–26]. The diagnosis may be suspected based on the US finding of a suspicious tumor in relation to the gallbladder or a significant thickening of the gallbladder wall that infiltrates the hepatic bed. Blood tests for liver function and abdominal/chest CT or MRI should be performed [16]. Elevated serum tumor markers such as CA 19-9 and carcinoembryonic antigen (CEA) are associated with advanced disease and are usually not useful for early diagnosis. The utility of PET–CT in the diagnosis and follow-up of patients with GBC has not yet been established, but it may be of use in assessing the extent of the disease [14, 15]. For patients who present with jaundice, additional workup should include MRC, endoscopic ultrasonography or endoscopic retrograde cholangiopancreatography, frequently with biliary stent placement in the same setting to relieve biliary obstruction. The use of percutaneous transhepatic cholangiography may be necessary for the placement of stents in advanced tumors.

Staging Most GBCs are adenocarcinomas, with papillary, tubular, and nodular histologic subtypes. Factors for poor prognosis include young age, poorly differentiated tumors, the flat subtype, the depth of invasion into the gallbladder wall, lymph node involvement, infiltration of neighboring organs, and presence of distant metastasis [37]. GBC disseminates through the lymphatic, hematogenous, and endoluminal routes, and by continuity. The lymphatic spread progresses to the cystic lymph node, then to the hepatoduodenal ligament, retropancreatic, and common hepatic artery lymph nodes. Dissemination to the intercaval-aortic lymph nodes indicates a poor prognosis [38, 39]. The American Joint Committee on Cancer (AJCC) TNM Staging for GBC [40] (Table 28.1) has established the standard classification which is most commonly used. It is based on the level of invasion of the cancer into the gallbladder wall, the involvement of lymph nodes, and the presence of distant metastasis. This allows grouping of patients into different stages. Local infiltration into the liver, the gallbladder bed, and neighboring organs (T3) is not considered to be metastasis [40]. For an adequate staging, it is necessary for the pathologist to perform a detailed examination of the extirpated gallbladder, to define, in addition to the histologic characteristics,

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Table 28.1 The American Joint Committee on Cancer (AJCC) TNM Staging for Gallbladder Cancer. (Reproduced from Greene et al [40], with permission from Springer.) (See also Chapter 4, Table 4.5.) Primary tumor (T)

Regional lymph nodes (N)

TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: Carcinoma in situ T1: Tumor invades lamina propria or muscle layer T1a: Tumor invades lamina propria T1b: Tumor invades muscle layer T2: Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver T3: Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one of the adjacent organs or structures, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts T4: Tumor invades main portal vein or hepatic artery or invades two or more extrahepatic organs or structures

NX: Regional lymph nodes cannot be assessed N1: Regional lymph node metastasis

the localization, and extension of and penetration into the gallbladder wall. A gallbladder that has been retrieved by laparoscopic cholecystectomy may sometimes be severely traumatized, making the histologic interpretation difficult [41]. The AJCC TNM Staging for GBC classification is handicapped by the fact that before operation there is no information on the T and N stage to aid the treatment decision. In the patient who has already undergone cholecystectomy and the diagnosis of GBC made by the pathology review, only the degree of penetration (T) of the cancer can be assessed. Sometimes the cystic lymph node has not been excised and the involvement of the lymph nodes (N) or neighboring structures is not known. In this case, the decision to reoperate with extended surgery is based on the level of invasion of the cancer into the gallbladder wall described in the pathology report, and the study of extension or dissemination (see Diagnosis and work-up above).

Surgical approach The treatment for GBC should be determined by a multidisciplinary team. If the patient has images that are suspicious for GBC, the cholecystectomy should be performed by a surgeon who is experienced in cancer surgery, and open surgery is recom-

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Distant metastasis (M) MX: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis

Stage grouping Stage Stage Stage Stage Stage

0 1A 1B IIA IIB

Stage Stage

III IV

Tis T1 T2 T3 T1 T2 T3 T4 Any T

N0 N0 N0 N0 N1 N1 N1 Any N Any N

M0 M0 M0 M0 M0 M0 M0 M0 M1

mended. If there are no distant metastases, laparoscopy is useful to rule out hepatic or peritoneal dissemination in patients who are potential candidates for resection surgery [34, 35]. The definite role for laparoscopic cholecystectomy in the treatment of gallbladder cancer has yet to be determined. There is evidence that in patients with GBC that is not suspected before operation and who have undergone laparoscopic cholecystectomy, the prognosis is worse than for those treated with open cholecystectomy. In these cases, rupture of the gallbladder during operation and not having extracted the gallbladder in a bag will increase the incidence of cancer recurrence [17–19]. Extended surgery may be recommended for the initial treatment of GBC, or to complete the treatment if the patient has already undergone cholecystectomy. In these cases, surgery starts with dissection of the retroduodenal lymph nodes between the cava and aorta. If these are involved by cancer, survival is usually limited to months, and extended surgery may not be worthwhile. If the retroduodenal lymph nodes are negative, the procedure will continue with hepatoduodenal ligament and common hepatic artery lymphadenectomy. Hepatic resection includes segments 4B + 5 and extirpation of the right prerenal peritoneum. In patients who have previously undergone laparoscopic cholecystec-

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Gallbladder Cancer

tomy, resection of the port sites is also recommended, so as to avoid the risk of local recurrence [4, 25, 27]. Whether or not to perform the bile duct excision is currently a controversial issue [42]. If the gallbladder neck or the cystic duct are invaded by cancer, there is agreement that the common bile duct should be excised. Nonetheless, routine common bile duct excision is currently debated and there is less support for this [38]. Extended hepatic resections have been advocated when the tumor is close to the cystic duct, or when there is cholecystitis, stage N1 lymph node involvement, jaundice, or large size lesions. However, this is accompanied by greater morbidity and mortality [43–45]. This recommendation needs to be supported by further clinical studies.

to detect distant disease. If there is evidence of progression of the disease, the initial work-up guidelines should be consulted again.

Adjuvant treatment

In these patients the disease is limited to the mucosa of the gallbladder and dissemination is unlikely. It is agreed that cholecystectomy is sufficient. The great majority of these cases are diagnosed after an open or laparoscopic cholecystectomy by the pathologic study of the surgical specimen. Ideally, the surgical specimen should contain the cystic lymph node. Five-year survival is more than 90%. A special situation occurs when there is invasion of the Rokitansky Aschoff sinuses that brings the cancer closer to the deep structures of the gallbladder wall. In this case there may be the need for extended surgery [19, 21, 22].

Different forms of chemotherapy and radiotherapy have been used to improve survival [30–33]. Because most of the series are small, they are difficult to interpret. Considering that most patients who recur do so locoregionally, radiotherapy has been used as adjuvant treatment together with 5-FU as a sensitizer. Likewise, chemotherapy and radiation have also been used preoperatively [33]. Resected patients who are classified as more than T2 or N1 should be considered for adjuvant 5-FU-based chemotherapy and radiation. The use of mitomycin with 5-FU, oral capecitabine, and other protocols based on gemcitabine have also been suggested [31]. In recent publications, the use of gemcitabine in patients with unresectable or recurrent disease, alone or in combination with 5-FU, carboplatin or capecitabine, has been evaluated but its survival benefit over the best supportive care has not been confirmed by RCTs [32].

Palliative care Frequently the diagnosis of GBC is late and treatments are limited to palliation of pain, pruritus or cholangitis. A palliative care specialist team must be in charge of the care of the patient and his/her family in this difficult stage, using techniques for pain control and psychologic support. When there is pruritus due to obstructive jaundice or clinical conditions of biliary infection, the use of stents may help to relieve the symptoms. The rate of biliary obstruction in patients with GBC exceeds 60% and gastric obstruction occurs in approximately 50% of patients who present with jaundice. Due to the limited life-expectancy of this group of patients, nonsurgical options of percutaneous or endoscopic endobiliary stents and endoscopic enteric stenting should be considered.

Surveillance Follow-up consists of clinical surveillance, imaging studies (chest/abdominal CT or MRI) and liver function tests every 6 months for 2 years, then annually. PET–CT may be useful

Treatment strategies and prognosis based on tumor stage The intensity of treatment and its extension will depend on how deep is the tumoral invasion of the gallbladder wall, and the lymph node involvement and that of neighboring organs (TNM).

In-situ tumors or those with mucosal invasion (Tis and T1a)

Tumors that invade the muscularis propria (T1b) This group of patients has a very good prognosis with a survival of about 80% at 5 years, independent of the treatment performed. There is no consensus as to whether extended surgery and simple cholecystectomy is the best treatment. The diagnosis is also usually made postoperatively by examination of the excised gallbladder. Factors that may indicate reoperation (extended surgery) are: young patient age, invasion of the cystic duct, microinvasion of cystic lymph node, undifferentiated or flat tumors, and vascular or lymphatic permeation [23].

Tumors that invade the subserosa (T2) These patients categorically benefit from an extended surgery. The survival of patients treated with simple, open or laparoscopic cholecystectomy is only 25% at 5 years. If extended surgery is added, survival is 50–65% at 5 years for T2 N0 M0 patients. In these patients, lymph node involvement is more frequent (close to 40%). Before completing the operation, it is necessary to rule out the involvement of the intercaval-aortic lymph nodes when survival benefit will be obtained with extended surgery [4, 39]. Once extended surgery is completed, the finding of lymph nodes or segment IV B + 5 resected hepatic tissue involvement is associated with a significantly worse prognosis, and adjuvant treatment as described above should be considered [31].

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Incidental finding on pathologic review

Tumor on imaging or jaundice

Incidental finding at surgery

Clinical work-up Imaging Surgical evaluation

Clinical staging Imaging Surgical evaluation

Resectable

Unresectable

Surgical staging Biopsy – intercaval-aortic lymphadenectomy Cholecystectomy

Tis/T1a T1b low risk M0

T1b high risk T2/T3 M0

Tis/T1a T1b low risk M0

Extended surgery (If negative intercaval-aortic lymph nodes)

T3 any N1 any M1

Surveillance

Adjuvant treatment and surveillance

T1/T2 N0 M0

Surveillance

Tumors with invasion of the serosa, and infiltration of the hepatic bed or of neighboring organs (T3 and T4) This group of patients has a poor prognosis, independent of the treatment performed. Only in rare cases is long-term survival seen after extended resections. There is usually involvement of the regional lymph nodes or infiltration of the bile duct, portal vein or hepatic artery. For many, these are criteria for nonresectability. Invasion of the transverse colon, duodenum or stomach is also an indication of an advanced stage of the disease. Resections that are not R0 are sometimes possible with a palliative intent. In unresectable patients, a biopsy should be obtained to confirm the diagnosis before proceeding to chemoradiotherapy. In patients who are not candidates for surgical exploration, chemora-

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Chemotherapy/ radiotherapy or supportive care

Figure 28.1 Gallbladder cancer: Therapeutic algorithm based on form of presentation.

diotherapy may be performed so as to obtain downstaging before attempting an R0 resection later [31].

Therapeutic algorithm based on presentation In order to define a therapeutic algorithm, the diverse forms of presentation of the disease must be considered.

Gallbladder cancer first discovered after cholecystectomy by pathology review (Figure 28.1) Patients in whom GBC is discovered incidentally after a cholecystectomy have to be assessed with liver function tests

CHAPTER 28

and abdominal/chest CT or MRI, so as to rule out dissemination of the disease. Inflammatory changes after a recent cholecystectomy may pose difficulty for the interpretation of CT or MRI. If the gallbladder was removed intact, with negative margins, and patients are classified as Tis or T1a, there is no indication for reoperation or adjuvant therapy [20–22]. T1b patients with risk factors (young patient age, microinvasion of the cystic lymph node, undifferentiated or flat tumors, vascular or lymphatic permeation) may benefit from extended surgery, as was mentioned in Tumors that invade the muscularis propria (T1b) above. The remaining patients may be followed up without reoperation or adjuvant therapy [23]. T2 patients should be considered for extended surgery as described above. If the pathologic review shows lymph nodes with cancer or there is neoplastic involvement of the resected segment IV B + 5 hepatic tissue, the prognosis is significantly worse and the patients should be considered for adjuvant treatment [31]. T3 and T4 patients are usually diagnosed during cholecystectomy and would not further benefit from a reintervention [28]. Nonetheless, in T3 patients with microscopic invasion of the gallbladder bed on pathology review only, surgical re-exploration for the purposes of extended surgery is acceptable [43–45]. Unfortunately, when these patients are re-explored, weeks after the cholecystectomy, they are often found to be unresectable, because of peritoneal infiltration, neoplastic involvement of periaortic lymph nodes, or other metastasis. Chemotherapy and radiotherapy may be considered for these patients.

Incidental gallbladder cancer found during cholecystectomy (Figure 28.1) If GBC is suspected during a laparoscopic cholecystectomy, conversion to open surgery is necessary. An assessment of the extent of the lesion must be performed, looking for metastasis and peritoneal infiltration. During cholecystectomy, excessive manipulation and rupture of the gallbladder should be avoided. The cholecystectomy specimen should include the cystic lymph node, and a frozen section should be performed on both the gallbladder and the node. In the meantime, a wide Kocher maneuver may be performed to resect the nodes between the cava and aorta. Once GBC is confirmed, the surgeon may have to stop further surgical procedure if: • There is peritoneal invasion, extension to adjacent organs or involvement of the common bile duct, portal vein, or hepatic artery; • Tumor invasion depth cannot be reliably assessed by the pathologist; • Intercaval-aortic lymph nodes are involved; • The surgeon is not experienced in extended surgery;

Gallbladder Cancer

• Adequate conditions for an extended surgery are not present (nonspecialized surgical center, high-risk patient, infection, operating theatre not prepared, insufficient patient consent, etc).

Suspicion of gallbladder cancer on imaging (Figure 28.1) It is uncommon for small GBC to be diagnosed in the preoperative phase, except for raised polypoid lesions. The presence of a suspicious mass on ultrasound studies mandates a complete work-up, as described above. The patient should be explored by a surgeon with experience in cancer surgery. Informed consent from the patient for extended surgery, and the necessary equipment and operating theatre facilities should be available. Treatment strategies follow the criteria described in the section on Treatment strategies and prognosis based on tumor stage above.

Suspicion of gallbladder cancer in patients with jaundice (Figure 28.1) Patients who present with jaundice require additional workup that must include MRC and endoscopic ultrasonography. Depending on these results, endoscopic retrograde cholangiography and in some cases percutaneous transhepatic cholangiography with temporal or definitive biliary decompression may be indicated. The majority of these patients have advanced disease and are not candidates for resection surgery. Some patients with disease considered to be localized and potentially resectable may be candidates for exploratory surgery for extended surgery [44, 45] according to the criteria described in Tumors with invasion of the serosa, and infiltration of the hepatic bed or of neighboring organs (T3 and T4) above.

Metastatic disease In the presence of metastatic disease, supportive care for pain relief and biliary decompression are mandatory. Gemcitabine and/or 5-FU-based chemotherapy may be considered, in the context of a clinical trial, as was mentioned above.

Acknowledgements The authors thank Eduardo Valdivieso MD, Xabier de Aretxabala MD, Ivan Roa MD, and Jorge Gallardo MD for their collaboration.

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Self-assessment questions 1 Which one of the following concepts holds the lowest evidence? A The resection of the biliary tract must be a routine procedure during gallbladder cancer surgery B Among the prognostic factors T and N, the involvement of N1 or N2 has the worst prognosis C T2 patients are sufficiently treated with a cholecystectomy plus hepatic resection D Chemotherapy after radical surgery in gallbladder cancer is required for better survival E Laparoscopy has no role in gallbladder cancer surgery 2 Which one of the following statements is most correct regarding gallbladder cancer? A One-step surgery is the best therapeutic option B All patients with a finding of gallbladder cancer after a laparoscopic cholecystectomy must be reoperated C Multiple gallbladder polyps have a greater risk of gallbladder cancer D T1b patients have a 5-year survival of more than 70% E The unexpected finding of gallbladder cancer during a laparoscopic cholecystectomy predicts a poor prognosis 3 “Extended resection” in gallbladder cancer includes which one of the following? A Cholecystectomy B Lymphadenectomy of the hepatic pedicle and hepatic artery C Resection of segments 4B + 5 and intercaval-aortic lymph nodes D None of the above E All of the above 4 Which one of the following in gallbladder cancer stages Tis and T1a is the most favored treatment? A Cholecystectomy B Extended resection C Cholecystectomy plus regional lymphadenectomy D Cholecystectomy plus hepatic resection E None of the above 5 Which one of the following describes the main risk factors for gallbladder cancer? A Cholelithiasis, gallbladder polyp > 10 mm, cholecystoenteric fistula B Cholelithiasis, obesity, cholecystoenteric fistula

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C Gallbladder polyp > 10 mm, obesity, “porcelain” gallbladder D Cholelithiasis, gallbladder polyp > 10 mm, anomalous pancreatobiliary junction E Gallbladder polyp > 10 mm, cholelithiasis, “porcelain” gallbladder

References 1 www.pubmed.gov (accessed March 2008). 2 www.tripdatabase.com (accessed March 2008). 3 National Cancer Comprehensive Network: NCCN Clinical Practice Guideline in Oncology Hepatobiliary Cancers V.2 2008. www.nccn.org (accessed March 2008). 4 Kondo S, Takada T, Miyazaki M, et al. Guidelines for the management of biliary tract and ampullary carcinomas: surgical treatment. J Hepatobiliary Pancreat Surg 2008;15:41– 54. 5 Garden OJ, Rees M, Poston GJ, et al. Guidelines for resection of colorectal cancer liver metastases. Gut 2006;55 (Suppl III): iii1–iii8 6 Sheth S, Bedford A, Chopra S. Primary gallbladder cancer: recognition of risk factors and the role of prophylactic cholecystectomy. Am J Gastroenterol 2000;95:1402–10. 7 Larsson SC, Wolk A. Obesity and the risk of gallbladder cancer: a meta-analysis. Br J Cancer 2007;96:1457–61. 8 Ishiguro S, Inoue M, Kurahashi N, Iwasaki M, Sasazuki S, Tsugane S. Risk factors of biliary tract cancer in a large –scale population-based cohort study in Japan (JPHC study); with special focus on cholelithiasis, body mass index and their effect modification. Cancer Causes Control 2008;19:33–41. 9 Roa I, Araya JC, Villaseca M, et al. Preneoplastic lesions and gallbladder cancer: an estimate of the period required for progression. Gastroenterology 1996;111:232–6. 10 Ransohoff DF, Gracie WA. Treatment of gallstones. Ann Intern Med 1993;119: 606–19. 11 Stephen AE, Berger DL. Carcinoma in the porcelain gallbladder: a relationship revisited. Surgery 2001;129:699–703. 12 Kokudo N, Makuuchi M, Natori T, Sakamoto Y, Yamamoto J, et al. Strategies for surgical treatment of gallbladder carcinoma base on information available before resection. Arch Surg 2003;138:741–50. 13 Miller G, Schwartz LH, D’Angelica M. The use of imaging in the diagnosis and staging of hepatobiliary malignancies. Surg Oncol Clin N Am 2007;16:343–68. 14 Anderson CD, Rice MH, Pinson CW, Chapman WC, Chari RS, Delbeke D. Fluorodeoxyglucose PET imaging in the evaluation of gallbladder carcinoma and Cholangiocarcinoma. J Gastrointest Surg 2004;8:90–7. 15 Petrowsky H, Wildbrett P, Husarik DB, et al. Impact of integrated positron emission tomography and computed tomography on staging and management of gallbladder cancer and cholangiocarcinoma. J Hepatol 2006;45:43–50. 16 Kim SJ, Lee JM, Lee JY, et al. Accuracy of preoperative T-staging of gallbladder carcinoma using MDCT. AJR Am J Roentgenol 2008;190:74–80.

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17 Sarli L, Contini S, Sansebastiano G, Gobbi S, Costi R, Roncoroni L. Does laparoscopic cholecystectomy worsen the prognosis of unsuspected gallbladder cancer? Arch Surg 2000;135:1340–4. 18 Whalen GF, Bird I, Tanski W, Russell JC, Clive J. Laparoscopic cholecystectomy does not demonstrably decrease survival of patients with serendipitously treated gallbladder cancer. J Am Coll Surg 2001;192:189–95. 19 De Aretxabala X, Roa I, Mora J, et al. Laparoscopic cholecystectomy: its effect on the prognosis of patients with gallbladder cancer. World J Surg 2004;28:544–7. 20 Wakai T, Shirai Y, Yokoyamma N, Nagakura S, Watanabe H, Hatakeyama K. Early gallbladder carcinoma does not warrant radical resection. Br J Surg 2001;88:675–8. 21 Shirai Y, Yoshida K, Tsukada K, Muto T. Inapparent carcinoma of the gallbladder: an appraisal of a radical second operation after simple cholecystectomy. Ann Surg 1992;215:326–31. 22 Roa I, de Aretxabala X, Araya JC, Villaseca M, Roa J, Guzmán P. Incipient gallbladder carcinoma. Clinical and pathological study and prognosis in 196 cases. Rev Med Chil 2001;129: 1113–20. 23 De Aretxabala X, Roa I, Mora J, et al. Management of gallbladder cancer with invasion of the muscular layer. Rev Med Chil 2004;132:183–8. 24 Wakai T, Shirai Y, Yokoyama N, et al. Depth of subserosal invasion predicts long term survival after resection in patients with T2 gallbladder carcinoma. Ann Surg Oncol 2003;10:447–54. 25 De Aretxabala X, Roa I, Burgos L, et al. Gallbladder cancer: an analysis of a series of 139 patients with invasion restricted to the subserosal layer. J Gastrointest Surg 2006;10:186–92. 26 Chan SY, Poon RT, Lo CM, Ng KK, Fan ST. Management of carcinoma of the gallbladder: a single-institution experience in 16 years. J Surg Oncol 2008;97:156–64. 27 Goetze TO, Paolucci V. Benefits of reoperation of T2 and more advanced incidental gallbladder carcinoma: analysis of the German registry. Ann Surg 2008;247:104–8. 28 Kayahara M, Nagakawa T. Recent trends of gallbladder cancer in Japan: an analysis of 4,770 patients. Cancer 2007;110: 572–80. 29 De Aretxabala X, Roa I, Burgos L, et al. Gallbladder cancer in Chile. A report on 54 potentially resectable tumors. Cancer 1992;69:60–5. 30 Gallardo J, Rubio B, Villanueva L, Barajas O. Gallbladder cancer, a different disease that needs individual trials. J Clin Oncol 2005;23:7753–4. 31 De Aretxabala X, Roa I, Berrios M, et al. Chemoradiotherapy in gallbladder cancer. J Surg Oncol 2006;93:699–704. 32 Dingle BH, Rumble RB, Brouwers MC. The role of gemcitabine in the treatment of cholangiocarcinoma and gallbladder cancer: a systematic review. Can J Gastroenterol 2005;19:711–6. 33 De Aretxabala X, Losada H, Mora J, et al. Neoadjuvant chemoradiotherapy in gallbladder cancer. Rev Med Chil 2004;132: 51–7.

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34 Goere D, Wagholikar GD, Pessaux P, et al. Utility of staging laparoscopy in subsets of biliary cancers : laparoscopy is a powerful diagnostic tool in patients with intrahepatic and gallbladder carcinoma. Surg Endosc 2006;20:721–5. 35 Shih SP, Schulick RD, Cameron JL, et al. Gallbladder cancer: the role of laparoscopy and radical resection. Ann Surg 2007;245:893–901. 36 Scheingraber S, Justinger C, Stremovskaia T, Weinrich M, Igna D, Schilling MK. The standardized surgical approach improves outcome of gallbladder cancer. World J Surg Oncol 2007;5: 55–62. 37 Fong Y, Wagman L, Gonen M, et al. Evidence-based gallbladder cancer staging: changing cancer staging by analysis of data from the National Cancer Database. Ann Surg 2006;243:767–71. 38 Ott R, Hauss J. Need and extension of lymph node dissection in gallbladder carcinoma. Zentralbl Chir 2006;131:474–7. 39 Kondo S, Nimura Y, Hayakava N, Kamiya J, Nagino M, Uesaka K. Regional and para aortic lymphadenectomy in radical surgery for advanced gallbladder carcinoma. Br J Surg 2000;87:418–22. 40 Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual, 6th edn. New York: Springer, 2002: 140. 41 Henson DE, Albores-Saavedra J, Compton CC. Protocol for the examination of specimens from patients with carcinomas of the gallbladder, including those showing focal endocrine differentiation: a basis for checklists. Cancer Committee of the College of American Pathologists. Arch Pathol Lab Med 2000;124:37–40. 42 Agarwal AK, Mandal S, Singh S, Bhojwani R, Sakhuja P, Uppal R. Biliary obstruction in gall bladder cancer is not sine qua non of inoperability. Ann Surg Oncol 2007;14:2831–7. 43 Reddy SK, Marroquin CE, Kuo PC, Pappas TN, Clary BM. Extended hepatic resection for gallbladder cancer. Am J Surg 2007;194:355–61. 44 Dixon E, Vollmer CM Jr, Sahajpal A, et al. An aggressive surgical approach leads to improved survival in patients with gallbladder cancer: a 12-year study at a North American Center. Ann Surg 2005;241:385–94. Shimizu H, Kimura F, Yoshidome H, et al. Aggressive surgical approach for stage IV gallbladder carcinoma based on Japanese Society of Biliary Surgery classification. J Hepatobiliary Pancreat Surg 2007;14:358–65.

Self-assessment answers 1 2 3 4 5

A D E A D

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Colorectal Liver Metastases Phuong L. Doan1, Jean-Nicolas Vauthey2, Martin Palavecino2, and Michael A. Morse1 1 2

Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

Initial evaluation and diagnosis Approximately 15% of patients with colorectal cancer will have liver metastases at diagnosis, and more than half will develop liver metastases during the course of their disease. The initial evaluation of a patient with colorectal cancer with liver metastases should include carcinoembryonic antigen (CEA) testing, colonoscopy, computed tomography (CT) of abdomen and pelvis, and fluorodeoxyglucose-positron emission tomography (FDG-PET; Figure 29.1) [1, 2]. More than 75% of colorectal cancers express CEA, and levels normalize after curative resection of colorectal primary. Secondary elevation indicates recurrent disease and should be further evaluated. In patients who did not previously undergo colectomy, colonoscopy is performed to exclude local recurrence as part of the evaluation for resection of liver metastases. FDG-PET is performed in some centers to rule out unexpected sites of extrahepatic disease. The addition of PET to identify patients who are candidates for resection of liver metastases was associated with better disease-free survival and overall survival in those with clinical risk score (Fong Score) greater than 2, but not those with a score of 2 or less [2].

Treatment (Figure 29.1) Resection of liver metastases and extrahepatic disease Hepatic resection is the gold standard treatment for colorectal liver metastases and provides a 5-year survival of 58% [3]. Another treatment option, such as radiofrequency ablation, provides only a slightly better survival than chemotherapy alone [4]. Simultaneous resection of the primary colorectal cancer and minor hepatic resection can be safely

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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performed [5, 6], but simultaneous major resections and colorectal resection are associated with an increased risk of severe complications. In the latter cases, patients should undergo staged primary and liver resections using the traditional approach (primary first) or the reverse approach (liver first) [7]. In addition, a two-stage hepatectomy can be offered if a single resection would not achieve complete treatment. In one study, 35 of 51 patients (69%) were able to undergo a two-stage hepatectomy with a 2-month mortality of 11% [5]. The mean interval between procedures was 4.3 months. Overall 3- and 5-year survival rates were 57% and 39%, respectively. The resection of liver metastases can be done simultaneously with the resection of extrahepatic disease. Seventyfive patients who underwent simultaneous R0 resection of colorectal liver metastases and extrahepatic disease had a 5-year survival rate of 28%. This cohort included 10 patients (13%) with lung metastases and 10 patients (13%) with hilar lymph node involvement. In patients with lung metastases, hepatectomy was performed first, followed by resection of lung metastases 2 months later, provided that there had been no interval disease progression and patients were still resectable at that time. This survival rate was not statistically different from 219 patients in the same study who did not have extrahepatic disease at the time of study enrolment. In addition to simultaneous resection of pulmonary metastases, simultaneous resection of regional lymph node metastases can improve overall survival [6]. In comparison to patients with colorectal liver metastases only, the involvement of a regional lymph node (RLN) with metastases is a poor prognostic factor [8]. Forty-seven patients with intraoperatively confirmed RLN metastases who underwent hepatectomy with simultaneous lymphadenectomy were compared with 710 patients without RLN metastases who underwent hepatectomy alone. Both groups had received preoperative systemic chemotherapy. Five-year overall survival for patients with and without RLN metastases was 18% and 53%, respectively. While there are no randomized studies comparing resection with no resection, natural history studies suggest 100% mortality at 5 years without resection of liver metastases.

CHAPTER 29

D I A G N O S I S

Preoperative consideration and work-up • Hx & PE • CEA[1] • Colonoscopy[2] • CT abd/pelvis + CXR or chest CT • FDG-PET scan[3]

Unresectable Colorectal liver metastasis

Resectable Systemic therapy

Follow resectable pathway

Colon resection if imminent risk of obstruction, bleeding

Resectable T R E A T M E N T

Colorectal Liver Metastases

Resectable

Simultaneous vs staged liver resection[4] ± colectomy ± lung resection of metastases[5–9]

FOLFIRI[10], FolFOX[11–14], or CapeOX[14] ± bevacizumab[15–17]

Unresectable

Second-line chemotherapy for advanced disease Unresectable

Selective internal radiation therapy[22]

Liver resection ± colectomy[4,5,18 ] A D J U V A N T T H E R A P Y S U R V E I L L A N C E

FolFIRI, FolFOX, or CapeOX ± bevacizumab for 6 months ±

Additional chemo to total 6 months if patient received neoadjuvant therapy

Evaluate for repeat hepatectomy

± Evaluate for repeat hepatectomy

Systemic chemo as for advanced disease

FUDR by intrahepatic arterial pump for 6 months[19–21]

If no evidence of disease, then: • CEA every 3 month x 2 year, then 6 month x 3–5 year • CT chest/abd/pelvis every 3–6 month x 2 year, then every 6–12 month to total of 5 year • Colonoscopy in 1 year or in 3–6 month if no preoperative colonoscopy done

Recurrence

Figure 29.1 Algorithm for the management of a patient with colorectal cancer with liver metastases. Hx & PE, history and physical examination; CEA, carcinoembryonic antigen; CT, computed tomography; CXR, chest X-ray; FDG-PET, fluorodeoxyglucose-positron emission tomography; FUDR, floxuridine.

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The 2006 American Hepato-Pancreato-Biliary Association (AHPBA) sponsored Consensus Conference on Colorectal Liver Metastases defined resectability as: (1) the ability to preserve two contiguous hepatic segments; (2) the preservation of adequate vascular inflow and outflow as well as biliary drainage; and (3) the ability to preserve adequate future liver remnant (>20% in a healthy liver). Unfortunately, 90% of patients are deemed unresectable at initial evaluation, with metastatic liver disease being the major cause of death in these patients [9]. Therefore, resection of liver metastases should be offered to all patients who are suitable candidates and neoadjuvant chemotherapy should be considered in patients who are deemed unresectable at initial evaluation (see also Chapter 17).

Neoadjuvant chemotherapy Neoadjuvant chemotherapy offers earlier treatment of micrometastases, predicts chemotherapy sensitivity to plan adjuvant therapy, and allows for systemic treatment of early progressive disease [10]. The most important goal of neoadjuvant chemotherapy is to downsize colorectal liver metastases such that unresectable disease becomes resectable. Neoadjuvant chemotherapy can convert unresectable liver metastases to resectable metastases in up to 38% of patients [11]. In this section, we will discuss selected references to support the use of irinotecan, oxaliplatin, 5-fluorouracil (5FU), and bevacizumab as neoadjuvant chemotherapy. Forty patients received neoadjuvant irinotecan 180 mg/m2 and infusional 5-FU with folinic acid for colorectal cancer with initially unresectable hepatic metastases. Objective responses were obtained in 19 patients (47.5%) with two complete responses. Thirteen patients (32.5%) were able to undergo potentially curative liver resection of metastases. Median time to progression was 14.3 months. All patients were alive at median follow-up of 19 months. Grade 3/4 hematologic and gastrointestinal toxicities were 35% and 12.5%, respectively [12]. In a study with oxaliplatin, 364 patients with colorectal cancer and up to four liver metastases were randomized to receive six cycles of FOLFOX preand post-operatively versus surgery alone. Neoadjuvant chemotherapy with FOLFOX was shown to increase progression-free survival by 7.3% at 3 years (from 28.1% to 35.4%). Overall survival is still being monitored [13]. In another study, 56 patients with high risk of early recurrence (using Fong score) were selected for a single center, nonrandomized phase II trial. Chemotherapy consisted of six cycles (biweekly) of bevacizumab plus capecitabine and oxaliplatin. The median time between last dose of bevacizumab and surgery was 5 weeks. The last cycle did not include bevacizumab. The authors observed no increased surgical or wound healing complications. Bevacizumab did not impair liver function and regeneration [14]. Thirty-two patients received bevacizumab prior to or after liver resection for colorectal metastasis and were compared to a matched

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control group. Morbidity between the two groups was statistically similar (41% versus 38%, respectively; p = 1) [15]. Taken together, these studies demonstrate that neoadjuvant chemotherapy improves progression-free survival and possibly overall survival in patients with colorectal liver metastases. The prolonged progression-free survival with neoadjuvant chemotherapy comes with chemotherapy-induced hepatotoxicity. Surgery should be performed as soon as resectability is determined so that hepatotoxicity from chemotherapy is limited. Chemotherapy can induce regimen-specific histopathologic changes. In a systematic review, 248 patients had histopathologic changes after neoadjuvant chemotherapy. Preoperative irinotecan was associated with increased steatohepatitis rate. The 90-day mortality in patients with steatohepatitis was higher (14.7% versus 1.6% in patients without steatohepatitis; p = 0.001). The risk was increased in patients with a body mass index (BMI) of 25 or more [16]. The study included 66 metastases with complete response. To compensate for severe chemotherapy-induced hepatotoxicity and reduce morbidity, portal vein embolization should be considered in patients who have received extensive chemotherapy (six or more cycles) with a future liver remnant of 30% or less of the total estimated liver volume [17]. Despite downsizing of lesions due to neoadjuvant therapy, all sites of original disease should be resected. Sixty-six metastases with apparent complete response were resected and 53 (83%) of these metastases contained residual disease [18]. Duration of neoadjuvant therapy is usually less than 3–4 months (see also Chapter 10).

Adjuvant chemotherapy Adjuvant chemotherapy is recommended to eliminate residual microscopic disease [19]. A hepatic arterial port or implantable pump can be placed during surgical resection of liver metastases to allow for infusion of cytotoxic agents through the hepatic artery to better target liver metastases. One hundred fifty-six patients with colorectal liver metastases were randomized at the time of resection to receive six cycles of hepatic arterial infusion (HAI) with floxuridine and dexamethasone plus intravenous 5-FU with or without leucovorin versus six cycles of systemic therapy alone. At 2 years, the overall survival for the combined therapy group was 86% compared to 72% in the group that received systemic chemotherapy. Median survival was 72.2 months in the combined therapy group compared with 59.3 months in the systemic chemotherapy group [20, 21]. Early studies suggest infusion of fluorodeoxyuridine by the hepatic artery with systemic chemotherapy prolongs overall survival and time to hepatic progression compared to chemotherapy alone. Until these results are validated, HAI should not be offered routinely outside the setting of a clinical trial. Future studies are investigating the use of HAI in combination with capecitabine and oxaliplatin. In total, the duration of

CHAPTER 29

adjuvant therapy is 6 months. Patients who received neoadjuvant therapy may be considered for an abbreviated course of adjuvant therapy (see also Chapter 10).

Salvage therapy for refractory disease or disease recurrence Patients who do not respond to first-line systemic chemotherapy therapy and are unresectable should receive salvage chemotherapy. If these patients have colorectal metastases limited to the liver only, they may benefit from selective internal radiation therapy. In a study of 30 patients with unresectable colorectal liver metastases previously treated with 5-FU-based chemotherapy, 33% of patients had response with selective internal radiation therapy compared to 21% response with standard chemotherapy. Selective internal radiation therapy should be reserved for patients with intrahepatic disease only. Additional studies are required [22].

Surveillance After initial therapies with resection of colorectal liver metastases and adjuvant chemotherapy, patients should have ongoing close surveillance for disease recurrence. If there is evidence of disease recurrence, then patients should have re-evaluation for repeat hepatectomy (see also Chapter 19) or systemic chemotherapy if lesions are not resectable (Figure 29.1).

Self-assessment questions 1 How did the 2006 AHPBA-sponsored Consensus Conference on Colorectal Liver Metastases define respectability? A The ability to preserve two contiguous hepatic segments B Preservation of adequate vascular inflow and outflow as well as biliary drainage C The ability to preserve adequate future liver remnant (>20% in a healthy liver) D All of the above 2 Which one of the following statements regarding neoadjuvant chemotherapy for initially unresectable hepatic metastases is false? A Neoadjuvant chemotherapy can convert unresectable liver metastases to resectable metastases in up to 38% of patients B Neoadjuvant chemotherapy including bevacizumb did not result in a higher rate of surgical or wound healing complications C Neoadjuvant chemotherapy including bevacizumab did not impair liver function and regeneration

Colorectal Liver Metastases

D As much chemotherapy as possible should be administered before attempting hepatic metastasis resection 3 Which one of the following statements regarding chemotherapy for patients undergoing hepatic metastasis resections is false? A Preoperative irinotecan was associated with an increased steatohepatitis rate B The 90-day mortality in patients with steatohepatitis is higher than in patients without steatohepatitis C Only sites of residual disease should be resected D Portal vein embolization should be considered in patients who have received extensive chemotherapy (≥6 cycles) with a future liver remnant of 30% or less of the total estimated liver volume 4 Which one of the following statements is incorrect regarding the evaluation of hepatic metastases of colorectal cancer? A Approximately 50% of patients with colorectal cancer will have liver metastases at diagnosis, and more than 80% will develop liver metastases during the course of their disease B In patients who did not previously undergo colectomy, colonoscopy is performed to exclude local recurrence as part of the evaluation for resection of liver metastases C More than 75% of colorectal cancers express CEA, and levels normalize after curative resection of colorectal primary D The addition of PET to identify patients who are candidates for resection of liver metastases was associated with better disease-free survival and overall survival in those with a clinical risk score (Fong score) > 2, but not those ≤2 5 Which one of the following statements about resections is false? A Resection of the primary colorectal cancer and hepatic resection should never be performed simultaneously B The resection of liver metastases can be done simultaneously with the resection of extrahepatic disease C In comparison to patients with colorectal liver metastases only, the involvement of regional lymph node with metastases is a poor prognostic factor

References 1 Goldstein MJ, Mitchell EP. Carcinoembryonic antigen in the staging and follow-up of patients with colorectal cancer. Cancer Invest 2005;23:338–51.

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2 Fernandez FG, Drebin JA, Linehan DC, et al. Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg 2004;240:438–50. 3 Abdalla EK, Vauthey J-N, Ellis LM, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 2004;239:818–27. 4 Abdalla EK, Adam R, Bilchi AJ, et al. Improving respectability of hepatic colorectal metastases: Expert Consensus Statement. Ann Surg Oncol 2006;13:1261–8. 5 Reddy SK, Pawlik TM, Zorzi D, et al. Simultaneous resections of colorectal cancer and synchronous liver metastases: a multiinstitutional analysis. Ann Surg Oncol 2007;14:3481–91. 6 Mentha G, Majno PE, Andres A, et al. Neoadjuvant chemotherapy and resection of advanced synchronous liver metastases before treatment of the colorectal primary. Br J Surg 2006;93:872–8. 7 Adam R, Wicherts D, Miller R, et al. Two-stage hepatectomy for irresectable colorectal cancer liver metastases: A 14-year experience. ASCO 2008 Gastrointestinal Cancers Symposium 2008: a283. 8 Adam R, de Haas RJ, Wicherts DA, et al. Is hepatic resection justified after chemotherapy in patients with colorectal liver metastases and lymph node involvement? J Clin Oncol 2008;26:3672–80. 9 Charnsangavej C, Clary B, Fong Y, et al. Selection of patients for resection of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol 2006;13:1261–8. 10 Leonard GD, Brenner B, and Kemeny NE. Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol 2005; 23:2038–48. 11 Giachetti S, Itzhaki M, Gruia G, et al. Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin, and surgery. Ann Oncol 1999;10:663–9. 12 Pozzo C, Basso B, Cassano A, et al. Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol 2004;15:933–9. 13 Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomized controlled trial. Lancet 2008;371:1007–16.

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14 Gruenberger B, Tamandl D, Schueller J, et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol 2008;26:1830–5. 15 D’Angelica M, Kornprat P, Gonen M, et al. Lack of evidence for increased operative mortality after hepatectomy with perioperative use of bevacizumab: a matched case-control study. Ann Surg Oncol 2007;14:759–65. 16 Vauthey JN, Pawlik TM, Rivero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006;24: 2065–72. 17 Zorzi D, Laurent A, Pawlik TM, et al. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg 2007;94:274–86. 18 Benoist S, Brouquet A, Penna C, et al. Complete response of colorectal liver metastases after chemotherapy: does it mean cure? J Clin Oncol 2006;24:3939–45. 19 Bartlett DL, Berlin J, Lauwers GY, et al. Chemotherapy and regional therapy of hepatic colorectal metastases: Expert Consensus Statement. Ann Surg Oncol 2006;13:1284–92. 20 Kemeny N, Huang Y, Cohen A, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999;341:2039–48. 21 Kemeny MM, Adak S, Gray B, et al. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy- an intergroup study. J Clin Oncol 2002;20:1499–505. 22 Lim L, Gibbs P, Yip D, et al. A prospective evaluation of treatment with selective internal radiation therapy (SIR-spheres) in patients with unresectable liver metastases from colorectal cancer previously treated with 5-FU based chemotherapy. BMC Cancer 2005;5:132–7.

Self-assessment answers 1 2 3 4 5

D D C A A

6

Emerging Therapies

Introduction Michael A. Morse1 and Josep M. Llovet2 1

Medical Oncology, Duke University Medical Center, Durham, NC, USA Mount Sinai Liver Cancer Program, Division of Liver Diseases, Mount Sinai School of Medicine, New York, USA and BCLC Group, IDIBAPS, Liver Unit, CIBEREHD, Hospital Clínic, Barcelona, Spain 2

The poor prognosis for unresectable or metastatic liver tumors, and the need to prevent progression or relapse following surgical or local therapies, remain the major drivers for developing new therapies. Previously, the negative results for a series of chemotherapeutic agents had deterred pharmaceutical interest, but an emerging understanding of the important pathways in liver tumor development and progression [1], coupled with the first supportive evidence of survival improvement from systemic treatment of a targeted agent, such as sorafenib, for hepatocellular carcinoma (HCC) [2, 3], have now spurred considerable development in the field. There is a blossom of studies testing novel molecular targeted therapies in experimental models and clinical trials in HCC [3]. Although HCCs and their host milieu are heterogeneous, a number of key pathways appear to be relevant to many HCCs, such as vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), Ras/extracellular signal-regulated kinase (ERK), phosphoinositid-3-kinase (PI3K)/mammalian target of rapamycin (mTOR), hepatocyte growth factor (HGF)/MET, Wnt, Hedgehog, and apoptotic signaling. Clearly, HCCs are vascular tumors with increased VEGF factor A (VEGF-A) levels and microvessel density [4]. High-level amplifications of VEGF-A have been described in 5–7% of HCCs [5]. Sorafenib, which includes among its roles inhibition of the kinase functions of the VEGF and platelet-derived growth factor (PDGF) receptors, inhibited tumor angiogenesis in an HCC model, PLC/PRF/5 [6]. In addition to sorafenib, a number of other drugs with antiangiogenic activity (bevacizumab, sunitinib, brivanib, AZD2171, and others) have entered the developmental path for HCC. In fact, in 2009 phase III studies testing sunitinib, brivanib, and bevacizumab are being conducted. Understanding the actual mechanism by which antiangiogenic therapy inhibits HCC clinically, and determining how resistance occurs, will now be major research directions.

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

In principle, it is established that after antiangiogenic therapy, there is an increase in systemic VEGF-A levels. However, in a recently published study of bevacizumab [7], VEGF levels were noted to decrease from baseline in all patients after 8 weeks of bevacizumab therapy, but at the time of disease progression, VEGF increased from the 8-week values to near-baseline levels. Whether this increase in VEGF is the cause of progression, and could be addressed by higher doses of bevacizumab or the addition of a VEGF receptor (VEGFR) tyrosine kinase inhibitor (TKI), or whether it is associated with other causes of progressive disease, which would not be addressed by anti-VEGF therapy, is unclear. Also, targeting other molecules relevant for angiogenesis, such as fibroblast growth factor receptor (FGFR), may be necessary. Drugs such as TSU-68, an oral multikinase inhibitor (VEGFR, PDGFR, FGFR), and brivanib (VEGFR and FGFR inhibitor) are under development currently in HCC. The EGFR pathway has also been implicated in hepatocarcinogenesis. The expression of EGFR and its ligands (EGF, transforming growth factor-alpha [TGF-α], and heparinbinding EGF) have been reported in HCC [8]. Mutations or amplification of EGFR have been described as marginal aberrations. Sorafenib, in addition to VEGFR, also inhibits Raf kinase, a molecule in the EGFR cascade. In the phase II experience with sorafenib, the time to progression was longer in patients whose pretreatment tumor demonstrated activation of the EGFR pathway. Nonetheless, the activity of EGFR-targeting agents remains unclear and clinical trials thus far have raised more unanswered questions. For example, although the EGFR TKI erlotinib (EGFR and Her2 TKI) have been reported to achieve modest response rates in HCC as single agents [9], cetuximab and lapatinib alone have not [10]. Furthermore, drugs or combinations of agents that target both the VEGF and EGFR pathways, such as sorafenib or bevacizumab plus erlotinib, have shown possibly enhanced activity. Several other signaling cascades have been implicated in the pathogenesis of HCC. A number of genomic analyses have been performed to identify genes or pathways important for HCC development in general [11], solitary or

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multinodular development [12], metastasis, and tumor recurrence after surgical resection [11–13]. In general, the main observations thus far are that there is significant heterogeneity of HCC, but multiple potential pathways for targeting it have been suggested by this work [14]. There is no common agreement on the molecular classification of HCC Nonetheless, the main whole-genome studies suggest two common subclasses: Wnt-β-catenin and proliferation subclass [5]. Other molecular classes, such as those defined by activation of TGF-β or polysomy of chromosome 7, need to be confirmed. Also, distinct expression profiles have been observed in HCC caused by chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection [15]. Among the newer pathways now being viewed as potential targets for HCC therapies is the c-MET/hepatocyte growth factor pathway. Overexpression of hepatocyte growth factor and c-MET is an adverse prognostic factor for patients with liver cancer. Another pathway signaling through insulin-like growth factor receptor-1 (IGFR-1) is also prominent within HCC. IGFR-1-mediated signaling promotes survival, oncogenic transformation, and tumor growth and spread. Hopfner et al [16] demonstrated that the IGFR-1 TKI NVP-AEW541 inhibited growth and caused apoptosis and cell cycle arrest in HCC cell lines. The PI3K/Akt/mTOR pathway plays an important role in liver carcinogenesis and its blockade with rapamycin or everolimus inhibits growth in HCC cell lines and in experimental models. Finally, dysregulation of the Wnt pathway was also found to be a frequent event. Activation of the Wnt cascade has been shown in one-third of HCCs, as a consequence of mutations in ßcatenin, aberrant methylation of the tumor suppressors adenomatosis polyposis coli (APC) and E-cadherin, or increase of autocrine/paracrine secretion of Wnt ligands. New drugs targeting this pathway are in early clinical development. Challenges for new drug development in HCC include the lack of a dominant, single pathway to target, the lack of completely predictive animal models or cell lines, and the need to contend with underlying comorbidity related to cirrhosis at the same time as the tumor. Experimental models that recapitulate human HCC subclasses are urgently needed. Only the double transgenic TGF-α/Myc is considered to mimic genomic aberrations common in the proliferation subclass [17]. Also, it will be important for the research community to develop appropriate systems for determining clinical activity. It is clear from the randomized studies with sorafenib that stable disease may occur without therapy in some patients. It is also clear from studies of targeted therapies that tumors may appear to have stable disease according to the tumor dimensions, but the majority of the tumor tissue will be necrotic, suggesting a response to therapy. Other measures of activity, such as changes in tumor perfusion, may be more relevant to the development of some drugs. Guidelines for clinical trials in HCC are important and

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have recently been promulgated. According to these guidelines, randomized phase II trials with a time-to-event primary endpoint, such as time to progression, are pivotal in clinical research on HCC. Survival remains the main endpoint to measure effectiveness in phase III studies, whereas time to recurrence is proposed as an appropriate endpoint in the adjuvant setting. It was recommended that new drugs should be tested in patients with well-preserved liver function (Child–Pugh class A). Biomarkers and molecular imaging should be part of the trials, in order to optimize the enrichment of study populations and identify drug responders. Thus, we are facing a new era in HCC management, where mechanical treatments will be progressively supplemented by combinations of molecular therapies in a more personalized medicine. Guidelines for clinical trials in HCC are important and have recently been promulgated [18].

References 1 Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 2006;6:674–87. 2 Llovet JM, Ricci S, Mazzaferro V, et al. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–90. 3 Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology 2008;48:1312–27. 4 Pang R, Poon RT. Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma. Cancer Lett 2006;242:151–67. 5 Chiang DY, Villanueva A, Hoshida Y, et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res 2008;68:6779–88. 6 Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 2006;66:11851–8. 7 Siegel AB, Cohen EI, Ocean A, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 2008;26:2992–8. 8 Kiss A, Wang NJ, Xie JP, Thorgeirsson SS. Analysis of transforming growth factor (TGF)-alpha/epidermal growth factor receptor, hepatocyte growth factor/c-met,TGF-beta receptor type II, and p53 expression in human hepatocellular carcinomas. Clin Cancer Res 1997;3:1059–1066. 9 Ramanathan RK, Belani CP, Singh DA, et al. Phase II study of lapatinib, a dual inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase 1 and 2 (Her2/Neu) in patients (pts) with advanced biliary tree cancer (BTC) or hepatocellular cancer (HCC). A California Consortium (CCC-P) Trial. J Clin Oncol 2006;24 (Suppl 18):a4010. 10 Zhu AX, Stuart K, Blaszkowsky LS, et al. Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer 2007;110:581–9. 11 Nam SW, Lee JH, Noh JH, et al. Comparative analysis of expression profiling of early-stage carcinogenesis using nodule-innodule-type hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2006;18:239–47.

Introduction 12 Okamoto M, Utsunomiya T, Wakiyama S, et al. Specific geneexpression profiles of noncancerous liver tissue predict the risk for multicentric occurrence of hepatocellular carcinoma in hepatitis C virus-positive patients. Ann Surg Oncol 2006;13:947–54. 13 Budhu AS, Zipser B, Forgues M, et al. The molecular signature of metastases of human hepatocellular carcinoma. Oncology 2005;69 (Suppl 1):23–7. 14 Lee JS, Thorgeirsson SS. Genome-scale profiling of gene expression in hepatocellular carcinoma: classification, survival prediction, and identification of therapeutic targets. Gastroenterology 2004;127:S51–S55 15 Iizuka N, Oka M, Yamada-Okabe H, et al. Comparison of gene expression profiles between hepatitis B virus- and hepatitis C

virus-infected hepatocellular carcinoma by oligonucleotide microarray data on the basis of a supervised learning method. Cancer Res 2002;62:3939–44. 16 Höpfner M, Huether A, Sutter AP, et al. Blockade of IGF-1 receptor tyrosine kinase has antineoplastic effects in hepatocellular carcinoma cells. Biochem Pharmacol 2006;71:1435–48. 17 Lee JS, Chu IS, Mikaelyan A, et al. Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nat Genet 2004;36:1306–11. 18 Llovet JM, Di Bisceglie A, Bruix J, Kramer B, Lencioni R, Zhu A, Sherman M, Schwartz M, Lotze M, Talwalkar J, and Gores GJ on behalf of Panel of Experts in HCC. Design and end-points of clinical trials in HCC. J Natl Cancer Inst 2008;100:698–711.

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Viral-Based Therapies for Primary and Secondary Liver Cancer Menghua Dai, Lorena Gonzalez, and Yuman Fong Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Introduction Viral-based gene therapy represents a promising field with many novel strategies directed at malignancies. Evidence has been presented in the literature from as early as 1912 linking viruses to regression of cancer [1]. Several laboratories have now accumulated evidence of antitumor activity of various viruses against a myriad of cancers [2–4] and such therapies have reached human clinical testing. This chapter focuses on the use of viral vectors against liver tumors of primary and metastatic origin. We will describe major vector systems, anticancer strategies, and preclinical data supporting their use. We will also summarize the clinical investigations to date.

History of viral therapy The initial observation of the beneficial effect that viruses could have on cancer came in 1912, when DePace noted the regression of cervical carcinoma in patients who had received viral treatment (Pasteur’s treatment) for rabies [2]. By the 1950s, several viruses were being studied for their therapeutic effects, including adenovirus and Newcastle disease virus. In the middle of that decade, a National Cancer Institute (NCI) study examined treatment of 30 patients with locally advanced cervical cancer by intra-arterial or intratumoral injection of wild-type adenovirus [5]. As the immune reaction to adenovirus was thought to be a major obstacle to success of such therapy, patients were given a serotype of adenovirus for which they did not have antibodies. Furthermore, half of the study group received concomitant corticosteroid therapy for immunosuppression [5]. The study found “marked-to-moderate” response in two-thirds of all patients, including those receiving steroid therapy [5]. Also encouraging was the lack of major side effects, though a

subset of patients experienced a flu-like syndrome [5]. Virus was clearly the effector of treatment as there was no response when patients received heat-inactivated virus or supernatant of virally infected cells [5]. However, virotherapy was not attractive at the time due to several factors: (1) the effects were variable in vivo and unpredictable; (2) there was no way to direct the activity of the virus to tumor cells while sparing normal host cells; (3) it was difficult to make high titers of pure virus, and equally difficult to assay its biologic activity; and (4) there was the inherent and unpredictable danger of high-dose viral systemic therapy. The combination of these factors led to the abandonment of oncolytic viral therapy by 1960. Advancements in technology and our understanding of viral and tumor biology have led to renewed interest in viral-based therapies. It is now feasible to make high titers of purified viruses. The herpesvirus and adenovirus can be made in titers up to 109 and 1012 plaque-forming units (pfu)/ mL, respectively. Furthermore, the elucidation of viral genomes and specific gene functions combined with the advance of recombinant DNA technology has given researchers the ability to delete nonessential viral genes, at the same time allowing for insertion of potential therapeutic genes of interest.

Strategies for viral therapy There have been many approaches to the utilization of viral vectors for treatment of malignancy. The four main strategies under active investigation that have shown the most promise are: suicide gene prodrug therapy; tumor suppressor gene replacement; immunomodulation; and oncolytic therapy. The characteristics of these strategies are enumerated in Table 30.1.

Suicide gene prodrug therapy Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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In this therapy, a gene encoding for a metabolically active enzyme is transduced into a cancer cell [6]. The enzyme converts a benign prodrug into its active, toxic metabolite,

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Viral-Based Therapies for Primary and Secondary Liver Cancer

Table 30.1 Viral-based strategies targeting primary and metastatic liver cancer. Strategy

Gene delivered

Effect

Virus

Suicide gene prodrug therapy

Thymidine kinase, cytosine deaminase

Tumor suppressor gene replacement

Wild-type p53

Immunomodulation

GM-CSF, IL-2, IL-4, IL-12, IL-18, IL-24, IFN, TNF, TRAIL

Conversion of benign prodrug to active metabolite, leading to interruption of DNA and RNA pathways and to apoptosis Apoptosis, normalization of cell-cycle regulation Immune system upregulation, local cytokine induction, antiangiogenesis, creation of immune memory

Retrovirus Vaccinia Adenovirus Herpesvirus Retrovirus Adenovirus Retrovirus Vaccinia Newcastle disease virus Adenovirus Herpesvirus Retrovirus Reovirus Newcastle disease virus Adenovirus Herpesvirus

Oncolytic therapy

Lysis of tumor and propagation of virus

GM-CSF, granulocyte macrophage colony-stimulating factor; IL, interleukin; IFN, interferon; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosisinducing ligand.

causing death in the cells that have been transduced [7]. Often, the process also induces killing of nontransduced cells via a bystander effect [7–9]. Many hypotheses have been proposed to explain the physiology behind the bystander effect, which seems to be mediated by a cell–cell interaction through gap junctions. The attractiveness of the prodrug approach is that benign compounds can be delivered systemically to a patient and have good effect locally, without the systemic effects that would otherwise occur with general administration of the toxic metabolite. The two genes most often exploited encode for herpes simplex virus (HSV) thymidine kinase (tk) or cytosine deaminase (CD). Thymidine kinase allows a cell to phosphorylate ganciclovir (GCV) to the monophosphorylated state, which is then converted further by native cellular kinases into genotoxic triphosphates, which cause DNA chain termination and apoptosis [10]. Cytosine deaminase causes conversion of the inactive prodrug 5-fluorocytosine (5-FC) into the toxic metabolite 5-fluorouracil (5-FU), the chemotherapeutic agent with the longest record in treating colorectal cancer (CRC) metastases [7]. 5-FU is a pyrimidine analog and inhibits thymidylate synthase, in turn halting DNA synthesis and preventing replication.

Tumor suppressor gene replacement The most common tumor suppressor gene targeted by gene therapy to date is p53. Fifty to 70% of colorectal liver metastases and up to 60% of hepatocellular carcinomas (HCCs) have p53 mutations [11]. This gene normally serves several

functions: maintenance of genomic stability, prevention of tumor development and growth by entry into apoptosis, and surveillance for DNA damage. With loss of p53, cells with DNA damage do not enter cell cycle arrest or undergo apoptosis, which can then lead to oncogenesis in these defective cells [12]. Overexpression of mutated p53 may also result in oncogenesis. Replacement with a functioning p53 gene can suppress tumor growth and induce apoptosis [12].

Immunomodulation Immunotherapy involves stimulation of the host immune system to recognize normally nonimmunogenic tumors, thereby enhancing tumor cell killing. This is accomplished by provoking both specific and nonspecific immune responses. The most commonly studied strategy involves delivery of an immunostimulatory molecule, such as a chemokine, cytokine or costimulatory molecule, to enhance local immunomodulation at the tumor site.

Oncolytic therapy Viral oncolysis evolved due to observations of the ability of viruses to lyse tumors [5, 13]. Several effects are at work: the ability of viruses to lyse cells directly and, perhaps more importantly, the ability of viruses to infect, replicate within, and produce progeny virions. These daughter virus particles are then able to infect and kill other tumor cells. There are many benefits to using replication-competent viral vectors. The amount of virus required to achieve an effect is theoretically smaller compared with what is needed when delivering

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Table 30.2 Characteristics of viruses used for gene therapy of liver cancer. Characteristic

Retrovirus

Vaccinia virus

Newcastle disease virus

Adenovirus

Herpes simplex virus type 1

RNA/DNA Viral integration Efficiency of infection Viral titer production Transgene insert size Duration of transgene expression Level of transgene expression Target cells

RNA Genomic Low–moderate Moderate (105–108) ∼ 8 kb Long-term

DNA Episomal High High (107–109) ∼ 25 kb Transient

RNA Episomal Moderate High (109) N/A N/A

DNA Episomal High High (109–1012) ∼ 7.5 kb Transient

DNA Episomal High Moderate (107–109) ∼ 30–50 kb Transient

Moderate

High

N/A

High

High

Dividing

Dividing

Dividing/quiescent

Replication competence Risks

Incompetent

Competent or incompetent Immune response, fast effect

Dividing/some quiescent Replication competent Immune response

Dividing/some quiescent Competent or incompetent Systemic infection

Insertional mutagenesis, lymphoma with chronic administration

Replication competent Systemic infection, immune response

NA, not applicable.

a replication-incompetent vector. The effect will be of longer duration, theoretically continuing until there are no more tumor cells left to infect and lyse. Further, replicationcompetent viruses that can accommodate transgenes will be able to exert a more durable effect as well, upregulating the host immune system to join in antitumor activity. Of course, introducing any vector with the capability of latent infection demands that it be thoroughly tested for safety. Overall, the potential for replication-competent oncolytic viruses is very promising and exciting.

Viruses A number of viral vectors are under development for use in man as cancer therapy. The major classes of vectors are summarized in Table 30.2 and are discussed below.

Retroviruses Retroviruses are distinct from other viruses due to the presence of reverse transcriptase, which allows the viral RNA to form DNA, which is then incorporated into the host genome. This provides the benefit of long-lasting gene expression, though this is limited to proliferating cells only [14]. Genes of interest are inserted in place of the packaging genes gag, pol, and env, and these recombinant vectors are unable to replicate unless a packaging cell line is introduced to provide the missing genes [14]. The insert size is limited to 7–8 kilobases (kb) and historically these viruses have been produced

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in low titers of 105–107 pfu/mL. More recently, changes in production technique have produced titers up to 108 pfu/mL [15]. Importantly, retroviruses do not cause significant host immune response [16]. These replication-deficient retroviral vectors have been used in a variety of clinical trials evaluating treatment for malignant tumors [17, 18].

Suicide gene prodrug therapy A retroviral vector containing HSV-tk under control of an albumin promoter and given in combination with GCV has shown efficacy in treating murine HCC [19]. One study showed complete regression of HCC flank tumors with multiple injections of HSV-tk retrovirus, as well as production of tumor immunity up to 60 days after rechallenge [19]. The low immunogenicity of retroviral vectors facilitates repeat administration without decreasing efficacy, which is important given the relatively low transduction efficacy, with only up to 16% of HCC or CRC tumor cells expressing tk postinjection [15, 16]. A phase I trial in which 16 patients with various tumors received serial intratumoral injections of retroviral vectors with HSV-tk followed by GCV revealed minimal side effects due to the treatment [17].

Tumor suppressor gene replacement A retrovirus has also been used to transduce p53 using an alpha-fetoprotein (AFP) promoter, causing apoptosis and slower growth in vitro of AFP-producing HCC cells, as well as increased sensitivity to chemotherapy [20]. AFP is usually expressed in the fetus and does not persist after birth.

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Viral-Based Therapies for Primary and Secondary Liver Cancer

However, most HCCs express the protein, which is rarely found in normal or cirrhotic liver tissue. Given this overexpression of AFP, the promoters associated with it have been targeted for therapeutic aims. Several viruses have been designed which utilize AFP transcriptional regulatory elements in order to make an HCC-specific oncolytic virus.

[2, 24, 25]. Reovirus is attractive as a potential vector because it appears to replicate in tumor cells while sparing normal tissue, without any modification [25].

Oncolytic therapy

Immunomodulation has also been successful in a retrovirus with an albumin promoter and AFP enhancer targeting and increasing expression of a fused interleukin (IL)-2/interferon (IFN)-2b gene in HCC cells producing AFP [21]. Nude mice with AFP-producing HCC tumors showed increased cytokine production proportional to the amount of AFP expressed in the cell, along with significantly increased tumor cell kill [21]. Another recent experiment has shown the in vivo efficacy of combined gene therapy of HCC with two different Moloney murine leukemia virus (MoMLV)derived retroviral vectors containing HSV-tk and human IL (hIL)-2, where treatment with GCV led not only to complete regression of hepatic tumors composed of transduced cells but also resulted in regression of distant nontransduced tumors [22].

Reovirus replication in untransformed NIH3T3 cells is restricted by its own early viral transcripts activating the double-stranded protein kinase (PKR) [25]. The PKR in turn inhibits translation of the viral transcripts. Reovirus is allowed to replicate by the activated Ras signal pathway, which alters PKR, allowing viral protein synthesis to proceed [25, 26]. The Ras mutations occur in about 30% of all tumors, particularly in pancreatic, colorectal, and lung carcinomas [27]. An in vivo study in mice using a tumor cell line with activated Ras showed tumor regression in 80% of immunocompetent mice with a multiple dosing regimen [27]. Moreover, no recurrence was noted for the follow-up period of 6 months. Prior immunity did not seem to have an effect on tumor kill, though an immune response was noted. Human phase I/II trials are planned, including a trial for colon cancer [24]. These will address some of the questions about reovirus, including dose-related effects and the effect of route of administration.

Oncolytic therapy

Vaccinia

A recent development is the creation of a retrovirus vector which is replication competent and has demonstrated efficacious and stable gene transfer to murine tumors [23]. Within 9 days, at least 75% of flank tumors were transduced with a marker green fluorescent protein (GFP) gene, with little transduction of normal cells [23]. While this is promising, chronic retroviral infection has been previously shown to lead to aggressive lymphoma in primates, though this was not an issue in this study [14, 23]. Another safety issue which has not been completely addressed is the possibility of insertional mutagenesis. Finally, there is no treatment available for disseminated retroviral infections, and this is an even more pressing concern if the use of replicationcompetent vectors becomes a reality.

Vaccinia is a linear, double-stranded DNA virus, best known for its use as a smallpox vaccine [2]. The genome is approximately 200 kb, and can tolerate gene inserts of 25 kb in length without compromising tumor lysis [28]. Studies have shown efficacy of treatment with recombinant vaccinia viral oncolysate injection and there is evidence of upregulation of the immune system by vaccinia [28].

Immunomodulation

Thus, retroviral vectors have yielded some success in in vivo animal models using several approaches to tumor cell killing. A phase I trial has shown a limited toxicity due to virus, though there was little to no effect on tumor growth (Table 30.3) [17]. Retroviral vectors provide durable gene transfer and if safety issues are addressed, the potential of replication-competent vectors will be promising.

Reovirus Reovirus is a double-stranded, nonenveloped RNA virus. Infections in humans affect the respiratory and enteral tracts, and are generally mild [24, 25]. In fact, reovirus is ubiquitous in the environment and studies have shown that at least 50% of adults in the third decade are seropositive

Suicide gene prodrug therapy A tk-negative strain of vaccinia was developed with a CD gene insertion [29]. Administration of this vector to mice with CRC metastases showed uptake of the virus preferentially in tumor, and increased survival in animals treated with the vector followed by 5-FC [29]. Though the therapy showed benefit, the mechanism of infection has not yet been worked out [29]. More recently, the genome of the modified vaccinia virus Ankara (MVA), a highly attenuated vaccinia virus which has been previously used safely in humans as a smallpox vaccine, has been customized to include FCU1 [30]. This suicide gene encodes a bifunctional chimeric protein that combines the enzymatic activities of FCY1 and FUR1, genes found in fungi which catalyze the direct conversion of 5-FC into the toxic metabolite 5-FU. Though the virus itself is nonreplicating in mammalian cells, rapid replication of the viral DNA does occur after infection with MVA, resulting in large amounts of FCU1. This provides a solution for generating therapeutic concentrations of 5-FU locally, while avoiding excessive toxicity in normal tissues [30]. This resulted in significant tumor growth delay when

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given to animals with various types of subcutaneously injected human tumors.

Immunomodulation From past experience with its use as a smallpox vaccine, vaccinia is known to induce long-term immunity [2]. A phase I trial using recombinant vaccinia with a carcinoembryonic antigen (CEA) promoter (rV-CEA) as a vaccine to treat patients with CRC with liver metastases established that administration of the vector caused minimal toxicity (Table 30.3) [31]. Furthermore, animal models have shown regression of tumor. However, dosing for humans remains to be worked out. Other recent work with vaccinia has used the virus as a vector for the transduction of genes encoding cytokines (granulocyte macrophage colony-stimulating factor [GMCSF]) and tumor antigens (CEA, AFP, 5T4 [TroVax], etc) into tumor cells. Expression of these immunomodulators activated host immune activity, resulting in oncolytic and immunologic therapy for primary and secondary liver cancer [31–33]. An MVA virus carrying the gene for the tumor antigen 5T4 (TroVax) has also been used as a vaccine in a phase I clinical trial and has been evaluated in an open-label phase II study of patients with CRC metastases to the liver. Ten of 12 patients evaluated mounted 5T4-specific antibody responses, and six of eight presenting with elevated CEA levels showed a greater than 50% reduction after chemotherapy treatment combined with the vaccine. Six of the 19 treated patients had complete or partial responses, one had a complete response, and five showed stable disease. Therefore, not only were 5T4-specific immune responses detected, but these also correlated with clinical benefit (Table 30.3) [31, 33].

tion with the tumor cells and is then delivered to the patient [36]. Studies using this therapy have been completed for patients with melanoma, primary and metastatic breast cancer, and CRC metastases, with some success. NDV greatly enhances the body’s immune response against tumor cells via upregulation of macrophages, T lymphocytes, and a variety of cytokines, including tumor necrosis factor (TNF), IL-1, and IL-6 [2, 37]. Using the Ulster strain of NDV and the patients’ own tumor cells, a phase II trial of autologous vaccine for treatment of micrometastatic CRC of the liver showed a significant increase in recurrence-free interval, though there was no significant increase in survival at 18 months [38].

Oncolytic therapy Two strains of NDV have been used for the study of oncolysis: 73T and MTH68. However, little was known of the mechanisms by which oncolysis occurs until recent in vitro work determined that NDV acts as an oncolytic agent by both intrinsic and extrinsic caspase-dependent apoptotic pathways [39]. The 73T strain has shown efficacy in treating fibrosarcoma and neuroblastoma xenografts with a single injection [37]. More recently, murine in vivo models of colon cancer have shown regression of tumor with 73T [40]. The MTH68 strain, available commercially as a poultry vaccine, was administered in a phase III trial to a cohort of patients with various terminal cancers [34, 41]. Eighteen of the 33 patients responded to treatment with tumor regression or stabilization [41]. In particular, seven of the eight patients in the treatment group who had CRC metastatic to the liver survived to 1 year, compared with one of five control patients [41].

Adenovirus Newcastle disease virus Newcastle disease virus (NDV) is an avian paramyxovirus first isolated in chickens in 1927 [2, 34]. It is an enveloped RNA virus with a genome of approximately 16 kb, encoding for six proteins [34]. Though potentially lethal in poultry, this virus causes little harm to humans, e.g. mild conjunctivitis or laryngitis [2]. Recognition of the oncolytic potential of NDV came from a case report detailing a farmer with a gastric tumor who went into remission during an outbreak of NDV within his poultry stocks [35]. There are several strains of NDV, differing by point mutations in the viral genome. The strain with the greatest oncolytic function has been 73-T. The Ulster strain is efficacious in induction of host-organism immunity against NDV antigens expressed by infected tumor cells [35].

Immunomodulation NDV vaccine is created in vitro by incubating NDV with tumor cells, whether from a cell line or the patient’s own tumor cells. The oncolysate is harvested after 1 h of incuba-

356

Adenovirus is a double-stranded DNA virus prevalent in humans, with 55–80% of individuals carrying antibodies to it. Its ability to replicate in mammalian cells is exploited for clinical use. Furthermore, the virus is known to have low pathogenicity in humans, usually causing only the common cold [2]. Its genome is approximately 38-kb long [2], so genes up to 7.5 kb can be inserted into the genome. Replication is achieved by promoting entry of infected cells into the S phase. The hepatotropic nature of adenovirus renders it especially suited for treating liver cancer [42].

Suicide gene prodrug therapy Adenoviral vectors with HSV-tk have produced significant tumor cell kill when administered along with GCV, partly due to the bystander effect previously discussed [8]. However, significant hepatotoxicity has been observed from the adenovirus (Ad)-tk/GCV combination. Administration of intratumoral Ad-HSV-tk to humans followed by intravenous GCV resulted in transient elevation of serum

CHAPTER 30

Viral-Based Therapies for Primary and Secondary Liver Cancer

aminotransferase levels, fevers, thrombocytopenia, and leukopenia, and in one study, a single death reportedly not due to viral administration [43]. In an effort to minimize toxicity, Ad-tk vectors have been engineered with AFP promoters. Though the vector can still infect a variety of human hepatoma cells, GCV only causes lysis in AFP-positive cell lines, producing excellent in vitro and in vivo lysis of tumor. Adenoviral vectors with CD have also produced promising results. A murine model of CRC liver metastases treated with Ad-cytomegalovirus (CMV)-CD showed transduction of the CD gene to normal hepatocytes with subsequent tumor growth suppression after systemic administration of 5-FC [44], and minimal hepatotoxicity and mortality. Direct intratumoral injections of CRC metastases to the liver have also been studied in a phase I human trial.

Selectivity for malignant tumor cells was preserved by employing the AFP promoter [52].

Tumor suppressor gene replacement Intravenous infusion of Ad-p53 vectors in animal models has failed due to greater than 80% animal death before reaching titers necessary to transduce tumor cells [45]. However, local infusion via the hepatic artery has produced suppression of tumor growth and induction of apoptosis in tumor cells [46]. Subsequently, a phase I/II trial of hepatic artery infusion of Ad-CMV-p53 for CRC metastases performed in 2001 showed that the virus was well tolerated when administered directly intratumorally, intra-arterially or intravenously.

Immunomodulation Adenovirus has been successful in delivering IL-2 to HCC, and CRC metastases and lung metastases to the liver, with lasting immunity and tumor burden reduction [47]. IL-2 recruits CD4 and CD8 cells to tumors, upregulates natural killer cell activity in the liver, and induces CD8-dependent cytotoxic response to tumor [48]. An adenoviral vector with an AFP promoter for the IL-2 gene has achieved significantly lower toxicity without loss of efficacy [49]. Many other immunomodulators and human cytokines, such as IL-18, IL-24 and the TNF-related apoptosis-inducing ligand (TRAIL), have been investigated in conjunction with adenovirus as vector. IL-18 augments the cytotoxicity of T and natural killer (NK) cells and the proliferation of T cells, and stimulates T helper (Th) cells to produce IL-12 and IFN-γ, suggesting that it has potential for the treatment of cancer by inducing tumor-specific cellular immunity as well as activating NK cells in the host [50]. A recombinant adenovirus expressing human (h)IL-18 exhibited a significant antitumor effect in a Huh-7 human hepatoma-bearing mouse tumor model with a defect in T-cell function [51]. Lastly, TRAIL, a member of the TNF cytokine family, has also been shown to induce apoptosis. Conditionally replicative adenovirus (CRAd) bearing the TRAIL gene increases the oncolytic activity of HCC in vitro and in vivo via apoptosis.

Oncolytic therapy Three general approaches are used to engineer tumor-selective adenoviral replication [53]. One approach involves the E1A gene. The adenoviral genome contains genes in the E1A region which bind and inhibit the retinoblastoma tumor suppressor protein (Rb) as well as other transcription factors [53]. As a result, the transcription factor E2F is released, with entry into S phase and upregulation of DNA synthesis for both host and virus. Another strategy to achieve tumor specificity is the use of tumor- or tissuespecific promoters, such as AFP, human telomerase reverse transcriptase promoter (hTERT), and hypoxia response promoter, to drive adenoviral genes that are essential for replication. CNHK500 is a dual-regulated oncolytic adenovirus modified with dual promoters: hTERT drives expression of the E1A gene and the hypoxia response promoter controls expression of the E1B gene. Preclinical experimental results with this virus showed efficient tumor cell specificity with significant regression of HCC xenografts as well as prolonged survival [54]. A third way to induce tumor specificity is to delete genes that are required for replication of the virus in normal cells but not in tumor cells [20]. To provide tumor specificity, Barker and Berk genetically engineered dl1520, also known as Onyx-015 or CI-1042, an adenovirus with a deletion of the E1B-55K-encoding gene [55]. This gene is theorized to inhibit apoptosis by binding the cellular p53 tumor suppressor protein [20]. With this deletion, the virus would replicate only in cells that had defective p53 protein, or in tumor cells. Normal cells with normal p53, and therefore normal apoptotic pathways, would not support viral replication. Direct oncolysis is achieved by several mechanisms. Expression of the E1A early protein causes cell sensitization to TNF-mediated killing. There is also direct cytotoxicity from the late viral proteins, E311.6 adenovirus death protein and E4ORF4. Finally, there is cytolysis from infection of tumor cells with subsequent replication and lysis. This replication and lysis also cause upregulation of cell-mediated immunity [54]. A number of clinical trials have been conducted to evaluate the antitumor effect and safety of adenovirus dl1520, both as a single therapeutic agent and in combination with systemic chemotherapy (5-FU, leucovorin) [4, 56, 57]. The maximally tolerated dose or dose-limiting toxicities were not identified following intratumoral or hepatic artery infusion in these studies. With intratumoral treatments, the most common side effects were limited to flu-like symptoms. Transient elevation in transaminases resolved spontaneously after 2 days and the reported mortality rate attributable to treatment with virus was zero. A trial looking at intra-arterial administration of dl1520 in combination with

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358 Table 30.3 Clinical trials with viral-based therapies for liver cancer. Mutant virus

Trial

Tumor type

Dosing regimen

Route of administration

Toxicity (due to viral treatment)

Results

Source

Retrovirus

HSV-tk insert

Phase I n = 16

Various

2 × 106–1 × 107 pfu × 5 daily doses

Intratumoral

Injection site pain, swelling/ cellulitis

No regression of tumor

Singh et al (2001) [17]

Vaccinia virus

rV-CEA

Phase I n = 17

CRCM

2 × 105–1 × 107 pfu, 3 doses at 4-week intervals

Intradermal

No regression of tumor

McAneny et al (1996) [31]

MVA

Phase II n = 17

Encoding the tumor antigen 5T4 (TroVax)

5 × 108 pfu for first 2 weeks and weeks 11 and 17, 5-FU, folinic acid, oxaliplatin for first 2 weeks/4 weeks

Intramuscular

Pruritus, erythema (injection site), adenopathy, fevers/ sweats/chills, flu-like symptoms, pain, nausea/ vomiting Rigors/chills, myalgia, fever/ sweating, dizziness, disorientation, hallucinations, headache

6/11 CR or PR

Harrop et al (2007) [33]

(Ulster)

Phase I/II n = 16

HCC, CRCM

Autologous vaccine 1 dose

Intradermal

Transient temperature elevation

Schlag et al (1992) [38]

(MTH68)

Phase III n = 33

Various

4000 U twice weekly

Inhalation

Transient fever

Increase in recurrence-free interval without survival benefit Increased survival in CRCM patients

dl1520 (ONYX015)

Phase I n = 16

GILM

108–1011 pfu, multiple dosing

Intratumoral

dl1520 (ONYX015)

Phase I/II n = 16

HCC, CRCM

3 × 109–3 × 1011 pfu, 3 escalating daily doses; 3 daily doses of 3 × 1011 pfu, in combination with 5-FU

Intravenous, intrahepatic, arterial, intratumoral

Flu-like symptoms, coagulopathy, lymphopenia, LFT elevation, transient hypotension Mild fever, injection site pain, shivers, LFTs normal.

Newcastle disease virus

Adenovirus

Csatary et al (1993) [41]

Bergsland et al (1998) [91]

3/6 with 50% reduction in CEA; 6/7 with SD by CT; 1/7 with PD

Habib et al (2001) [92]

Emerging Therapies

Virus family

Virus family

Tumor type

Dosing regimen

Route of administration

Toxicity (due to viral treatment)

Results

Source

dl1520 (ONYX-015)

Phase II n = 27

GILM

3 × 1010 pfu on days 1 and 8, combined with 5-FU and leucovorin at day 22

Intrahepatic arterial

3/27 PR; 4/27 MR; 9/27 SD; 11/27 PD

Reid et al (2002) [57]

dl1520 (ONYX-015) dl1520 (ONYX-015)

Phase I n = 10 Phase II n = 19

HCC

3 × 1010 pfu

Intratumoral

Fever , chills, alkaline phosphate increase, AST, ALT increase, lymphopenia, bilirubinemia, hypochronic anemia, granulocytosis, asthenia Pain, fever, rigors

PR 1/5; PD 4/5

HCC

6 × 109–3 × 1010 pfu

Intratumoral

8/16 Reductions in tumor marker by >50% 1/16 PR; 12/16 SD

dl1520 (ONYX-015)

Phase I and II n = 34

2 × 1012 pfu

Intrahepatic arterial

CTL102

Phase I n = 17

Cholangiocarcinoma, gallbladder carcinoma HCC and CRCM CRCM

Hypotension, leukopenia, anemia, thrombocytopenia, fever, hepatic cytotoxity, hypotension, hypertension, atrial fibrillation Transient liver function abnormalities

Habib et al (2002) [56] Makower et al (2003) [93]

1 × 108–5 × 1011 pfu

Intratumoral

Local pain, pyrexia

Adv-RSV-tk

Phase I n = 16

CRCM

1 × 1010–1 × 1013 pfu

Intratumoral

Minimal transient increase of aminotransferase, transient fever, thrombocytopenia, leukopenia

Sung et al (2001) [43]

NV1020

Phase I n = 12

CRCM

3 × 106– 1 × 108 pfu

Hepatic artery

Transient rise in serum γ-glutamyltransferase diarrhea, leukocytosis

Kemeny et al (2006) [88]

7/17 SD

Au et al (2007) [94]

Dose-related increase of nitroreductase antibody in tumor tissue

Palmer et al (2004) [59]

HCC, hepatocellular carcinoma, CRCM, colorectal carcinoma liver metastases; GILM, gastrointestinal tumors with liver metastases; PR, partial response; MR, moderate response; SD, stable disease; PD, progressive disease; CEA, carcinoembryonic antigen; 5-FU, 5-fluorouracil; LFT, liver function test; HSV-tk, herpes simplex virus thymidine kinase.

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Viral-Based Therapies for Primary and Secondary Liver Cancer

Trial

CHAPTER 30

Herpesvirus

Mutant virus

SECTION 6

Emerging Therapies

chemotherapy reported reversible yet significant grade 3/4 hyperbilirubinemia in two patients and grade 4 dyspnea in one patient [23]. Response to single agent therapy with dl1520 was poor in patients with HCC or CRC metastasis, but significantly better if combined with chemotherapy, suggesting that adenoviruses are better suited for use in combination with chemotherapy (see Table 30.2). Although the side effects are mild to moderate in all clinical trials, safety remains an important issue when considering adenoviridae as potential vectors for gene therapy. This is secondary to an isolated yet infamous case at the University of Pennsylvania in 1999 where, within hours of hepatic arterial infusion with a replication-incompetent adenovirus, a patient developed thrombocytopenia, a severe coagulopathy, pyrexia, and jaundice. He expired within 3 days, succumbing to multiple organ failure and acute respiratory distress syndrome [3]. To date there is no consensus as to what caused the events that led to the patient’s death. In general, adenoviral vectors have been associated with relatively mild and self-limiting side effects, including transient flu-like symptoms, pain at injection site, mild left ventricular function changes, and a subclinical disseminated intravascular coagulation (DIC)-like state [3]. The DIC-like state is associated with Ad-p53 vectors and is manifested by small elevations in fibrin split products and the partial thromboplastin time, as well as by thrombocytopenia [3]. Reid et al determined that some side effects are associated and likely secondary to elevations of specific cytokines, specifically IL-6 and IL-10, which may lead to an acute inflammatory response [57]. Furthermore, other in vitro studies found that activation of complement may occur even at low doses of adenovirus (5 × 107 pfu) in clinical samples of subjects who had adenovirus antibodies present, independent of the transgene carried by the virus [24, 58]. A clinical trial of intratumoral injections of either primary or secondary (colorectal) hepatic tumors with the adenovirus vector CTL102 prior to undergoing surgical resection examined the safety and tolerability of the vector. This trial of 18 patients was not able to establish a dose-limiting toxicity (up to and including the maximum dose of 5 × 1011 virus particles), suggesting that direct intratumoral inoculation of CTL102 to patients with liver cancer is well tolerated [59]. The safety profile of adenoviral vectors continues to be elucidated.

Herpes simplex type 1 virus The herpes simplex type 1 virus (HSV-1) is a DNA virus which, like adenovirus, remains episomal post infection [2]. The genome is approximately 152-kb long, and of 84 characterized genes, only 45 are required for viral replication in cultured cells [60, 61]. In fact, 30–50 kb of genetic material can be inserted without compromising replication. The wildtype virus usually only causes cold sores. However, it can also produce keratoconjunctivitis and encephalitis [61]. HSV

360

can remain latent for years, residing in nerve ganglia. It is this neurotropism that initially drew researchers to the use of mutated HSV vectors for the treatment of central nervous system (CNS) tumors [13, 62]. There are several ways in which the HSV-1 virus has been used as a vector for gene therapy of hepatic tumors. For example, amplicons of HSV have been constructed to package and deliver transgenes [63]. In this case, the DNA is derived from HSV but is itself replication deficient. Amplicons can be delivered with or without “helper” virus; however, a packaging cell line is required [63]. Another subset of HSV vectors, called defective infection single-cycle HSVs (DISCs), are replication competent for one cycle of replication only, and can be used for short-term amplification of transgenes without long-term viral production [64]. Finally, mutated HSV can be used as an oncolytic vector, not only to kill tumor cells, but also to infect, replicate within, and subsequently produce progeny to infect and kill other surrounding tumor cells not infected initially. After successful initial work with CNS tumors [13], oncolytic HSV vectors have been used to treat experimental models of tumors of the stomach [65], pancreas [66], head and neck [67], gallbladder, and liver [68], etc. Notably, a significant amount of work has been done with HCC and CRC metastatic to the liver [64, 69].

Immunomodulation HSV amplicons Amplicons are replication-defective viral vectors, which are utilized as gene transfer vectors. Genes of interest are cloned into these bacteria-based plasmids, which have an origin of replication and cleavage/packing signals from HSV [63]. For HSV amplicons to be converted into infectious particles, they require a packaging cell line and “helper” viruses to produce the other viral elements, as previously mentioned. An HSV IL-2 amplicon has been used as a vaccine to confer antitumor immunity when transduced into irradiated tumor cells and injected into animal models [70, 71]. Not only can single amplicons have a good effect, but multiple amplicons can be used in the same site to deliver several genes with synergistic effect, as has been shown in a murine HCC model [72]. Delivery of an IL-12 amplicon and an IL-2 amplicon together produced stronger immunization than did either amplicon alone [72]. Use of an HSV IL-12 amplicon as neoadjuvant therapy for HCC in a murine model produced a significant reduction in postoperative recurrence [69]. Oncolytic herpesviruses have also been used as helper viruses for packaging amplicon vectors showing efficacy in experimental tumor models [71]. Furthermore, when combining multiple transgenes for infection with the use of an HSV amplicon, the effect is significantly increased. A preclinical experiment transferring the multiagents GM-CSF (cytokine), B7-1 (adhesion/costimulatory molecule), and RANTES (chemokine) with HSV amplicon into tumor cells produced a

CHAPTER 30

Viral-Based Therapies for Primary and Secondary Liver Cancer

Table 30.4 HSV-1 mutants investigated for oncolysis in primary and secondary liver cancers. Virus

tk

RR

ICP34.5

Dlsptk hrR3 rRp450

− + +

+ − −

+/+ +/+

R3616 G207 R7020 (NV1020) NV1023 NV1034

+ + + + +

+ − + + +

−/− −/− +/− +/− +/−

NV1042 NV1066

+ −

+ +

+/− +/+

Transgene

E. coli lacZ Rat P450 2B1 (CYP2B1)

E. coli lacZ HSV-2 Murine GM-CSF Murine IL-12 GFP

Reference Martuza et al (1991) [13] Goldstein et al (1988) [77] Pawlik et al (2000, 2002) [95, 96] Zhao et al (2001) [81] Chou et al (1990) [97] Mineta et al (1995) [82] Meignier et al (1989) [87] Wong et al (2001) [90] Wong et al (2001) [90] Malhotra et al (2007) [98] Wong et al (2001) [90] Adusumilli et al (2006) [99]

GM-CSF, granulocyte macrophage colony-stimulating factor; tk, thymidine kinase; HSV, herpes simplex virus; RR, ribonucleotide reductase; GFP, green fluorescent protein; IL, interleukin.

significantly stronger host immune response to tumor cells compared with single-agent therapy [73]. DISC is a herpes simplex type 2 virus (HSV-2) vector originally designed as a vaccine for genital herpes. DISCHSV lacks the essential glycoprotein H, thus limiting viral infection. DISC-HSV grown in a cell line that expresses glycoprotein H produces viral progeny that infect cells but are unable to initiate further infection. These viruses have also been used to deliver transgenes to upregulate tumor cell expression of various immunostimulatory molecules, thereby enhancing tumor immunogenicity and tumor cell kill [64]. DISC-HSV containing murine GM-CSF caused tumor regression in murine CRC flank tumors and yielded tumor immunity when rechallenged [64]. Human tumor cells harvested from patients have also been successfully transduced with the vector, with resultant secretion of GM-CSF by the host tumor cells [64]. This new gene therapy can be used to target tumor angiogenesis in hepatic malignancies. An HSV amplicon-mediated delivery of a hypoxiainducible soluble vascular endothelial growth factor (VEGF) receptor was found to substantially reduce new vessel formation and tumor growth in hepatoma flank tumor models in mice [74].

Oncolytic therapy HSV-1 is well suited for use as an oncolytic agent. The virus is able to infect a wide variety of tumor types and its life cycle is well described [75, 76]. Furthermore, the viral genome has been mapped out and the majority of the genes have been correlated to function [60]. With the development of recombinant gene technology, the genome can be manipulated to create selective deletions or alterations that

make safe and efficacious vectors (Table 30.4). As previously mentioned, there is room for up to 50 kb of genetic material to be placed within the HSV viral genome without compromising the ability of the virus to infect and replicate within tumor cells [60]. The major safety advantage of HSV compared with any of the other replication-competent viruses in use is the existence of antiviral drugs which can halt replication of HSV.

First-generation oncolytic herpesviruses Dlsptk The first generation of HSV mutants each contained a single gene deletion or mutation. The first virus used, dlsptk, contains a deletion of the gene encoding tk [13]. Thymidine kinase is required for viral replication; deletion of this enzyme results in viral dependence on host replication machinery [13, 60]. This virus can only replicate when the host cell tk gene is upregulated during its own replication. Thus, the virus replicates best in rapidly proliferating cells, such as tumor cells. This virus demonstrated excellent in vitro glioblastoma cell infection and oncolysis [13]. Yet with deletion of the tk locus, there was no safety mechanism to halt further replication of the virus if the infection became uncontrollable. Due to this and the toxicity associated with administration of this virus, there was little further study. hrR3 Derived from the HSV wild-type KOS strain, hrR3 targets another enzyme critical to viral replication. Ribonucleotide reductase (RR) is an enzyme required for DNA synthesis and replication of HSV [60, 77]. This enzyme is found in

361

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abundance in dividing cells, allowing an HSV mutant deficient in RR to replicate in this subpopulation. To render the gene inactive, an insertional mutation of Escherichia coli lacZ gene was placed into the UL39 region, which encodes for ICP6, the large subunit of RR [77]. lacZ is a marker gene encoding for β-galactosidase, a histochemically identifiable protein. Importantly, this HSV vector retained tk, allowing for antiviral therapy if needed [77]. A biodistribution study with radiolabeled virus injected into nontumorbearing rats showed viral uptake predominantly in the liver and spleen, with moderate uptake in the kidneys and minimal uptake at 12 h in the brain, lung, pancreas, and blood [78]. hrR3 preferentially infects colon carcinoma tumor cells and replicates well within them, while replicating poorly in normal hepatocytes, as expected since RR levels are much higher in the tumor cells. Intraportal delivery of hrR3 resulted in 95% infection of liver nodules in a murine model, with minimal infection of normal parenchyma [79]. However, when mice received a 75% hepatectomy, the regenerating liver cells were also infected with virus, raising the clinical question of timing of virus administration in relation to resection [80].

phamide [81]. Thus, the rRp450 virus can not only produce tumor cell kill by direct oncolysis, but can also activate alkylating metabolites. Ideally, the drug and its actions would only have an effect intratumorally. In vitro and rat model in vivo studies showed that the rRp450 virus in combination with cyclophosphamide enhanced tumor cell kill [81]. Further, the presence of cyclophosphamide did not inhibit viral replication [81].

Second-generation oncolytic herpesviruses The second-generation viruses are multimutated, making the possibility of reversion back to wild-type extraordinarily rare. Among the nonessential viral genes are two regions encoding for neurovirulence, and many of the second-generation viruses are deleted for one or both of the copies [60, 61]. This adds an important safety feature in this virus that otherwise normally has selective tropism for the CNS. Other genes which are variably deleted or altered are RR and tk. Like the first-generation oncolytic viruses, these vectors are replication conditional and are engineered to replicate in rapidly proliferating cells. The result of this is minimal toxicity to normal host tissue.

G207 G207 is an attenuated, multimutated virus derived from R3616. This virus was originally constructed for treatment of malignant CNS neoplasms, and was therefore designed to be non-neurovirulent [82]. Both copies of γ134.5 are deleted, and as with hrR3, an insertional mutation of E. coli lacZ gene has been inserted into the UL39 region, which encodes for ICP6 [82]. The tk is retained, rendering the virus sensitive to GCV and acyclovir, for control of overwhelming infection [82]. Further, the virus was shown to be temperature sensitive, with poor replication at temperatures of 39.5 °C or higher [82]. Thus, a patient with fever or encephalitis would not support further replication of G207. The combination of these mutations provides the final safety factor for G207; it would be highly unlikely for all of the mutations to revert to wild-type at one time. G207 is active against human CRC metastases as well, both in vitro and in animal models. The distribution of virus in in vivo models of hepatic CRC metastases showed virus to be only in the liver in the metastatic model, and scarcely present in the normal liver parenchyma. Furthermore, by 24 h, no virus was detectable by polymerase chain reaction (PCR) in any organ but the liver [82]. Therefore, multimutated oncolytic virus G207 preferentially infects, replicates within, and lyses human CRC cells in an in vivo model [82]. Replication, and thereby amplification of tumor lysis, are dependent on cell cycle and doubling time. The animal models also showed that intratumoral or intravenous injection of virus is safe and effective [82]. In addition, when AFP-regulated RR is driven by an AFP-alb enhancer–promoter complex or a CEA enhancer–promoter (CEA E-P), the cytotoxicity and specificity of G207 in AFP-producing HCC cells and CRC is improved [83].

rRp450 This virus is derived from the hrR3 virus, and contains two mutations. The large subunit of RR is again rendered dysfunctional, but in this virus, a significant portion of the ICP6 coding region is deleted instead of simply disrupted with lacZ [81]. It was felt that this conferred an extra measure of safety by further decreasing the possibility of reversion to wild-type. The second mutation is an insertion into the viral genome of rat P450 2B1 (CYP2B1) transgene, which encodes an enzyme that activates prodrugs, particularly cyclophos-

Oncolysis with immunomodulation. G207 shows greater efficacy when combined with other vectors and chemotherapy or radiotherapy. The combined, intrasplenic injection of G207 and the HSV-IL-2 amplicon into mice with HCC or CRC metastases was more efficacious than either therapy alone, and the effect was T-cell mediated [84]. With this combination therapy, smaller doses of each may be used clinically, maintaining the overall beneficial effect while decreasing the potential for toxicity from either vector. G207 synergizes with floxuridine (FUDR), which upregulates RR in tumor

Though the single mutation viruses showed some efficacy in treating liver cancers, they were quickly abandoned for fear that the single-site mutations could revert back to wildtype in one step. This was admittedly a rare possibility, but a possibility nonetheless.

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cells, providing a complement for the lack of viral RR. A similar synergy was observed between G207 and radiation [85], possibly due to an increase in RR levels following external beam radiation. Given the neurotropism of the wild-type herpesvirus, safety has always been a primary concern in the use of oncolytic mutant herpesviruses. Initial studies established safety of intracerebral inoculations [86]. However, a maximum tolerated dose was not reached due to the inability to concentrate higher titers of virus in small enough volumes for intracerebral inoculation. The same study established safety of intrahepatic injections of 3 × 107 pfu in mice, which survived over 10 weeks compared with no survivors among those receiving injections of 1 × 106 pfu of HSV wild-type strain KOS. Multiple studies have examined organs by PCR and found little to no virus outside peritumoral areas. G207 is currently being tested in phase I and II clinical trials for neurologic malignancies. No clinical trials of G207 to treat hepatic malignancies have been performed to date. NV1020 NV1020, also known as R7020, was originally constructed with the intent of creating a vaccine to HSV-1 and -2 [87]. The virus is constructed on the backbone of HSV-1 with an HSV-2 insert, containing several glycoproteins and a copy of tk. NV1020 has shown efficacy in both in vitro and in vivo models against HCC and CRC metastases. A phase I, openlabel, dose-escalating study was performed to prove that NV1020, a genetically engineered but replication-competent HSV-1 oncolytic virus, can be safely administered into the hepatic artery without significant effects on normal liver function [88]. Oncolysis with immunomodulation. NV1034 and NV1042 each contain cytokine gene inserts and the viruses generate their effects by a combination of oncolysis and immune modulation. NV1034 contains the gene for murine GM-CSF and NV1042 contains the gene encoding murine IL-12 [89]. In this way, not only is there tumor lysis, but there can potentially also be systemic and specific tumor immunity. NV1034 has shown equivalent or better oncolytic properties against head and neck cancers [90]. Similar results have been achieved for CRC and HCC. NV1042 therapy combined with local immune stimulation with IL-12 offers effective control of parent hepatic tumors and also protects against microscopic residual disease after resection. Results of this preclinical study support potential clinical relevance for the virus, both as a primary treatment for patients with unresectable tumors and as a neoadjuvant strategy for reducing recurrence after resection [1]. These viral vectors take the next step of modulating the immune system while providing tumor lysis.

Viral-Based Therapies for Primary and Secondary Liver Cancer

Conclusion The large number of patients whose tumors are unresectable or who are failing conventional therapies for liver cancers continues to grow. Gene therapy presents alternatives to treating these tumors; the data become stronger with every study. Replication-competent oncolytic viruses hold particular promise for achieving tumor kill with small initial doses of virus which can then propagate to an amount necessary to further lyse tumor cells. These replication-competent viruses can also provide prolonged immune upregulation with transgene delivery, such as the insertion of GM-CSF into the herpes vector. Though certain safety issues and regulatory obstacles remain, the efficacy of viral vectors in treating liver cancers is clear in animal models and continues to be elucidated in preclinical and clinical trials. Furthermore, there is a growing body of evidence that viral vectors may be synergistic with conventional chemotherapy or radiotherapy. Future directions of research will involve elucidating the mechanisms of interaction between viruses and these modalities, and working out the proper dose, route, and timing of administration.

Self-assessment questions 1 When was the notion that viruses possess oncolytic properties first established? A In 1912 when DePace noted the regression of cervical carcinoma in patients who had received viral treatment for rabies B In 1950 when farmers had regression of squamous cell carcinoma after a Newcastle disease virus outbreak in their poultry stocks C In 1981 when Bluming and Ziegler reported remissions of Burkitt and Hodgkin lymphomas following natural infections with measles virus D In 1940 when the National Cancer Institute performed a clinical study employing wild-type virus 2 Which one of the following is not a strategy employed in viral therapy of cancer? A Transgene expression B Oncolytic therapy C Immunomodulation D Methylation of viral genome E Suicide gene prodrug therapy 3 With which one of the following viruses have clinical trials not been conducted? A Myxoma virus B Vaccinia virus

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Herpes virus Newcastle disease virus Reovirus Adenovirus A and F A and E

4 Regarding Newcastle disease virus (NDV), which one of the following statements is true? A NDV upregulates natural killer cells, macrophages, and both B and T lymphocytes in humans B NDV causes a mild conjunctivitis and laryngitis in humans while being lethal to poultry C While all poultry in the United States are vaccinated against NDV, there is no treatment for the virus in humans D A, B and C E B and C 5 Regarding oncolytic herpesviruses, which one of the following statements is true? A First-generation viruses easily revert back to the wild-type strain B First-generation viruses contain a single gene deletion or mutation while second-generation viruses are multimutated C The oncolytic herpes viral genome has regions encoding for neurovirulence, which are essential for viral proliferation D B and C

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94 Au T, Thorne S, Korn WN, Sze D, Kirn D, Reid TR. Minimal hepatic toxicity of Onyx-015: spatial restriction of coxsackie adenoviral receptor in normal liver. Cancer Gene Ther 2002; 14:139–50. 95 Pawlik TM, Nakamura H, Yoon SS, et al. Oncolysis of diffuse hepatocellular carcinoma by intravascular administration of a replication-competent, genetically engineered herpesvirus Cancer Res 2000;60:2790–5. 96 Pawlik TM, Nakamura H, Mullen JT, et al. Prodrug bioactivation and oncolysis of diffuse liver metastases by a herpes simplex virus 1 mutant that expresses the CYP2B1 transgene. Cancer 2002;95:1171–81. 97 Chou J, Kern ER, Whitley RJ, Roizman B. Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nonessential for growth in culture. Science 1990;250:1262–6. 98 Malhotra S, Kim T, Zager J, et al. Use of an oncolytic virus secreting GM-CSF as combined oncolytic and immunotherapy for

treatment of colorectal and hepatic adenocarcinomas. Surgery 2007;141:520–9. 99 Adusumilli PS, Stiles BM, Chan M-K, et al. Real-time diagnostic imaging of tumors and metastases by use of a replication-competent herpes vector to facilitate minimally invasive oncological surgery. FASEB J 2006;20:726–8.

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Signaling Pathways and Rationale for Molecular Therapies in Hepatocellular Carcinoma Augusto Villanueva1, Clara Alsinet1, and Josep M. Llovet2 1 HCC Translational Research Lab, Barcelona-Clinic Liver Cancer (BCLC) Group, IDIBAPS, CIBEREHD, Liver Unit, Hospital Clínic, Barcelona, Spain 2 Liver Cancer Program (Division of Liver Diseases), Mount Sinai School of Medicine, New York, NY, USA, and HCC Translational Research Lab, Barcelona-Clinic Liver Cancer (BCLC) Group, IDIBAPS, CIBEREHD, Liver Unit, Hospital Clínic, Barcelona, Spain

Introduction Hepatocellular carcinoma (HCC) is a global health problem and it is the leading cause of death among cirrhotic patients [1], being the sixth most common cancer worldwide with 626 000 new cases every year. In some Western countries, its incidence has doubled in the past four decades, increasing the attention it receives in the medical and scientific communities. The most relevant factor involved in the increase in the HCC incidence is associated with hepatitis C viral (HCV) infection [2]. HCC is considered a neoplasm with a dismal prognosis, and only 40% of patients are eligible for potential curative treatment at the time of presentation [3]. However, with the advent of surveillance programs, a switch in the type of tumors has been detected, as well as the medical interventions potentially effective for them. In the future, most newly diagnosed HCC probably will be in early stages [4] (Figure 31.1) that are suitable for effective treatment with potentially curative therapies (i.e. resection, transplantation, and percutaneous ablation) [3, 5]. Since genetic aberrations tend to accumulate during tumor progression, it seems reasonable that early tumors will be less genetically polymorphic and hence, easier to target with molecular therapies. Nevertheless, and due to the current high prevalence of advanced tumors, new therapeutic approaches are urgently needed. Systemic therapies, such as traditional chemotherapy, have been extensively evaluated in HCC [6]. No robust single phase III randomized clinical trial (RCT) has shown any of the traditional agents studied (e.g. tamoxifen, immu-

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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notherapy, systemic chemotherapy, etc [6]) to increase survival. Indeed, some therapeutic regimens have shown unacceptable rates of toxicity. Recently, a phase III trial with a combination chemotherapeutic regimen (cisplatin, interferon-α2b, doxorubicin, and fluorouracil; PIAF regimen) versus doxorubicin has shown rates of treatment-related death close to 10%. As will be discussed below, HCC is very heterogenic from a molecular perspective [7]. Unlike most other human malignancies, HCC usually develops in the context of inflammation and organ injury. This high molecular variability, added to the number of different etiologies responsible for liver damage (e.g. viral hepatitis, alcohol, etc), precludes any simplistic approach to understand the molecular pathogenesis of this disease. In order to move towards so-called personalized medicine, identification of the activation of specific pathways on an individual basis is required. It is hoped that by clarifying the genomics and signaling pathways implicated in human hepatocarcinogenesis, new therapeutic targets will be uncovered in order to tackle this devastating disease [7].

Molecular pathogenesis of hepatocellular carcinoma During the preneoplastic stage of human hepatocarcinogenesis, there is an upregulation of mitogenic pathways, leading to the selection of certain clones of dysplastic cells. These clones, organized as dysplastic nodules and surrounded by fibrous septa of connective tissue, may acquire a malignant phenotype after undergoing different genomic alterations [8]. Multiple genetic alterations that activate oncogenes or disrupt tumor suppressor genes are thought to accompany the observed histologic changes, yet the precise molecular mechanisms involved in this process are not fully understood (Table 31.1). Notably, different combinations of

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HCC

Stage 0 PST 0, Child–Pugh class A

Very early stage (O) Single < 2 cm Carcinoma in situ

Stage A–C Okuda 1–2, PST 0–2, Child–Pugh class A and B

Early stage (A) Single or 3 nodules < 3 cm, PS 0

Intermediate stage (B) Multinodular, PS 0

Stage D Okuda 3, PST > 2, Child–Pugh class C

Advanced stage (C) Portal invasion, N1, M1, PS 1–2

Terminal stage (D)

1980–1990 Early HCC Curative treatments: 5–10% 1990–2010 Early HCC Curative treatments: 30–40%

2010–2015 Early HCC Curative treatments: 50–60% Figure 31.1 Changes in the clinical spectrum of hepatocellular carcinoma (HCC). In the last three decades, and due to the establishment of surveillance programs, the number of patients diagnosed with early HCC has increased significantly. Predictions suggest that this trend will continue during the next 20 years. Since genetic aberrations tend to accumulate during tumor progression, it can be assumed that early tumors will be less polymorphic in terms of molecular pathogenesis and hence, easier to target with molecular therapies. The top part of the panel shows the different HCC stages according to the BCLC (Barcelona Clinic Liver Cancer) classification. (Adapted from Llovet & Bruix et al [51], with permission.)

genetic alterations are often observed among different individuals, and sometimes even within different nodules arising in the same individual [9]. Thus, an important goal is to classify HCC into subgroups based on the observed spectrum of genetic alterations, and to determine the treatment modalities that are most effective for each subgroup. Probably, dysregulation of certain pathways is specific for each tumor and accounts for cell proliferation and survival (i.e. Wnt-ß-catenin, IGF/Akt/mTOR, etc). Identification of these pathways is pivotal to allowing the classification of patients based on molecular data. In addition, there may be other genomic disturbances common to different tumors, such as cell-cycle checkpoint inactivation, limitless replicative potential, angiogenesis, and metastasis (Figure 31.2).

Genetic alterations: DNA copy number changes and point mutations In HCC, genetic alterations can range from point mutations in individual genes to the gain or loss of entire chromosomal arms. Several candidate genes in hepatocarcinogenesis emerged from surveys of genetic alterations, including c-Myc (8q), cyclin A2 (4q), cyclin D1 (11q), Rb1 (13q), AXIN1 (16p), p53 (17p), IGFR-II/M6PR (6q), p16 (9p), E-cadherin (16q),

SOCS (16p), and PTEN (10q) [7]. The most frequently mutated genes in HCC include p53, PIK3CA, and ß-catenin, although mutation prevalence varies depending on etiology. Dozens of studies have investigated chromosomal alterations in HCC using comparative genomic hybridization (CGH), as reviewed by Moinzadeh et al [10]. Genes in regions of chromosomal gain with increased expression levels are more likely to represent oncogenes, while genes in regions of chromosome loss with decreased expression probably represent tumor suppressor genes. The most frequently affected chromosome arm is 1q, with rates of amplification ranging between 58% and 78% in HCC. Other chromosome arms commonly altered with amplifications include 6p, 8q, 17q, and 20q, and with deletions include 4q, 8p, 13q, 16q, and 17p. The majority of the reports include patients with hepatitis B virus (HBV)-related liver disease, but associations between chromosomal alterations and etiology of the underlying liver disease have been inconsistent [11]. The application of more sophisticated technologies (e.g. bacterial artificial chromosome [BAC] array comparative genomic hybridization [CGH] studies, single nucleotide polymorphism [SNP] array, etc) to assess copy number

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Table 31.1 Genomic alterations in hepatocellular carcinoma (HCC). (Adapted from Llovet & Bruix [50].) Function

Gene

Genomic alteration

Growth factors and receptors

IGF-2 IGF-2R (M6PR) EGF EGFR TGF-α k-Ras RASSF1 PIK3CA PTEN Akt mTOR HGF/c-MET

Overexpression LOH, decrease in copy number Overexpression Overexpression, infrequently mutated Overexpression Mutated in 11% of HCC (associated with vinyl chloride exposure) Downregulation, aberrant methylation Variable mutation rate (0–35%) Mutations (< 10%), downregulation, aberrant methylation Activated by phosphorylation (Ser 473) Overexpression Overexpression

Cell differentiation

ß-Catenin E-cadherin Sonic Hedgehog Gli

Variables mutation rate (0–44%), frequent nuclear translocation Downregulation, aberrant methylation Overexpression Overexpression

Angiogenesis

VEGFA VEGF-2R Angiopoietin-2

Overexpression, high gain amplifications Overexpression Overexpression

Metastasis

MMP-9 Topoisomerase 2A Osteopontin

Overexpression Overexpression Overexpression

Cell cycle

Rb Cyclin D1 p53 p16 p27kip Survivin Gankyrin

High level amplification, overexpression Variable mutation rate (0–67%) Downregulation, aberrant methylation Downregulation Overexpression Overexpression

LOH, loss of heterozygosity; IGF, insulin-like growth factor; IGFR, insulin-like growth factor receptor; TGF-α, transforming growth factor-α; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; HGF, hepatocyte growth factor; VEGFA, vascular endothelial growth factor A; VEGFR, vascular endothelial growth factor receptor; MMP-9, matrix metalloproteinase 9.

changes in HCC specimens confirm the initial findings obtained with CGH. Recurrent high-level amplification at 11q13 was reported in three studies at a combined frequency of 5% [12]. This evolutionarily conserved locus contains several genes in the Wnt-ß-catenin and mitogenactivated protein kinase (MAPK) pathways. Several other high-level amplifications have been reported in individual tumors, yet none of them has been replicated in multiple studies. The potential predictive power of genetic alterations regarding other clinical parameters like prognosis, recurrence after surgery, and tumor stage remains unclear. In a meta-analysis including 785 patients [10], there was a significant correlation between several high-frequency genomic imbalances and tumor grade (loss of 4q and 13q), as well as

370

HBV infection (loss of 4q, 8p, 13q, and 16q). Similarly, additional studies reported significant associations with stage (gain of 1q, 3q, and 7q), tumor size (loss of 8p and gain of 8q), and vascular invasion (gain of 1q, 6q, and 17q, and loss of 11q). However, two recently published studies failed to show any correlation between CGH data and clinicopathologic features [13, 14]. This discrepancy may arise from the multifactorial and heterogeneous contributions of genetic alterations to clinicopathologic variables. The genes that have been most comprehensively studied for mutations in HCC are p53 and ß-catenin. In HCC, the rate of p53 mutations is variable and ranges from 0% to 67% [7]. Indeed, there are remarkable differences in the mutation rate depending on the geographic area: higher rates have been documented in West Africa and South-East Asia and

CHAPTER 31

Molecular alterations specific to each subclass

Signaling Pathways and Rationale for Molecular Therapies in Hepatocellular Carcinoma

Wnt-b-catenin (proliferation and differentiation)

Tyrosine kinase receptor (proliferation)

IFN response (immunomodulation)

Others (gains in Chr7, TGF-β, etc)

Inactivation of checkpoints (p53, RB, CCND) Molecular alterations common to different tumors

Replicative potential (TERT)

Angiogenesis (VEGF, angiopoietin, PDGFR)

Metastasis (osteopontin, MMPs)

Figure 31.2 Implication of genomic alterations in the molecular pathogenesis of hepatocellular carcinoma (HCC). Activation analysis of specific signaling pathways allows HCC classification into different molecular subgroups. In addition, there are common alterations in almost all tumors that have limitless replicative potential resulting from activation of telomerase reverse transcriptase (TERT), neoangiogenesis, insensitivity to antigrowth signals, and checkpoint disruption, and metastasis. TGF-β, transforming growth factor-β; MMP, matrix metalloproteinase; VEGF, vascular endothelial growth factor; PDGFR, platelet-derived growth factor receptor. (Adapted from Llovet & Bruix [50], with permission.)

lower rates in Western countries. This difference is tightly correlated to aflatoxin B exposure. The p53 G-to-T mutation at the third position of codon 249 is the target for this carcinogen. In Western countries where aflatoxin B exposure is not endemic, high mutation rates of p53 are seen only in patients with hemochromatosis-related HCC. In addition, findings from a European cohort of 42 patients showed significant differences in median survival after surgery when patients were clustered according to p53 mutations. On the other hand, the mutation rate of CTNNB1 in HCC ranges from 0% to 44%, and these mutations are mostly located in exon 3 of the CTNNB1 gene, the phosphorylation site for glycogen synthase kinase 3 beta (GSK3B). Mutations of genes transcribing other components of the Wnt pathway also have been described, including AXIN1 and AXIN2, and several extracellular inhibitors of Wnt signaling [7].

Gene expression dysregulation Gene expression profiles obtained from studies using highthroughput technologies (e.g. oligonucleotide gene expression microarray) have revolutionized the approach to human malignancies, including HCC. These technologies allow the simultaneous analysis of thousands of transcripts that cover the entire genome. The application of clustering algorithms to the dysregulated genes permits the classification of samples on the basis of expression profiles. These

clusters (i.e. gene signatures) can be used for diagnostic purposes, as well as to assess response to treatment and to predict survival in several types of tumors [15]. Several clinical staging systems have been proposed to predict HCC prognosis but only the Barcelona Clinic Liver Cancer (BCLC) staging system has gained wide recognition among scientific communities [16, 17]. It, however, does not incorporate biologic information from the tumor. Considerable efforts have been made to obtain a molecular classification of HCC, most of them based on gene expression microarrays. Initial studies compared gene expression between HCC and nontumoral tissue, and were later improved by gene expression analysis of the whole hepatocarcinogenic process (including cirrhotic tissue and preneoplastic lesions [4]). Ye et al studied 67 primary and metastatic HCC by an unsupervised hierarchical clustering algorithm interrogating 9180 genes [18]. They found that primary metastasis-free HCC had a gene expression profile markedly different from that of primary HCC with metastatic lesions, as well as differences in patient survival. The 153-gene model provided a robust signature that correctly classified 100% of the training samples during cross-validation. All these data implied that genes favoring metastasis progression are initiated in the primary tumors, and the authors argued that primary HCC with metastatic potential may be evolutionarily distinct from metastasis-free primary HCC.

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Furthermore, stringent analysis of expression data unleashed osteopontin as a relevant mediator in metastatic HCC. Similarly, another study using high-density oligonucleotide microarray reported a 12-gene signature able to predict early intrahepatic HCC recurrence with an accuracy of 93% [19]. Subsequently, and using a different technology (adaptor-tagged competitive polymerase chain reaction [PCR]), Kurokawa et al studied gene expression in 60 HCC patients [20]. The authors selected a 20-gene signature out of 92 candidate genes able to predict early recurrence (<2 years). The recurrence signature (“poor signature”) was validated in an independent cohort of 40 patients with a predictive accuracy close to 73%. In 2004, Lee et al analyzed global gene expression patterns in 91 HCC to define the molecular characteristics of HCC, and to test the prognostic value of expression profiles [21]. Unsupervised hierarchic clustering revealed two classes of HCC patients characterized by significant differences in survival. After supervised analysis, the authors found 406 genes whose expression was significantly informative of length of survival. Expression of typical cell proliferation markers was greater in Child class A. Data reported in this study did not exclude the possibility that different mechanisms were primarily responsible for the two molecularly different types of tumors, referred to as the “etiologic footprint” by the authors. This was further explored in a second study where they tested if global gene expression analysis of human HCC would identify subtypes of HCC derived from different cell lineages (hepatocytes and hepatic progenitor cells [22]). They uncovered a new subclass of HCC (“hepatoblast signature, HB”) when HCC genomic data were compared with data from fetal hepatoblasts. This signature was independently associated with both recurrence and worse survival, and was enriched in Jun and Fos activity. The HB signature also displayed markers of hepatic progenitor cells (KRT7, KRT19, and VIM). Whether this signature is a consequence of malignant transformation of mature hepatocytes with dedifferentiation remains unclear. Finally, a recent study identified five different molecular classes after interrogating gene expression in 91 HCV-related HCC [23]. Among them, activation of Wnt and upregulation of pathways involved in cellular proliferation were the most robust clusters.

Signal transduction pathways Despite the important data gathered in the last decade from genomic studies, our understanding of the molecular pathogenesis of HCC is still very elementary. An integrative analysis of genomic alterations and their functional repercussion in cell biology is needed. In fact, an understanding of the complexity of the signal transduction pathways, as well as their relevance in normal and malignant cells, will enable the identification of key regulators in cancer, with farreaching implications for the potential development of

372

molecular-targeted therapies. We will briefly discuss some of the most relevant signaling pathways in human HCC (Figure 31.3).

Wnt-ß-catenin pathway The Wnt pathway, which has a fundamental role in embryogenesis, has been implicated in liver tumorigenesis. In normal cells, ß-catenin associates with E-cadherin at the cell membrane, linking E-cadherin to the cytoskeleton. The signaling cascade is normally initiated extracellularly, when enough Wnt ligands accumulate to outnumber the secreted Wnt antagonists, stimulating relay of the message via the transmembrane receptor, Frizzled (FZD). FZD signals to ßcatenin to escape its association with E-cadherin. In addition, certain cytoplasmic elements of the Wnt pathway, once activated via FZD, prevent ß-catenin from being phosphorylated by a degradation complex made up of a serinethreonine kinase (GSK3B) and a protein scaffold (Axin and adenomatosis polyposis coli [APC]). Normally, when the Wnt pathway is not activated, cytoplasmic ß-catenin is marked for degradation by proteosomes. However, mutations in these proteins can allow ß-catenin to escape into the nucleus and to promote transcription of its target genes in a constitutive manner. Nuclear localization of ß-catenin is considered a hallmark of its oncogenicity. Immunohistologic studies have demonstrated abnormal cytoplasmic and nuclear accumulation of ß-catenin in 17–40% of human HCCs [7].

Hedgehog pathway The Hedgehog signaling pathway is also fundamental to cell differentiation, regeneration, and stem cell biology, and more specifically plays a leading role in the development and homeostasis of gut tissue. The structure of the pathway resembles Wnt signaling. There are three potential ligands: Indian, Sonic, and Desert Hedgehog, although the former is the predominant isoform in the liver. In the absence of ligand activation, the receptor Patched (Ptc) exerts an inhibitory effect on Smoothened (Smo), a transmembrane homolog of G-couple receptors that in combination with Cos-2 impairs nuclear translocation of Gli. Similarly to ßcatenin, after ligand stimuli, Gli accumulates inside the nucleus and induces transcription of genes related to the cell cycle and growth. The role of Hedgehog signaling in human malignancies is well established [24]. Recent studies have identified a possible role for this pathway in HCC: one study documents expression of Sonic Hedgehog in 60% of 115 human HCC samples with downregulation of Gli-related target genes after specific blockade of the pathway. Moreover, tumorigenic activation of Smo can mediate c-Myc overexpression, which plays an important role in hepatocarcinogenesis. All these data suggest that Hedgehog signaling may become a relevant molecular-based target in HCC treatment [7].

CHAPTER 31

Signaling Pathways and Rationale for Molecular Therapies in Hepatocellular Carcinoma

Cetuximab Bevacizumab

VEGF

EGF c-Kit

IGF-1R

A12

PDGFR

Cediranib

XL-228

Sorafenib

Lapatinib Erlotinib

VEGFR

FGFR

EGFR

Cell membrane

Her2/neu

Gefitinib

Brivanib

Sunitinib

AEE788 Ras/MAPK pathway

Ras

PI3K/Akt/mTOR pathway

PTEN

Raf

Sorafenib

PI3K

XL-765 Akt

Mek Rapamycin Erk

Everolimus

Mdm2

mTOR

FKHR

Bad

Proliferation, apoptosis, protein synthesis and cell cycle Cell differentiation β-catenin

ICG-001

Wnt/β-catenin pathway

Gli Hedgehog pathway

Frizzle receptor

Smo

XL-0984

Ptc

Cell membrane

Wnt ligand

Hh ligand

Figure 31.3 Signaling pathways and molecular target therapies in hepatocellular carcinoma (HCC). The most relevant pathways in human hepatocarcinogenesis are summarized, as well as the blockade strategies used to specifically target these pathways in experimental models of HCC, as well as in clinical trials. EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor; IGF-1R, insulin-like growth factor 1 receptor; MAPK, mitogen-activated protein kinase; Ptc, patched; SMO, smoothened. (Adapted from Villanueva et al [4], with permission from Wolters Kluwer Health.)

Growth factor-dependent pathways (EGF, IGF and c-MET signaling) The epidermal growth factor receptor (EGFR) is a member of a family of related receptors (Her2/Neu, ErbB3, and ErbB4) that upon ligand binding trigger tyrosine kinase activity and consequently initiate signal transduction. Overexpression of EGFR in some malignancies was the rationale for the development of specific EGFR antagonists, some of which have already gained approval for use in clinical practice (e.g. erlotinib in nonsmall cell lung cancer, and cetuximab in metastatic colorectal cancer). Moreover, EGFR mutations were significantly correlated with response to some of these blockers, which reinforced the relevance of pathway addiction [25] in molecular-targeted therapies. Her2/ neu is another important molecule in human cancer since

trastuzumab, a monoclonal antibody against Her2/neu, has shown antineoplastic activity in some types of breast cancer [26]. In HCC, data regarding EGFR dysregulation are scarce and inconsistent, ranging from 4% to 53% [7]. Moreover, Her2/neu overexpression and EGFR mutations are uncommon events in HCC. In HCC, erlotinib has shown activity both in preclinical and clinical studies. In vitro studies with HCC cell lines using erlotinib alone or in combination with chemotherapy showed a significant inhibition of cell proliferation and an increase in apoptosis [27]. Further studies have shown similar antitumoral activity of another EGFR inhibitor (cetuximab) in experimental models of HCC [28]. Transforming growth factor-α (TGF-α), one of the eight potential ligands of EGFR, is active in the initiation, promotion, and progression of experimental HCC, and likely con-

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tributes to hepatocarcinogenesis via autocrine, paracrine, and “juxtacrine” mechanisms. TGF-α promotes neoangiogenesis, tumor cell survival, and proliferation indirectly via the induction of vascular endothelial growth factor (VEGF). Inhibition of TGF-α via anti-EGF-receptor antibody reduces VEGF expression in epithelial tumor lines and results in diminished tumor growth and tumor-related angiogenesis after implantation in mice [7]. Insulin-like growth factor (IGF) signaling has a major role in the regulation of fetal development, proliferation, differentiation, cell growth, and apoptosis. Studies have shown paradoxical effects of IGF-binding proteins under different conditions, which increases the difficulty of dissecting this signaling pathway. IGF-2 can bind both IGF-1 receptor (IGF1R) and IGF-2R, but its affinity for IGF-1R is significantly lower than that of IGF-1. IGF-2 gene expression is increased in multiple malignancies, including HCC. Nardone et al [29] reported that the pattern of IGF-2 expression differs according to its active promoters. Variants active in the fetus are upregulated in HCC compared with surrounding tissue, whereas the variant present in adults remains stable. Interestingly, IGF-2R has no tyrosine kinase activity, so its action consists of binding and degrading IGF-2, and hence, it acts as a tumor suppressor gene. These data are consistent with the frequent chromosomal deletions described at the IGF-2R locus (6q). Hepatocyte growth factor (HGF) is a potent molecule in hepatocyte regeneration after injury. In this setting, it is secreted by stellate cells and exerts its actions by binding to c-MET. Over-expression of c-MET and HGF are both common events in HCC [30]. Unfortunately, reports of the correlation between their expression and clinical features are contradictory. Some reports show correlation with poor prognosis [31], whereas others fail to find such associations [30].

PI3K/Akt/mTOR pathway The oncogenic capacity of PI3KCA mutations is well established in human cancer. In HCC, currently there are only two studies that have investigated mutations in PIK3CA, with contradictory results (mutation rate ranging from 0% to 35% [7]). Also, the precise role of Akt in HCC is still uncertain; however, recent studies suggest that the presence of phosphorylated Akt in resected HCCs predicts poor patient outcome [32]. Loss of heterozygosity in 10q (location of PTEN, a well-known tumor suppressor gene) is frequently encountered in HCC and several studies have analyzed the role of PTEN in HCC. The published frequency of PTEN mutation is fairly low in HCC in contrast to other malignancies, ranging from 0% to 11%. Similar to other cancers, epigenetic mechanisms may account for the inactivation of PTEN (methylation of CpG islands). An important mediator of the phosphoinositid-3-kinase (PI3K)/Akt pathway is mTOR (mammalian target of rapamycin), which acts as a central regulator of cell growth and proliferation, sensing

374

nutritional status and allowing progression from G1 to S phase. Sahin et al reported that the mTOR pathway is upregulated in a subset of HCCs [33], and another study demonstrated that its blockage with rapamycin inhibits growth in HCC cell lines [34]. This molecule has special relevance in HCC because mTOR inhibitors (rapamycin and analogs) are already approved as antirejection therapies in liver transplantation.

Molecular-targeted therapies: a novel approach in the management of hepatocellular carcinoma Evaluation of candidate drugs in preclinical settings Similarly to other human cancers, HCC lacks robust and reproducible experimental models to evaluate new therapies in preclinical settings. The molecular complexity of HCC warrants activation of numerous oncogenic pathways. Hence, genetically-engineered animals need to carry several molecular hits to resemble what happens in human liver cancer. Also, HCC frequently arises in a previously damaged organ, so animal models need to recapitulate not only the tumoral disease, but also the cirrhotic background [35]. All these drawbacks have made obtaining an accurate animal model of HCC a major challenge. Xenografts have demonstrated several advantages, which explain their persistence as the mainstay of preclinical models testing antineoplastic drugs in vivo: the tumors are rapidly induced and easy to measure. However, new models are emerging to test new drugs, such as orthotopic implantation of intact fragments of human cancer taken directly from a patient into the corresponding organ of immunodeficient rodents, or the implantation of murine cancer cell lines into immunocompetent mice with underlying liver fibrosis. Ideally, the best model to test new drugs would be geneticallyengineered mice recapitulating specific pathway abnormalities (i.e. double transgenic TGF/c-Myc, transgenic for platelet-derived growth factor receptor [PDGFR], transgenic for β-catenin, etc) in animals with an underlying fibrotic milieu. Unfortunately, preclinical drug efficacy does not always correlate with efficacy in clinical trials. This fact may be influenced by several variables: degree of heterogeneity of tumors in humans versus in cell lines, molecular aberrations of the cell line chosen, ectopic versus orthotopic location of tumor, dosage, and scheduling of the compounds, and variability in selected endpoints. However, the greatest discrepancies between success of cancer therapies in xenograft models and in human clinical trials are likely due to critical differences in the microenvironment; this is particularly relevant to HCC [36], which arises in an environment of inflammation, regeneration, and fibrosis.

CHAPTER 31

Signaling Pathways and Rationale for Molecular Therapies in Hepatocellular Carcinoma

New paradigm in clinical trial design in hepatocellular carcinoma In modern oncology, the benefits of treatments should be assessed through RCTs and meta-analysis. Other sources of evidence, such as nonrandomized clinical trials or observational studies, are considered less robust. The increasing number of clinical trials ongoing in HCC has prompted the need for a common framework to test novel drugs. As a consequence, a multidisciplinary panel of experts has reported new guidelines on the design of clinical trials and endpoints in HCC [17]. The introduction of biologic agents as therapeutic options in oncology has changed the traditional paradigm to measure the antitumoral effect of new agents in the clinical trial scenario. In HCC, survival and time to recurrence are proposed as primary endpoints for phase III studies assessing primary and adjuvant therapies, respectively [17]. Composite endpoints, such as disease-free survival or progression-free survival, are vulnerable in HCC research, particularly when the target population is ill-defined, and should mostly be tested as secondary endpoints. Randomized phase II studies are considered pivotal prior to conducting phase III trials in HCC, with time to progression as the recommended endpoint, and overall survival and safety as the secondary endpoints. Phase II studies consider response rate as the surrogate for efficacy. However, clinically significant survival advan-

BCLC 0-A (early HCC)

Standard of care

First line

tages have been reported with tumor responses less than 10% [37]. Thus, response rate is formally discouraged as a reliable endpoint to capture benefit of molecular drugs in phase II studies. This represents a major change in the paradigm of design of clinical trials in HCC. Time to progression has been endorsed as the most reliable time-to-event endpoint in phase II studies. In order to minimize undesirable events as a result of the natural history of cirrhosis that might lead to death due to bleeding, hepatorenal syndrome, infections, and other complications, selection of Child–Pugh class A patients as the target population was recommended for these studies. By selecting this population, it is expected that more than 90% of deaths in the first 2 years will be due to tumor progression. The control arm for clinical trials should be the standard of care, i.e. chemoembolization for intermediate HCCs and sorafenib for advanced cases. Therefore, for the assessment of first-line systemic treatments for advanced HCC, a design adding a new agent to sorafenib versus sorafenib alone is recommended. Comparison of single agents head to head with standard of care therapy might jeopardize the recruitment of patients for ethical reasons, unless the novel agent has shown very promising efficacy in early phase II studies (Figure 31.4). Finally, studies testing molecular-targeted therapies should include the analysis of tissue and/or serum biomarkers, aiming to identify molecular markers of response.

BCLC B (intermediate HCC)

BCLC C (advanced HCC)

Resection, transplantation, percutaneous ablation

Chemoembolization (TACE)

Sorafenib

Adjuvant

Primary treatment

Primary treatment

Placebo

versus

Drug

TACE

versus

TACE + drug/device

Sorafenib

versus

Sorafenib + drug

In case phase II findings were very promising TACE

Second line

versus

Drug/device

Sorafenib

versus

Drug

Placebo

versus

Drug

Figure 31.4 Clinical trial design in hepatocellular carcinoma (HCC). Patients with HCC in stage BCLC (Barcelona Clinic Liver Cancer) 0 or A should be evaluated for adjuvant therapies after curative treatments (resection, transplantation or percutaneous ablation). These trials should be designed to capture differences between the drugs evaluated versus placebo, since to date, no agent has been approved as an adjuvant therapy in human HCC. Patients in stage BCLC B or C should participate in trials evaluating the standard of care in each stage (i.e. transarterial chemoembolization [TACE] in BCLC B and sorafenib in BCLC C) versus a combination of the standard of care plus the drug/device evaluated. Exceptionally, if the drug/device shows very promising results in phase II trials, a face-to-face comparison with the standard of care could be considered.

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Targeting signal transduction pathways in hepatocellular carcinoma We will discuss in some depth the molecular therapies already tested within phase II and III clinical trials in HCC (Table 31.2 [38–45]). Most of the treatments aim to block signaling pathways related to proliferation and cell survival. Other treatments rely on the blockade of growth factors and signals related to dissemination of the disease (e.g. angiogenesis, telomerase activation, etc).

Tyrosine kinase inhibitors Most of the agents currently under investigation block membranous tyrosine kinase receptors (TKRs). Effective blockade of EGF signaling can be achieved by the use of monoclonal antibodies against EGFR (cetuximab) or ErbB2/Her2/neu (trastuzumab). Cetuximab is Food and Drug Administration (FDA)-approved for the treatment of colorectal cancer, and trastuzumab for overexpressing-Her2/neu metastatic breast cancer. Alternatively, pathway activation can also be successfully inhibited with small molecules against the catalytic domain of EGFR, like erlotinib or gefitinib. Also, lapatinib is a small molecule that is able to block at the same time EGFR and Her2/neu. Erlotinib is active in advanced stages of nonsmall cell lung cancer. As previously discussed, erlotinib has shown preclinical activity in HCC. Regarding clinical trials, Philip et al published clinical findings with erlotinib in 38 patients with intermediate and advanced HCC [42]: 47% of their subjects had been treated with at least one prior systemic regimen; 39% had extrahepatic metastases. Although responses were infrequent, disease-control rates were significant (59% combined response and stability); 6-month progression-free survival was seen in 32% of patients (12 of 38). Using a similar design, Thomas et al published a phase II trial with erlotinib in 40 HCC patients and reported similar findings to the previous study: absence of objective responses and median survival of 25 weeks [43]. An ongoing clinical trial is evaluating the role of combination therapy with erlotinib plus bevacizumab (monoclonal antibody against VEGF). Although Her2/neu overexpression and EGFR mutations are uncommon events in HCC, there are some encouraging preliminary data with dual receptor blockade (EGFR and Her2/neu) in experimental models of HCC, and the combination is under evaluation in phase II clinical trials (lapatinib). A phase II trial analyzing imatinib (PDGFR and c-Kit inhibitor) in HCC did not show encouraging results, although the sample size was very small (n = 17) and insufficient to allow any robust conclusions. Interestingly, none of the patients included in this trial was positive for c-Kit and only one was positive for PDGFR [39]. It remains unclear whether a more carefully selected patient population (e.g. one enriched in patients with tumors harboring activated forms of c-Kit or PDGFR) would translate into a better outcome.

376

mTOR inhibitors Between 25% and 45% of patients with HCC have activation of the mTOR pathway as assessed by immunohistochemical analysis of phosphorylated Akt or mTOR [33]. This activation may be the result of increased signaling due to overexpression of ligands (i.e. EGF and IGF-2), mutations in key genes of the pathway (PI3KCA, PTEN, etc) or methylation of promoter regions of tumor suppressor genes (PTEN). As discussed previously, Akt activation promotes cell survival through different molecules, mTOR being one of the most relevant. Rapamycin is a well-known inhibitor of mTOR activity and has shown antineoplastic activity in vitro in HCC [46]. Since rapamycin is approved as an immunosuppressant in liver transplant patients, there is a scientific rationale for using it as first-line antirejection therapy in the setting of liver transplantation for HCC. However, this hypothesis has not been tested extensively and there is a need for specific trials to address this issue. Preclinical studies with other analogs of rapamycin (i.e. everolimus, temsirolimus) have shown encouraging results [47].

Inhibitors of angiogenesis HCC is a notoriously hypervascular malignancy. This is seen even in early stages of the disease, when tumor size is less than 2 cm. In fact, the high sensitivity of modern imaging techniques, such as magnetic resonance imaging, is based on this characteristic, allowing accurate diagnosis of small HCC lesions (1–2 cm) in 33% of patients. Accordingly, overexpression of proangiogenic factors like VEGF, PDGF, and angiopoietin 2 has been demonstrated in HCC; indeed, some reports suggest a prognostic value of plasma levels of VEGF. This provides the rationale for the use of antiangiogenic therapies in HCC, by means of monoclonal antibodies (bevacizumab) or small molecules (sunitinib, sorafenib). Bevacizumab is a humanized monoclonal antibody against VEGF approved for the treatment of liver metastasis of colorectal and breast cancer. A phase II trial with this compound in HCC revealed modest antitumoral activity (10% objective response), with almost 60% of patients showing stable disease for more than 4 months. However, five of 33 patients included in the treatment arm in this trial had significant adverse effects; among these, there were two treatmentrelated deaths due to gastrointestinal bleeding. Recently, another phase II trial evaluating antiangiogenic therapy has shown modest antitumoral activity when combining bevacizumab with gemcitabine plus oxaliplatin. Of note, 30% of the patients had grade 3 hypertension and leukopenia [43]. There are other VEGFR inhibitors currently under evaluation: sunitinib and BMS-582664 are both in phase II trials. Sunitinib is a multikinase inhibitor recently granted accelerated FDA approval for renal cancer after its promising results in clinical trials. In HCC, two studies have analyzed two different dosages of sunitinib, and preliminary data suggest

Table 31.2 Molecular targeted therapies tested in phase II/III clinical trials in hepatocellular carcinoma. Treatment arms

n

Child class A (%)

Stage

Partial response (%)

Llovet et al (2007) [41]

III

Sorafenib Placebo

299 303

Gish et al (2007) [31]

III

Nolatrexed Doxorubicin

222 223

75 73

67% Karnofsky ≥ 90%, 70% CLIP ≤ 2 62% Karnofsky ≥ 90%, 70% CLIP ≤ 2

Thomas et al (2007) [43]

II

Erlotinib

40

75

95% PS ≤ 1, 62% CLIP ≤ 2

ND

42*

Zhu et al (2006) [44]

II

Gemcitabine, oxaliplatin and bevacizumab

33

ND

ECOG ≤ 1, CLIP ≤ 3

18

24

Eckel et al (2005) [39]

II

Imatinib

17

77

77% Karnofsky ≥ 80%, 30% CLIP ≤ 2

0

Zhu et al (2007) [45]

II

Cetuximab

30

60

Median ECOG 0, 83% CLIP ≤ 2

0

Philip et al (2005) [42]

II

Erlotinib

38

71

89% PS ≤ 1

Abou-Alfa et al (2006) [38]

II

Sorafenib

137

72

50% ECOG 0, 34% TNM < IV

Stable disease (%)

Median survival (weeks)

2.3 0.7

42.8 31.6

1.4 4

22.3 32.3

2.2

Comments

25

Patients stratified according to EGFR status (IHC of total EGFR)

33

12

One tumor was positive for PDGFR and none was positive for c-kit

17

38.4

Patients studied for EGFR status (IHC of total EGFR). No correlation between EGFR expression and clinical efficacy

59*

52

Patients studied for EGFR status (IHC of total EGFR). Correlations between EGFR status and response could not be explored

46

36.8

Significant differences in time to progression according to p-ERK staining status

*Disease control: partial response + stable disease CLIP, Cancer of the Liver Italian Program; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; PDGFR, platelet-derived growth factor receptor. 377

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Phase

CHAPTER 31

Authors

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induced impairment of liver function in patients receiving the highest dosage (50 mg/day).

Molecular therapies approved in hepatocellular carcinoma Sorafenib is an oral multikinase inhibitor with activity against several tyrosine kinases (VEGF-2R, PDGFR, c-Kit receptors) and serine/threonine kinases (b-Raf, p38). This drug targets two of the main pathways involved in hepatocarcinogenesis by blocking angiogenesis (VEGF-2R and PDGFR) and cell proliferation through Ras/MAPK signaling (b-Raf). Preclinical studies showed antitumoral activity in xenograft models of HCC [48]. Subsequently, a phase II clinical trial involving 137 patients with advanced HCC showed that sorafenib induced stable disease for 4 months in 35% of patients, with an overall median survival of 9.7 months. Partial response rate was less than 10%. Interestingly, patients with activation of the Ras/MAPK pathway, as measured by the presence of p-ERK immunostaining, had a time to progression of 178 days versus 46 days in those with no activation of the pathway [38]. A randomized phase III double-blind placebo-controlled clinical trial conducted in patients with advanced HCC treated with sorafenib has shown improvement in survival of 3 months in patients with advanced HCC, which was not only statistically significant, but also clinically meaningful [41]. The median overall survival was 10.7 months with sorafenib and 7.9 months with placebo (hazard ratio for death, 0.69; 95% CI, 0.55–0.87; p < 0.001). Median time to progression was 5.5 months with sorafenib versus 2.8 months with placebo (hazard ratio 0.58; 95%; 95% CI, 0.45–0.74; p < 0.001; Figure 31.5). These hazard ratios are among the lowest values when compared to several molecular targeted

Since the Wnt pathway is activated in at least 30% of HCCs [49], it would make an appealing target for blockade; however, no drugs are yet available that effectively block its activation without significant side effects. Molecular targets within the pathway are multiple, including Wnt ligands and Frizzled receptors. Preclinical studies show some activity of ICG-001, a small molecule that interferes with the interaction of ß-catenin and TATA-binding protein (TBP)-like factor (TLF). There are also interesting preclinical data with drugs that inhibit proteasome activation. Results of a phase II trial with bortezomib, which is approved for multiple

(b) Sorafenib Median: 46.3 weeks (10.7 months) Placebo Median: 34.4 weeks (7.9 months)

1.00 Survival probability

Other molecular agents

0.75

0.50

0.25

0

0

8

16

24

32 40 Weeks

48

56

64

Hazard ratio: 0.69 (95% CI: 0.55–0.87) p = 0.00058

72

80

1.00 Probability of progression

(a)

therapies in other malignancies, which reflects this drug’s considerable magnitude of effect in terms of improving survival (Table 31.3). Seven patients (2.3%) in the sorafenib group and two patients (0.7%) in the placebo group achieved a partial response. Diarrhea, weight loss, hand–foot skin reaction, and hypophosphatemia were more frequent with sorafenib. The results of this RCT represent a breakthrough in the management of this complex disease: sorafenib is the first systemic therapy to prolong survival in HCC and, consequently, is the new reference standard treatment of patients with advanced HCC. Sorafenib has been approved both by the FDA and European Medicines Agency (EMEA) for the treatment of HCC. It will soon be assessed in the adjuvant setting after potentially curative treatments, such as resection or local ablation, in combination with chemoembolization for intermediate HCC, and with other molecular targeted therapies in advanced cases. As previously explained, since sorafenib is the new standard of care in advanced HCC, it should also constitute the control arm of clinical trials targeting this population.

0.75

0.50

Sorafenib Median: 24.0 weeks (5.5 months) Placebo Median: 12.3 weeks (2.8 months)

0.25

0

0

6

12

18

24

30

36

42

48

54

Weeks Hazard ratio: 0.58 (95% CI: 0.45–0.74) p = 0.000007

Figure 31.5 Kaplan–Meier figures of (a) survival and (b) time to progression in the SHARP trial (phase III trial of sorafenib versus placebo in advanced hepatocellular carcinoma [HCC]). This is the first phase III clinical trial to demonstrate significant differences in survival and time to progression with a systemic agent in patients with advanced HCC. (Reproduced from Llovet et al [41], with permission from the Massachusetts Medical Society.)

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Table 31.3 Comparison of antineoplastic activity (hazard ratio) between different molecular targeted therapies in human malignancies. (Adapted from Llovet & Bruix [50].) Cancer

Molecular therapy evaluated

Primary endpoint

Hazard ratio (95% CI)

Hepatocellular carcinoma

Sorafenib

Survival

0.69 (0.55–0.86)

Colorectal cancer (metastatic)

IFL + bevacizumab Cetuximab

Survival Survival

0.66 (N/A) 0.77 (0.64–0.92)

Nonsmall cell lung cancer

Paclitaxel + carboplatin + bevacizumab Erlotinib

Survival Survival

0.79 (0.69–0.93) 0.70 (0.58–0.85)

Renal cancer

Temsirolimus Sunitinib Sorafenib

Survival Progression-free survival Progression-free survival

0.73 (0.58–0.92) 0.42 (0.32–0.54) 0.44 (0.35–0.55)

Breast cancer

Paclitaxel + trastuzumab Chemotherapy + trastuzumab Paclitaxel + bevacizumab Capecitabine + lapatinib

Disease-free survival Time to progression Progression-free survival Time to progression

0.48 0.51 0.60 0.49

Head and neck

Radiotherapy + cetuximab

Time to progression

0.68 (0.52–0.89)

(0.39–0.59) (0.41–0.63) (0.51–0.7) (0.34–0.71)

IFL, irinotecan plus fluorouracil/leucovorin.

myeloma, are encouraging. Finally, telomerase, thought to be essential in cancer cell immortality, may also be considered a potential target in HCC; there are some ongoing studies in phase II applying telomerase reverse transcriptase (TERT) immunization.

Future research The encouraging positive results of the multikinase inhibitor sorafenib represent a first step towards curative treatment for HCC. The molecular complexity of HCC warrants further studies that combine therapies targeting enriched populations, which is a natural approach to more personalized medicine. Identification of drug responders in HCC is far from an achieved goal, and should represent a priority for future clinical and translational research. In order to move the field forward we need to improve our understanding of the pathogenesis of liver cancer, design experimental models able to recapitulate known hepatocarcinogenic aberrations in humans, and improve the design of trials to capture the benefits of molecular therapies in well-characterized populations [50].

Self-assessment questions 1 Which one of the following signaling pathways has not been described as frequently dysregulated in hepatocellular carcinoma?

A B C D E

Wnt-ß-catenin PI3K/Akt/mTOR IGF signaling Ras/MAPK Toll-like signaling

2 Which one of the following statements is true regarding the role of xenografts in hepatocellular carcinoma research? A Tumor growth in xenografts is difficult to monitor B Xenografts usually require long periods to develop tumors C Subcutaneous xenografts do not allow investigation of the role of fibrosis in hepatocarcinogenesis D Xenograft models allow an accurate evaluation of the inflammatory response of the host to the implanted tumoral cells E Xenografts are rarely used in drug development research 3 Different molecular targeted therapies have been tested in clinical trials in human hepatocellular carcinoma. However, which of the following drugs is the only one to have demonstrated clear benefits in terms of patient survival? A Erlotinib B Sorafenib C Cetuximab D Bevacizumab E Bortezomib

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4 In clinical trial design, what should be the design of a phase III clinical trial evaluating a new compound as first-line treatment of patients with advanced hepatocellular carcinoma (stage C of the BCLC classification)? A Sorafenib versus sorafenib plus new drug B Placebo versus new drug C Doxorubicin versus new drug D Transarterial chemoembolization versus new drug E None of the above 5 Which of the following are frequent adverse effects of sorafenib in patients with hepatocellular carcinoma? (more than one answer is possible) A Diarrhea B Hand–foot syndrome C Myocardial infarction D Liver dysfunction E Weight loss

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for growth control of hepatocellular cancer. Biochem Pharmacol 2005;70:1568–78. Nardone G, Romano M, Calabro A, et al. Activation of fetal promoters of insulinlike growth factors II gene in hepatitis C virus-related chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Hepatology 1996;23:1304–12. Boix L, Rosa JL, Ventura F, et al. c-met mRNA overexpression in human hepatocellular carcinoma. Hepatology 1994;19:88–91. Ueki T, Fujimoto J, Suzuki T, Yamamoto H, Okamoto E. Expression of hepatocyte growth factor and its receptor, the c-met proto-oncogene, in hepatocellular carcinoma. Hepatology 1997;25:619–23. Schmitz KJ, Wohlschlaeger J, Lang H, et al. Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection. J Hepatol 2008; 48:83–90. Sahin F, Kannangai R, Adegbola O, Wang J, Su G, Torbenson M. mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 2004;10:8421–5. Schumacher G, Oidtmann M, Rueggeberg A, et al. Sirolimus inhibits growth of human hepatoma cells alone or combined with tacrolimus, while tacrolimus promotes cell growth. World J Gastroenterol 2005;11:1420–5. Newell P, Villanueva A, Friedman SL, Koike K, Llovet JM. Experimental models of hepatocellular carcinoma. J Hepatol 2008;48:858–79. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 2006;6:674–87. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271–81. Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006;24:4293–300. Eckel F, von Delius S, Mayr M, et al. Pharmacokinetic and clinical phase II trial of imatinib in patients with impaired liver function and advanced hepatocellular carcinoma. Oncology 2005;69:363–71. Gish RG, Porta C, Lazar L, et al. Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol 2007;25:3069–75.

41 Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–90. 42 Philip PA, Mahoney MR, Allmer C, et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 2005;23:6657–63. 43 Thomas MB, Chadha R, Glover K, et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer 2007;110:1059–67. 44 Zhu AX, Blaszkowsky LS, Ryan DP, et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006;24:1898–903. 45 Zhu AX, Stuart K, Blaszkowsky LS, et al. Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer 2007;110:581–9. 46 Sieghart W, Fuereder T, Schmid K, et al. Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation. Transplantation 2007; 83:425–32. 47 Villanueva A, Chiang D, Newell P, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 2008; 135:1972–83. 48 Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004;64:7099–109. 49 Boyault S, Rickman DS, de Reynies A, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 2007;45:42–52. 50 Llovet J, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology 2008;48:1312–27. 51 Llovet JM, Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol 2008;48 (Suppl 1): S20–37.

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Novel Therapies Targeted at Signal Transduction in Liver Tumors Fidel D. Huitzil-Melendez1, Ghassan K. Abou-Alfa2, and Michael A. Morse3 1 Departamento de Hematología y Oncología, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, Mexico, D. F. Mexico 2 Department of Medicine, Division of Gastrointestinal Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 3 Department of Medicine – Oncology, Duke University School of Medicine, Durham, NC, USA

Introduction Normal cell proliferation, differentiation, and apoptosis depend on the transfer of information from outside the cell to the nucleus where it ultimately impacts gene expression. This process involves a complex network that comprises growth factors, cell surface receptors, and their associated downstream signal transduction pathways, and under normal conditions is highly regulated. In pathologic conditions, dysregulation of any of the components of this network can occur, leading to neoplastic transformation [1]. Nowadays, specific sites and mechanisms of dysregulation have been identified for a wide spectrum of human cancers, opening the window of opportunity for targeted therapies [2]. Since the last edition of this chapter, the body of evidence showing that dysregulation of these signal transduction pathways is implicated in liver neoplastic cell growth and survival has grown [3]. It is now evident that signal transduction pathways offer the potential for therapeutic targeting at multiple levels in liver cancer: extracellular signaling, membrane receptors, and intracellular pathways. Furthermore, therapeutic targeting of signal transduction for hepatocellular carcinoma (HCC) has become a reality and, for the first time, a systemic agent, sorafenib, has clearly demonstrated survival improvement in patients with advanced HCC [4]. Not surprisingly, interest in the molecular pathways implicated in pathogenesis of HCC, and therefore, of therapeutic potential, has been renewed. This chapter aims to provide a clear understanding of the signal transduction process in liver tumors, emphasizing clinical evidence linking dysregulation of a particular pathway with the development of liver cancer. The potential therapeutic benefit of targeting

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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abnormal pathways will be discussed, and if available, results of targeted therapy will also be reviewed.

Receptor tyrosine kinase in hepatocellular carcinoma Dysregulation of receptor tyrosine kinases (RTKs) by mutation, gene rearrangement, gene amplification, and overexpression of both receptor and ligand has been implicated as a causative factor in the development and progression of numerous human cancers. Therapies directed against these targets have shown benefit in other neoplasms. Here, we examine promising data relevant to dysregulation of RTKs in HCC and the potential for targeted intervention.

Epidermal growth factor receptor The epidermal growth factor receptor (EGFR) is a member of a proto-oncogene family of receptors. Ligand binding to EGFR results in receptor dimerization and autophosphorylation of several tyrosine residues. These phosphorylated residues act as docking sites for cytoplasmic proteins that undergo conformational modifications during the interaction and ultimately result in the initiation of intracellular signaling through potentially several different pathways, including the signal transducers and activators of transcription (STAT), phospholipase C, phosphoinositid-3-kinase (PI3K)/protein kinase B (Akt), Src, and mitogen-activated protein kinase (MAPK) [5]. The MAPK and Akt pathways are described in Chapter 31. Phospholipase C-gamma (PLCγ) interacts directly with activated EGFR and hydrolyzes phosphatidylinositol 4, 5-diphosphate to give inositol 1, 3, 5-triphosphate and 1, 2-diacylglycerol (a cofactor in protein kinase C [PKC] activation). PKC activation can in turn result in MAPK and c-Jun NH2-terminal kinase activation. Signal transducers and activators of transcription proteins interact with EGFR phosphotyrosine residues and on dimerization, translocate to the nucleus where they drive the expression

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of target genes. Src is a non-receptor tyrosine kinase, located in the cytosol, that activates a series of substrates, including focal adhesion kinase, PI3K, and STAT proteins, and therefore serves as a signal transducer of EGFR activation. EGFR has been detected by immunohistochemistry in 68 of 100 human HCCs examined [6]. The expression was noticed in greater than 50% of the cells in 42 cases and in 10–50% of the cells in 26 cases. In 53 cases, EGFR was expressed more than in noncancerous lesions. This is in contrast to 21% expression of c-ErbB2 in the same samples. EGFR expression correlated with proliferating activity (Ki67 labeling index), stage, intrahepatic metastasis, and carcinoma differentiation. As will be noted below, the exact percentage of HCC patients who have an activated EGFR pathway is difficult to discern, since not all studies that will be discussed included correlative markers in their design and, even in those that did, only pretreatment markers were considered. Furthermore, in the case of EGFR expression, this marker did not show correlation with outcome. Only pretreatment expression of p-ERK, a marker of activation of the MAPK pathway, was noted to correlate with time to progression (TTP) in 18 of 33 patients treated with sorafenib. Erlotinib, an EGFR small-molecule kinase inhibitor, has been studied in HCC. Recently, the molecular mechanisms of erlotinib-induced growth inhibition in human HCC cell lines have been described. Erlotinib inhibited the MAPK and STAT pathways with corresponding altered expression of apoptosis and cell cycle regulating genes. Erlotinib also inhibits the transactivation of EGFR by the insulin-like growth factor-1 receptor (IGF-1R), suppressing the receptor–receptor cross-talk, by-passing a potential mechanism of resistance towards EGFR blockade [7]. Several phase II trials testing erlotinib in HCC have been reported. An initial study reported on 40 patients without prior systemic treatment for advanced HCC [8]. All patients received erlotinib at 150 mg po daily. The primary endpoint was the rate of progression-free survival (PFS) at 16 weeks. Of note, 80% of the patients belonged to the Child–Pugh class A and 20% to the Child–Pugh class B. Cancer of the Liver Italian Project (CLIP) scores of 0, 1, 2, 3, 4, and 5 were reported for 15%, 20%, 27.5%, 17.5%, 15%, and 5% of the patients, respectively. Eastern Cooperative Oncology Group (ECOG) score 0–1 was observed in 95% of the patients. Patients accrue to one of two strata based on low (0–2+, 27.5%) or high (3–4+, 67.5%) tumor EGFR expression by immunohistochemistry. Overall, PFS at 16 weeks was 42.5% and median overall survival was 25 weeks. Survival was not influenced by the level of EGFR expression. The most frequent grade 3 toxicities included diarrhea (7.5% of patients) and fatigue (7.5%). It was concluded that erlotinib was well tolerated in patients with HCC. A modest benefit was suggested and erlotinib combination therapy was recommended for future trials.

A second phase II trial looked at 6-month PFS in 38 patients with advanced HCC [9]. Prior chemotherapy was allowed and 47% had received it. Background chronic liver disease was observed in 58% of the patients and Child–Pugh class could be A or B. The endpoint was achieved in 23% of patients. Disease control was observed in 59%, with three patients achieving a partial radiologic response (RECIST). Median overall survival was 13 months. EFGR expression was not associated with outcome. Grade 3–4 adverse events were observed in 61% of the patients. The most frequent grade 3–4 toxicities were skin rash (13%), diarrhea (8%), and fatigue (8%). Again, disease control by erlotinib was highlighted. Lapatinib, a dual inhibitor of EGFR tyrosine kinase 1 and 2 (Her2/Neu), has also been tested in HCC. In a two-stage design study, 17 patients with advanced HCC were treated with lapatinib at 1500 mg/day orally. Two confirmed partial responses were observed and eight patients exhibited stable disease. The reported PFS was 1.8 months [10]. Cetuximab has shown preclinical activity in HCC. In human HCC cell lines, cetuximab induced growth inhibition through an increase in expression of the cyclin-dependent kinase inhibitors p21 and p27 and decreased expression of cyclin D1, resulting in cell cycle arrest in the G0/G1 phase. The combination of cetuximab with tyrosine kinase inhibitors or doxorubicin resulted in a synergistic antiproliferative effect. Mutations in p53 were associated with less sensitivity to the cetuximab effect [11].

Insulin-like growth factor and insulin-like growth factor receptor In transgenic mouse models, IGF-2 has been implicated in hepatocarcinogenesis via autocrine mechanisms [12]. Recently, overexpression of IGF-2 and its receptor IGF-2R has been implicated in human HCC [13]. IGF-2 and IGF-2R have been noted to be overexpressed in patients with resected HCC. Interestingly, poorly differentiated HCC showed higher positive ratios than well-differentiated HCC. Overexpression was also detected in patients with cirrhosis without HCC. However, in these patients, overexpression was mainly detected in regenerative nodules and liver cell dysplasia. In addition, IGF-2 has been implicated in angiogenesis in HCC [14]. IGF-2 substantially increases vascular endothelial growth factor (VEGF) mRNA and protein levels in a timedependent manner in human hepatoma cells. The potential therapeutic implications of targeting IGF/ IGFR in patients with HCC are supported by the observed antineoplastic effects of inhibiting IGF-1R signaling in HCC cells by the novel IGF-1R tyrosine kinase inhibitor NVPAEW541 [15]. In a different model, antisense oligodeoxynucleotides of IGF-2 were used to arrest the translation of IGF-2 mRNA in human HCC cell lines. A decrease of IGF-2 was observed and this resulted in cell line growth inhibition

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[16]. Furthermore, in HCC cells, IGF-2 is a relevant protumorigenic growth factor that significantly reduces susceptibility to apoptosis and chemotherapeutic treatment. Therefore, interference with IGF-2 activity may improve response of HCCs to otherwise inefficient chemotherapeutic agents [17]. Humanized antibodies against IGF-1R have been developed and have proven effective inhibitors of ligand-dependent receptor phosphorylation and downstream signaling, and also have shown antitumor activity in a xenograft model for colon, pancreas, and breast cancer [18]. Clinical trials testing the human anti-IGF-1R antibody IMC-A12 in HCC are underway.

c-MET The proto-oncogene, c-MET, encodes the high-affinity receptor for hepatocyte growth factor (HGF) or scatter factor (SF). HGF and c-MET are each required for normal mammalian development and are implicated in cell growth and angiogenesis. At a molecular level, binding of activated HGF to the c-MET extracellular ligand-binding domain results in receptor multimerization and phosphorylation of multiple tyrosine residues at the intracellular region. Tyrosine phosphorylation at the c-MET juxtamembrane, catalytic, and cytoplasmic tail domains regulate the internalization, catalytic activity, and docking of regulatory substrates, respectively. Activation of c-MET results in the binding and phosphorylation of adaptor proteins such as Gab-1, Grb2, Shc, and c-Cbl, and subsequent activation of signal transducers such as PI3K, PLC-γ, STAT, extracellular signal-regulated kinase (ERK)-1 and -2, and focal adhesion kinase (FAK) [19]. Data regarding the pathogenic role of HGF/MET are conflicting. Preclinical experimental evidence supports the role of c-MET and HGF in the development or progression of neoplasms. Transgenic mice overexpressing HGF or the c-MET receptor in their germline can develop a variety of neoplasms. Of interest, transgenic mice overexpressing human wild-type MET in hepatocytes can develop HCC, even in the absence of HGF, through a mechanism dependent on cell adherence rather than ligand attachment [20]. Furthermore, tumors elicited by transgenic MET regressed even at advanced stages of tumor progression when the transgene was inactivated. Apoptosis and cessation of proliferation were both involved in tumor regression. This observation may suggest that genetic abnormalities leading to hepatocarcinogenesis do not lose relevance once the neoplasm is established, but rather constitute potential targets. On the contrary, HGF has been shown to inhibit the growth of several different HCC cell lines, and antibodies against HGF resulted in normalization of the growth of cell lines [21]. In a c-Myc transgenic mouse model, coexpression of HGF resulted in inhibition of hepatocarcinogenesis [22]. These results suggest that HGF may act as a tumor suppressor in the liver, selectively blocking growth of transformed

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hepatocytes and stimulating the proliferation of the normal ones. It appears that both the level and intactness of the HGF/c-MET signal transduction system may be required for effective suppression of the neoplastic process in this transgenic mouse model. The relevance of this pathway in human HCC is also controversial. In surgical biopsies from human HCC, HGF was overexpressed in 33% and downregulated in 21% of the tumors, when compared to surrounding hepatic tissue. The c-MET receptor was overexpressed in 20%, equally expressed in 48%, and downregulated in 32% of the neoplasms [23]. A positive correlation of c-MET expression with degree of differentiation [24], higher proliferative index [25], higher incidence of intrahepatic metastases, and decreased survival after hepatectomy [24] have been reported. In contrast, HGF has been reported as underexpressed by several authors [25, 26] and no correlation with clinicopathologic characteristics is consistent. At Memorial Sloan-Kettering Cancer Center, the expression of mRNA for both MET and HGF was studied in HCC resected from 49 patients and compared to the expression in nontumoral liver tissue. The tumor-to-nontumor ratio for MET expression was 7.1; confirming MET overexpression in this population of patients with relatively early-stage and preserved liver function. Overexpression of MET was correlated with earlier tumor stage and more favorable pathologic characteristics, suggesting that MET may be required in early tumor progression, but its importance may be lost in more advanced cases, where other pathways such as the MAPK pathway may become more relevant. In contrast, the tumor-to-nontumor ratio for HGF expression was 0.59; possibly explained by paracrine action of HGF produced in surrounding cell types. Again, tumor HGF expression showed a negative correlation with tumor stage. Clinical testing of c-MET inhibition in early-stage human HCC is warranted [27].

Intracellular signal transduction pathways Intracellular signal transduction pathways are organized as a phospho-relay system composed of sequentially activated protein kinases. Protein kinases are enzymes that covalently attach phosphate to the side chain of serine, threonine, or tyrosine of specific proteins inside cells. Such phosphorylation of proteins can control their enzymatic activity, their interaction with other proteins and molecules, their location in the cell, and their propensity for degradation by proteases [28]. Protein kinase substrates not only include other downstream protein kinases to allow their sequential activation and signal transmission, but also downstream effectors that upon phosphorylation can modulate gene expression and cellular activities such as proliferation, movement, metabolism, and apoptosis. Finally, negative regulatory mechanisms

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involve phosphatases to reverse the phosphorylation and return enzymes to inactive state. Although different stimuli may activate different pathways, conferring some specificity to the system, the overall organization remains the same, and has been conserved from unicellular organisms to humans.

MAPK pathway The MAPK (or Raf/MEK/ERK) pathway is a ubiquitous intracellular signal transduction pathway that relays extracellular signals from a number of growth factors to the nucleus to regulate cellular proliferation, survival, and differentiation. The initial Raf serine/threonine kinases (MAPKKK) are activated by upstream Ras, a GTPase associated with the inner cell membrane, and several other regulatory kinases. Upon activation, Raf kinases phosphorylate and activate downstream mitogen-activated protein kinase kinase (MEK)-1 and -2 (MAPKK), which, in turn, activates the terminal MAPK, ERK-1 and -2. Activated ERKs can translocate to the nucleus, where they phosphorylate and regulate various transcription factors, including the Ets family (Elk-1), ultimately leading to changes in gene expression [29]. The most common sites of dysregulation of the Ras/Raf/MEK/ERK pathway implicated in the development of human cancer are the Ras and Raf kinases. The relevance of this pathway in the pathogenesis of liver tumors has also been studied. MAPK expression and activity has been shown to be higher in human HCC compared to surrounding liver tissue [30, 31]. Furthermore, MAPK/ERK expression is positively correlated with tumor size and protein expression of transcription factor c-Fos [32]. Hepatitis B (HBV) and C (HCV) viruses may also increase HCC risk through Raf-1 signaling. The genome of the HBV encodes two transcriptional activators (HBX protein and PreS2-activator large surface protein), both of which trigger activation of Raf-1/ MEK signaling, which is also essential for HBV gene expression [33]. The HCV core protein also promotes cellular proliferation and inhibits apoptosis by activating the Raf-1/ MEK/ERK pathway [34]. Therefore, the rationale to support the inhibition of signaling through Raf-1 in the management of HCC is ample. Sorafenib is an oral multikinase inhibitor that targets the Raf/MEK/ERK pathway at the level of Raf kinase. In addition, sorafenib exerts an antiangiogenic effect by targeting VEGF-2 and -3 receptors (VEGF-2R and VEGF-3R), and platelet-derived growth factor receptor beta (PDGFR-β) tyrosine kinases. A phase II trial of sorafenib in patients with advanced HCC and Child–Pugh class A or B demonstrated stabilization of disease (≥16 weeks) in 33.6% of patients and a partial response in 2% of patients [35]. Median TTP was 4.2 months and median overall survival was 9.2 months. An interesting observation of central tumor necrosis was found in many patients in the study, suggesting that sorafenib causes necrosis without tumor shrinkage. Another finding

worth noting in this study is the significant difference in TTP in 18 of 33 patients with higher (2–4+) p-ERK staining versus those with lower (0–1+) intensity (p = 0.00034), suggesting the importance of Raf inhibition as one of the mechanisms of action of sorafenib. Despite a similar drug-related toxicity profile between Child–Pugh class A and B patients, Child– Pugh class B patients were noted to have more frequent worsening of their bilirubin (40% versus 18%), ascites (18% versus 11%), and encephalopathy (11% versus 2%) compared to Child–Pugh class A patients; all signs of worsening of liver disease. While the increased bilirubin could be at least partly explained by the UGT1A1 inhibiting activity of sorafenib, it remains unclear if the worsening liver function status is drug induced or just a natural progression of the disease. Caution should be exerted in using sorafenib in patients with low Child–Pugh class B, and sorafenib should be avoided in worse degrees of cirrhosis until further data are available to establish its safety in patients with HCC and advanced cirrhosis [36]. A double-blinded, randomized phase III study was conducted to compare overall survival in patients with advanced HCC and Child-Pugh class A, treated with sorafenib or placebo [4]. A planned interim analysis after 603 patients had been randomized and 321 deaths had occurred revealed a 2.8-month statistically significant (p = 0.00058) improvement in overall survival for patients treated with sorafenib (10.7 months) versus placebo (7.9 months) and the trial was interrupted. Response rates were limited in the same way as in the phase II study described above. The median time to radiologic progression was improved for patients treated with sorafenib (5.5 months) versus placebo (2.8 months) (p < 0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months versus 4.9 months, respectively; p = 0.77). Most adverse events related to sorafenib were grade 1 or 2. Grade 3 adverse events that were more common in sorafenibtreated patients compared with placebo included diarrhea (8% versus 2%), hand–foot skin reaction (8% versus <1%), hypertension (2% versus <1%), abdominal pain (2% versus 1%), and hypophosphatemia (11% versus 2%). Grade 3 or 4 thrombocytopenia occurred in 4% (sorafenib) versus less than 1% (placebo). Grade 3–4 toxicities potentially related to treatment included diarrhea (8%), hand–foot skin reaction (8%), abdominal pain (2%), weight loss (2%), and vomiting (1%). Grade 3–4 anorexia, nausea, liver dysfunction, and bleeding were present in less than 1% of the patients. While bleeding had an extremely low incidence of less than 1%, it remains a concern considering the antiangiogenic activity of sorafenib. This positive outcome was also commensurate with that of a second randomized phase III trial in an Asian population, with hepatitis B as the predominant risk factor. This trial randomized 226 patients from China, Korea, and Taiwan with advanced HCC to sorafenib versus placebo. Overall survival, PFS, and TTP were all

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significantly improved among the group of patients treated with sorafenib compared to those receiving placebo. Median overall survival was 6.5 months (sorafenib group) versus 4.2 months (placebo) (p = 0.014). Median TTP was 2.8 months (sorafenib group) versus 1.4 months (placebo) (p = 0.0005). Similar types of adverse events were reported in this study as were seen in the SHARP trial [37]. Despite the improvement in survival using sorafenib in HCC, efforts to improve outcome should continue. Future studies should focus on the identification of predictive factors of benefit from sorafenib therapy, testing sorafenib in combination with both other biologic agents and chemotherapy, and search for novel therapies. Sorafenib has also been tested in combination with chemotherapy in advanced HCC. A phase II study involving 96 patients with previously untreated advanced HCC was recently reported [38]. Patients were randomized to receive doxorubicin plus sorafenib or doxorubicin plus placebo. The median age of these patients was 65 years. The primary objective of the study, TTP, was 8.6 months for the doxorubicin plus sorafenib group, which is clearly an improvement compared to the reported historical TTP of about 4 months for doxorubicin alone. In an exploratory analysis, overall survival was 13.7 months for the doxorubicin plus sorafenib group and 6.5 months for the doxorubicin plus placebo group (p = 0.0049; hazard ratio, 0.45). In view of the positive outcome of the above-mentioned phase III study, an unplanned interim analysis of this trial was performed. In view of the clear disadvantage of receiving doxorubicin plus placebo, the trial was unblinded and the remaining patients on the doxorubicin plus placebo arm were allowed to crossover and receive doxorubicin plus sorafenib. The trial supports the growing body of evidence of the activity of sorafenib in HCC. However, any synergistic role between sorafenib and doxorubicin in HCC still needs to be further defined. The doxorubicin plus sorafenib arm had a higher incidence of left ventricular dysfunction (all grades 19% versus 2%), which raises a concern about a synergistic cardiac toxicity effect for the combination. A proposal for a trial to evaluate sorafenib plus doxorubicin versus sorafenib in patients with advanced HCC led by the North American Gastrointestinal Steering Committee Hepatobiliary Task Force is soon to be started. Patients on the sorafenib plus doxorubicin arm will receive prophylactic dexrazoxane. Sorafenib is also being evaluated in combination with tegafur/uracil as part of a phase II trial [39]. No trials of combination therapy of sorafenib with another biologic agent have been reported for the treatment of HCC as of yet. Ample Phase I data evaluating sorafenib plus other biologic agents support the concept of simultaneous inhibition of two different signal transduction pathways or the inhibition of the same signal transduction pathway at different levels in HCC. Whether this will result in additive or

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synergistic activity remains to be determined. The combination of sorafenib with mammalian target of rapamycin (mTOR) inhibitors is an example of the first scenario, given that angiogenesis, MAPK pathway, and Akt pathway are potential therapeutic targets, as discussed above. A study of sorafenib plus sirolimus is underway. An example of the second scenario is the combination of sorafenib with erlotinib, given that the EGFR is the initial component of the MAPK pathway. In this regard, a phase I trial evaluating this combination in solid malignancies has shown that there is no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. The recommended daily doses for the combination to be tested in phase II trials remained at 400 mg twice daily sorafenib and 150 mg daily erlotinib, the full single-agent recommended dose. One HCC patient showed stable disease and another patient with cholangiocarcinoma showed a partial response. Overall, the combination was well tolerated: the only grade 3/4 toxicity observed in more than 5% of the patients was hypophosphatemia [40]. Identification of salvage pathways responsible for resistance to sorafenib therapy may provide further insight into potentially beneficial combination therapies. Sorafenib plus bevacizumab is being tested. Sorafenib with transarterial chemoembolization (TACE) is also being evaluated in patients with HCC [39].

PI3K/Akt/mTOR pathway The activation and regulation of the PI3K/Akt pathway, also known as the mammalian target of rapamycin (mTOR) pathway, has been extensively studied, given its role as an important modulator of normal mammalian cell proliferation and survival, and the recognition that dysregulation of its components can lead to neoplastic transformation [41]. PI3Ks are heterodimeric lipid kinases that are composed of a regulatory (p85) and catalytic (p110) subunit. Class IA PI3Ks are activated by receptor tyrosine kinases. One of the main functions of PI3K is to synthesize the second messenger PtdIns (3, 4, 5) P3 (PIP3) from PtdIns (4, 5) P2 (PIP2). Phosphatidylinositol 3, 4, 5-trisphosphate (PIP3) recruits Akt, a serine/threonine kinase, to the plasma membrane. Akt is subsequently activated by pyruvate dehydrogenase kinase (PDK) 1 and PDK 2 through phosphorylation. Activated Akt mediates, through phosphorylation, the activation and inhibition of several downstream targets that regulate many biologic processes, such as proliferation, apoptosis, and cell growth. As such, phosphorylation of mTOR (a serine/threonine kinase) has been implicated in regulation of cell growth. Akt antiapoptotic effects have been explained by phosphorylation of Bad, FKHR and NF-κB. Regarding proliferation, Akt prevents cyclin D1 degradation by negatively regulating the activity of the glycogen synthase kinase3 β (GSK3-β). In addition, Akt can also negatively influence the expression of cyclin-dependent kinase inhibitors (CKIs),

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such as KIP1 and WAF1. Finally, Akt can also influence the activity of the tumor suppressor p53 through phosphorylation of the p53-binding protein MDM2, a negative regulator that targets p53 for degradation by proteasomes. PIP3 phosphatases, like phosphatase and tensin homolog (PTEN), convert PIP3 to PIP2, and provide a regulatory mechanism for this pathway. PTEN has also been involved in oncogenesis as a tumor suppressor gene. Thus, constitutive activation of this pathway can result from increased stimulation of RTKs (such as EGFR or IGFR) or downstream kinases, or from decreased PTEN expression. The importance of PI3K/Akt pathway dysregulation in the development of liver malignancies is suggested by the presence of PTEN/MMAC mutations in HCC. Loss of heterozygosity analysis and mutational screening of the PTEN/MMAC gene in 96 human HCCs identified allelic loss in 25 patients and somatic mutations in five of those tumors [42]. In a clinicopathologic study of 135 patients with HCC, phosphorylated Akt detected by immunohistochemistry was associated with both early recurrence and poor prognosis after resection in a multivariate analysis [43]. Global transcriptome analysis of 120 HCCs has identified a subgroup of patients in whom specific Akt pathway activation was detected [44]. These patients were noted to have a high rate of chromosomal instability and, interestingly, their main risk factor for HCC was HBV infection. Two subgroups were defined: subgroup G1 included HBV-related tumors of younger patients, frequently from Africa, associated with low viral load, high serum alpha-fetoprotein (AFP) levels, frequent AXIN1 mutations, absence of TP53 mutations, and overexpression of parentally imprinted genes (IGF-2); subgroup G2 included HBV-related tumors associated with high viral load, frequent local and vascular invasion, and TP53 mutations. The rare PIK3CA mutation was noted only in two patients, both included in the G2 subgroup. In addition, immunohistochemistry analysis of PTEN and the phosphorylated forms of Akt, mTOR, p70S6 kinase, and 4EBP-1 was consistent with pathway activation in 47%, 94%, 41%, 49%, and 37% of 166 HCC specimens of patients undergoing orthotopic liver transplantation, respectively [45]. Tumor size correlated negatively with PTEN and p-Akt. No influence of activated mTOR pathway proteins on disease-free survival (DFS) or overall survival could be identified. The study failed to demonstrate an inverse correlation between PTEN and downstream pathway proteins, and therefore the authors recommended direct determination of p-mTOR and p-p70s6K to determine mTOR activation status in HCC. In addition, the authors tested the activity of RAD001 on growth of HCC cells in vitro. Treatment with RAD001 resulted in hypophosphorylation of both p70s6kinase and 4EBP-1 with a concomitant upregulation of p-Akt. Cell growth was decreased by 32% and 42% in two different cell lines. The

combination with doxorubicin resulted in a synergistic antitumor effect. This is also supported by the clinical activity of mTOR inhibitors in HCC noted in the setting of posttransplant recurrence. A complete remission of lung metastases from HCC after conversion of the immunosuppressive therapy from cyclosporine to sirolimus and mycophenolate mofetil has been documented [46]. Further testing of Akt pathway inhibitors is needed.

Ras family In normal quiescent cells, Ras is GDP-bound and inactive. Extracellular stimuli (e.g. EGF) cause transient formation of the active GTP-bound form of Ras. Mutant Ras encodes mutated proteins that harbor single amino-acid substitutions primarily at residues G12 or Q61, with resulting proteins constitutively GTP bound and activated. Downstream of activated Ras, the Raf/MEK/ERK cascade mediates Rasinduced oncogenesis. Additional effectors involved in Ras oncogenesis include: the p110 catalytic subunit of class I PI3Ks, the Tiam1 Rac small GTPase-specific guanine exchange factor (GEF), the Ral small GTPase-specific GEFs (RalGDS, Rgl, Rgl2 and Rgl3), and phospholipase C epsilon [47]. Although Ras-activating mutations have been reported in 30% of all cancers, with the highest frequency reported for pancreas cancer (90%), Ras mutations in human liver tumors are not common [48, 49]. Ras mutations have only been reported in chemically-induced liver tumors in animals [50]. In human HCC, Ras mutations have been correlated to vinyl chloride exposure [51], but not to aflatoxin exposure [52]. However, Ras overexpression has been documented in HCC [53, 54]. Furthermore, suppression of proliferation of human HCC cell lines by acyclic retinoid has been associated with Ras activity downregulation and concomitant suppression of p-ERK [55]. This molecular mechanism may be relevant to explain the results of a positive randomized placebo-controlled trial that demonstrated reduced incidence of a second HCC and improved survival for patients treated with adjuvant oral acyclic retinoid for 12 months after curative treatment for HCC. In detail, eligible patients were free of disease after surgical resection of a primary hepatoma or the percutaneous injection of ethanol: 89 patients were randomly assigned to receive either polyprenoic acid (600 mg daily) or placebo for 12 months. The remnant liver was evaluated by ultrasonography every 3 months after randomization. With a median follow-up of 38 months, a reduced incidence of recurrent or new hepatomas was demonstrated (primary endpoint). A Cox proportionalhazards analysis demonstrated that as an independent factor, polyprenoic acid reduced the occurrence of second primary hepatomas (adjusted relative risk, 0.31; 95% CI, 0.12–0.78). With longer follow-up (median follow-up 62 months) a survival advantage for the acyclic-retinoid group could also

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be demonstrated. The estimated relative risk of death was 0.3 (95% CI, 0.1–0.8) in the acyclic-retinoid group as compared with the placebo group [56].

Wnt/β-catenin signaling pathway Secreted Wnt proteins act as ligands that bind transmembrane receptors known as Frizzled proteins (Fz). To initiate the Wnt signal, surface coexpression of a second transmembrane molecule, LRP5/6, is required. Upon ligand binding to the Fz/LRP coreceptor complex, phosphorylation of Dishevelled (Dsh) through Fz interaction and phosphorylation of LRP by GSK3-β and casein kinase 1-γ (CK1-γ) occur. Phosphorylated LPR interacts with Axin, resulting in docking of this molecule at the membrane level. In the absence of Wnt signaling, Axin interacts with β-catenin, tumor suppressor protein APC, and the serine threonine kinases GSK3 and CK1 at the cytoplasm level. This interaction results in phosphorylation of β-catenin, an initial step for ubiquitination and proteosomal degradation. In contrast, Axin docking during Wnt activation prevents β-catenin degradation and allows its intracellular accumulation and subsequent transfer to the nucleus where it converts T-cell factor (TCF) from a repressor to a transcriptional activator. Wnt target genes include c-Myc, cyclin D1, and others related to cell proliferation [57]. The value of targeting this pathway with therapeutic intent has been suggested as small molecules and antibodies against components of the pathway have been developed [58, 59] and have shown activity against colon cancer and melanoma both in vitro and in mouse xenograft models [60, 61]. Evidence implicating dysregulation of the Wnt pathway in hepatocarcinogenesis is also ample: of 497 HCCs analyzed by different authors, 91 (18%) had activating CTNNB1 mutations, 8 of 91 HCCs without CTNNB1 mutations harbored inactivating mutations in AXIN1, nuclear β-catenin was detected by immunostaining in 25 of 95 (26%) HCCs, and β-catenin mutations are much more common (41%) in HCC associated with HCV infection. Correlation between the presence of nuclear and non-nuclear β-catenin and patient clinical outcome has been described: in a series of 60 patients with resected HCC, nuclear accumulation of β-catenin was observed in 17% of the cases. In the remainder, non-nuclear overexpression of β-catenin was observed in 62% of HCCs and correlated with larger tumors, poorer cellular differentiation, and decreased DFS [62]. Overall, these data suggest that the Wnt/β-catenin signaling pathway is relevant in hepatocellular oncogenesis. Cyclooxygenase-2-independent anticarcinogenic effects of celecoxib have been attributed to downregulation of βcatenin in human carcinoma cell lines [63]. Finally, HCC cell lines (HepG2) exhibiting hyperactivity of β-catenin signaling exhibited sensitivity to an adenoviral vector that targets the β-catenin/Tcf responsive transcription [64]. Clinical testing of targeted therapies to this pathway in HCC is pending.

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Angiogenesis as a therapeutic target in liver cancer HCC is known for being a hypervascular tumor and this characteristic has been exploited for therapeutic use. Early strategies focused on mechanical interruption of blood supply in the form of embolization. More recently, with the advent of targeted agents, pharmacologic inhibition of angiogenesis is possible and has been tested in advanced liver cancer. Evidence to support angiogenesis as a target for therapeutic intervention is ample. Liver angiogenesis has been correlated with the development of HCC in patients with cirrhosis. Microvessel density in 150 HCV-cirrhotic patients was found to be significantly correlated to the development of HCC after a median follow-up of 64 months [65]. An earlier study supports these findings in the HCVpositive population, but not in HBV-positive patients, and suggested a link between HCV infection, angiogenesis, and hepatocarcinogenesis. Furthermore, it has been suggested that the different clinical characteristics observed in HBV + HCC patients versus HCV + HCC patients may be attributed to the differential significance of angiogenesis in these populations: smaller tumors, higher rate of microsatellite tumor formation, and higher microvessel density values were noted in the HCV-positive population [66]. Several drugs with antiangiogenic effect are currently available and have been tested in HCC. An early trial with bevacizumab, a monoclonal antibody against VEGF, demonstrated the feasibility of this approach and delineated the toxicity profile. Administered at 5 or 10 mg/kg every 14 days, three of 28 patients developed esophageal bleeding and one patient developed a transient ischemic attack. Of 25 patients evaluable for efficacy, 8% experienced a partial response and 72% experienced stable disease. Median TTP was 6.5 months [67]. A second trial used bevacizumab at 5–10 mg/kg bimonthly in 30 patients. Again, bevacizumab therapy was associated with 20% discontinuation secondary to variceal bleeding. Grade 3 transient ischemic attack, hemorrhagic ascites, and proteinuria were reported in one patient each. Among 24 patients evaluable for efficacy, 12.5% had a partial response and 54% had stable disease [68]. Sunitinib at 37.5 mg/day 4 weeks on/2 weeks off was associated with a 3.9% response rate, a 38.5% stable disease rate, a median PFS of 4.1 months, and a median overall survival of 11.6 months, suggesting some clinical activity in a study of 26 patients [69]. At 50 mg/day 4 weeks on/2 weeks off, a 2.7% response rate, a 35.1% stable disease rate, a median TTP of 21 weeks, and a median overall survival of 45 weeks were reported in 37 HCC patients [70]. This study showed, however, an elevated frequency of grade 3/4 adverse events, including asthenia (21%), ascites (16%), thrombocytopenia (35.1%), neutropenia (24.3%), and anemia (18.9%), and four deaths attributable to sunitinib

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(bleeding, drowsiness, hepatic encephalopathy, and renal failure) were reported among the 37 treated patients. The authors argued that attribution of causality in this context can be difficult given overlapping signs and symptoms of underlying disease. Two studies have evaluated bevacizumab as a single agent in HCC. Finally, as already discussed, sorafenib has a dual mechanism of action: MAPK signaling pathway inhibition and antiangiogenic activity, explained by its anti-VEGF/PGDGF effect. The relative contribution to the therapeutic benefit in HCC has not been clearly discerned but sorafenib remains the only targeted agent with proven survival advantage as a single agent. This concept of combined therapy discussed above is well supported by the encouraging results of the combination of erlotinib with bevacizumab [71]. In 27 evaluable patients, one achieved a complete response, while five achieved a partial response and nine achieved stable disease at 16 weeks for a 55% PFS at 16 weeks. This combination deserves to be tested further.

Conclusion Advances in understanding of cancer cell biology have made it possible to identify specific sites of dysregulation responsible for neoplastic transformation in multiple human cancers. As a result, it is now possible to develop drugs that can selectively target abnormal pathways. Even for the case of neoplasms such as HCC, traditionally considered resistant to therapy, targeted therapies have shown encouraging clinical results. Outcomes, however, are far from perfect. It has become evident that HCC represents a heterogeneous disease. Different etiologies likely have different predominant aberrant pathways. Improvement of results demands a better dissection of the molecular pathways, specifically of how different pathways interact at the same time, in the same tumor, and in a particular patient. Microarray analysis has made it possible to study the expression of thousands of genes simultaneously. Transcriptome– genotype–phenotype correlations in HCC allow identification of activated biologic pathways in specific subsets of patients defined by clinical characteristics, risk factors, or genetic abnormalities [44]. Microarray analysis therefore can aid in the understanding of the molecular diversity of HCC and offers potential therapeutic implications, as soderived classifications of HCC may be the clue to rationally designed custom therapy in an era of unprecedented explosion of drug development. Until then, phase III clinical trials should focus on determining survival advantage of combination therapy over single agent sorafenib in the control arm. Both the combination of biologic agents, such as erlotinib and bevacizumab or sorafenib plus erlotinib, and the combination of chemotherapy with a biologic agent, such as doxorubicin and sor-

afenib, should be investigated. Phase I/II clinical trials should specifically evaluate pharmacokinetic interaction of new agents or new combinations in the setting of different degrees of liver dysfunction, which is so common in liver cancer.

Self-assessment questions 1 Which of the following anticancer targets belong to the class of receptor tyrosine kinases? (more than one answer is possible) A c-MET B Raf C TGF-β D EGFR E Frizzled 2 Which of the following anticancer drugs are directed towards the epidermal growth factor receptor (EGFR)? (more than one answer is possible) A Lapatinib B Sorafenib C Everolimus D Erlotinib E Cetuximab 3 Sorafenib has been identified as the sole single agent treatment with proven improvement in survival, because it acts on two different pathways, the Raf/MEK/ ERK and the Wnt canonical pathway. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 4 The hepatocyte growth factor (HGF) does not represent a valid target for the treatment of hepatocellular carcinoma, because its expression poorly correlates with clinical liver pathology. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 5 As suggested by the authors, what should be the control treatment for future prospective randomized studies in

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phase III clinical trials for the cure of hepatocellular carcinoma? A Chemotherapy B Liver embolization C Placebo D Sorafenib E Bevacizumab

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48 Teufel A, Staib F, Kanzler S, Weinmann A, Schulze-Bergkamen H, Galle PR. Genetics of hepatocellular carcinoma. World J Gastroenterol 2007;13:2271–82. 49 Tannapfel A, Sommerer F, Benicke M, et al. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 2003;52:706–12. 50 Jaworski M. Buchmann A, Bauer P, Riess O, Schwartz M. B-raf and Ha-ras mutations in chemically induced mouse liver tumors. Oncogene 2005;24:1290–5. 51 Weihrauch M, Benicke M, Lehnert G, Wittekind C, Wrbitzky R, Tannapfl A. Frequent k-ras-2 mutations and p16(INK4A)methylation in hepatocellular carcinomas in workers exposed to vinyl chloride. Br J Cancer 2001;84:982–9. 52 Chao HK, Tsai TF, Lin CS, Su TS. Evidence that mutational activation of the ras genes may not be involved in aflatoxin B(1)-induced human hepatocarcinogenesis, based on sequence analysis of the ras and p53 genes. Mol Carcinog 1999;26:69–73. 53 Jagirdar J, Nonomura A, Patil J, Thor A, Paronetto F. ras oncogene p21 expression in hepatocellular carcinoma. J Exp Pathol 1989;4:37–46. 54 Zhang XK, Huang DP, Qiu DK, Chiu JF. The expression of c-myc and c-N-ras in human cirrhotic livers, hepatocellular carcinomas and liver tissue surrounding the tumors. Oncogene 1990;5:909–14. 55 Matsushima-Nishiwaki RR, Okuno M, Takano Y, Kojima S, Friedman SL, Moriwaki H. Molecular mechanism for growth suppression of human hepatocellular carcinoma cells by acyclic retinoid. Carcinogenesis 2003;24:1353–9. 56 Muto Y, Moriwaki H, Saito A. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. N Engl J Med 1999;340:1046–7. 57 Clevers H. Wnt/beta-catenin signaling in development and disease. Cell 2006;127:469–80. 58 Lepourcelet M, Chen YN, France DS, et al. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell 2004;5:91–102. 59 Roberts LR, Gores GJ. Emerging drugs for hepatocellular carcinoma. Expert Opin Emerg Drugs 2006;11:469–87. 60 Emami KH, Nguyen C, Ma H, et al. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proc Natl Acad Sci U S A 2004;101:12682–7. 61 You L, He B, Xu Z, et al. An anti-Wnt-2 monoclonal antibody induces apoptosis in malignant melanoma cells and inhibits tumor growth. Cancer Res 2004;64:5385–9. 62 Wong CM, Fan ST, Ng IO. beta-Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance. Cancer 2001;92:136–45. 63 Maier TJ, Janssen A, Schmidt R, Geisslinger G, Grösch S. Targeting the beta-catenin/APC pathway: a novel mechanism to explain the cyclooxygenase-2-independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. FASEB J 2005;19:1353–5. 64 Dvory-Sobol H, Sagiv E, Kazanov D, Ben-Ze’ev A, Arber N. Targeting the active beta-catenin pathway to treat cancer cells. Mol Cancer Ther 2006;5:2861–71. 65 Mazzanti R, Messerini L, Comin CE, Fedeli L, Ganne-Carrie N, Beaugrand M. Liver angiogenesis as a risk factor for hepatocellular carcinoma development in hepatitis C virus cirrhotic patients. World J Gastroenterol 2007;13:5009–14.

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66 Messerini L, Novelli L, Comin CE. Microvessel density and clinicopathological characteristics in hepatitis C virus and hepatitis B virus related hepatocellular carcinoma. J Clin Pathol 2004; 57:867–71. 67 Schwartz JD, Schwartz M, Sung M, et al. Bevacizumab in unresectable hepatocellular carcinoma (HCC) for patients without metastasis and without invasion of the portal vein. ASCO Annual Meeting Proceedings Part I, 2006. J Clin Oncol 2006;24 (Suppl 18):a4144. 68 Malka D, Dromain C, Farace F, et al. Bevacizumab in patients (pts) with advanced hepatocellular carcinoma (HCC): Preliminary results of a phase II study with circulating endothelial cell (CEC) monitoring. ASCO Annual Meeting Proceedings Part I, 2007. J Clin Oncol 2007;25 (Suppl 18):a4570. 69 Zhu AX, Sahani DV, di Tomaso E, et al. Part I. A phase II study of sunitinib in patients with advanced hepatocellular carcinoma. ASCO Annual Meeting Proceedings Part I, 2007. J Clin Oncol 2007;25 (Suppl 18):a4637. 70 Faivre SJ, Raymond E, Douillard J, et al. Assessment of safety and drug-induced tumor necrosis with sunitinib in patients (pts)

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with unresectable hepatocellular carcinoma (HCC). ASCO Annual Meeting Proceedings Part I, 2007. J Clin Oncol 2007;25 (Suppl 18):a3546. 71 Thomas MB, Chadha R, Iwasaki M, Glover K, Abbruzzese JL. The combination of bevacizumab (B) and erlotinib (E) shows significant biological activity in patients with advanced hepatocellular carcinoma (HCC). ASCO Annual Meeting Proceedings Part I, 2007. J Clin Oncol 2007;25 (Suppl 18):a4567.

Self-assessment answers 1 2 3 4 5

A, D A, D, E B E D

33

Induction of Apoptosis in Liver Tumors Markus Selzner1 and Pierre-Alain Clavien2 1

Department of Surgery, Division of Multi Organ Transplantation, Toronto General Hospital, Toronto, Canada Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland 2

Cancer has been traditionally regarded as an accumulation of atypical cells resulting in excessive proliferation. Accordingly, anticancer treatment, such as chemotherapy or radiation, has focused on abrogating the normal proliferation process by damaging deoxyribonucleic acid (DNA) or other elements involved in cell division. Significant success has been achieved by chemotherapy in various hematologic malignancies, e.g. increasing the 5-year survival rate for acute lymphatic lymphomas from 34% in 1972 to 75% in 2000 [1]. However, chemoradiation was less successful in most solid gastrointestinal tumors with often poor response rates. Even the use of more toxic drugs or higher doses has not significantly increased long-term survival. For example, aggressive regimens, such as ablative chemotherapy with bone marrow support for breast cancer, have shown disappointing outcome [2]. The dismal results of conventional chemotherapy and radiation has prompted research on the mechanisms leading to induction of cell death in tumors. In 1951 Glücksman et al [3] described for the first time that cell death is an important element of normal development. Saunders suggested in 1966 that the cell death in embryos was integrated in a development program [4]. In 1971 Kerr described a programmed cell death, called apoptosis [5], which in contrast to necrosis is an active energyrequiring mechanism of cell death. The cell death program is well preserved in evolution and is similar in tape worms (nematodes) and humans [1]. Recently, it has been shown that apoptosis plays a key role in clearance of unwanted cells, during development or as a response to cell damage or mutation. For example, it is estimated that 50 billion cells perish in an adult each day by apoptosis, to accommodate the amount of new cells produced [6]. In addition, it has been demonstrated that almost all chemotherapeutic drugs and radiotherapy induce apoptosis [7]. Impaired apoptosis plays a major role in the development of cancer. Defects of the apoptotic pathway can extend the life span of cells,

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

diminish the need for external survival factors of tumor cells, and increase the tumor cell’s resistance to hypoxemia and oxidative stress. Therefore, tumor development should currently be regarded as a combined effect of increased proliferation and blocked apoptosis.

Apoptosis Apoptosis is associated with distinct morphologic changes, which occur rapidly after activation of the cell death program [7]. In the early phase of apoptosis, nuclear chromatin and cell organelles are compacted and segregated as uniform masses that become marginated against the nuclear envelope. The DNA is cleaved by endonucleases in 180–200 base pair fragments and the nucleus breaks up into fragments surrounded by double layer membranes. Finally, the cytoplasm is condensed and the cell membrane convolutes, forming blebbings. The cell disintegrates into small apoptotic bodies, which are encapsulated by remnants of the cell membrane. The apoptotic bodies are rapidly removed by macrophages without evidence of inflammation (Figure 33.1). The morphologic changes of apoptosis are reflected in a network of intracellular pathways for the regulation of programmed cell death. Apoptosis can be induced by an extrinsic and an intrinsic pathway [8]. The extrinsic pathway is activated by the tumor necrosis factor (TNF) receptor family, which is a group of cell membrane-bound death receptors for TNF-α or Fas. Binding of TNF-α or Fas to their respective receptor results in the recruitment of intracellular proteins (called FADD or TRADD) to the intracellular receptor domain. The binding of FADD or TRADD activates a cascade of intracellular caspases. Caspases are calcium-dependent cysteine proteinases, which are activated during apoptosis and represent the backbone of the apoptotic cascade. FADD/ TRADD activation induces caspase 8. Caspase 8 activation can induce directly caspase 3, which executes the apoptotic cell death by activation of endonucleases and cleaving DNA repair enzymes. In contrast, in many cell lines, caspase 8 is

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1 2

7 3

4

8

5

6

Necrosis

Apoptosis

Figure 33.1 Apoptosis (2–6) and necrosis (7 and 8) are characterized by defined ultrastructural changes. In the early phase (2) of apoptosis, the cell develops compactation and margination of the nuclear chromatin, condensation of the cytoplasm, and convolution of the nuclear outlines. Then, the nucleus fragments and apoptotic bodies are formed by blebbing of the cell membrane (3). The apoptotic bodies are phagocytosed by macrophages (4) and degraded within lysosomes. In contrast, the necrosis is associated with swelling of the cell organelles (7), and disruption of the cell membrane (8). The necrotic cell disintegrates and the cytoplasm is released into the interstitium.

unable to stimulate caspase 3 directly. In these cells, caspase 8 activation results in cytochrome c release from the mitochondria, which activates an apoptosis protease activating factor (APAF-1), resulting in activation of caspase 9 and subsequently in activation of caspase 3 (Figure 33.2). This extrinsic pathway of apoptosis is often used by natural killer cells or cytotoxic lymphocytes, which can stimulate Fas receptors on tumor cells and delete these cells before tumor cell proliferation can occur. A second pathway of apoptosis, the intrinsic pathway, is independent from death receptors [9]. Most carcinogenic mutations induce double-strand breaks in the DNA. Physiologic mechanisms exist to repair DNA breaks. However, severely damaged DNA is a sufficient stimulus to induce apoptosis. Following DNA damage, a cell cycle arrest is induced by a cell cycle protein, p53. During the temporary cell cycle arrest, the cell has the ability to repair DNA damage. If DNA repair is not possible, then p53 induces proapoptotic mitochondrial proteins, such as Bax or Bad, which promote cytochrome c release and activation of APAF-1, caspase 9, and caspase 3 [10] (Table 33.1) The intrinsic apoptotic pathway is frequently induced after DNA targeting therapies, such as radio- or chemo-therapy. The apoptotic pathway is highly regulated. A family of pro- or anti-apoptotic mitochondrial membrane proteins, such as Bcl-2, Bcl-xL, Bad, and Bax, regulate the cytochrome c release and therefore the apoptotic pathway in the extrinsic and intrinsic system [11]. Furthermore, ceramides, membrane-derived sphingolipids, can activate the apoptotic pathway by stimulating cytochrome c release and activation of caspase 3 [12, 13]. A group of ‘inhibitor of apoptosis proteins’ has been described, which directly block caspase 3 and 9 [14].

Table 33.1 Key features of apoptosis and necrosis. Features

Necrosis

Apoptosis

Stimuli

Overwhelming injury, ATP depletion No known mediators involved No regulation

Defined physiologic conditions, no ATP depletion Activation of a cascade of caspases Highly regulated by pro- and antiapoptotic mediators Single cells ATP dependent Chromatin condensation, apoptotic bodies Ladder of fragments in internucleosomal multiples of 185 bp Intact, formation of apoptotic bodies by blebbing No inflammation

Mechanism Regulation Pattern of dying cells Energy requirement Histology

Confluent necrotic areas None Cell swelling, disruption of organelles Randomly sized fragments

DNA breakdown pattern Plasma membrane

Lysed

Tissue reaction

Inflammation

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Extracellular death receptor (Fas/TNF)

Intracellular death domain (FADD/ TRADD) Caspase 8 Extrinsic pathway

Bid

Mitochondria Cyt C Figure 33.2 Apoptosis can be induced by an extrinsic death receptor-dependent pathway. Caspase 8 binds to the intracellular death domain. Activated caspase 8 can either directly activate the effector caspase 3, or induce cytochrome c release, which induces activation of apoptosis protease activating factor 1 (APAF-1), caspase 9, and caspase 3. Alternatively, apoptosis can be initiated by the receptor-independent intrinsic pathway. DNA damage induces p53, which results in cell cycle arrest. If DNA repair is not possible, then p53 induces cytochrome c release from the mitochondria by upregulation of proapoptotic mitochondrial membrane proteins, such as Bad. Cytochrome c release activates APAF-1, caspase 9, and caspase 3. TNF, tumor necrosis factor.

Necrosis Necrosis is a nonphysiologic form of cell death resulting from an overwhelming catastrophic injury, such as severe ischemia. Necrosis is associated with cell swelling and rupture of the cell membrane (see Figure 33.1). Necrosis is always pathologic, with the release of intracellular cell content into the interstitial space, causing inflammation and additional damage. While apoptosis is limited to single, scattered cells, necrosis usually affects large areas of adjacent cells, causing severe structural tissue damage. Necrotic cell death is not regulated and occurs if the cell cannot undergo apoptosis. This is the case either with severe injury, such as prolonged ischemia, or in cells that are unable to activate the ATP-dependent apoptotic cascade, e.g. because of ATP depletion, such as in steatotic hepatocytes or because of a dysfunction of the apoptotic cascade [15].

APAF-1

Caspase 9

Caspase 3 Intrinsic pathway

Cell death p53 Nucleus

Inhibition of the apoptotic pathway in cancer cells Cancer cells are produced commonly during life, but are effectively removed by apoptosis. Tumor development is considered to be a result of a mutation leading to a hyperproliferative cell. A second mutation results in a defect of the apoptotic cascade, which helps the tumor cell to escape the natural defense mechanisms and to develop into a clinically relevant tumor. In addition, the defect of apoptosis will render the cancer cells less responsive to chemotherapy or radiation. Downregulation of apoptosis appears to be critical to the early changes of hepatocellular carcinoma (HCC) development [7, 11]. For example, hepatitis B is frequently associated with the development of HCC. Infection with the hepatitis B virus (HBV) has been linked with an altered regulation of apoptosis, including abrogation of p53-mediated apoptosis [16], downregulation of Bid [17],

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upregulation of survivin [18], and downregulation of c-Fos and Myc [19]. In particular, survivin was identified as a poor prognostic factor for the survival rate of patients with HCC [20]. The apoptotic cascade can be interrupted at different sites. The simplest way to avoid lethal signals from a ligand death receptor (Fas, TNF-α), is to downregulate or delete the receptor. Decreased expression of Fas has been reported in HCC in comparison to normal hepatocytes [21]. The tumor cells without death receptors do not undergo apoptosis if natural killer cells or cytotoxic T cells are activated and present death ligands to the tumor. Furthermore, if the cancer cell does not express death receptors on the cell membrane, death ligands can be expressed at the outer membrane without the risk of autoactivation of apoptosis. Some tumors express death ligands instead of death receptors and induce apoptosis themselves in approaching T cells, a process called counter attack [22]. Furthermore, other cells, such as endothelial cells, can be deleted by the tumor to facilitate tumor cell migration. Instead of downregulating the death receptors, tumor cells can develop decoy receptors, which are death ligands without activation of the death pathway. The decoy receptor DcR3 binds to the Fas receptor and inhibits FAS-mediated apoptosis [23]. Cells expressing DcR3 have the ability to survive a Fas ligand attack of cytotoxic lymphocytes. It has been estimated that the gene for DcR3 is amplified in 50% of all colon and lung cancers. A third possible means to inhibit death receptor-mediated apoptosis is the downregulation of caspase 8 as the intracellular mediator of both death receptors Fas and TNF-α. Decreased caspase 8 levels have been identified in nonsmall lung cancer and neuroblastoma cell lines [24]. Interruption of the mitochondrial pathway and prevention of cytochrome c release is a second target of interruption of the apoptotic cascade. It has been demonstrated in a rat model that animals fed with the carcinogen 2-acetylaminofluorene develop mitochondria that are much more resistant to depolarization and cytochrome c release than mitochondria from control rats [25]. Overexpression of the antiapoptotic mitochondrial membrane proteins has been described in several human cancers [26]. The overexpressed Bcl-2 protein prevents the release of cytochrome c from the mitochondria and therefore the activation of downstream mediators such as APAF-1 and caspase 3. A similar effect can be achieved by decreasing proapoptotic mitochondrial proteins, such as Bax or Bad. Bax and Bad are counterplayers of Bcl-2 and induce mitochondrial pore formation and cytochrome c release [9]. Overexpression of Bcl-2 was found in 90% of all B-cell lymphomas [27] and colorectal tumors [28]. However, only 6% of all HCCs [29] and 5% of all cholangiocarcinomas [30] overexpress Bcl-2. While the absolute levels of Bcl-2 and Bax are not associated with survival in most human cancer, the ratio of Bcl-2

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Table 33.2 Antiapoptotic mediators and mechanisms in tumor cells. Antiapoptotic mechanism

Effect

Deletion of death receptor

No response to lymphocytes or natural killer (NK) lymphocytes Deletion of lymphocytes or NK lymphocytes Deletion of nonparenchymal cells Dysfunction of the death receptor Inhibition of cytochrome c release Inhibition of cytochrome c release No induction of Bad, failure to induce cytochrome c release No caspase 9 or 3 activation after cytochrome c release No caspase 3 activation after cytochrome c release Blockage of caspase 3 and 9

Expression of Fas ligand

Downregulation of caspase 8 Overexpression of Bcl-2 Decrease of Bax or Bad Mutation of p53 Deletion of Apaf-1 Deletion of caspase 9 Inhibitors of apoptosis proteins (IAPs) Blockage of ceramide generation

Decreased cytochrome c release

to Bax is associated with an unfavorable survival time in patients with gastrointestinal tumors [27]. A different way to block the mitochondrial pathway is to decrease effectors of cytochrome c release, such as APAF-1 or caspase 9. It has been shown in cell culture models that oncogeneoverexpressing cells have an improved growth and seeding capacity if APAF-1 or caspase 9 are deleted [29]. However, studies demonstrating APAF-1 or caspase 9 deletion in human cancer are still lacking (Table 33.2). The intrinsic pathway of apoptosis is induced by DNA damage, such as mutations, but also radiation or DNAtargeting chemotherapy [31]. The key mediator of this pathway is p53, a cell cycle protein, which induces cell cycle arrest to allow DNA repair. However, in cases of severe DNA damage, p53 can induce the proapoptotic mitochondria membrane protein Bax, which results in cytochrome c release followed by activation of effector caspases and apoptosis [10]. Mutations of p53 are common in tumor cells. It has been estimated that 50% of all tumors have a mutant p53 with no or decreased function [32]. In particular, HCCs have frequent mutation of p53, resulting in a loss of p53 function. This allows a survival of liver cells in the presence of telomere-induced instability, leading to the formation of malignant tumor clones [33]. This has two important consequences. First, tumor cells are not deleted after a mutation, resulting in hyperproliferation. In addition, subsequent mutations are possible and will not induce cell death. Second, most anticancer therapies are dependent on the activation of p53 and therefore will be less effective. Radiation or chemotherapy may still cause cell cycle arrest by damaging the DNA; however, apoptosis is not induced due to the missing mediator p53. Therefore, in the absence of

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functioning p53, a therapy might just reduce tumor cell proliferation instead of inducing cell death. Alterations have been identified in cancer cells that inhibit both the extrinsic receptor-mediated pathway as well as the intrinsic p53-mediated pathway. This includes the overexpression of inhibitor of apoptosis proteins (IAPs) [6]. IAPs are able to decrease the activation of various caspases. Interestingly, only caspases that are located distally in the pathway (caspase 3, 7, and 9) have been identified to be blocked by IAPs. In contrast, initiator caspases, which are further upstream in the apoptotic cascade (caspases 1, 6, and 8) are not targets of IAPs [9]. This provides tumor cells with protection against receptor-based pathways and against the mitochondrial-mediated induction of apoptosis. In addition, high levels of IAPs will result in increased resistance to chemotherapy or radiation, which both depend on the mitochondrial pathway with subsequent activation of caspase 3 and 9. Overexpression of IAPs has been observed in a large variety of human cancers, such as colorectal tumors and nonsmall cell lung cancers [9]. The levels of “survivin,” the best studied IAP, correlate with a poor prognosis and short survival [9]. Survivin is expressed in 70% of all HCC cells, while only minimal expression is found in normal liver tissue [34]. However, survivin levels also correlate with Bcl2 overexpression and p53 mutation, which makes these findings difficult to interpret.

Strategies to induce apoptosis in tumor cells All classes of available anticancer agents induce apoptosis in tumor cells. Most drugs involve the intrinsic pathway mediated by cytochrome c release, APAF-1 and caspase 9, while a Fas-mediated pathway was suggested for 5-fluorouracilinduced apoptosis in some cell lines [35]. Considering that failure of apoptosis is a critical component of tumor development, the limited effects of chemotherapies might be due to the same mechanism. The understanding that apoptosis is inhibited in cancer cells indicates the need for new strategies to restore the blocked pathway. Administration of the death mediator TNF-α was tested 15 years ago. Unfortunately TNF-α is associated with profound side effects, such as hypotension [36]. However, TNF-α seems to increase the effectiveness of chemotherapeutic agents. Similarly, administration of Fas is not possible due to its profound toxicity on hepatocytes [37]. Other groups have targeted the mitochondrial pathway. Bcl-2 antisense oligonucleotides have been used in a phase I trial [38]. It was demonstrated in B-cell lymphomas that the antisense therapy downregulates Bcl-2 expression and can induce regression in these patients. Recently IAPs have been a focus of induction of apoptosis in tumor cells. IAPs inhibit effector caspases and therefore

Induction of Apoptosis in Liver Tumors

can block the intrinsic and the extrinsic pathway of apoptosis. Survivin is expressed in various tumors and has been a focus of oligonucleotide antisense therapy [39]. A novel approach to induce apoptosis is the induction of ceramides, which are proapoptotic sphingolipids. Ceramides are generated from sphingomyelin by hydrolyzation and are degraded by ceramidase. They are frequently generated as a response to radiation or chemotherapy. Ceramides are an important second messenger for apoptosis with various effects on the apoptotic cascade. They accumulate within the mitochondria [40] and upregulation of ceramides has been linked to inhibition of the complex I/III of the mitochondrial respiratory chain, which leads to a decrease of ATP production [41]. Other ceramide effects include decreased mitochondrial membrane potential, facilitating cytochrome c release [42], dephosphorylation, and inactivation of Bcl-2 [43], and increased reactive oxygen species within mitochondria [44]. Experimental multidrug resistance can be induced by transfecting cells with genes of sphingomyelin transport molecules, such as p-glycoprotein or MRP1, which decrease intracellular sphingomyelin and ceramide levels [42]. It has been demonstrated that human primary colon cancer has lower ceramide levels than normal large bowel mucosa [12], and the failure to generate ceramides might enhance tumor development by inhibition of apoptosis. Injection of ceramidase inhibitors increases ceramide levels in mice tumor cells. In a mouse model, ceramide injection induced apoptosis in liver metastasis from colon cancer and prevented tumor development [13]. Combination of ceramides and ceramidase inhibitors with chemotherapeutic agents such as doxorubicin has a synergistic effect for the induction of apoptotic death in cancer cells [40].

Conclusion Apoptosis has been known about for 30 years. However, only recently has it become clear that programmed cell death is a widely used mechanism to delete tumor cells. The apoptotic pathway is a complex energy-requiring cascade, which is highly regulated by numerous pro- and antiapoptotic mediators. The development of cancer depends largely on the failure to induce apoptosis in the tumor cells. Resistance to apoptosis helps the tumor cells to escape natural defense mechanisms and to survive unfavorable conditions, such as a low oxygen environment. In addition, most traditional anticancer therapies, such as chemotherapy or radiation, rely on the induction of apoptosis, but are frequently resistant to apoptotic stimuli. Future strategies should focus on a combined approach of restoring the apoptotic pathway in tumor cells and providing a potent apoptotic signal.

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Self-assessment questions 1 Which of the following are morphologic features of apoptosis? (more than one answer is possible) A Chromatin condensation B Blebbing C Cell swelling D DNA fragmentation E Cell membrane rupture 2 Antiapoptotic changes in hepatitis B-positive livers include which of the following? (more than one answer is possible) A Increased expression of the Fas receptor B Abrogation of p53 function C Downregulation of Bid D Decrease of survivin expression E Decreased caspase activity 3 Ceramide promotes apoptosis by which of the following mechanisms? (more than one answer is possible) A Increase in ATP synthesis B Inactivation of Bcl-2 C Increase in reactive oxygen species within mitochondria D Inhibition of Fas ligand E Degradation of sphingomyelin 4 Which of the following are experimental approaches to induce apoptosis in cancer cells? (more than one answer is possible) A Administration of ceramides B Inhibition of TNF-α C Survivin oligonucleotide antisense therapy D Bcl-2 overexpression E Administration of pan-caspase inhibitors 5 TNF-α administration is clinically used for cancer therapy, because it can be a potent inducer of apoptosis. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct

References 1 Makin G, Hickman J. Apoptosis and cancer chemotherapy. Cell Tissue Res 2000;301:143–52.

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2 Budman D, Berry D, Cirrincione C, et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. J Natl Cancer Inst 1998;90:1205–11. 3 Glücksmann A. Cell deaths in normal vertebrate develpment. Biol Rev 1951;26:59–86. 4 Saunders J. Deaths in embryonic systems. Science 1966;154: 604–12. 5 Kerr J. Shhrinkage necrosis: a distinct mode of cellular death. J Pathol 1971;105:13–20. 6 Reed J. Dysregulation of apoptosis in cancer. J Clin Oncol 2000;17:2941–53. 7 Kanzler S, Galle PR. Apoptosis and the liver. Semin Cancer Biol 2000;10:173–84. 8 Roy S. Caspases at the heart of the apoptotic cell death pathway. Chem Res Toxicol 2000;13:961–2. 9 Kaufmann S, Gores G. Apoptosis in cancer: cause and cure. BioEssay 2000;22:1007–17. 10 Ding H, Fisher D. Mechanisms of p53-mediated apoptosis. Crit Rev Oncogen 1998;9:83–98. 11 Mott JL, Gores GJ. Piercing the armor of hepatobiliary cancer: Bcl-2 homology domain 3 (BH3) mimetics and cell death. Hepatology 2007;46:906–11. 12 Selzner M, Bielawaska A, Morse M, et al. Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Cancer Res 2001;61: 1233–40. 13 Dahm F, Bielawska A, Nocito A, et al. Mitochondrially targeted ceramide LCL-30 inhibits colorectal cancer in mice. Br J Cancer 2008;98:98–105. 14 LaCasse E, Baird S, Korneluk R, MacKenzie A. The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene 1998;17:3247–59. 15 Selzner M, Rüdiger H, Sindram D, et al. Mechanisms of ischemic injury are different in the steatotic and normal rat liver. Hepatology 2000;32:1280–8. 16 Diao J, Garces R, Richardson CD. X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis. Cytokine Growth Factor Rev 2001;12:189–205. 17 Chen GG, Lai PB, Chan PK, et al. Decreased expression of Bid in human hepatocellular carcinoma is related to hepatitis B virus X protein. Eur J Cancer 2001;37:1695–702. 18 Li D, Chen X, Zhang W. The inhibition of apoptosis of hepatoma cells induced by HBx is mediated by up-regulation of survivin expression. J Huazhong Univ Sci Technolog Med Sci 2003;23: 383–6. 19 Kalra N, Kumar V. c-Fos is a mediator of the c-myc-induced apoptotic signaling in serum-deprived hepatoma cells via the p38 mitogen-activated protein kinase pathway. J Biol Chem 2004;279:25313–9. 20 Ikeguchi M, Ueda T, Sakatani T, et al. Expression of survivin messenger RNA correlates with poor prognosis in patients with hepatocellular carcinoma. Diagn Mol Pathol 2002;11:33–40. 21 Ogawa K, Yasumura S, Atarashi Y, et al. Sodium butyrate enhances Fas-mediated apoptosis of human hepatoma cells. J Hepatol 2004;40:278–84. 22 Villunger A, Strasser A. Does death receptor signaling play a role in tumorgenesis and cancer therapy. Oncol Res 1998;10:541– 50.

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23 Pitti R, Marsters S, Lawrence D, et al. Genomic amplification of a decoy receptor for fas ligand in lung and colon cancer. Nature 1998;396:699–703. 24 Joseph B, Ekedahl J, Sirzen F, et al. Differences in the expression of pro-caspase in small cell and non-small cell lung carcinoma. Biochem Biophys Res Comm 1999;262:381–7. 25 Klohn P, Bitsch A, Neumann H. Mitochondrial permeability transition is altered in early stages of carcinogenesisof 2-acetylaminofluorene. Carcinogenesis 1998;19:1185–90. 26 Reed J. Bcl-2 family proteins. Oncogene 1998;17:3225–36. 27 Jäättelä M. Escaping cell death: survival proteins in cancer. Exp Cell Res 1999;248:30–43. 28 Berghella A, Pellegrini P, Contasta I, et al. Bcl-2 and drugs used in the treatment of cancer: new strategies of biotherapie which should not be underestimated. Cancer Biother 1998;13:225–37. 29 Soini Y, Virkajarvi N, Lehto V, Paako P. Hepatocellular carcinoma with high proliferation index and a low degree of apoptosis and necrosis. Br J Cancer 1996;73:1025–30. 30 Terada T, Nakanuma Y. Expression of apoptosis, proliferating cell nuclear antigen, and apoptosis-related antigens (bcl-2, c-myc, Fas, Lewis(y) and p53 in human cholangiocarcinoma and hepatocellular carcinomas. Pathol Int 1996;46:764–70. 31 Soengas M, Alacron R, Yoshida H, et al. Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. Science 1999;284: 156–9. 32 Asker C, Wiman K, Selivanova G. p53-induced apoptosis as a safeguard against cancer. Biochem Biophys Res Comm 1999;265: 1–6. 33 Farazi PA, Glickman J, Horner J, Depinho RA. Cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression. Cancer Res 2006;66:4766–73. 34 Ito T, Shiraki K, Sugimoto K, et al. Survivin promotes cell proliferation in human hepatocellular carcinoma. Hepatology 2000; 31:1080–5. 35 Kaufmann S, Earnshaw W. Induction of apoptosis by cancer chemotherapy. Exp Cell Res 2000;256:42–9.

Induction of Apoptosis in Liver Tumors

36 Hieber U, Heim M. Tumor necrosis factor for the treatment of malignancies. Oncology 1994;51:142–53. 37 Ogasawara J, Watanabe-Fukunaga R, Adachi A, et al. Lethal effect of the anti-Fas antibody in mice. Nature 1993;364: 806–9. 38 Cotter F. Antisense therapy of hematologic malignanvies. Semin Hematol 1999;36:9–14. 39 Ambrosini G, Adida C, Sirugo G, Altieri D. Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting. J Biol Chem 1998;273:11177–82. 40 Dindo D, Dahm F, Szulc Z, et al. Cationic long-chain ceramide LCL-30 induces cell death by mitochondrial targeting in SW403 cells. Mol Cancer Ther 2006;5:1520–9. 41 Di Paola M, Cocco T, Lorusso M. Ceramide interaction with the respiratory chain of heart mitochondria. Biochemistry 2000;39: 6660–8. 42 Modrak DE, Gold DV, Goldenberg DM. Sphingolipid targets in cancer therapy. Mol Cancer Ther 2006;5:200–8. 43 Ruvolo PP, Deng X, Ito T, et al. Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A. J Biol Chem 1999;274:20296–300. 44 Colell A, Garcia-Ruiz C, Mari M, Fernandez-Checa JC. Mitochondrial permeability transition induced by reactive oxygen species is independent of cholesterol-regulated membrane fluidity. FEBS Lett 2004;560:63–8.

Self-assessment answers 1 2 3 4 5

A, B, D B, C B, C A, C C

399

34

Antiangiogenic Agents for Liver Tumors Mathijs Vogten1, Emile E. Voest2, and Inne H. M. Borel Rinkes1 1 2

Department of Surgery, University Medical Center, Utrecht, The Netherlands Department of Medical Oncology, University Medical Center, Utrecht, The Netherlands

Angiogenesis: a new target for cancer therapy Angiogenesis is defined as the formation of new blood vessels from pre-existing microvasculature. The realization that blood vessel formation is an integral part of tumor progression has led to the development of a new subject for cancer research: how to reduce blood vessel growth in tumors. In contrast to previous work (focusing primarily on killing tumor cells), efforts in the field of angiogenesis have concentrated on inhibiting proliferation and migration of the endothelial cell. The increased scientific attention that angiogenesis has received over the last years has yielded many promising results and has provided the basis for a new approach to fighting cancer. The application of experimental knowledge to everyday practice is now being tested in clinical trials involving many antiangiogenic agents. In this chapter we review recent work on basic angiogenesis mechanisms, experimental antiangiogenic treatments, and current clinical studies that evaluate the use of antiangiogenic therapy to combat liver tumors.

Angiogenesis: vessel proliferation All healthy microvessels are lined with endothelial cells (ECs), which are connected by tight junctions and surrounded by a basement membrane and pericytes. In addition to forming vessel lining, ECs are an integral part of the blood coagulation system and the immune response, and they participate in metabolic processes. In steady-state physiologic situations, ECs undergo virtually no proliferation (0.01% of cells are in S-phase at any given time). However, in certain physiologic conditions involving tissue repair (e.g.

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

400

wound healing and liver regeneration), ECs become activated and will proliferate rapidly (with over 25% of cells in S-phase). This physiologic angiogenesis is a self-limiting response, with the spontaneous return of ECs to their nonproliferative state. In addition to cellular insights, understanding at a molecular level has improved over recent years. To date, over 300 signalling compounds that influence angiogenesis have been identified. The main concepts regarding this issue are that angiogenesis modulators can be categorized as positive and negative regulators (Table 34.1), and that control of angiogenesis depends largely on the relative balance of these regulators. In quiescent tissues, positive and negative regulators are balanced and therefore no notable angiogenesis occurs. Changing this balance to a relative excess of positive regulators provides the signal for onset of angiogenesis (termed the angiogenic switch) and will lead to vessel growth in four stages: EC activation, proliferation, migration, and finally tube formation. As the EC undergoes these proliferative events, the surrounding extracellular matrix (ECM) undergoes changes as well. The ECM is an intricate, dynamic network of collagen fibers and other macromolecules that provides structural support for cells. It is clear that angiogenesis is dependent on tightly controlled interactions between cells and the ECM. These interactions are mediated by proteins that selectively bind cells to the ECM (such as the integrin family), and by proteases and their inhibitors (including plasmin, plasminogen activators, metalloproteinases, and their respective inhibitors), which facilitate the controlled breakdown and remodeling of the ECM. Controlled breakdown and remodeling of the ECM is a crucial process in angiogenesis: excessive proteolysis will prevent migrating cells from establishing contact with the ECM (leading to apoptosis), whereas insufficient ECM breakdown will prevent migrating cells from invading surrounding tissues. Balanced proteolysis is a prerequisite for outgrowth of vessels into the surrounding tissue. Finally, the connection of newly formed vessels with existing vasculature will allow for perfusion of the surrounding tissues to occur.

CHAPTER 34

Tumor growth is dependent on angiogenesis

Table 34.1 Positive and negative regulators of angiogenesis. Stimulators

Inhibitors

Fibroblast growth factors (FGFs) Vascular endothelial growth factors (VEGFs) Transforming growth factors (TGFs) Platelet-derived endothelial cell growth factor (PD-ECGF) Angiogenin Placenta growth factor (PIGF) Interleukins (IL-1, -6, -8) Angiotensin Angiotropin Tumor necrosis factor (TNF)

Angiostatin

Hepatocyte growth factor/ scatter factor (HGF/SF) Histamine Heparin

Granulocyte macrophagecolony stimulating factor (GM-CSF) Substance P

Endostatin Thrombospondins Platelet factor 4 (PF-4) Tumor necrosis factor (TNF-α) Transforming growth factor (TGF-β) Interferons (IFNs) Plasminogen activator inhibitors (PAIs) Prolactin fragment Tissue inhibitors of metalloproteinase (TIMP) Placental proliferin-related protein Interleukins (IL-1, -2, -10, -12) Synthetic metalloproteinase inhibitors (MMPIs) (batimastat, marimastat) Hydrocortisone

Thalidomide Tamoxifen Pentosan

Antiangiogenic Agents for Liver Tumors

Tumor hypervascularity has been noted for decades; however, it was not until 1971 that Folkman claimed that hypervascularity of solid tumors could be ascribed to the formation of new blood vessels from pre-existing host blood vessels. The concept behind tumor angiogenesis is as follows. Small tumors and micrometastases (<2 mm3) are diffusion limited for their metabolism, and therefore dormant. For growth beyond this diffusion-limited volume, expansion of tumor vasculature is necessary. This occurs when the angiogenic switch takes place: proangiogenic regulators are upregulated and/or antiangiogenic regulators are downregulated, thereby tilting the balance toward proliferation. After tumors have undergone this angiogenic switch, ECs proliferate and migrate to form new vascular structures (Figure 34.1). Experimental evidence for this hypothesis was summarized by Folkman in 1990 [1] and includes the following observations: • The growth rate of tumors implanted subcutaneously in mice is slow and linear before vascularization, and rapid and near exponential after vascularization. • Tumors grown in isolated perfused organs where blood vessels do not proliferate are limited to 1–2 mm3, but expand rapidly to 1–2 cm3 after vascularization or transplantation to mice.

Tumor

Secretion and signaling

Cellular mediators (e.g. macrophages)

Factors

Angiogenic factors

EC proliferation and migration

Proteases

Breakdown

Extracellular matrix

Figure 34.1 Schematic representation of angiogenesis.

Microvessel lining: endothelial cells (EC)

401

SECTION 6

Emerging Therapies

• Within a solid tumor, the 3H-thymidine labeling index of tumor cells decreases with increasing distance from the nearest open capillary. The mean labeling index for a given tumor is a function of the labeling index of the vascular ECs in that tumor. • Vascular casts of metastases to the liver in rabbits show that these tumors are avascular up to 1 mm in diameter. Beyond that size, tumors are vascularized. • After subcutaneous injection of tumor cells into mice, tumors become vascularized at about 0.4 mm3. With increasing tumor size, the blood vessels occupy approximately 1.5% of the tumor volume, a 400% increase over normal subcutaneous tissue. The tumor infiltrates surrounding connective tissue and expands into the newly formed vessels in that tissue. • Angiogenesis inhibitors that are not cytostatic to tumor cells in vitro inhibit tumor growth in vivo.

Angiogenesis in liver tumors The liver presents a unique microenvironment for the angiogenic process. First, it the main source of plasma proteins, including proangiogenic factors such as hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF). In addition, the liver is the main source for precursors of naturally occurring antiangiogenic compounds: plasminogen (which in its active form modulates breakdown of ECM components) can be converted to angiostatin, and collagen XVIII (a basement membrane component) can be converted to endostatin. It has been noted that the synthesis and secretion of these precursors by the liver may indicate a distinct hepatic function: control of angiogenesis. A final indication that the liver is a distinctive environment for angiogenesis is best illustrated by a study reported by Fukumura et al regarding the influence of host microenvironment on tumor growth [2]. In this study, tumor vasculature in mice bearing either liver metastases or subcutaneous tumors was analyzed in vivo. Liver tumors exhibited lower vessel diameter and lower vessel density than subcutaneous tumors. These findings were consistent with the measurement of lower VEGF mRNA in liver tumor samples compared with tissue from subcutaneous tumors. In contrast, vessel permeability was higher in liver tumors than in subcutaneous tumors, likely the result of a higher degree of fenestration in liver tumor endothelium, which is derived from highly fenestrated sinusoidal endothelium. The above study illustrates the uniqueness of the angiogenic process in the hepatic environment. Current concepts from these and other investigations include the notion that angiogenesis is a heterogeneous process, requiring different mediators in different situations and displaying apparent tissue specificity. This implies that tumor angiogenesis may be different from angiogenesis in physiologic conditions (e.g. liver regeneration).

402

Moreover, it indicates that angiogenesis in liver tumors has unique features that are different from those in other tumors.

Hepatocellular carcinoma Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, accounting for an estimated 600 000 deaths annually and 1 000 000 new cases annually. Surgery is the only curative treatment for HCC, but prognosis after resection remains poor due to a high recurrence rate. Moreover, conventional cytotoxic chemotherapy has not been shown to be effective for HCC. HCC is a hypervascular liver tumor, justifying the study of angiogenic growth mechanisms in HCC progression. One of the first observations in this area, by Gleadle et al, was that cultures of HCC cells under hypoxic conditions produce several angiogenic growth factors, including VEGF [3]. Further investigation into the role of VEGF in HCC has revealed differential overexpression of VEGF and its receptors, and increased expression of VEGF genes, mRNA, and protein, and its receptors in a majority of HCC resection specimens [4, 5]. Moreover, VEGF expression gradually increases with stepwise progression from low-grade to highgrade dysplasia, early HCC, and then advanced HCC [6]. The expression of VEGF has also been found to correlate with histologic characteristics of HCC specimens, including tumor microvessel density (MVD), poor differentiation, nonencapsulation, histologic grade [7], and metastasis [8]. Taken together, these data firmly establish a role for VEGF in the development and progression of HCC. There is other evidence for the involvement of angiogenesis in HCC. Basic fibroblast growth factor and angiopoietin-2 [9] were found to be expressed at a higher level in HCC tissue than in surrounding nontumor tissue. These studies have found that the overexpression of these angiogenic factors in HCC tissue appears to correlate with histologic tumor features, such as hypervascularity, capsular infiltration, and portal vein invasion. More recently, it has been reported that in ECs derived from human HCC, expression levels for several angiogenic genes are higher than in human liver sinusoidal ECs. Functional analysis showed that HCC ECs displayed higher angiogenic ability (i.e. ability to form capillary networks, release of matrix metalloproteinases, proliferation, and fibrinolytic capacity) than normal sinusoidal ECs [10]. Regardless of the array of angiogenic growth factors that may play a role in HCC growth, a relevant issue to be considered is the correlation of MVD in HCC to clinical parameters. Further analysis of tumor samples and clinical records of HCC patients showed that tumor size, poor differentiation, and portal invasion were significantly related to the high MVD subgroup of HCC [11]. In another study, MVD was correlated with intrahepatic recurrence after curative hepatic resection. The authors concluded that MVD can be

CHAPTER 34

Survival rate (%)

100 80 60 40 20 0 20

40 60 Time (months)

80

100

Figure 34.2 Impact of tumor microvessel density (MVD) on disease-free survival (DFS) in hepatocellular carcinoma. Patients with low MVD tumors (blue line) had a significantly better DFS rate than those with high MVD tumors (red line) (log rank; p = 0.0035). The estimated 1-, 3-, and 5-year DFS rates were 73%, 48%, and 42% in patients with low MVD tumors compared with 60%, 16%, and less than 6% in those with high MVD tumors, respectively. (Reproduced from El-Assal et al. Hepatology 1998;27:1554–62, with permission.)

used as an independent predictor of disease-free survival [12] (Figure 34.2). In more recent work, gene profile analysis of subclasses of HCC has revealed that unfavorable HCC subclass (associated with a decreased length of survival and increased MVD [13]) exhibits increased activation of the Ras signaling pathway and subsequent activation of several angiogenic genes, including VEGF and hypoxia-inducible factor 1 alpha (HIF1α) [14]. As patients can clearly benefit from early detection of HCC, levels of angiogenic factors in human blood have been investigated. The first few studies with reasonable series (n ≥ 44) reported elevated concentrations of VEGF in the blood of HCC patients compared to those in non-HCC patients [15]. In a more recent study, serum VEGF was measured prior to tumor resection in 100 HCC patients. Findings included a positive correlation between elevated serum VEGF and absence of tumor capsule, presence of microscopic venous invasion, and advanced disease stage. In addition, it was found that 48% of patients with high VEGF serum concentrations developed postoperative recurrence, compared to 27% of patients with low VEGF concentrations (in a 12-month follow-up period, using a cut-off concentration of 500 pg/mL [16]). Another group has reported on the prognostic value of serum concentrations of several angiogenic factors in 98 patients with resectable HCC with a median follow-up of 43 months. They found that preoperative serum VEGF was increased compared to healthy controls. Multivariate analysis showed that preoperative serum VEGF was a significant independent predictor of disease-free

Antiangiogenic Agents for Liver Tumors

survival and overall survival after surgery [17]. In addition, a recent study reported that microarray analysis of human serum showed higher expression levels for VEGF, plateletderived growth factor (PDGF), tissue inhibitor of metalloproteinases (TIMP), and angiopoietins in HCC patients than in hepatitis C virus (HCV) cirrhosis patients [18]. These studies indicate that serum analysis of VEGF might be useful for monitoring high-risk HCV patients and for the prediction of invasiveness and recurrence of HCC. However, because a wide range of factors (e.g. tumor load, platelets) can influence VEGF expression and release, and because VEGF polymorphisms may be significant prognostic indicators in HCC, the sensitivity and specificity of such assays remain to be determined.

Hepatic metastases A crucial study on the significance of angiogenesis in liver metastases was done by Warren et al [19]. They reported an analysis of liver metastasis samples from 30 colon carcinoma patients that revealed strong VEGF expression in metastatic tumor cells in all samples. In addition, mRNA of two VEGF receptors (KDR and Flt-1) was expressed in hepatic metastases but not in surrounding liver tissue, suggesting that VEGF-driven angiogenic events in hepatic metastases are receptor mediated. Moreover, a positive relationship between VEGF overexpression in the primary tumor and the occurrence of liver metastases has been reported. These investigations strongly suggest that VEGF acts (through its receptor) as a proangiogenic growth factor during the progression of hepatic metastases. In addition, they suggest that VEGF expression in tumors might have predictive value with respect to the development of liver metastases. If activity of VEGF is indeed important for the development of metastases in the liver, then it could be expected that the amount of microvessels present in primary tumors is associated with highly angiogenic tumors and, therefore, the occurrence of liver metastases. There are several reports confirming the hypothesized correlation between MVD and metastasis to the liver. One paper reports a positive correlation between high MVD in colorectal carcinoma and the occurrence of liver metastases [20]. Another study analyzed tissues from 100 colorectal carcinoma patients and found that expression of VEGF correlated with MVD. Moreover, MVD correlated with clinical tumor stage and the occurrence of liver metastasis [21]. In addition, the density of microvessels in metastatic liver tumors was found to be inversely related to disease-free interval following partial hepatic resection for tumor removal [22]. These data suggest that the angiogenic activity in both the primary tumor and metastatic tumor, as measured by MVD, may be predictive of the subsequent development of colorectal liver metastasis after initial curative resection. This hypothesis is supported by the recent observation that plasma concentrations of the angiogenic factors VEGF,

403

SECTION 6

Emerging Therapies

basic fibroblast growth factor (bFGF), EGF, and HGF can identify patients with a low versus high risk of liver metastasis recurrence after hepatectomy [23]. Other factors that are under investigation for their angiogenic roles in the development of liver metastasis progression include Thomsen–Friedenreich-related antigen (TF), platelet-derived EC growth factor (PD-ECGF), TIMP, interleukin (IL)-8, CD2, CD14, CD44, transforming growth factor (TGF)-β, and the angiopoietins. Evidence for the involvement of these proteins is mounting, and more research is necessary before considering their application in the management of hepatic metastases. The advent of new molecular techniques, such as microarray gene expression profiling and antisense oligonucleotides, can provide powerful tools to facilitate the identification of new therapeutic targets. A relatively new technique that has been used to investigate tumor microcirculation is intravital microscopy (IVM). This technique combines the advantages of selective fluorescent labeling of cells (tumor cells, hepatocytes, EC, etc) with real-time video imaging and computer image analysis. Experimental animal models provide useful tools for studying various aspects of the metastatic process in the liver using IVM. Fukumura et al described increased vascular permeability in a liver metastasis model, providing key evidence for host specificity in angiogenesis [24]. Naumov et al delivered an interesting account in another paper of fluorescentlabeled tumor cells metastasizing to the liver [25]. IVM was elegantly employed to visualize the different steps of metastasis, including arrest of tumor cells in the liver microvasculature, extravasation, growth into micrometastases, and continued growth into macroscopic tumors in which angiogenesis has taken place. In addition, Gervaz et al have studied the role of sinusoidal endothelial cells (SECs) in angiogenesis during growth of liver metastases. Fluorescent labeling of SECs in tumor-bearing mice and subsequent IVM revealed that tumor vessels contained ECs of sinusoidal origin. Furthermore, labelled SECs were initially found at the periphery of intrahepatic tumors; however, when tumors grew beyond 200 μm, there was an invasion of fluorescent SECs into the tumor in a tubular pattern, indicating angiogenesis [26]. These studies illustrate that the combination of microbiologic techniques with advanced intravital imaging will help provide valuable insights to angiogenesis, encouraging the continued development of antiangiogenic agents.

Antiangiogenic agents Due to the various stages that comprise angiogenesis (breakdown of surrounding matrix, EC activation, proliferation, migration, and tube formation) and the vast array of growth factors, receptors, and signalling pathways mediating these events, extensive efforts in basic research have provided a wide variety of potential antiangiogenic drugs that are being

404

Table 34.2 Clinical trials with antiangiogenic drugs for primary or metastatic liver tumors. Most compounds are administered in combination with other treatment modalities including surgical resection, local ablation, radiotherapy and multidrug chemotherapy schemes. (Source www.cancer.gov, accessed 10 Dec 2007.) Drug

Phase

Category

Arginine deiminase AZD2171

I, II II

Prevents NO synthesis Anti-VEGFR

Bevacizumab (Avastin®)

II, III

Anti-VEGF

Brivanib

I, II

Anti-VEGFR

Cetuximab (Erbitux®)

I, II, III

Anti-EGFR

Erlotinib (Tarceva®)

I, II

Anti-EGFR

Pazopanib

I

Anti-VEGFR

Sorafenib (Nexavar®)

II

Anti-VEGFR, anti-PDGFR

Sunitinib (Sutent®)

I, II

Anti-VEGFR, anti-PDGFR

Thalidomide

III

Unknown

Vandetanib (Zactima®)

II

Anti-VEGFR

EGFR, epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor.

tested in clinical trials (Table 34.2). As the first indications for antiangiogenic action are mostly the result of in vitro and in vivo animal experiments, results from these pioneering studies need to be interpreted with caution. Issues such as side effects, drug mechanisms of action, and extrapolation from murine to human situations have yet to be resolved. Nevertheless, preliminary results are promising and certainly warrant clinical testing of these compounds. An interpretive review on this subject has been published [27] and illustrates the potential of angiogenesis inhibition as a successful cancer therapy.

Inhibition of angiogenic factors Inhibition of vascular endothelial growth factor Together with their findings of increased expression of VEGF and its receptors in human liver metastasis tissue, Ferrara’s group also reported proof of concept that VEGF targeting can be used to counter tumor progression. In a mouse model of hepatic metastases, animals receiving anti-VEGF antibody showed a 10-fold reduction in the number of metastases and an 18-fold reduction in estimated metastasis volume compared to control mice. In addition, an abundance of smaller (<1 mm), poorly vascularized tumors was noted in livers from mice treated with anti-VEGF antibody (as opposed to an abundance of larger tumors with extensive vascularization in untreated controls) (Figure 34.3), providing further evidence for antiangiogenic activity in these experiments [28]. Other researchers have applied the concept of VEGF

CHAPTER 34

Control mAb

Anti-VEGF mAb

Figure 34.3 Neutralizing antibody to human vascular endothelial growth factor (VEGF) inhibits growth of experimental hepatic metastases in mice 4 weeks after tumor inoculation. (Reproduced from Warren et al [19], with permission.)

inhibition to HCC. Yoshiji et al reported an interesting model in which VEGF expression can selectively be switched off and on by adding or removing tetracycline in the animal’s drinking water. In HCC-bearing mice, the degree of tumor growth corresponded with the level of VEGF expression. Conversely, suppression of VEGF expression led to decreased tumor growth, even in established carcinomas. In addition, the observed stimulation of tumor growth by VEGF could be negated by administrating anti-KDR/Flk-1 antibody, providing elegant evidence that the stimulatory effect by VEGF on HCC is receptor mediated [29]. Ellis et al have reported that VEGF (receptor-mediated) events not only mediate formation of tumor vasculature, but also function as EC survival factor [30]. This group has extensively investigated VEGF in tumor models and has reported a decrease of tumor MVD in conjunction with increased apoptosis of ECs in tumor-bearing mice treated with the VEGF receptor antagonists DC101, SU6668, and SU5416 [31]. These data have prompted the evaluation of VEGF inhibitors in clinical trials. Bevacizumab (BV), a recombinant humanized monoclonal antibody against VEGF, has been tested in metastatic colon cancer in combination with conventional chemotherapy regimens. In a phase II trial, 104 previously untreated patients with metastatic disease were randomly assigned to receive 5-fluorouracil (5-FV)/leucovorin (LV), 5-FU/LV and low-dose BV, or 5-FU/LV and high-dose BV. Median survival was 13.8 months in the 5-FU/LV arm, 21.5 months in the 5-FU/LV/low-dose BV arm, and 16.1 months in the 5-FU/LV/high-dose BV arm. The most significant side effects were thrombosis (fatal in one patient), hypertension, proteinuria, and epistaxis [32]. These results prompted a phase III study that included 813 patients with previously untreated metastatic colon cancer. Patients were randomly assigned to receive irinotecan, 5-FU, and leucovorin (IFL) plus BV (n = 402), or IFL plus placebo (n = 411). Median duration

Antiangiogenic Agents for Liver Tumors

of survival was 20.3 months in the IFL/BV group compared to 15.6 months in the IFL/placebo group (hazard ratio for death, 0.66; p < 0.001). Progression-free survival was 10.6 months in the IFL/BV group and 6.2 months in the IFL/ placebo group (hazard ratio for progression, 0.54; p < 0.001). The median duration of the response was 10.4 months in the IFL/BV group and 7.1 months in the IFL/placebo group (hazard ratio for progression, 0.62; p = 0.001). Grade 3 hypertension was more common in the IFL/BV group than in the IFL/placebo group (11% versus 2.3%; p < 0.01). The authors concluded that the addition of BV to combination chemotherapy treatment results in improved survival in metastatic colorectal cancer (CRC) patients [33] (Figure 34.4). An additional report after inclusion of a third cohort showed similar results [34]. In a report by the same group, data from three clinical trials were pooled to analyse the efficacy of adding BV to the first-line 5-FU/LV chemotherapy in patients with previously untreated metastatic colon cancer. This combined analysis resulted in the inclusion of 241 patients receiving either FU/LV or IFL, and 249 patients receiving 5-FU/LV/ BV. Results showed an increase in median survival from 14.6 months in the control group to 17.9 months in the FU/ LV/BV group, corresponding to a hazard ratio for death of 0.74 (p = 0.008). Median duration of progression-free survival increased from 5.6 months in the control group to 8.8 months in the FU/LV/BV group (hazard ratio for disease progression, 0.63; p < 0.001) [35]. Systematic review of three randomized clinical trials substantiated these findings but concluded that this improvement in overall survival and disease-free progression comes at considerable financial cost. The authors provide suggestions for further research, including the optimal role for BV alongside sequences of conventional chemotherapy and the impact of BV treatment on quality of life [36]. Recently, BV treatment in combination with oxaliplatin, 5-FU, and LV (FOLFOX4) for previously treated metastatic colon cancer was tested in a randomized clinical trial [37]. Eight hundred twenty nine patients previously treated with fluoropyrimidine and irinotecan were randomized to receive FOLFOX4 plus BV, FOLFOX4 without BV, or BV alone. Median overall survival was 10.2 months for patients treated with BV alone, 10.8 months for patients treated with FOLFOX4 alone, and 12.9 months for patients treated with FOLFOX4/BV (hazard ratio for death, 0.75; FOLFOX4/BV versus FOLFOX4 alone, p = 0.0011). The median progression-free survival for the group treated with FOLFOX4/BV was 7.3 months, compared with 4.7 months in the group treated with FOLFOX4 alone (hazard ratio for progression, 0.61; p < 0.001) and 2.7 months in patients treated with BV alone. Side effects of BV that were statistically significant included hypertension, bleeding, and vomiting.

405

SECTION 6

Emerging Therapies

Overall survival (%)

100 15.6

80

20.3

60 40 IFL + bevacizumab 20

IFL + placebo

0 0

20

10

30

40

Time (months) Number at risk IFL + bevacizumab IFL + placebo

402 411

362 363

320 292

178 139

73 51

20 12

Similarly, the addition of BV to standard chemotherapy has proven to prolong disease-free survival (but not overall survival) in metastatic breast cancer patients treated with paclitaxel (11.8 versus 5.9 months; hazard ratio of progression, 0.6; p < 0.001) [38]. Hypertension, proteinuria, headache, infection, and cerebral ischemia were significantly increased in the BV arm. In another study of metastatic breast cancer patients, however, addition of BV to capecitabine, although significantly improving response rate, did not prolong progression-free survival or overall survival [39]. Similarly, metastatic renal cell carcinoma patients treated with BV and interferon-alpha (IFN-α) have increased progression-free survival compared to treatment with IFN-α alone (10.2 versus 5.4 months, respectively; hazard ratio, 063; p < 0.0001) [40]. Together, these results support the use of BV in firstand second-line treatment of metastatic colon cancer and certainly warrant further inclusion of BV in chemotherapy schedules in other metastatic disease. As the use of BV in patients who are to undergo hepatic resection for metastatic disease will become more frequent, the influence of BV treatment on hepatic resection was recently investigated in a retrospective study. Fifty-seven patients underwent hepatic resection after treatment with irinotecan/ oxaliplatin alone, whereas 39 patients were treated with irinotecan/oxaliplatin/BV prior to surgery. There were no differences in overall complications (43.6% versus 38.6%), severe complications (28.2% versus 24.6%), hepatic complications (17.9% versus 26.3%), wound complications (10.3% versus 7%), or thromboembolic or bleeding (2.6% versus 5.3%) complications (all p > 0.05). However, although not statistically significant, overall complications were more common in patients in the irinotecan/oxalipla-

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1 0

0 0

Figure 34.4 Kaplan–Meier estimates of survival in metastatic colorectal patients. The median duration of survival (indicated by the dotted lines) was 20.3 months in the irinotecan, 5-fluorouracil, and leucovorin (IFL) + bevacizumab group, as compared with 15.6 months in the IFL + placebo, corresponding to a hazard ratio for death of 0.66 (p < 0.001). (Reproduced from Hurwitz et al [33], with permission.)

tin/BV group when resection was performed within 8 weeks after the last BV dose (62.5% versus 30.4%; p = 0.06) [41].

Epidermal growth factor inhibitors Epidermal growth factor (EGF) can induce VEGF production in tumor cells, and the EGF receptor is highly expressed in several types of cancer cells, including metastatic colon carcinoma. Moreover, the expression of the EGF receptor (EGFR) is directly correlated with the ability to form hepatic metastases in vivo. Therefore, researchers have sought to reduce the development of liver metastases by blocking the EGF receptor. Indeed, when a blocking agent of EGFR (PKI166) was administered orally for 4 weeks, the development of liver metastases was significantly inhibited [42]. Similar results were achieved with administration of the anti-EGFR antibody C225 (cetuximab). After systemic therapy, liver metastases from pancreatic cancer were present in 20% of C225-treated animals, compared to 50% of control animals [43]. Findings of reduced tumor growth in both studies were correlated with decreased production of VEGF and IL-8 by the tumor, which in turn was associated with increased EC apoptosis and decreased MVD in treated tumors, suggesting an antiangiogenic mechanism for these agents. These preclinical results have led to the application of cetuximab in clinical trials. In a randomized trial that included 329 patients with metastatic colon cancer refractory to irinotecan treatment, the addition of cetuximab to treatment (as a single agent or in combination with irinotecan) led to a significant increase in response rate, time to disease progression, and median survival [44]. In a phase II study on first-line combination treatment including cetuximab that enrolled 43 patients with metastatic colon cancer,

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Tyrosine kinase inhibitors The biologic functions of VEGF are mediated by binding to receptor tyrosine kinases VEGF-R1 (Flt-1), VEGF-R2 (KDR/ Flk-1), and VEGF-R3 (Flt-4). Binding of a ligand to its receptor subtype assembles a specific set of signaling molecules, leading to specific signal transduction, e.g. the Ras-dependent signaling pathway. Targeting these pathways in cancer has yielded promising new therapeutic options in recent years. Sorafenib is an orally administered multikinase inhibitor that acts on Raf kinase and VEGF-R2. Sorafenib was first approved for advanced renal cell carcinoma, and subsequent phase I studies in pancreatic, ovarian, colorectal, and hepatocellular cancers showed good tolerance. A phase II trial in 137 HCC patients taking sorafenib reported median time to progression of 4.2 months and stable disease for at least 16 weeks in 33.6% of patients [49]. Further analysis showed that patients whose tumors expressed higher baseline levels of phosphorylated extracellular signal-regulated kinase (ERK) (a downstream signaling molecule of Raf) had significantly longer time to progression than those with lower expression levels of ERK. In concordance with these preliminary data, a randomized controlled trial of sorafenib versus placebo in 602 HCC patients reported improved survival (10.7 versus 7.9 months) and longer time to progression (5.5 versus 2.8 months) in the sorafenib group [50]. Adverse effects included skin reactions and hypertension. These results have led to the recent Food and Drug Administration (FDA) approving sorafenib for advanced liver cancer. Numerous other tyrosine kinase inhibitors (including imatinib and sunitinib) are currently being evaluated in clinical trials.

Endogenous antiangiogenic compounds Angiostatin Angiostatin, a naturally occurring proteolytic fragment of plasminogen, is one of the most potent antiangiogenic compounds to date. Angiostatin was discovered in tumorbearing mice as an endogenous peptide generated by the primary tumor, and capable of suppressing metastases growth. After removal of the primary tumor, metastases became vascularized and displayed accelerated growth. Interestingly, angiostatin from these mice was not able to prevent propagation of the primary tumor. This finding was attributed to local production of proangiogenic factors by the tumor, which outweighed the antiangiogenic regulators such as angiostatin, shifting the angiogenic balance toward vessel formation. In contrast, exogenous angiostatin has been shown to effectively suppress growth of primary tumors in mice, regardless of tumor cell type [51]. As residual dormant micrometastases in the remaining liver also display stimulated growth after partial hepatic resection, Drixler et al hypothesized that exogenously administered angiostatin could suppress this outgrowth of dormant micrometastases after partial hepatectomy. In a mouse model, outgrowth of colorectal liver metastases in the remnant liver was inhibited by 60% and 49% in mice treated with angiostatin for 7 and 14 days, respectively, compared to untreated mice [52] (Figure 34.5). Naturally occurring angiostatin appears to play a role in HCC as well. In resected tissue specimens from HCC patients, human macrophage elastase (HME, an enzyme believed to play a role in angiostatin generation from plasminogen) and endogenous angiostatin were analyzed. HME mRNA was detected in HCC samples, primarily located in HCC tumor cells. The presence of angiostatin in these tissues was shown to correlate with HME expression. Interestingly, patients

80 Hepatic replacement area (%)

response rate was 72% and median progression-free survival rate was 12.3 months [45]. Moreover, 10 patients (23%) underwent resection with curative intent of previously unresectable liver metastases. In another report on patients with iridotecan-refractory metastases, treatment with irinotecan, BV, and cetuximab showed increased activity in terms of time to tumor progression and response rate compared to treatment with cetuximab with or without irinotecan [46]. In patients with metastatic colon carcinoma who progressed after oxaliplatin-based chemotherapy, the addition of cetuximab to a treatment regimen showed an overall response rate of 20%, whereas 27% of patients showed stable disease [47]. These results warrant further investigation of cetuximab in the treatment of metastatic colon cancer. Moreover, these trials may also lead to an increase in the number of metastatic patients who become eligible for potentially curative resection of previously unresectable liver metastases [48]. Other EGF inhibitors that are currently being tested in clinical trails include panitumumab, matuzumab, nimotuzumab, and zalutumumab.

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70 60 50 40 30 20 10 0

PH PH + AS POD7

PH PH + AS POD14

Figure 34.5 Angiostatin (AS) inhibits outgrowth of colorectal liver metastases in remnant liver 7 (POD7) and 14 (POD14) days after partial hepatectomy (PH). (Reproduced from Drixler et al [52], with permission.)

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whose tumors did not express HME (and thus did not produce angiostatin) showed poorer survival than those whose tumors showed high expression of HME and angiostatin. HME gene expression was associated with hypovascularity of HCC tumors on hepatic angiography [53]. These data suggest that HME-mediated angiostatin production inhibits angiogenesis of HCC and that HME expression is a potential prognostic marker for HCC patients after partial hepatectomy.

Endostatin Endostatin was discovered as a product of hemangioendothelioma cells and is a naturally occurring proteolytic fragment derived from collagen XVIII. The antiangiogenic effects of endostatin have been attributed to inhibition of EC proliferation and migration, resulting in decreased tumor vascularity and tumor regression, including inhibition of liver metastasis. Serum concentrations of endostatin are elevated in CRC patients with liver metastases and correlate with disease progression following surgery. From these results a number of important questions arise: Which cells regulate production and cleavage of collagen and endostatin? Why does a tumor produce an antiangiogenic compound, basically inhibiting its own angiogenesis and progression? Which signaling mechanisms, paracrine or other, are at work? Musso et al have investigated the production of endostatin precursor by the liver. Analysis of human HCC samples revealed that a lower expression of collagen XVIII is associated with larger tumor size, increased microvessel density, and architectural features associated with tumor progression, indicating that expression of the endostatin precursor decreases with tumor progression in HCC. Hepatocytes, stromal cells, and malignant hepatocytes all produce collagen XVIII, albeit in different isoforms. The authors concluded that production of the endostatin precursor in liver cancer results from combined expression profiles of tumor cells, stromal cells, and hepatocytes particular to each type of cancer [54]. Even though the exact mechanism of action of endostatin remains to be elucidated, the promising results that have been achieved so far have led to the admission of endostatin to clinical trials. Recent reports have tested whether adenoviral gene vectors can induce high circulating levels of antiangiogenic drugs in a tumor-bearing host. In mice, adenoviral vectors encoding for angiostatin, but not the vector encoding for endostatin, inhibited tumor growth in models for metastatic colon carcinoma and HCC.

Thalidomide Thalidomide was first introduced in 1953 as an oral sedative. After withdrawal for teratogenicity, it was reintroduced as an immunomodulator. Additional insight into the biologic effects of thalidomide revealed antiangiogenic activity, including inhibition of bFGF- and VEGF-induced vessel

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growth. These findings have prompted its application to cancer treatment. Initial clinical testing of thalidomide in HCC patients reported antitumor activity. The most important side effect appears to be drowsiness. Interestingly, disease stability was associated with an increase in survival, even in patients with progressive disease. In a recent retrospective study of 45 patients who were not eligible for surgery or locoregional therapy, treatment with thalidomide showed modest clinical activity (5% partial response and 21% stable disease) and an overall median survival of 3.2 months [55]. Taken together, these reports suggest that thalidomide could be considered for treatment of advanced HCC.

Protease inhibitors The concept behind protease inhibitors as antiangiogenic agents is that breakdown and remodeling of the ECM is an integral part of angiogenesis and tumor progression. Experimental evidence includes observations that tumor growth is impaired in metalloproteinase-deficient mice and that tumor growth can be inhibited by inhibition of metalloproteinase activity. Synthetic metalloproteinase inhibitors (MMPIs) have long been regarded as a promising category of antiangiogenic drugs; experimental testing with these drugs has indeed demonstrated antimetastatic activity. In one study using a murine liver metastasis model, a reduced number of liver metastases was observed in mice treated with batimastat for several weeks. Studies with marimastat, a synthetic MMPI that can be administered orally, also have produced promising initial results; therefore, marimastat has been evaluated for treatment of pancreatic cancer. Problems with these broad-spectrum MMPIs have been encountered, however. Administration of MMPIs has produced severe side effects, mainly of musculoskeletal origin (e.g. arthritis). In addition, experimental studies have reported adverse effects after MMPI use. Tumor-bearing mice treated with batimastat were found to have a higher number of liver metastases 52 days after tumor inoculation as compared to untreated controls. At the same time, overexpression of metalloproteinases was found in livers of batimastat-treated animals [56]. This study indicates that treatment with synthetic MMPIs can induce liver-specific overexpression of metalloproteinases, which can actually promote hepatic tumor progression. Moreover, clinical efficacy of broad-spectrum MMPIs has been disappointing. These poor results have been explained by additional experimental data that MMPs appear to be important in early stages of tumor progression (local invasion and micrometastasis) but have been tested in late-stage cancer patients in whom metastases were already established. The development of selective MMPIs may have significant clinical advantages by reducing side effects and improving efficacy for selected tumors. For example, a phase I study with BAY12-9566, an MMPI selective for MMP-2, -3, and

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-9, reported minimal toxicity, absence of musculoskeletal side effects, and adequate dose tolerance [57]. Taken together, these reports urge further efforts in preclinical aspects of protease inhibition before therapeutics can be tested in clinical setting. New insights into protease inhibitors and their exact role in tumor progression and angiogenesis need to be understood in detail before this aspect of antiangiogenic treatment can be applied safely.

Vascular targeting Vascular targeting is a therapy aimed directly against existing tumor vasculature, rather than tumor cells or the development of new blood vessels. Attacking a tumor’s vasculature has several advantages over attacking tumor cells, including accessibility of tumor ECs, reduction of side effects due to regional administration, and lack of drug resistance due to genetic stability of ECs. One of the first examples of vascular targeting was reported in the early 1970s when surgeons attempted to induce tumor necrosis by hepatic artery ligation in patients with primary and secondary hepatic neoplasms. An example of vascular targeting in the treatment of liver tumors is chemoembolization, which can be used to treat HCC. Another example of vascular targeting is isolated limb perfusion. One paper reports that isolated limb perfusion of melanoma patients with tissue necrosis factor-alpha and IFN-γ causes detachment and apoptosis of angiogenic ECs. This effect is mediated by the integrin αvβ3, an EC adhesion receptor that plays an important role in angiogenesis. Antibody-mediated vascular targeting also has been examined. The ideal antibody for vascular targeting of solid tumors recognizes a cell surface antigen that is present on a high proportion of ECs in different tumors and shows no cross-reactivity with endothelium in nontumorous tissue. Possible antigen candidates include integrins, receptors for VEGF, uPA, and angiopoietins. One study reported on the effect of the vascular targeting agent ZD 6126 in a liver metastasis model in mice. After a single dose treatment with ZD 6126, histology revealed a significant reduction in hepatic tumor load and increased tumor necrosis associated with a reduction in tumor-associated vasculature. IVM of these livers revealed disrupted, nonfunctional vascular channels without blood flow in metastatic lesions [58]. Several vascular targeting agents are currently being evaluated in clinical trials [59].

Combination of antiangiogenic drugs with conventional treatment modalities The concept that antiangiogenic therapy specifically targets the EC has led to the idea of combining antiangiogenic drugs with conventional treatment modalities to achieve syner-

Antiangiogenic Agents for Liver Tumors

gism in tumor inhibition. This idea of targeting two cell populations important for tumor progression has been supported by experimental findings. In a study from our group, mice were subjected to induction of liver metastases and subsequently received angiostatin or endostatin in combination with a conventional chemotherapeutic, doxorubicin. Mice treated with both angiostatin and doxorubicin showed a greater reduction in tumor hepatic replacement area (HRA) compared to mice treated with either angiostatin or doxorubicin alone. Combination treatment of similar mice with endostatin/doxorubicin also showed a greater reduction of HRA compared to mice treated with either drug alone [60]. Indeed, the combination of antiangiogenic compounds with conventional treatment modalities is a fundamental concept in current clinical practice. Examples include the combination of VEGF inhibitors BV [61] and cetuximab with conventional chemotherapy for treatment of metastatic disease and HCC, but also the treatment of patients with unresectable liver metastases to downsize liver metastases prior to surgery, increasing the possibility of performing curative resection [62]. The efficacy of combination therapy could very well be dependent on the “vascular status” of the tumor, including perfusion dynamics and permeability. The importance of this concept has been demonstrated by the group of Jain. One study reports the presence of so-called “mosaic” vessels in various tumors. It was shown that approximately 15% of perfused vessels of colon carcinoma xenografts have tumor cells in contact with vessel lumen [63]. In addition, it was shown that vasculature from various tumors has a characteristic pore cut-off size that limits permeability. This pore size is tumor specific and hormone dependent. These studies show that the vascular status of various tumors has important implications for drug delivery and provide important insights into potential strategies for combining antiangiogenic agents with conventional anticancer drugs. Tumor vessels are leaky, which results in elevation of interstitial fluid pressure and a hostile microenvironment characterized by hypoxia and acidosis. These conditions may facilitate metastasis and hinder the delivery and effectiveness of conventional therapeutic agents such as radiation therapy and chemotherapy. The manipulation of pro- and anti-angiogenic factors in tumor vasculature may in fact “normalize” blood vessels and improve delivery of cytotoxic agents, and may therefore prove to be of use in combination therapy schemes.

Future perspectives It is clear that antiangiogenic therapy has become a new paradigm in oncology, including for both primary and metastatic liver tumors. Insights into the process of angiogenesis have provided several categories of antiangiogenic agents

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that are currently being tested in clinical trials; however, there are still several difficulties that remain to be overcome. First, the concept behind antiangiogenic therapy is that instead of killing tumor cells, it builds a diffusionlimited barrier for tumors by inhibiting new vessel growth. The usefulness of this strategy is illustrated by the relatively high incidence of tumors found in autopsy studies. As the actual incidence is much higher than the clinical incidence of many tumors, a considerable portion of tumors in the general population is subclinical. Therefore, the reduction of clinically apparent tumors to a level below this “clinical threshold” could be adequate anticancer therapy. Consequently, rather than evaluating tumor regression per se, clinical evaluation of antiangiogenic drugs should include survival and time to progression as endpoints. In accordance with this angiogenic barrier concept, the first indications from human studies are that antiangiogenic drugs will probably be most effective when administered for prolonged periods of time. Studies of the possible side effects of antiangiogenic drugs will need to incorporate this concept into their design. On the other hand, this concept has been the starting point for preclinical studies that apply gene transfection techniques to develop antiangiogenic vaccine therapy in which the tumor produces its own antiangiogenic treatment. These insights have resulted in the development of new criteria for antiangiogenic drug testing by the Angiogenesis Foundation. The investigation of the above-mentioned issues and the combination of antiangiogenic drugs with other treatment modalities – including surgery, radiation therapy, vascular targeting, and cytotoxic drugs – should facilitate optimal application of antiangiogenic therapy to liver tumors. The abundant support from preclinical models for the hypothesis that tumor growth is angiogenesis dependent has ignited great enthusiasm for the development of antiangiogenic agents for treatment of liver malignancies. However, it must be kept in mind that this area of research is new and that the mature use of these agents may require extensive clinical investigations that may take several years to complete.

Self-assessment questions 1 What is the evidence from experimental studies that liver metastases is angiogenesis dependent? (more than one answer is possible) A Antiangiogenic drugs are cytotoxic to tumor cells in culture B Vascular casts of metastases to the liver in rabbits show that these tumors are avascular up to 1 mm in diameter. Beyond that size, tumors are vascularized

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C In mice with liver metastases, removal of the primary tumor results in reduction in growth rate of liver metastases D Neutralizing antibody to human vascular endothelial growth factor inhibits growth of experimental hepatic metastases in mice 4 weeks after tumor inoculation E Gene profile analysis of subclasses of hepatocellular carcinoma (HCC) has revealed that unfavorable HCC subclass exhibits increased activation of the Ras signaling pathway and subsequent activation of several angiogenic genes 2 What was the first antiangiogenic substance that was FDA approved for the treatment of liver metastases and what is its mechanism of action? A Angiostatin; its mechanism is, to date, unknown B Angiostatin; it binds to and inactivates vascular endothelial growth factor (VEGF) C Endostatin; it binds to and inactivates VEGF D Bevacizumab; its mechanism is, to date, unknown E Bevacizumab; it binds to and inactivates VEGF 3 Which of the following are reasons for the continued analysis and evaluation of the clinical application of antiangiogenic drugs for liver tumors? (more than one answer is possible): A They will eventually prove to be ineffective B Survival of hepatocellular carcinoma (HCC) and liver metastasis patients is still relatively poor compared to some other malignancies C Combination with conventional chemotherapeutics appears to yield best results D Surgery is the only curative treatment to date for HCC and liver metastases and cannot be augmented by antiangiogenic drugs E Surgery is the only curative treatment to date for HCC and liver metastases and could be augmented by antiangiogenic drugs 4 The use of antiangiogenic drugs such as bevacizumab has great potential consequence for liver surgery because less than 50% of patients with liver metastasis are eligible for curative resection. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 5 Which of the following are reasons why normalizing tumor vasculature (instead of destroying it) can be of clinical use? (more than one answer is possible)

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A Antiangiogenic drugs only work on normal blood vessels B Delivery of conventional chemotherapeutic drugs is improved by normalizing tumor vasculature C Appearance of normal blood vessels facilitates tumor imaging on computed tomography D Tumor microenvironment is hostile to radiotherapy E Abnormal tumor microvasculature may favor tumor cell dissemination and metastasis

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31 Shaheen RM, Tseng WW, Vellagas R, et al. Effects of an antibody to vascular endothelial growth factor receptor-2 on survival, tumor vascularity, and apoptosis in a murine model of colon carcinomatosis. Int J Oncol 2001;18:221–6. 32 Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/ leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003;21:60–5. 33 Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–42. 34 Hurwitz HI, Fehrenbacher L, Hainsworth JD, et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol 2005;23:3502–8. 35 Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar S. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 2005;23: 3706–12. 36 Tappenden P, Jones R, Paisley S, Carroll C. Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. Health Technol Assess 2007;11:1–128. 37 Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25:1539–44. 38 Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357:2666–76. 39 Ulukus M, Ulukus EC, Seval Y, Zheng W, Arici A. Expression of interleukin-8 receptors in endometriosis. Hum Reprod 2005;20: 794–801. 40 Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007;370:2103–11. 41 Reddy SK, Morse MA, Hurwitz HI, et al. Addition of bevacizumab to irinot. J Am Coll Surg 2008;206:96–106. 42 Bruns CJ, Solorzano CC, Harbison MT, et al. Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res 2000;60: 2926–35. 43 Bruns CJ, Harbison MT, Davis DW, et al. Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res 2000;6:1936–48. 44 Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337– 45. 45 Tabernero J, Van Cutsem E, Diaz-Rubio E, et al. Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2007;25:5225–32.

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46 Saltz LB, Lenz HJ, Kindler HL, et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol 2007;25: 4557–61. 47 Souglakos J, Kalykaki A, Vamvakas L, et al. Phase II trial of capecitabine and oxaliplatin (CAPOX) plus cetuximab in patients with metastatic colorectal cancer who progressed after oxaliplatin-based chemotherapy. Ann Oncol 2007;18: 305–10. 48 Lee JJ, Chu E. First-line use of anti-epidermal growth factor receptor monoclonal antibodies in metastatic colorectal cancer. Clin Colorectal Cancer 2007;6 (Suppl 2):S42–S46. 49 Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006;24:4293–300. 50 Llovet J, Ricci S, Mazzaffero V, Hilgard P, Raoul J, Zeuzem S. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–90. 51 O’Reilly MS, Holmgren L, Chen C, Folkman J. Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 1996;2:689–92. 52 Drixler TA, Rinkes IH, Ritchie ED, van Vroonhoven TJ, Gebbink MF, Voest EE. Continuous administration of angiostatin inhibits accelerated growth of colorectal liver metastases after partial hepatectomy. Cancer Res 2000;60:1761–5. 53 Gorrin-Rivas MJ, Arii S, Mori A, et al. Implications of human macrophage metalloelastase and vascular endothelial growth factor gene expression in angiogenesis of hepatocellular carcinoma. Ann Surg 2000;231:67–73. 54 Musso O, Theret N, Heljasvaara R, et al. Tumor hepatocytes and basement membrane-Producing cells specifically express two different forms of the endostatin precursor, collagen XVIII, in human liver cancers. Hepatology 2001;33:868– 76. 55 Yau T, Chan P, Wong H, et al. Efficacy and tolerability of lowdose thalidomide as first-line systemic treatment of patients with advanced hepatocellular carcinoma. Oncology 2007;72 (Suppl 1):67–71. 56 Kruger A, Soeltl R, Sopov I, et al. Hydroxamate-type matrix metalloproteinase inhibitor batimastat promotes liver metastasis. Cancer Res 2001;61:1272–5. 57 Heath EI, O’Reilly S, Humphrey R, et al. Phase I trial of the matrix metalloproteinase inhibitor BAY12-9566 in patients with advanced solid tumors. Cancer Chemother Pharmacol 2001;48: 269–74. 58 Varghese HJ, Mackenzie LT, Groom AC, et al. In vivo videomicroscopy reveals differential effects of the vascular-targeting agent ZD6126 and the anti-angiogenic agent ZD6474 on vascular function in a liver metastasis model. Angiogenesis 2004;7: 157–64. 59 Tozer GM, Kanthou C, Baguley BC. Disrupting tumour blood vessels. Nat Rev Cancer 2005;5:423–35. 60 te Velde EA, Vogten JM, Gebbink MF, van Gorp JM, Voest EE, Borel RI. Enhanced antitumour efficacy by combining conventional chemotherapy with angiostatin or endostatin in a liver metastasis model. Br J Surg 2002;89:1302–9. 61 Zhu AX, Blaszkowsky LS, Ryan DP, et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in

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patients with advanced hepatocellular carcinoma. J Clin Oncol 2006;24:1898–1903. 62 Min BS, Kim NK, Ahn JB, et al. Cetuximab in combination with 5-fluorouracil, leucovorin and irinotecan as a neoadjuvant chemotherapy in patients with initially unresectable colorectal liver metastases. Onkologie 2007;30:637–43. 63 Chang YS, di Tomaso E, McDonald DM, Jones R, Jain RK, Munn LL. Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc Natl Acad Sci U S A 2000;97:14608–13.

Antiangiogenic Agents for Liver Tumors

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Integrative Oncology: Alternative and Complementary Treatments Barrie R. Cassileth and Jyothirmai Gubili Integrative Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Introduction Numerous disparate approaches, from clearly bogus cancer “cures” to soothing, adjunctive regimens, are subsumed under single umbrella terms such as “complementary,” “alternative” or “complementary and alternative medicine,” known commonly by the acronym “CAM.” Although often discussed in the aggregate, it is necessary to distinguish between the two categories because they comprise profoundly different therapies. Alternative approaches usually are promoted as viable cancer treatments, often as literal alternatives to mainstream therapy. By definition, however, alternative therapies are unproved. If they were backed by solid data, they would be not alternative, but rather used in oncology settings as viable cancer treatments. Alternative regimens typically are invasive and biologically active. They tend to be very costly. They may harm directly through physiologic activity, or indirectly when patients are persuaded to postpone receipt of mainstream care. Late-stage patients are especially vulnerable to these therapies, as promoters often promise cure even in advanced disease. By contrast, complementary therapies are used as adjuncts to mainstream care for symptom management and to enhance well-being. These therapies provide symptom relief and address patients’ quality of life. Most such interventions are not specific to a particular cancer diagnosis, but can relieve pain and other symptoms in cancer patients across diagnostic categories. Complementary therapies increasingly are available not only directly to patients on a private basis, but also in hospitals, clinics, and homes as part of symptom control and efforts to ease the physical, psychosocial, and spiritual distress associated with cancer and cancer treatment. Patients need the knowledge and support to ignore the siren calls of alternative therapies. At the same time, they

deserve access to helpful complementary modalities. Physicians and other caregivers should be aware of problematic alternatives, and equally knowledgeable about the complementary therapies that can provide relief to their patients (Table 35.1). This chapter reviews the current state of complementary and alternative therapies commonly used for cancer treatment.

Complementary and alternative medicine today Dozens of surveys indicate that up to 85% of cancer patients use complementary or alternative therapies for depression, anxiety, and insomnia, as well as for medical problems and symptoms associated with cancer treatment [1–4]. Patients surveyed report that these therapies improve their quality of life by decreasing symptoms, helping them cope with stress, and offering them control over their treatment and well-being. The National Center for Complementary and Alternative Medicine (NCCAM), a branch of the National Institutes of Health (NIH) groups CAM therapies into four basic categories: mind–body medicine, including meditation and hypnotherapy; biologically-based practices, including dietary supplements and herbal products; manipulative and bodybased practices, including massage and “energy therapies,” such as Reiki; and “therapeutic touch,” which involves no touch. The NCCAM also recognizes whole medical systems that cross these multiple categories, such as Ayurveda, the traditional system of India, and traditional Chinese medicine. Traditional systems typically encompass mind–body practices, manipulative techniques, and herbal treatments; traditional Chinese medicine also includes acupuncture.

Alternative medical systems Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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“Ayurveda” comes from the Sanskrit words “ayur” (life) and “veda” (knowledge). Ayurveda’s ancient healing techniques

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Table 35.1 Reliable sources of information on complementary therapies and “alternatives.” Medline Plus: http://www.nlm.nih.gov/medlineplus/druginformation. html Memorial Sloan-Kettering Cancer Center: http://www.mskcc.org/ aboutherbs National Center for Complementary and Alternative Medicine (NCCAM): http://nccam.nih.gov American Cancer Society: http://www.cancer.org NIH Office of Dietary Supplements: http://dietary-;supplements.info. nih.gov US Pharmacopeia: http://www.usp.org/dietarySupplements

are based on the classification of people into one of three predominant body types. There are specific remedies for disease, and regimens to promote health, for each body type. This medical system includes botanical medicines and incorporates a strong mind–body component, stressing the need to keep consciousness in balance. It uses techniques such as yoga and mediation to do so. Ayurveda also emphasizes regular detoxification and cleansing through all bodily orifices. Traditional Chinese medicine comprehends the body in terms of its relationship to the environment and the cosmos. Concepts of human physiology and disease are interwoven with geographic features of ancient China and with the forces of nature. Chi, the life force said to run through all of nature, flows in the human body through energy channels known as meridians. The 12 main meridians are believed to be dotted with acupoints. Each acupoint corresponds to a specific body organ or system. Needling or pressing the proper acupoints is said to redress the life–force imbalance causing the problem in a particular organ. To determine the source of the blockage, the practitioner relies on pulse diagnosis, a technique applied by doctors of traditional Chinese medicine today as it was millennia ago. Pulse diagnosis involves concentration on several body pulses by the practitioner. The existence of chi or a “vital energy force” remains unproved, but practitioners as well as many patients strongly believe in the validity of the concept. Traditional Chinese medicine also includes a full herbal pharmacopoeia with remedies for most ailments, including cancer. Chinese herbal teas and relaxation techniques are soothing and appealing to many patients with cancer, who use them as complementary therapies. The potential anticancer benefits of many Chinese herbal compounds and other botanicals are under investigation in the United States and elsewhere.

Pharmacologic and biologic treatments As this group of alternative treatments is invasive and biologically active, it is highly controversial. A well-known and popular pharmacologic therapy is antineoplastons, developed by Stanislaw Burzynski, and available in his clinic in Houston, Texas, USA. Patients with most cancer diagnoses are treated, but the clinic specializes in pediatric brain tumors. A National Cancer Institute (NCI)-supported trial was suspended in 1995 when trial data were not forthcoming from the clinic [5]. Interest in shark cartilage as a cancer therapy began with a 1992 book by I. William Lane, Sharks Don’t Get Cancer, and a television special that displayed apparent remission in patients treated with shark cartilage in Cuba. The televised outcome was strongly disputed by oncologists in the United States. Advocates claim this nonprescription remedy has putative antiangiogenic properties, but the shark cartilage protein molecules contained in the over-the-counter food supplement are too large to be absorbed by the gut and would be destroyed even if absorbed. Shark cartilage decomposes into inert ingredients and is excreted. A phase I–II trial of the shark cartilage dietary supplement found no clinical benefit [6]. In 2001, however, the NCI launched a large, randomized clinical trial of shark cartilage in combination with chemotherapy and radiotherapy in patients with advanced cancer. This investigation was initiated with shark cartilage extract previously shown to slow tumor growth in preclinical studies and believed to have antiangiogenic and antimetastatic activity. However, the trial found no benefit for shark cartilage [7]. Cancell is another biologic remedy that appears to be especially popular in Florida and the Midwestern United States. Proponents claim that it returns cancer cells to a “primitive state” from which they can be digested and rendered inert. The Food and Drug Administration (FDA) laboratory studies, which showed Cancell to be composed of common chemicals, including nitric acid, sodium sulfite, potassium hydroxide, sulfuric acid, and catechol, found no basis for proponent claims of Cancell’s effectiveness against cancer [8].

Diet and nutrition Advocates of dietary cancer treatments typically extend mainstream assumptions about the protective effects of fruits, vegetables, fiber, and avoidance of excessive dietary fat in reducing cancer risk, to the idea that food or vitamins can cure cancer. Proponents of this belief make their claims in books with titles such as The Food Pharmacy: Dramatic New Evidence that Food is your Best Medicine, Prescription for Nutritional Healing, and New Choices in Natural Healing. The macrobiotic diet is a persistently popular example of such dietary approaches. Despite claims in publications and websites, there is no evidence that the macrobiotic diet can cure or is beneficial for patients with cancer [9]. No diet has ever been shown to treat a diagnosed cancer.

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Metabolic therapies and detoxification Metabolic therapies continue to draw patients from North America and Europe to the many clinics in Tijuana, Mexico. These therapies involve practitioner-specific combinations of diet plus vitamins, minerals, enzymes, and “detoxification.” In one well-known Tijuana clinic, treatment is based on the belief that toxic products of cancer cells accumulate in the liver, leading to liver failure and death. The treatment aims to counteract liver damage with a low-salt, high-potassium diet, coffee enemas, and a gallon of fruit and vegetable juice daily [10]. The clinic’s use of liquefied raw calf liver injections was suspended in 1997, following sepsis in a number of patients. Other Tijuana clinics and practitioners provide their own versions of metabolic therapy, each applying an individualized dietary and “detoxification” regimen. Additional components of treatment are included according to practitioners’ preferences. Metabolic regimens are based on belief in the importance of “detoxification,” which is thought necessary for the body to heal itself. Neither the existence of toxins nor the benefit of colonic cleansing has been documented. Modern variations on the older approach to internal cleansing are drinkable cleansing formulas, said to detoxify and rejuvenate the body. Many variations are available in health food stores, books, and on the Internet. A shake of liquid clay, psyllium seed husks, and fruit juice, for example, is said to remove harmful food chemicals and air pollutants [11]. These products tend to function as major laxatives, potentially dangerous when taken over days or weeks or on a regular basis as recommended by promoters, and of special concern for cancer patients. Metabolic therapies are being administered to cancer patients irrespective of their status. This is a major concern for cancer patients as they may delay much needed treatment and may be detrimental. Consequences can be serious.

Herbal treatments for cancer Herbal remedies are part of traditional and folk healing methods with long histories of use. Herbal medicine is found in most areas of the world and across all cultures historically. Although many herbal remedies are claimed to have anticancer effects, only a few have gained substantial popularity as alternative cancer therapies. For decades, Essiac has remained a popular herbal cancer alternative in North America. Developed initially by a Native healer from Southwestern Canada, it was popularized by a Canadian nurse, Rene Caisse (Essiac is Caisse spelled backwards). Essiac is comprised of four herbs: burdock, Turkey rhubarb, sorrel, and slippery elm. Researchers at the NCI and elsewhere found that it has no anticancer effect [8]. Iscador, a derivative of mistletoe, is a popular cancer remedy in Europe, where it is said to have been in continuous use as a folk treatment since the Druids. It is used today in many mainstream European cancer clinics, typically in

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conjunction with chemotherapy. Despite many studies, definitive data in support of the utility of Iscador has not emerged [8].

Problems A plethora of botanical products and dietary supplements are now sold over-the-counter, and cancer patients use many of them to treat their cancer. It is therefore important to recognize herbal remedies that are toxic or tend to interact with other medications, as well as those that may help cancer patients. As neither the FDA nor any other United States agency examines herbal remedies for safety and effectiveness, few products have been formally tested for side effects or quality control. Patients and the general public tend not to realize that herbs and other botanicals are dilute natural drugs that contain scores of different chemicals, most of which have not been documented. Effects are not always predictable. Moreover, the potential for herb–drug interaction is such that many medical institutions recommend that patients on chemotherapy or other major medications stop using herbal remedies. Herbs such as feverfew, garlic, ginger, and ginkgo have anticoagulant effects and should be avoided by patients on coumadin, heparin, aspirin, and related agents [8]. The risk of herb–drug interactions appears to be greatest for patients with kidney or liver problems. Herbs and other supplements that have caused hepatotoxicity include borage, chaparral, comfrey, kava, sassafras, valerian, germanium, hydrazine sulfate, and chronic high doses (>1000 μg/day) of selenium. Concerns have also been raised about dietary antioxidants, which may interact with chemotherapeutic agents [12].

Beneficial liver-related products Milk thistle (Silybum marianum) is used by patients to protect liver function and to manage various liver diseases. Anecdotal data suggest that milk thistle may prevent liver damage from hepatotoxic medications, including butyrophenones, phenothiazines, and phenytoin. Animal studies demonstrate reductions in kidney damage following cisplatin plus milk thistle without diminished antitumor activity. Placebocontrolled trials show efficacy in reducing aminotransferases in alcoholic liver disease, but research in other types of hepatic disease is flawed. Rare and limited toxicity, but no significant adverse events, has been reported. As milk thistle inhibits cytochrome p450 3A4, it may inhibit metabolism of some medications [13]. Only one other botanical product is used primarily for liver problems. This is Sho-Saiko-To, a Chinese botanical compound known commonly by its Japanese name, and as “liver kampo” in the United States. It has been prescribed to an estimated 1.5 million patients in Japan, predominantly for hepatitis, and there is support from randomized trials for this indication [14].

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Sho-Saiko-To and some of its components showed marked antiproliferative effects on hepatoma lines [15], and morphologic analysis of cells grown with the compound showed apoptosis. Sho-Saiko-To also was found to prevent liver injury [16] and to promote liver regeneration in animal models, and to enhance immune function in humans [17]. A single study of Sho-Saiko-To in patients with cirrhosis reported reduced incidence of hepatocellular carcinoma at 5-year follow-up [18]. Larger, well-designed studies are needed to confirm such effects.

Complementary therapies Complementary therapies are safe and nontoxic, noninvasive, easy to use, and inexpensive. Many may be selfmanaged, meaning that practitioners often are unnecessary, which gives patients the rare and important opportunity to maintain a measure of control over their well-being. Supportive or complementary modalities also are soothing, comforting, and distracting, and they are backed by good efficacy data.

Acupuncture Acupuncture is the insertion of fine needles for therapeutic purposes into points on the skin. As described above, according to traditional Chinese medicine theory, these acupoints are located along channels or meridians believed to conduct “chi” or energy. Stimulation can be enhanced by heat, electrical current, or pressure. Acupuncture points have been shown to coincide with trigger points that are sensitive to pressure, indicating enriched enervation at the anatomic locations. Seminal research conducted in the 1970s demonstrated that acupuncture could induce analgesia in mice that could be blocked by naloxone [19]. Moreover, mice deficient in opiate receptors showed poor electroacupuncture analgesia [20]. Levels of endogenous opioids in the cerebrospinal fluid have been directly observed to increase following acupuncture in humans [21]. There is preliminary evidence that acupuncture may lead to changes in the genetic expression of opioids, an observation that, if confirmed, may provide a basis for understanding the persisting effect of acupuncture treatment [22, 23]. Clinical research supports acupuncture as an effective treatment for pain relief [24, 25]. Further, a systematic review indicates that acupuncture effectively reduces nausea, a problem affecting many patients with hepatobiliary malignancies [26]. Pruritus, a common sequela of hepatobiliary and pancreatic cancer, is a source of major distress for many patients, as pharmacologic management often works poorly. Two controlled trials of acupuncture for pruritus were conducted. A randomized, blinded, placebo-controlled trial for hista-

mine-induced pruritus in healthy volunteers found that electroacupuncture reduced itching by about half compared to placebo, and two-thirds compared to no treatment. Both results were statistically significant. Acupuncture also reduced the area of wheal and flare [27]. The second study involved six patients with end-stage renal disease and pruritus. Patients received electroacupuncture or electrical stimulation without needling three times a week. Acupuncture was reported to reduce pruritus scores by about a half, while superficial electrical stimulation apparently had no effect [28]. Pain and pruritus are related sensory qualities. Both are transmitted through nociceptive C fibers. Acupuncture stimulates A delta fibers which causes segmental inhibition of impulses carried in the slower, unmyelinated C fibers. Serotonin has a key role in both nociception and pruritus. Application of serotonin to a blister induces pain [29], serotonin potentiates the painful effect of algetic substances [30], and serotonin-receptor antagonists reduce pain from induced inflammation in rats [31]. Serotonin induces pruritus in animals and humans, and serotonin antagonists prevent morphine-induced pruritus. Decreased serotonin following acupuncture has been reported in human studies [32]. Acupuncture’s antiemetic activity, notably in the postoperative setting, also suggests modulation of a serotonergic pathway.

Music therapy Music has the power to evoke deep-seated emotion. Particular types of music may hold special meaning depending on a person’s life experience. Music therapy is provided by professional musicians who are also trained music therapists. They often hold professional degrees in music therapy, and are adept in dealing with the psychosocial issues faced by patients and family members. Music therapy is particularly effective in the palliative care setting in improving quality of life and enhancing a sense of comfort and relaxation. Formal music therapy programs in palliative medicine exist in many major institutions. Controlled trials indicate that music therapy produces emotional and physiologic benefits, reducing anxiety, stress, depression, and pain. Music intervention significantly reduced heart rate, respiratory rate, and anxiety scores among inpatients following myocardial infarction [33] and ventilatory assistance [34]. Music therapy was shown to be effective against pain in cancer patients [35]. Music also reduced intraoperative analgesic requirements compared to controls, and patients randomized to a music intervention reported significantly less pain and required less pain medication. In a trial of 500 surgical patients, subjects were randomized to control, recorded music, jaw relaxation, or a music/jaw relaxation combination. Music led to significant decreases in both pain intensity and pain-related distress [36].

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In a randomized trial of cancer patients undergoing autologous stem cell transplantation, anxiety, depression, and total mood disturbance scores were significantly lower in the music therapy group as compared with standard care controls [37].

Massage therapy Massage involves using varying degrees of pressure on muscles and soft tissues to reduce tension and pain, improve circulation, and encourage relaxation. Swedish massage, the most common type in the United States, is gentle and comprised of five basic strokes (stroking, kneading, friction, percussion, and vibration). The movement is rhythmic and free-flowing. Other variations include reflexology (foot massage), shiatsu, and tui-na (acupressure). The benefits of massage therapy are documented for seriously ill and palliative care patients. In one study, 87 hospitalized cancer patients were randomized to foot massage or to control on a cross-over basis. Pain and anxiety scores fell with massage, with differences between groups achieving substantial significance (p = 0.001) [38]. In a randomized cross-over study, 230 cancer patients on chemotherapy received massage therapy, healing touch, or personal visit without therapy. Results showed that both massage therapy and healing touch reduced blood pressure, respiratory rate, and heart rate. Pain, mood disturbance, and fatigue also decreased [39]. In another study, 42 patients with advanced cancer were randomized to receive weekly massage with lavender oil, massage with an inert oil, or no intervention for 4 weeks. Patients in both the massage groups experienced improvement in sleep and significant reduction in depression scores compared to those in the control group [40]. A significant decrease in anxiety and pain following reflexology was observed in a cross-over study involving 23 inpatients with breast or lung cancer [41]. In the largest study of massage, 1290 cancer patients were treated over a period of 3 years. Patients reported a 50% reduction in severity of symptoms following massage therapy. Symptoms included pain, fatigue, stress/anxiety, nausea, and depression [42]. Patients should be directed to massage therapists who have training or experience working with cancer patients.

Mind–body therapies Attending to the psychologic health of cancer patients is a fundamental component of good cancer care. Mind–body interventions often have been adopted by mainstream institutions as complementary therapies. Yoga, a 5000-year-old exercise regimen developed in India, also involves proper breathing, movement, and posture. Research documents its value in improving physical fitness and decreasing respiratory rate and blood pressure; yoga is often part of integrative management for heart

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disease, asthma, diabetes, drug addiction, acquired immunodeficiency syndrome (AIDS), migraine headaches, and arthritis, as well as cancer. A randomized clinical trial of 39 lymphoma patients evaluated the effectiveness of Tibetan yoga, which incorporates controlled breathing, visualization, mindfulness, and lowimpact postures. Patients under treatment or who had concluded treatment in the prior 12 months participated in seven weekly sessions. Researchers concluded that the yoga program significantly improved sleep-related outcomes, including better quality, longer duration, and decreased use of sleep medications [43]. In another study, 59 breast cancer patients and 10 prostate cancer patients participated in an 8-week mindfulness-based stress reduction (MBSR) program that incorporated yoga as well as relaxation and meditation. Patients were assessed before and after the intervention, which significantly enhanced patients’ quality of life and decreased symptoms of stress [44]. Hypnotherapy has been shown to reduce chemotherapyrelated nausea and vomiting in children, and possibly to control anxiety and nausea [45]. It is also effective in controlling pain. Other techniques, including visualization and progressive relaxation, also decrease pain and promote well-being. Guided imagery may be viewed as a lighter form of hypnosis and is based on the reciprocal relationship between mind and body. It is another simple and powerful technique that directs imagination and attention in ways that produce symptom relief. Often termed “visualization” or “mental imagery,” guided imagery lowers blood pressure and produces other physiologic benefits, including decreased heart rate. Imagery also can relieve pain and anxiety. A study of 96 women with locally advanced breast cancer compared standard treatment with relaxation training and imagery during chemotherapy. Women in the experimental group reported increased relaxation and better quality of life [46]. Guided imagery also may be effective in controlling nausea, which is commonly experienced by cancer patients. In a study of 110 breast cancer patients undergoing autologous bone marrow transplantation, patients were randomized to standard care versus education, cognitive restructuring, and relaxation with guided imagery. The experimental group experienced significantly reduced nausea and anxiety [47].

Conclusion Symptom control during and after cancer treatments remains a challenge for many physicians and their patients. Many cancer patients are interested in complementary and alternative therapies, which have variable benefit and risk ratios.

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Alternative therapies are unproved or disproved and potentially harmful. Complementary therapies, on the other hand, are noninvasive, gentle techniques that help manage symptoms and improve quality of life. Even though many of these therapies have been in use for centuries around the world, scientific examination of complementary therapies started only in the past few decades. Much of the data from research to date support the use of acupuncture, music, massage, and mind– body therapies for both physical and emotional symptoms. These are especially valuable for cancer patients and are now provided along with mainstream care in many cancer hospitals and programs around the developed world. While the overall number of randomized controlled trials of complementary therapies remains somewhat small and additional methodologically sound research is essential, sufficient promising evidence exists to merit professional and public attention.

Self-assessment questions 1 Which one of the following statements regarding alternative therapies is true? A Are viable alternatives for conventional cancer treatment B Are backed by scientific evidence C Are unproven and may be harmful D Are inexpensive E Are offered in some cancer hospitals 2 Which one of the following is not a mind–body therapy? A Tibetan yoga B Hypnotherapy C Isolation D Guided imagery E Relaxation 3 Which one of the following statements regarding herbal supplements is true? A Are safe B Patients should discuss their use with physicians C Do not interact with chemotherapy drugs D Marketing practices are reliable E Are strictly monitored by the FDA 4 Which of the following statements regarding complementary modalities are true? (more than one answer is possible) A Are supported by evidence from clinical trials B Are unaffordable C Alleviate cancer-related symptoms D Patients should consult physicians before use E May cause harm

5 Which of the following statements regarding acupuncture are true? (more than one answer is possible) A Involves insertion of fine needles B Regulates flow of “chi” C Is a painful procedure D Should be avoided in some cases E Should be administered by a licensed practitioner

References 1 Ernst E, Cassileth BR. The prevalence of complementary/alternative medicine in cancer: a systematic review. Cancer 1998;83: 777–82. 2 Shen J, Andersen R, Albert PS, et al. Use of complementary/ alternative therapies by women with advanced-stage breast cancer. BMC Complement Altern Med 2002;2:8. 3 Vapiwala N, Mick R, Hampshire MK, Metz JM, DeNittis AS. Patient initiation of complementary and alternative medical therapies (CAM) following cancer diagnosis. Cancer J 2006;12: 467–74. 4 Boon HS, Olatunde F, Zick SM. Trends in complementary/alternative medicine use by breast cancer survivors: comparing survey data from 1998 and 2005. BMC Womens Health 2007; 7:4. 5 Green S. “Antineoplastons”. An unproved cancer therapy. JAMA 1992;267:2924–8. 6 Miller DR, Anderson GT, Stark JJ, Granick JL, Richardson D. Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of advanced cancer. J Clin Oncol 1998;16:3649–55. 7 Loprinzi CL, Levitt R, Barton DL, et al. Evaluation of shark cartilage in patients with advanced cancer: a North Central Cancer Treatment Group trial. Cancer 2005;104:176–82. 8 AboutHerbs Web site. http://www.mskcc.org/aboutherbs. (accessed November 27 2007). 9 Questionable methods of cancer management: ‘nutritional’ therapies. CA Cancer J Clin 1993;43:309–19. 10 Green S. A critique of the rationale for cancer treatment with coffee enemas and diet. JAMA 1992;268:3224–7. 11 Detoxification at http://www.holisticmed.com/detox. http:// www.holisticmed.com/detox/ (accessed November 27 2007. 12 D’Andrea GM. Use of antioxidants during chemotherapy and radiotherapy should be avoided. CA Cancer J Clin 2005;55: 319–21. 13 Etheridge AS, Black SR, Patel PR, So J, Mathews JM. An in vitro evaluation of cytochrome P450 inhibition and P-glycoprotein interaction with goldenseal, Ginkgo biloba, grape seed, milk thistle, and ginseng extracts and their constituents. Planta Med 2007;73:731–41. 14 Hirayama C, Okumura M, Tanikawa K, Yano M, Mizuta M, Ogawa N. A multicenter randomized controlled clinical trial of Shosaiko-to in chronic active hepatitis. Gastroenterol Jpn 1989; 24:715–9. 15 Yano H, Mizoguchi A, Fukuda K, et al. The herbal medicine shosaiko-to inhibits proliferation of cancer cell lines by inducing

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apoptosis and arrest at the G0/G1 phase. Cancer Res 1994;54: 448–54. Sakaida I, Matsumura Y, Akiyama S, Hayashi K, Ishige A, Okita K. Herbal medicine Sho-saiko-to (TJ-9) prevents liver fibrosis and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. J Hepatol 1998;28: 298–306. Yamashiki M, Nishimura A, Suzuki H, Sakaguchi S, Kosaka Y. Effects of the Japanese herbal medicine “Sho-saiko-to” (TJ-9) on in vitro interleukin-10 production by peripheral blood mononuclear cells of patients with chronic hepatitis C. Hepatology 1997;25:1390–7. Oka H, Yamamoto S, Kuroki T, et al. Prospective study of chemoprevention of hepatocellular carcinoma with Sho-saiko-to (TJ-9). Cancer 1995;76:743–9. Pomeranz B, Chiu D. Naloxone blockade of acupuncture analgesia: endorphin implicated. Life Sci 1976;19:1757–62. Peets JM, Pomeranz B. CXBK mice deficient in opiate receptors show poor electroacupuncture analgesia. Nature 1978;273: 675–6. Clement-Jones V, McLoughlin L, Tomlin S, Besser GM, Rees LH, Wen HL. Increased beta-endorphin but not met-enkephalin levels in human cerebrospinal fluid after acupuncture for recurrent pain. Lancet 1980;2:946–9. Guo HF, Tian J, Wang X, Fang Y, Hou Y, Han J. Brain substrates activated by electroacupuncture of different frequencies (I): Comparative study on the expression of oncogene c-fos and genes coding for three opioid peptides. Brain Res Mol Brain Res 1996;43:157–66. Guo HF, Tian J, Wang X, Fang Y, Hou Y, Han J. Brain substrates activated by electroacupuncture (EA) of different frequencies (II): Role of Fos/Jun proteins in EA-induced transcription of preproenkephalin and preprodynorphin genes. Brain Res Mol Brain Res 1996;43:167–73. Manheimer E, White A, Berman B, Forys K, Ernst E. Metaanalysis: acupuncture for low back pain. Ann Intern Med 2005; 142:651–63. Melchart D, Linde K, Fischer P, et al. Acupuncture for idiopathic headache. Cochrane Database Syst Rev 2001(1):CD001218. Ezzo J, Streitberger K, Schneider A. Cochrane systematic reviews examine P6 acupuncture-point stimulation for nausea and vomiting. J Altern Complement Med 2006;12:489–95. Belgrade MJ, Solomon LM, Lichter EA. Effect of acupuncture on experimentally induced itch. Acta Derm Venereol 1984;64: 129–33. Duo LJ. Electrical needle therapy of uremic pruritus. Nephron 1987;47:179–83. Orwin JM, Fozard JR. Blockade of the flare response to intradermal 5-hydroxytryptamine in man by MDL 72.222, a selective antagonist at neuronal 5-hydroxytryptamine receptors. Eur J Clin Pharmacol 1986;30:209–12. Richardson BP, Engel G, Donatsch P, Stadler PA. Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs. Nature 1985;316:126–31. Eschalier A, Kayser V, Guilbaud G. Influence of a specific 5-HT3 antagonist on carrageenan-induced hyperalgesia in rats. Pain 1989;36:249–55. Sprott H, Franke S, Kluge H, Hein G. Pain treatment of fibromyalgia by acupuncture. Rheumatol Int 1998;18:35–6.

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33 White JM. Effects of relaxing music on cardiac autonomic balance and anxiety after acute myocardial infarction. Am J Crit Care 1999;8:220–30. 34 Chlan L. Effectiveness of a music therapy intervention on relaxation and anxiety for patients receiving ventilatory assistance. Heart Lung 1998;27:169–76. 35 Beck SL. The therapeutic use of music for cancer-related pain. Oncol Nurs Forum 1991;18:1327–37. 36 Good M, Stanton-Hicks M, Grass JA, et al. Relaxation and music to reduce postsurgical pain. J Adv Nurs 2001;33:208–15. 37 Cassileth BR, Vickers AJ, Magill CA. Music therapy for mood disturbance during hospitalization for autologous stem cell transplantation: a randomized controlled trial. Cancer 2003;98: 2723–9. 38 Grealish L, Lomasney A, Whiteman B. Foot massage. A nursing intervention to modify the distressing symptoms of pain and nausea in patients hospitalized with cancer. Cancer Nurs 2000; 23:237–43. 39 Post-White J, Kinney ME, Savik K, Gau JB, Wilcox C, Lerner I. Therapeutic massage and healing touch improve symptoms in cancer. Integr Cancer Ther 2003;2:332–44. 40 Soden K, Vincent K, Craske S, Lucas C, Ashley S. A randomized controlled trial of aromatherapy massage in a hospice setting. Palliat Med 2004;18:87–92. 41 Stephenson NL, Weinrich SP, Tavakoli AS. The effects of foot reflexology on anxiety and pain in patients with breast and lung cancer. Oncol Nurs Forum 2000;27:67–72. 42 Cassileth BR, Vickers AJ. Massage therapy for symptom control: outcome study at a major cancer center. J Pain Symptom Manage 2004;28:244–9. 43 Cohen L, Warneke C, Fouladi RT, Rodriguez MA, Chaoul-Reich A. Psychological adjustment and sleep quality in a randomized trial of the effects of a Tibetan yoga intervention in patients with lymphoma. Cancer 2004;100:2253–60. 44 Carlson LE, Speca M, Patel KD, Goodey E. Mindfulness-based stress reduction in relation to quality of life, mood, symptoms of stress, and immune parameters in breast and prostate cancer outpatients. Psychosom Med 2003;65:571–81. 45 Zeltzer LK, Dolgin MJ, LeBaron S, LeBaron C. A randomized, controlled study of behavioral intervention for chemotherapy distress in children with cancer. Pediatrics 1991;88:34–42. 46 Walker LG, Walker MB, Ogston K, et al. Psychological, clinical and pathological effects of relaxation training and guided imagery during primary chemotherapy. Br J Cancer 1999;80: 262–8. 47 Gaston-Johansson F, Fall-Dickson JM, Nanda J, et al. The effectiveness of the comprehensive coping strategy program on clinical outcomes in breast cancer autologous bone marrow transplantation. Cancer Nurs 2000;23:277–85.

Self-assessment answers 1 2 3 4 5

C C B A, C, D A, B, D, E

7

Special Tumors, Population, and Special Considerations

Introduction Stefan Breitenstein and Pierre-Alain Clavien Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland

In this last section of the book, we address special aspects of liver tumors, otherwise not covered elsewhere. Particular emphasis is given to liver tumors in different populations: the elderly, different ethnic groups, immunosuppressed patients and pregnant women. Specific types of liver tumors, such as metastases of neuroendocrine origin and tumors of rare etiologies, are also covered here. As in the previous edition, a chapter is dedicated to the anesthetic management of patients requiring liver surgery, since optimal intra- and post-operative management plays an important part in determining the outcome of patients subjected to extensive liver resection. Finally, no healthcare system today can avoid giving special attention to cost and cost-effectiveness. A new chapter is therefore included on economic aspects in the treatment of patients with liver tumors. The incidence of liver tumors is still largely underestimated in many countries. Although the diagnosis and management of liver tumors has been refined worldwide, the best outcomes remain the privilege of the most developed countries. Variations in the type of liver tumors, and approaches around the globe, are addressed by local experts, who allow the reader to become more familiar with different patterns of epidemiology and clinical presentation of hepatic tumors in specific ethnicities. The first two chapters address specific issues related to the management of non-colorectal liver metastasis, including liver metastases from neuroendocrine tumors (Chapter 36) and from unknown origin (Chapter 37). Both chapters bring new insights into how to select those difficult cases for extensive resection or nonsurgical approaches. Chapters 38

and 39 cover liver tumors in special populations, including elderly, pregnant or immunosuppressed patients, as well as in the pediatric population. Patterns specific to different regions, including Asia, South America, and Africa, are covered in Chapters 40−42. For example, available data from Asia and Africa disclosed a high prevalence of HCC, not only in adults, but also in children due to endemic infection (e.g. hepatitis B virus in Asia and Africa, and human immunodeficiency virus [HIV] in Africa), and heavy exposure to toxins, such as aflotoxin B1. While Asian liver surgeons have performed pioneering surgical treatment of HCC, most cases in Africa are still detected at an advanced stage, possibly due to public health barriers. From an epidemiologic point of view, the South American population, in particular Chileans, suffer from the highest incidence of gallbladder cancer worldwide, which is partially related to a high incidence of cholelithiasis at a young age. A significant part of the outcome of complex liver surgery depends on optimal perioperative management, in which anesthesia play a significant role. An entire chapter (Chapter 43) is dedicated to several aspects of relevance for anesthetists, including intraoperative fluid and blood pressure management. The last chapter (Chapter 44) deals with the challenge of rising costs for complex medical procedures, which is incompatible with the increasing resource constraints on most healthcare systems. The increasing spectrum of diagnostic and therapeutic options in liver tumors requires an optimization of economic aspects regarding patients and health systems.

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36

Liver Metastases from Endocrine Tumors Clayton D. Knox and C. Wright Pinson Vanderbilt University School of Medicine, Nashville, TN, USA

Introduction Endocrine tumors (ETs) as discussed in this chapter, regardless of their location, are derived from cells from the embryonal neural crest and have historically been referred to as neuroendocrine tumors. The tumors variably express hormonal proteins and related regulatory peptides, which may or may not cause clinical syndromes (termed functional versus nonfunctional ET). The syndromes relate to the physiologic effects of the hormones produced, and usually correlate with overall tumor burden. The resulting specific clinical syndromes, and location and biology of the primary tumor define the nomenclature. ETs ultimately metastasize to the liver in approximately 75% of cases and may result in extensive hepatic disease, while the primary site is not always evident. Local extension of primary lesions is frequent, as are nodal and other distant metastases to bone, lung, and brain. Since the liver metabolizes many endocrine peptides, some ETs (e.g. carcinoid tumors) require systemic release of the peptide from the liver or other metastasis to cause the associated syndrome. Other ETs, such as insulinomas and gastrinomas, produce peptides that are not metabolized by the liver and may produce symptoms in the absence of liver metastasis. With bulky liver metastasis (Figure 36.1), symptoms also arise from hepatomegaly, and include early satiety, pain, pressure, and in advanced disease, cachexia. The appropriate nomenclature and classification of ETs remain the subject of much debate. In the past, ETs were often discussed using the American convention, where gastrointestinal ETs were historically divided into carcinoid and pancreatic islet cell tumors. However, in this chapter the more recent World Health Organization (WHO) classification system has been adopted, whereby tumors are defined as well-differentiated versus poorly-differentiated ETs. This chapter focuses on the management of liver metastasis from ET (LMET), and all discussions refer to well-

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differentiated ETs unless otherwise indicated. Poorlydifferentiated ETs carry a dismal prognosis, with median survival often reported as less than 1 year. While cure is rare, palliation and potential prolongation of life are reasonable goals for patients with well-differentiated LMETs. Variable 5-year survival for untreated LMETs has been reported in the range of 13−54% [1, 2], averaging 30−40% [2]. Welldifferentiated intestinal ETs have a more favorable prognosis, with a mean survival of 8.1 years from the onset of symptoms, although the development of liver metastasis decreases 5-year survival to 20−30% [2]. As these tumors are relatively slow growing and treatment response rates are quite different from other types of metastasis, these patients deserve careful and thoughtful attention. The treatment options must be considered with respect to their morbidity and mortality, the natural history of the tumor, and the severity of symptoms. Aggressive medical and surgical therapy is more worthwhile than it is for a comparable tumor load from many other cancer types, and functional hormonal blockade often significantly improves quality of life. Alternatively, tumor debulking and/or ablation can improve quality of life by decreasing the levels of circulating hormones produced by the tumor, decreasing resulting hormonal symptoms, improving symptoms of organ dysfunction (e.g. heart failure), and improving gastrointestinal function/nutrition. Nonetheless, debulking of less than 90% of tumor burden is rarely indicated.

Primary tumors Gastrointestinal endocrine tumors The frequency of all ETs within the body correlates directly with the concentration of endocrine cells, and thus almost 67% arise in the gastrointestinal tract, these being most prone to liver metastasis. An additional 25% arise in the lung, with the remainder occurring with varying frequencies throughout other sites in the body [3]. The heterogeneous ETs of gastrointestinal origin have classically been referred to as carcinoid tumors, although this term should be reserved exclusively for tumors that secrete serotonin. The biologic

CHAPTER 36

Figure 36.1 Gross photograph of metastatic endocrine tumors in the liver.

activity of gastrointestinal ETs varies considerably, depending on the site of origin, size, stage, cell type, and peptides secreted [4]. Classic carcinoid syndrome with flushing and diarrhea is present in only 10−20% of patients at diagnosis, and strongly suggests liver metastases. Again, all discussions refer specifically to WHO–classified, welldifferentiated ETs. Asymptomatic gastrointestinal ETs of less than 1 cm are often discovered at autopsy, while clinically significant symptomatic tumors are usually larger than 1 cm with local invasion of the mesentery and an intense desmoplastic reaction that can lead to small bowel obstruction. Multiple tumors are found in 20−40% of these cases. Tumors greater than 2 cm are usually malignant with regional lymph node metastasis. Metastasis has been reported in only 2% of patients with tumors of less than 2 cm in size and with no invasion of the submucosa, compared to 88% for tumors larger than 2 cm that invade the submucosa [5]. Gastrointestinal ETs of the stomach, pancreas, duodenum, and proximal jejunum are heterogeneous in nature. Gastric ETs account for 8.1% of all gastrointestinal ETs, an increase from 2.4% in 1969 [6]. They occur in patients with chronic atrophic gastritis (CAG), Zollinger−Ellison syndrome (ZES), or as sporadic cases [4]. CAG and ZES both produce hypergastrinemic states that stimulate hyperplasia of enterochromaffin-like (ECL) cells in the stomach. Sporadic gastric ETs, which are not associated with a hypergastrinemic state, tend to follow a more aggressive clinical course, and liver metastases occur in 50−60% of patients [4]. Gastric ETs produce an atypical carcinoid syndrome associated with histamine release in up to 30% of cases. The small bowel accounts for nearly 40% of all gastrointestinal ETs, with approximately 13% of these arising in the duodenum, 8.8% in the jejunum, and more than 70% in the ileum [3]. Duodenal ETs most often occur in the ampulla of Vater, are usually clinically nonfunctional, have meta-

Liver Metastases from Endocrine Tumors

static disease to regional lymph nodes or the liver on initial evaluation in up to 45% of cases, and are associated with pheochromocytomas in up to 30% of cases [4, 6]. Clinicians should be reluctant to diagnose duodenal ETs as carcinoids initially, as these tumors frequently turn out to be gastrinomas or somatostatinomas, which have different prognoses and treatment. More than 20% of all gastrointestinal ETs occur in the distal ileum, and most secrete serotonin, substance P, or both. ETs of the colon and rectum account for up to 50% of gastrointestinal ETs [3]. Patients with colorectal ETs rarely present with carcinoid syndrome, even when metastases are present. Colorectal cancer is present in a significant proportion of patients with rectal ETs, warranting careful evaluation for this second tumor [5]. Appendiceal ETs account for 35−50% of gastrointestinal ETs, but are usually small (<2 cm). Due to the low frequency of metastasis (1−8%), presentation with carcinoid syndrome is relatively uncommon [4, 3, 7]. Five-year survival is stage dependent: over 75% for patients with local invasion, 60% for regional nodal disease, and 20−35% for patients with liver metastases [4, 7]. Primary ETs of the liver, gallbladder, and biliary system are very uncommon.

Pancreatic endocrine tumors Islet cell tumors of the pancreas and duodenum, although relatively rare (1−2 per 200 000 population), generate the second largest group of LMETs after gastrointestinal ETs, and unfortunately have a significantly worse prognosis [8, 9]. As with gastrointestinal ETs, the proper classification of these tumors is subject to some debate, and this chapter considers all ETs of the pancreas to be islet cell tumors, regardless of degree of differentiation, functionality, or metastasis. It is also useful to classify islet cell tumors as being functional (symptomatic hormone secreting) or nonfunctional, as nonfunctional tumors carry a worse prognosis. Gastrinomas and insulinomas are the most common functional islet cell tumors, followed by glucagonomas, VIPomas, and somatostatinomas. The vast majority (∼ 85%) of pancreatic ETs are nonfunctional [10]. Many of these tumors secrete hormones that do not cause obvious symptoms, including pancreatic polypeptide (PP) in 50–75% of cases [11]. Additionally, patients with pancreatic ETs should be evaluated for multiple endocrine neoplasia type I (MEN-I). Regardless of functionality, 40−60% of pancreatic ETs metastasize to the liver, and in particular patients with nonfunctioning tumors frequently have liver metastases at presentation. Gastrinomas, accounting for approximately 3.1% of all islet cell tumors, over-secrete gastric acid and patients eventually develop duodenal or jejunal ulcers. Presentation with gastrointestinal hemorrhage is common (30−50%), and 5−10% of patients present with perforation. Around 40−50% of patients will present with diarrhea, but these symptoms

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Special Tumors, Population, and Special Considerations

can be controlled with proton pump inhibitors or H2 blockers. Metastases typically occur in 70% of cases (50−90% in small studies) and primarily develop in regional lymph nodes and the liver. Liver metastases occur in approximately 50−60% of patients. However, as with all LMETs, less than 20% will be resectable [10, 12]. Approximately 20% of gastrinomas occur as part of MEN-I, although 40% of MEN-I patients develop gastrinomas. The most common site of MEN-I-associated gastrinomas is actually the duodenum, not the pancreas. MEN-I-associated gastrinomas are usually multiple and small (<1 cm). Insulinomas occur in 0.8−0.9 patients per million population per year, with a peak incidence in the fifth decade. Historically, insulinomas were thought to be malignant in less than 10% of cases, but a recent review of more than 9000 patients with pancreatic ETs showed that almost 70% developed distant metastases, and 53% had liver metastases [10]. Insulinomas occur most frequently in the pancreatic head (>16%) and tail (>30%). Multicentric tumors are associated with MEN-I syndrome, although only 10−30% of MEN-I patients develop insulinomas, making these tumors a less common first expression of MEN-I. Most patients will present with confusion, visual changes, sweating, tachycardia, and weakness. These symptoms of hypoglycemia are most severe at night, following exercise, and during fasting. The majority of insulinoma patients become symptomatic during a 3-day fast, and measurement of blood glucose and insulin levels during a fast provides reliable diagnosis. An insulin-to-glucose ratio of 0.3 or greater is diagnostic for insulinoma. Serum C-peptide and proinsulin levels are measured to rule out factitious hypoglycemia from insulin administration. Glucagonomas account for approximately 1% of islet cell tumors and arise from islet α-cells. Their anatomic distribution is identical to that of insulinomas [10]. Glucagonomas are generally greater than 5 cm when symptomatic, and metastases occur in 65−80% of patients [10]. Liver metastases develop in 50% of patients, and up to 70% of patients will have necrolytic migratory erythema. Other findings include mild diabetes, malnutrition, chronic anemia, and deep venous thrombosis despite normal coagulation parameters. VIPomas arise from the pancreas in 80% of cases and are usually large, with a median tumor size of 5 cm [10]. The rest arise from the retroperitoneum, lung, and esophagus. Approximately 50% of pancreatic VIPomas will metastasize, and the liver is the primary metastatic site in 50%. The incidence is 1 per 10 million population per year. Oversecretion of vasoactive intestinal peptide (VIP) produces the Verner−Morrison or WDHA syndrome, characterized by watery diarrhea, hypokalemia, and achlorhydria. The voluminous watery diarrhea frequently exacerbates the hypokalemia.

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More than half of somatostatinomas arise in the pancreas, and these solitary tumors are almost always located in the pancreatic head. The rest arise in the periampullary duodenum and jejunum [11]. The incidence is only 1 per 40 million population per year. Seventy percent are malignant, the liver and lymph nodes being the most common sites of metastasis. The syndrome from somatostatin over-secretion includes diabetes, cholelithiasis, diarrhea, hypochlorhydria, and weight loss.

Imaging for diagnosis, staging, and follow-up As with all evaluations of liver masses, triple-phase helical computed tomography (CT), magnetic resonance imaging (MRI), and arteriography can all be useful to define the relationship of LMETs to the hepatic vasculature. Intraoperative ultrasonography, with or without contrast, can add important information and can change operative strategy, especially considering that up to 20% of liver metastases are not detected with traditional imaging modalities. Imaging with radiopharmaceuticals can be particularly useful when evaluating patients with LMET, the three most common modalities being the radiolabeled somatostatin analog (111In-octreotide) scan, the norepinephrine analog radiolabeled meta-iodobenzylguanidine (MIBG) scan, and positron emission tomography (PET) using 18F-fluorodeoxyglucose (18FDG). These studies take advantage of selective uptake and concentration of the radionuclide carrier molecules by ET cells. These nuclear medicine studies help differentiate benign from malignant lesions, differentiate postsurgical scar from recurrent tumor, monitor treatment response, and stage patients by identifying extrahepatic disease. They are also useful when tumor markers are rising in the absence of an identifiable source, and for further evaluation of equivocal lesions. 111 In-octreotide scintigraphy is 70−100% sensitive for ETs [13], and is the initial diagnostic modality of choice for these tumors (Figure 36.2). Sensitivity for insulinomas is lower (66%) due to the frequent absence of subtype II somatostatin receptors. Single photon emission computed tomography (SPECT) imaging is more sensitive than planar imaging in assessing the presence of localized hepatic metastasis. Intraoperative use of a hand-held gamma probe may potentially aid in identification and resection of small tumor foci, but gallbladder physiologic activity must be distinguished from hepatic tumors. More recently, 111In-octreotide scintigraphy has been found to be a reliable predictor of response to systemic somatostatin analog therapy. 111In-octreotide imaging is preferable to 131I-MIBG scintigraphy for ETs, with the exception of pheochromocytomas. MIBG scintigraphy is most effective in the localization of pheochromocytomas and paragangliomas, but also has been useful in some other

CHAPTER 36

Liver Metastases from Endocrine Tumors

Figure 36.2 In this 51-year-old patient with flushing and nausea, CT scan demonstrated multiple lesions in the liver. Transaxial 111In-octreotide images show uptake in the lesions and central necrosis with no uptake in what was later proven to be metastatic intestinal endocrine tumor.

ETs. Typical gastrointestinal ETs exhibit some MIBG uptake in 55−70% of cases. Sensitivity is highest using SPECT imaging and the 123I-MIBG analog [14]. PET using 18FDG is an option for ETs that are not detected by the other radiopharmaceuticals. There is controversy about the relative sensitivity of FDG-PET versus 111In-octreotide scintigraphy for ETs, but ETs that are FDG positive and 111 In-octreotide negative tend to be less differentiated and have a poor prognosis. Almost all 111In-octreotide-negative ETs will accumulate FDG and can therefore be imaged with PET. Some consider that these functional imaging techniques are more sensitive than the standard radiologic imaging techniques mentioned above for defining the extent of metastatic disease, especially at extrahepatic sites (Figure 36.3). More recent studies using PET imaging with 11C-labeled 3,4-dihydroxyphenylalanine (DOPA) or 5-hydroxytryptamine (5-HT) show that these techniques may be more sensitive than 111In-octreotide or CT for localizing the extent of ETs. A 2007 study showed sensitivity of 96% and specificity of 92% for ETs using PET with 68Ga-octreotide, suggesting future potential for this modality [15]. If necessary, needle aspirate and core biopsy can be performed to make or confirm the diagnosis. Diagnosis of LMET can be made with cytologic or histologic methods followed by immunohistochemical studies. It is worthwhile to determine levels of biochemical markers prior to treatment. A useful battery often includes chromogranin A, neuron-specific enolase, urinary 5-hydroxyindoleacetic acid (5-HIAA), pancreatic polypeptide, gastrin, VIP, insulin, proinsulin, calcitonin, and general tumor markers such as carcinoembryonic antigen (CEA), CA 19-9, and CA 125. Echocardiography should be performed in patients with carcinoid symptoms to evaluate for tricuspid valvulopathy.

Treatment Biotherapy Biotherapy is defined as the pharmacologic treatment of hormonal hypersecretion syndromes using substances, or

derivatives thereof, occurring naturally in the body. Somatostatin analogs are the most commonly used biotherapeutic agents, although interferon-α (IFN-α) is also used in some centers. Somatostatin provides significant relief in a majority of symptomatic patients with LMETs and may exert antiproliferative and even apoptotic effects in some instances, and it is therefore an important part of treatment [16]. This is especially true in the 80−90% of patients who are not candidates for tumor resection or ablation, as well as in the remaining patients as an adjunct to total or partial debulking procedures. These drugs tend to be very well tolerated with minimal side effects. Somatostatin inhibits the synthesis and secretion of many gastrointestinal hormones. Most ETs express a high density of somatostatin receptors, and therefore analogs with long half-lives (e.g. octreotide) are very useful in the treatment of symptomatic ETs and LMETs. Both short- and long-acting octreotide are mainstays of therapy for patients with carcinoid syndrome, and 70−80% of patients enjoy subjective symptomatic improvement. There is an associated decrease in tumor markers in 70% of patients [17]. Octreotide will induce tumor shrinkage by apoptosis in about 10% of patients. Stable disease is observed in 37−45% of patients with documented tumor progression prior to initiation of somatostatin therapy, with a median duration of stabilization of 18−26.5 months [18]. Unfortunately, tachyphylaxis develops after months or years in virtually all patients, requiring increasing doses of octreotide and eventually leading to therapeutic failure. In a randomized controlled trial, octreotide reduced symptoms and improved quality of life, but there was no evidence of survival benefit [17]. In patients developing recurrent symptoms after resection, long-acting octreotide extended the symptom-free interval by a median of 4 years in one report [19]. Since the introduction of somatostatin analogs, bulky hepatic tumor progression has replaced hormonal complications as the leading cause of mortality [20]. IFN-α is the other agent to be considered for treatment of ET, and is often combined with octreotide. IFN-α may increase expression of class I MHC antigens on tumor cells

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Figure 36.3 This 61-year-old woman underwent a left hemihepatectomy and segment VII and VIII resection for carcinoid tumor. At the time of this study she presented with jaundice. 111In-octreoscan was negative, but this PET scan and CT scan demonstrate further metastases (arrows) in the liver, cardiophrenic lymph node, and the head and tail of the pancreas in the corresponding cuts. She successfully underwent further tumor resection.

and induce cytotoxic T-cell activity against the tumor. IFN-α also induces tumor fibrosis [21]. Oberg reported a biochemical response rate to IFN-α of 42%, lasting a median of 32 months for midgut ETs, with tumor stabilization in 39%. Response rates for pancreatic ETs were similar but with a duration of only 2 months [22]. H2 blockers and proton pump inhibitors, while not technically biotherapy, control gastric acid secretion in 90−100% of patients with ZES and should almost always be used. Serial evaluation of gastric acid production and appropriate dose adjustments are required [12].

Surgical resection Resection of both the primary tumor and all gross metastatic disease is the treatment of choice for LMETs when possible (Figure 36.4). In patients undergoing complete resection (100% of gross disease), 5-year survival is usually 70−85%. Operative mortality in patients without underlying liver dysfunction has decreased to 1−3% due to advances in surgical

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and anesthetic technique. The morbidity associated with hepatic resections for LMETs is similar to hepatic resections of the same magnitude for other indications. Steinmueller et al published an outstanding consensus review on the treatment paradigms for these patients, which are further summarized in the Conclusion below [9]. As LMETs commonly involve both hepatic lobes, present with a miliary pattern of disease, and have concomitant distant disease, only 10−20% of patients with LMETs will be candidates for complete resection (resection of 100% of gross disease), and truly curative resection is virtually impossible. Regardless of initial response, long-term disease-free survival following resection for LMET is rare. However, even when complete resection cannot be accomplished, palliative incomplete resection of primary tumors to prevent obstruction or local mass effects and debulking of metastatic disease can be considered [20]. A cytoreductive approach reduces clinical symptoms and improves the likelihood of response to adjunctive medical therapy. This strategy is reasonable for

CHAPTER 36

Liver Metastases from Endocrine Tumors

Figure 36.4 CT scans before and after a liver resection for metastatic endocrine tumor.

LMETs because of the slow kinetics of ET growth, the nodular displacing rather than invading growth pattern in the liver, the efficacy of hormonal blockade, and the fact that the liver often represents the majority of tumor burden. In general, palliative resection is indicated when more than 90% of tumor is resectable and the surgical risk is very low [23, 24]. Symptomatic improvement can be expected in the majority of these patients, but this improvement may be short lived. For example, McEntee et al reported a 6-month duration of symptom relief in patients with carcinoid syndrome undergoing resection [23]. In general, the duration of the clinical response is felt to be inversely proportional to the volume of residual tumor. For this reason, palliative resection should be offered only to highly selected patients, examples being patients with extreme hormonal symptoms unresponsive to other therapies and patients with bulky disease in locations likely to affect short-term quality of life [25]. Good candidates for operation in general are patients with resectable tumors who are unresponsive to medical management, without extrahepatic dissemination, and of good functional performance. Elevated venous pressure associated with carcinoid heart disease represents a contraindication to liver resection. Functional and volume analysis help prevent liver failure. Intraoperative ultrasonography and biopsy to evaluate for steatosis are also useful. Tumors can be enucleated or resected. Resection is often more difficult after chemoembolization or ablation due to the scleroses that adhere the residual tumor mass to adjacent structures. Additionally, up to 20% of liver metastases may be undetectable by traditional imaging techniques, and some authors advocate the use of intraoperative contrast-enhanced ultrasonography to further evaluate for occult lesions. No prospective randomized controlled trial for LMET resection has been published. One of the greatest problems

with the retrospective comparisons of LMET patients in the literature is the extent of disease. The results of many reports from the literature will be discussed here and are summarized in Table 36.1. Many authors consider that LMET patients cannot be meaningfully compared because surgeons offer resection to patients with localized or predominantly unilobar disease. Chen et al attempted to avoid this problem by comparing resected and unresected patients who did not differ significantly on the basis of serum alkaline phosphatase levels, pathology, age, primary tumor site, or percentage of liver involved (mean 19% in both groups) [1]. The 15 patients who underwent complete resection had a 5-year actuarial survival of 73%, while 23 patients who did not undergo resection had a 29% 5-year survival. There was a significant difference in bilobar tumor involvement between the two groups (76% in unresected versus 27% in resected patients). Nonetheless, this study utilized a less biased retrospective design, and demonstrated significantly better prognosis for resected patients. Osborne et al retrospectively quarried a prospectively gathered database of 734 patients with ETs, identifying 59 patients undergoing embolization and 61 undergoing resection (38 complete, 23 incomplete) for LMET [26]. The groups were similar in age, gender, tumor type, and pretreatment performance status. The majority of patients in both groups reported a complete symptomatic response, but the response was significantly longer in patients undergoing resection (35 ± 22 months versus 22 ± 13 months). Overall survival was the same in both groups, but the median symptom-free interval for patients undergoing resection was significantly longer (56 versus 37 months). Performance status increased slightly following resection, but decreased significantly following embolization. Knox et al also showed a clinically and statistically significant and sustained increase in performance status in patients undergoing resection [27].

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Table 36.1 Results from selected publications on resection for liver metastatic endocrine tumors. (Adapted from Steinmueller et al[9].) Authors

Year

Number of patients

Resolution of symptoms (%)

Survival (%)

Que et al [60] Chen et al [1] Chamberlain et al [32] Grazi et al [30] Coppa et al [33] Jaeck et al [34] Yao et al [20] Sarmeinto et al [31] Knox et al [27] Touzios et al [28] Musunuru et al [29]

1995 1998 2000 2000 2001 2001 2001 2003 2003 2005 2006

74 15 34 19 20 13 16 170 13 19 13

90 NR 90 NR NR NR NR 96 82 95 100

74 73 76 93 67 91 70 75 85 72 83

at at at at at at at at at at at

4 5 5 4 5 3 5 3 5 5 3

years years years years; 79 at 10 years years years years years; 61 at 5 years years years years

NR, not reported.

Mean survivals for patients undergoing complete resection, incomplete resection, and embolization were 50 ± 28, 32 ± 19, and 2 4 ± 16 months, respectively, in the Osborne et al study [26]. Touzios et al reported on 60 patients with LMETs who were treated with aggressive resection and/or cryoablation (32%), transarterial chemoembolization (30%), or no aggressive therapy (38%) [28]. Median and 5-year survivals in the three groups were 96 months and 72%, 50 months and 50%, and 20 months and 25%, respectively. These three groups did not differ with respect to metastatic disease, symptoms, radiologic work-up, or the four parameters of tumor burden evaluated by the authors: greater than 50% liver involvement, unilobar versus bilobar disease, size of largest tumor, and total number of tumors. The 5-year survival in the patients with greater than 50% liver involvement was 8%, versus 67% in the group with less than 50% involvement, regardless of treatment. Musunuru et al compared 48 patients with liver-only metastasis from ETs (36 gastrointestinal ETs, 12 islet cell ETs) who underwent resection and/or ablation (27%), hepatic artery embolization (58%), or conservative treatment with chemotherapy, octreotide, or observation (35%) [29]. Three-year survival was 83% for resected patients and 31% for patients treated conservatively or with embolization, but treatment did not significantly affect symptomatic palliation. Grazi et al, using a highly aggressive policy of liver resection, reported that 19 of 28 patients with LMETs presenting over a 16-year period underwent hepatic resection with no operative deaths [30]. Four- and 10-year survivals were 93% and 79%, respectively, for the patients undergoing resection, compared with 19% survival at 4 years for those who could not undergo resection due to extensive disease.

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Yao et al reported on 16 patients who underwent complete resection for LMET with no perioperative deaths and 70% 5-year survival [20]. Even with palliative incomplete resection, results have been favorable. Sarmiento et al reviewed 170 patients who underwent liver resection over 21 years for LMETs (120 “carcinoid,” 18 non-functioning islet cell, 32 functioning islet cell) [31]. Resection was complete in 75 patients (44%). Operative mortality was 1.2%. The 5- and 10-year survival rates were 61% and 35%, respectively, with a reported symptomatic response rate of 96% lasting a median of 4 years. Survival was similar for complete versus incomplete resection. Chamberlain et al reported on 34 patients who underwent hepatic resection, with 15 being complete and 19 incomplete [32]. Five-year survival was 76%. Symptoms were controlled in 90−100%. The amount of liver involved was the only predictor of survival. Coppa et al reported on 20 patients undergoing resection for LMETs with 5-year survival of 67% and 5-year disease-free survival of 29% [33]. Factors influencing survival were resection of the primary tumor, number of metastases, and metachronous versus synchronous hepatic resection. Jaeck et al reported on 13 of their own patients (five “carcinoid,” seven nonfunctioning, and one glucagonoma) and 131 patients from a French multicenter study undergoing resection for LMETs [34]. In the multicenter experience, the mean and diseasefree survivals were 66 months and 41 months, respectively. Finally, Chung et al reported complete resolution of symptoms in 87% of 31 patients for a median of 11 months after hepatic resection, only in two of whom was greater than 90% of tumor volume removed [19]. Taken together, these studies suggest that it is reasonable to consider liver resection when greater than 90% of tumor bulk can be removed. In carefully selected patients,

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significant palliation may be achieved by resecting less than 90% of tumor burden, although this should not be routinely performed for most patients.

Cryotherapy Cryotherapy and other methods of ablation have been applied in certain circumstances to LMET with satisfactory results. Cozzi et al published a series of six patients with unresectable LMETs treated either by resection and cryotherapy or cryotherapy alone [35]. Five of the six patients also underwent simultaneous resection of the primary tumor. No perioperative deaths occurred and all patients were alive at a mean follow-up of 2 years. Seifert et al treated 13 patients with a total of 52 tumors using cryosurgery [36]. Complications occurred in 31% and included coagulopathy, renal failure, and pulmonary embolism. Symptoms improved in all seven who had them preoperatively. Tumor markers were reduced by 85% in the three patients who were tested. At a mean follow-up of 29 months (median 13.4 months), 12 of 17 patients were alive. While it is clear that in selected patients, especially those with multiple bilobar low volume disease, cryotherapy can be beneficial, it is being replaced by radiofrequency ablation (RFA) in most centers.

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Radiofrequency ablation RFA has more recently been added to the armamentarium for treatment of LMETs and allows for open, laparoscopic, and percutaneous approaches (Figure 36.5). Mazzaglia et al reported on 63 patients with LMETs treated with 80 laparoscopic RFA sessions, ablating a total of 378 lesions (mean 6 ± 0.5 lesions/patient; range 1−16) with a mean diameter of 2.3 ± 0.1 cm [37]. Perioperative morbidity was 5% and there were no additional 30-day deaths. Of the 57% of patients who were symptomatic prior to treatment, 70% had significant or complete relief and 92% had partial relief for 11 ± 2.3 months. The local recurrence rate was 6.3% on follow-up CT. The mean overall survival after RFA was 3.9 years, with mean survivals post initial diagnosis and diagnosis of liver metastasis being 11.0 and 5.5 years, respectively. Chung et al used either cryosurgery or RFA in a majority of 31 patients operated on for LMETs. Approximately 30% had recurrence at the site of ablation [19]. This and several other reports demonstrate the relative safety and effectiveness of RFA, and technologic advances are allowing attack of larger lesions. Symptomatic control is achieved in most patients, but is usually short lived. The development of methods for real-time thermometry to ensure adequate and even tissue

Figure 36.5 CT scans before and after radiofrequency ablation of a nonfunctioning endocrine recurrent hepatic metastasis from a pancreatic islet cell primary.

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destruction may offer significant improvements in RFA outcomes, although this technology is not yet widely available. The long-term role of RFA in LMET management is not settled.

Percutaneous ethanol injection therapy For lesions of less than 3 cm in diameter, percutaneous ethanol injection therapy has been used as an alternative therapy, but is falling out of favor. Ethanol causes tissue dehydration which leads to coagulation necrosis. It is difficult to predict the size and shape of the necrosis, which depends on the presence of capsules and septa, vascularization, and the consistency of the tissue. The experience with LMETs is very limited in the literature, but extrapolation from the results for hepatocellular carcinoma (HCC) indicates that the mortality and morbidity of this approach are attractively low. Leoncini et al published a prospective randomized trial in patients with cirrhosis and small HCCs, demonstrating that while overall survival rates were similar, local recurrence-free survival was better after RFA than ethanol injection [38]. In the LMET patients, partial and complete responses have been reported.

Liver and multivisceral transplantation The use of orthotopic liver transplantation (OLT) in the setting of unresectable LMETs is highly controversial. Patients have typically done poorly, owing mostly to early recurrence and tumor spread secondary to immunosuppression, and other treatment options should always be considered prior to transplantation. The published results of liver transplantation for LMETs have been mixed, but are worse for pancreatic ETs. Due to the favorable biology and slower growth rates seen with ETs, some centers have demonstrated that OLT for LMETs results in better outcomes than for other cancers. While a few patients have experienced asymptomatic long-term survival, almost none is cured. In 1998, Lehnert et al reviewed 103 patients transplanted at 23 institutions for extensive LMET, showing 2- and 5-year survivals of 60% and 47%, respectively [39]. Recurrence-free 5-year survival was less than 25%. Multivariate analysis revealed age older than 50 and combined upper abdominal exenteration to be adverse prognostic factors. They concluded that liver transplantation may be justified in highly selected young patients with liver-only disease for relief of symptoms. In a retrospective multicenter analysis of 85 liver transplants performed for LMET (primary tumor in the duodenum or pancreas in 41, other gastrointestinal origin in 26, bronchial tree in 5, and unknown 14) in France between 1989 and 2005, LeTreut et al reported 2- and 5-year actuarial survivals of 67% and 47%, respectively; 5-year disease-free survival was 20% [40]. Previous resection of the primary and/or liver metastases had been performed in 80% of patients, and 12 of the 85 patients died in the postoperative period due mainly to surgical complications. The worst prog-

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nostic indicators were concomitant upper abdominal exenteration (RR, 3.72), primary tumor in the duodenum or pancreas (RR, 2.94), and hepatomegaly (RR, 2.94). After excluding the seven patients undergoing upper abdominal exenteration, the authors showed that 5-year survival for the remaining patients presenting with both hepatomegaly and a duodenal or pancreatic primary tumor was 12%, but this increased to approximately 70% for patients presenting with none or one of these prognostics. A number of small, single-center reports have been added to the literature over the past decade. Marín et al in Spain reviewed 10 patients undergoing OLT for liver metastases from various gastrointestinal ETs, showing 75% morbidity, 10% mortality (n = 1), and 1- and 3-year survival rates of 86% and 57%, respectively [41]. Olausson et al from Sweden published on 15 patients undergoing OLT (n = 10) or multivisceral transplantation (n = 5) for well-differentiated LMET, and achieved 5-year survival of 90%, while diseasefree survival was 20% at 5 years [42]. Florman et al performed OLT on 11 patients; three received living-donor grafts, three underwent concurrent distal pancreatectomy, and one underwent concurrent Whipple procedure [43]. The 1- and 5-year survivals were 73% and 36%, respectively (mean follow-up, 34 ± 40 months), and only one patient alive at 5 years was disease free. With these results, the role of liver transplantation in patients with LMET remains controversial, especially given the shortage of donors. Less than 1% of all liver transplants have been performed for LMET and, outside of a few small studies, survival does not seem to be improved compared to overall averages for the disease. Frilling et al suggested a set of criteria for transplantation of patients with LMET: age younger than 65, primary tumor under control, absence of extrahepatic disease proven over a 6-month period, progression of liver tumors, and excessive hormonal symptoms refractory to medical therapy [44]. Taken together, the results of these studies offer conflicting views on the true prognostic indicators for OLT in LMET. The results of many of the OLT reports have been summarized [9]. In the past, en bloc resection of the liver and much of the gastrointestinal tract along with involved lymph nodes was reported, followed by multivisceral transplantation. However, high early mortality, tumor recurrence, and limited survival have led to almost total abandonment of this approach. Alternatively, earlier consideration for liver transplantation is likely to achieve better long-term results, and may be a reasonable approach in selected patients [45].

Chemotherapy Systemic chemotherapy with various agents may have short-lived success in 20−70% of patients with metastatic ETs. The limited response is thought to be related to the high degree of tumor differentiation and low kinetic activity. For patients with unresectable islet cell tumors, the combination

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of streptozocin and doxorubicin has been shown to be superior to streptozocin and 5-FU in combination or chlorozotocin alone, with tumor regression rates of 69%, 45%, and 30%, respectively, in a randomized trial [46]. Unfortunately, this regimen is relatively ineffective against gastrointestinal ETs, with brief (∼ 3 month) regression in 10−30% of patients. Glucagonomas have a high response rate to dacarbazine. The more aggressive anaplastic ETs have been reported to respond to cisplatin and etoposide in up to 67% of cases [47]. Almost no 5-year survivors have been reported in patients with LMETs treated solely with any chemotherapeutic regimen [32].

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progressive disease (32% versus 12%). Additionally, patients with extensive liver metastasis had reduced time to progression of 26 months. Nausea and vomiting were common side effects (31% and 14%, respectively), as was reversible hair loss, and there were two serious side effects (hepatic and renal failure) in the months following treatment [52]. Based on these studies, it is clear that radiolabeled somatostatin analogs, although unproven in large randomized studies and potentially having reduced efficacy in the setting of liver metastases, may offer significant hope for LMET patients in the future.

Hepatic artery occlusion and embolization Directed radiotherapy External beam radiotherapy is too hepatotoxic to be of any benefit for LMET, but recent reports on the use of radiolabeled somatostatin analogs have shown promising results in some cases. Symptomatic improvement has been demonstrated with many different isotopes, including 111In-, 90Y-, and 177Lu-labeled somatostatin analogs, the latter two being developed after unimpressive effects on tumor size with the 111 In-labeled analog, which typically shrank tumors by 25−50% in 20% of patients, with rare partial responses [48]. Treatment with 90Y-labeled somatostatin has typically been more efficacious, resulting in partial or complete responses in approximately 30% of patients. Intestinal ETs have lower response rates than islet cell tumors (∼ 10% versus 30−50%), and overall response rates were as low as 9% in one study [49, 50]. Significant improvements in both systemic and local tumor-related side effects have been observed in 60−70% of patients [51]. 177 Lu-octreotate represents the third generation in the evolution of these therapies and has increased binding affinity for somatostatin receptor subtype 2. It also allows higher doses to be delivered to tumors without increasing the dose to dose-limiting organs. Additionally, because 177Lu is a lowenergy gamma ray emitter, it enables dosimetry and imaging following therapy. Kwekkeboom’s group in Rotterdam reported on 131 patients with ETs (70 “carcinoid,” 33 nonfunctioning islet, 28 other) with the following disease growth patterns documented during the year prior to treatment with 177Lu-octreotate: 37 (28%) with stable disease, 55 (42%) with progressive disease, and 39 (30%) with unknown status [52]. Of the 125 patients with evaluable disease following therapy, the following responses were seen: 44 (35%) had stable disease, 22 (18%) had progressive disease, 24 (19%) had minor responses (25−50% shrinkage), 32 (26%) had partial responses, and 3 (2%) had complete remission. For the 103 of 125 patients with stable disease or any type of positive response, median time to progression was 36 months (median follow-up, 16 months). Compared with patients having no or limited liver metastasis, patients with extensive liver involvement had reduced response rates (32% versus 53%) and increased rates of

The selective arterial blood supply of hepatic tumors and the dual blood supply of the normal liver allow tumor ischemic therapy by arterial interruption using a variety of methods. In an early report on hepatic artery ligation in a single patient with liver metastatic carcinoid, once the sequelae of acute hepatic ischemia resolved, urinary 5-HIAA decreased to normal and the patient’s carcinoid syndrome resolved for 7 months [53]. Thus, proximal arterial ligation provides palliation, but due to revascularization via collaterals, this is short lived. Also, there is a risk of hepatic failure after acute dearterialization of the entire liver. Another method to induce tumor ischemia is intermittent hepatic artery occlusion. Via laparotomy, an implantable arterial occlusion cuff connected to a subcutaneous port is placed around the hepatic artery, allowing intermittent inflation of the occluder. Authors have experienced greater than 50% mean reduction in 5-HIAA with this method. Another method, distal intrahepatic selective arterial embolization, limits rearterialization and thus prolongs response while avoiding the morbidity and mortality of laparotomy. Nonetheless, patients must be screened to avoid progressive hepatic failure following embolization. Patients with decreased synthetic or clearance function, and especially those with documented cirrhosis, should be treated with caution. Those with Child class C cirrhosis are rarely candidates due to the high mortality and morbidity rates. Carrasco et al treated 25 patients and demonstrated that distal or peripheral embolization was more efficacious than proximal embolization or surgical ligation of arterial inflow [54]. Procedure mortality was 8%, but 87% of survivors improved symptomatically for a median duration of 11 months.

Chemoembolization A further variation on the theme of ischemia is embolization of the tumor vasculature with intra-arterial chemotherapeutic agents (Figure 36.6). One advantage of hepatic arterial chemoembolization (HACE) is that high levels of drug are delivered to the tumor while systemic effects are minimized by the hepatic clearance of the drug. Tumor ischemia purportedly decreases drug clearance from the tumor. Emboli-

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Figure 36.6 Series of CT scans and angiograms before and after chemoembolization for carcinoid liver metastasis.

zation or chemoembolization can be performed repeatedly, allowing for partial dearterialization at one setting, often applied to the hemiliver or highly selectively to specific tumor vasculature. Response rates and outcomes were comparable for gastrointestinal ETs and islet cell tumors in one study [55], while a larger study showed more favorable results with gastrointestinal ETs [56]. HACE has also been used as a preliminary treatment before OLT. A variety of chemotherapeutic regimens have been described, but most include doxorubicin with or without streptozocin. Perry et al treated 30 patients with LMETs (15 “carcinoids,” 5 nonfunctioning islet cells, 10 functioning islet cells) using 40−60 mg of doxorubicin emulsified in iodized oil and intravenous contrast media [57]. The clinical response rate was 90%, and a 77% mean decrease in circulating tumor markers was observed. Radiologic response was seen in 92%. Interestingly, CT findings initially and post therapy did not correlate with clinical or hormonal response. The median survival time in these patients was 24 months after treatment or 53 months after diagnosis. Better survival and response rates were noted in patients whose primary tumor had been resected. Yao et al reported on 20 patients undergoing HACE for liver-dominant disease [20]. Actuarial 5-year survival was 40%. Tumor growth and symptoms were controlled in 90% of patients. Predictors of outcome included volume of tumor, removal of the primary tumor, and multiple procedures. Chamberlain et al treated 39 patients with HACE and 90−94% had symptoms relieved

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and 5-year survival was 51% [32]. Kamat et al published a series of 38 patients with LMET and greater than 75% liver involvement treated with embolization and/or HACE [58]. Treatment resulted in radiologic response or disease stabilization in 82% and symptomatic response in 65%. The mean progression-free survival was 9.2 months and overall survival was 17.9 months post treatment. Gupta et al, at the same center, published on 123 patients with “carcinoid” (n = 69) or islet cell tumors (n = 54) undergoing embolization or HACE at the discretion of the physician [56]. Patients with carcinoid metastases had higher response rates (67% versus 35%; p = 0.0001), longer progression-free survival (28 versus 16 months; p = 0.046), and longer overall survival (34 versus 23 months; p = 0.012) than patients with islet cell tumor metastasis. Patients with 75% or less liver involvement were nearly four times as likely as patients with greater than 75% liver involvement to respond to treatment (p = 0.06). Interestingly, patients undergoing embolization alone were six times more likely to respond than patient undergoing HACE (p = 0.002). In addition to these reports, other studies add to the confusion about whether HACE or bland embolization is the preferred treatment for appropriate patients. Ruutiainen et al compared embolization to HACE with cisplatin, doxorubicin, mitomycin-C, iodized oil, and polyvinyl alcohol in 67 patients who underwent a total of 219 embolization procedures [59]. The percentages of progression-free patients at 1, 2, and 3 years were 49%, 49%, and 35%, respectively,

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after HACE, and 0%, 0%, and 0%, respectively, after bland embolization (log-rank test, p = 0.16). The mean duration of symptomatic relief was 15 months following HACE and 7.5 months following embolization alone (p = 0.14). The 1-, 3-, and 5-year survival rates were 86%, 67%, and 50%, respectively, following HACE, and 68%, 46%, and 33%, respectively, after embolization (log-rank test, p = 0.18). Gupta et al reviewed 15 studies on HAE and HACE published between 1983 and 2003 and showed that in patients with intestinal gastrointestinal ETs, the average overall response (complete + partial) across all studies was 55% for embolization (70 of 127) and 32% (31 of 96) for HACE [80]. In patients with islet cell tumors, the average overall response was 56% for embolization (31 of 55) and 53% for HACE (18 of 34). It should be noted that the studies that were compared varied greatly in both clinical methodology and patient characteristics. These results suggest that HACE is tolerated as well as embolization alone, but it remains to be seen which modality is superior for particular patient groups. Prognostic indicators remain controversial, although it appears that greater than 75% liver involvement is associated with less favorable outcomes.

Liver Metastases from Endocrine Tumors

Table 36.2 2007 Concensus guidelines for the treatment of liver metastases from endocrine tumors (LMETs) [9]. 1 LMET without extrahepatic disease: a Preferred treatment: surgical resection of both primary and all liver metastasis ± local ablative techniques (may be one- or two-step procedure) b Treatment if unresectable disease or poor surgical candidate: continued biotherapy, hepatic artery chemoembolization (TACE) or embolization, radiofrequency ablation (RFA) c Liver transplantation considered in rare cases (<1%) 2 LMET with extrahepatic disease: a Preferred treatment: biotherapy or other systemic nonsurgical treatment b Palliative treatment if symptoms progress: i If small number of isolated liver metastases < 3–4 cm: RFA, TACE or embolization; may consider minor or anatomic resection in selected cases ii If complex pattern or liver metastases: RFA, TACE or embolization; may consider major liver resection together with RFA for selected cases iii If diffuse pattern of liver metastases: TACE or embolization

Conclusion Patients with LMET represent a unique population and respond to treatments differently from those with metastases from other origins. They can often expect prolonged survival despite extremely low chances for cure. Treatment aimed at relief of symptoms caused by hormonal excess is very well accepted, and is the first-line treatment and an important adjunct to other treatment modalities. Somatostatin analog therapy should be considered for all patients unless there is a contraindication. The literature is inconclusive regarding the preferred follow-on treatment when biotherapy is contraindicated or becomes ineffective. The 2007 concensus guidelines published in Neuroendocrinology perhaps best represent the current thoughts on the approach to treating LMETs [9] (Table 36.2). Additionally, while not included in the official recommendations, radioactive somatostatin analogs and other emerging treatments can always be considered in selected patients who are not eligible for the preferred treatment of their disease. While the role of palliative debulking remains loosely characterized and controversial, it appears that liver resection of greater than 90% of the volume of the LMET outweighs the operative morbidity and mortality in most reports by offering improved outcomes for symptomatic patients and probably extending survival. Many clinicians argue that HACE is an equally attractive option. For patients with a small number of tumors (e.g. three to four), that are easily

accessible and no more than 3−4 cm in diameter, RFA should be considered, provided there is an experienced center to perform the procedure. Unfortunately, RFA fails to achieve local control in up to 20% of tumors. Transplantation in younger patients with metastasis confined to the liver is advocated by some clinicians. Regardless of the initial treatment approach, the vast majority of patients will experience recurrence. Even more troubling, most patients are not eligible for surgery or other cytoreductive techniques, and designing the best treatment regimen for these patients is often a challenge. In cases where the primary tumor and regional or other metastatic disease is unresectable, or for recrudescent disease, systemic therapy offers the best palliation. The rapidly growing field of radiolabeled peptide therapy may offer the next generation of therapeutic options, and preliminary results with the newest radiolabeled somatostatin analogs have been very encouraging. HAE and HACE yield high response and symptom palliation rates, but do not significantly affect survival; it is unclear when one is indicated as opposed to the other. There is little role for treatments such as cryotherapy, ethanol injection, and traditional chemotherapy. Treatment of patients with LMET involves a variety of techniques that should be applied in sequential fashion depending on the type of tumor, symptoms, location, size, distribution, extrahepatic disease load and location, hepatic functional reserve, and the overall condition and wishes of the patient.

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Self-assessment questions 1 Which one of the following is the least useful in treating well-differentiated hepatic endocrine metastasis? A Liver resection B Radiofrequency ablation C Chemotherapy D Biotherapy E Chemoembolization 2 Debulking surgery for LMET is defined as the procedure when what percentage of tumor bulk can be removed? A >20% B >50% C >75% D >90% E 100% 3 Currently the preferred nuclear imaging modality for both carcinoid and islet cell tumors is 111In-octreotide scintigraphy, because it has greater than 95% sensitivity and specificity for both tumor types. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 4 Liver metastases ultimately occur in what percentage of patients with carcinoid tumors? A 10% B 25% C 50% D 75% E 90%

6 Biotherapy with somatostatin analogs is useful in treating carcinoid symptoms but offers palliative benefits only, with no chance of tumor stabilization or shrinkage. A True B False 7 Which of the following laboratory results are often elevated in patients with endocrine tumors? (more than one answer is possible) A 5-HIAA B Chromogranin-A C α-Fetoprotein D Neuron-specific enolase E Transferrin 8 Which one of the following therapeutic radiolabeled somatostatin analogs represents the most recent addition to the class? A 90Y-somatostatin B 111In-octreotide C 177Lu-octreotate D 131I-MIBG E 91Y-somatostatin 9 Which of the following are common symptoms of carcinoid syndrome? (more than one answer is possible) A Flushing B Constipation C Diarrhea D Wheezing E Paraesthesias 10 The literature clearly demonstrates that hepatic artery embolization is superior to chemoembolization. A True B False

References 5 Whenever a complete resection of liver metastasis from endocrine tumor is possible, the operation should be performed, because randomized controlled trials have demonstrated a survival benefit in patients undergoing resection. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct

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42 Olausson M, Friman S, Herlenius G, et al. Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors. Liver Transpl 2007;13:327–33. 43 Florman S, Toure B, Kim L, et al. Liver transplantation for neuroendocrine tumors. J Gastrointest Surg 2004;8:208–12. 44 Frilling A, Rogiers X, Malago M, et al. Treatment of liver metastases in patients with neuroendocrine tumors. Langenbeck’s Arch Surg 1998;383:62–70. 45 Ringe B, Lorf T, Dopkens K, Canelo R. Treatment of hepatic metastases from gastroenteropancreatic neuroendocrine tumors: role of liver transplantation. World J Surg 2001;25:697–99. 46 Moertel CG, Lefkopoulo M, Lipistz S, et al. Streptozotocin-doxorubicin, streptozotocin-fluorouracil, or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992; 326:519. 47 Moertel CG, Kvols LK, O’Connell MJ, Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 1991;68:227–32. 48 Anthony LB, Woltering EA, Espanan GD, et al. Indium-111pentetreotide prolongs survival in gastroenteropancreatic malignancies. Seminars Nucl Med 2002;32:123–32. 49 Waldherr C, Schumacher T, Maecke HR, et al. Does tumor response depend on the number of treatment sessions at constant injected dose using 90Yttrium-DOTATOC in neuroendocrine tumors? Eur J Nucl Med Mol Imaging 2002;29 (Suppl 1): S100. 50 Paganelli G, Bodei L, Junak D, et al. 90Y-DOTA-D-Phe1-Tyr3octreotide in therapy of neuroendocrine malignancies. Biopolymers 2002;66:393–8. 51 Bushnell D. Therapy with radiolabeled somatostatin peptide analogs for metastatic neuroendocrine tumors. J Gastrointest Surg 2006;10:335–6. 52 Kwekkeboom DJ, Teunissen JJ, Bakker WH, et al. Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol 2005;23:2754–62. 53 Aune S, Schistad G. Carcinoid liver metastases treated with hepatic dearterialization. Am J Surg 1972;123:715–17.

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54 Carrasco CH, Charnsangavej C, Ajani J, et al. The carcinoid syndrome: palliation by hepatic artery embolization. AJR Am J Roentgenol 1986;147:149–154. 55 Ho AS, Picus J, Darcy MD, et al. Long-term outcome after chemoembolization and embolization of hepatic metastatic lesions from neuroendocrine tumors. AJR Am J Roentgenol 2007;188: 1201–7. 56 Gupta S, Johnson MM, Murthy R, et al. Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival. Cancer 2005;104:1590–602. 57 Perry LJ, Stuart K, Stokes KR, Clouse ME. Hepatic arterial chemoembolization for metastatic neuroendocrine tumors. Surgery 1994;116:1111–17. 58 Kamat PP, Gupta S, Ensor JE, et al. Hepatic arterial embolization and chemoembolization in the management of patients with large-volume liver metastases. Cardiovasc Intervent Radiol 2008;31: 299–307. 59 Ruutiainen AT, Soulen MC, Tuite CM, et al. Chemoembolization and bland embolization of neuroendocrine tumor metastases to the liver. J Vasc Interv Radiol 2007;18:847–55. 60 Que FG, Nagorney DM, Batts KP, et al. Hepatic resection for meteastatic neuroendocrine carcinomas. Am J Surg 1995; 169:36–43.

Self-assessment answers 1 2 3 4 5 6 7 8 9 10

C D B D B B A, B, D C A, C, D B

37

Uncommon Primary and Metastatic Liver Tumors Stefan Breitenstein, Ashraf Mohammad El-Badry, and Pierre-Alain Clavien Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland

While a large amount of data is available on hepatocellular carcinoma, cholangiocellular carcinoma, and liver metastases from colorectal cancer, only a few studies have presented other liver tumors. Treatment and outcome of these uncommon tumors remain largely controversial, and therapeutic strategies for them have not been clearly defined [1]. This chapter will review the data available on (1) rare primary hepatic tumors, including sarcomas (angiosarcomas, undifferentiated sarcomas, schwannomas, epithelioid hemangioendotheliomas) and primary liver lymphomas; (2) liver metastases from breast cancer, melanoma, and gastric cancer; and finally (3) liver tumors of unknown origin. The topic of neuroendocrine tumors metastatic to the liver is covered in Chapter 36.

Uncommon primary tumors of the liver Sarcomas Sarcomas of the liver are rare, representing less than 1% of all hepatic malignancies in adults, with only exceptional reports in the pediatric population. The most common histologic types are angiosarcoma, undifferentiated sarcoma, epithelioid hemangiosarcoma, and schwannoma.

Angiosarcoma Angiosarcoma is the most common type of liver sarcoma in adults with a peak incidence in the sixth and seventh decades. The annual incidence in the general population is 1.4 per 100 million [2] with a tendency toward elderly males [3]. Several etiologic factors have been identified, including exposure to vinyl chloride, thorotrast, and arsenic [4]. A link has been suggested between the development of angiosarcoma and the long-term use of oral contraceptives [5]. The clinical presentation is nonspecific, with abdominal pain, fatigue, jaundice, and loss of weight [6]. More dra-

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

matic presentations include intra-abdominal bleeding [7] and high output heart failure [2]. Most of these tumors are very large at the time of diagnosis [2] with massive hepatomegaly and ascites [6, 8]. Hepatic angiosarcoma may appear as scattered multiple small nodules, a solitary large mass with multiple small lesions or a diffusely infiltrating tumor [9]. The contrast computed tomography (CT) scan often shows patchy enhancement of the tumor. Angiosarcomas can be distinguished from benign hemangiomas by the absence of peripheral enhancement completely encircling the low-density areas, together with the heterogeneous enhancement. At angiography, angiosarcoma appears as a focal hepatic mass with peripheral contrast staining, puddling of contrast, and central areas of hypovascularity. Due to the risk of bleeding, the diagnosis is usually made by open or laparoscopic biopsy. Percutaneous biopsies have been associated with a 5% mortality rate [2]. The prognosis of angiosarcoma is very poor, with a rapid progressive clinical course in most cases. Overall, the mean survival of patients with hepatic angiosarcoma is 6 months, with a 2-year survival rate of only 3%. Distant metastases develop in about 60% of patients with angiosarcoma. Hemorrhage and thrombocytopenia are frequent clinical features in advanced stages of the disease. The number of reported cases of hepatic angiosarcoma remains low. The results of different therapeutic modalities are summarized in Table 37.1. In early stages when the tumor is still localized, resection in combination with chemotherapy has been used with limited success. For instance, of three adult patients treated with liver resection and adjuvant doxorubicin hydrochloride (adriamycin), none survived beyond 2 years [10]. A 4-yearold child survived 44 months after hemihepatectomy and adjuvant chemotherapy containing ifosfamide, etoposide, cisplatinum, and adriamycin [11]. Arima-Iwasa et al [12] reported a patient with hepatic angiosarcoma who was alive without evidence of recurrence 16 months after resection. Ozden et al [13] reported the case of a 54-year-old female patient with a solitary large angiosarcoma treated by right hemihepatectomy and postoperative chemoembolization of the remnant liver. The patient was alive for more than 5

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Table 37.1 Outcome of primary angiosarcoma of the liver treated by various modalities. Authors (year)

Number of patients

Treatment

Death (months)

Locker et al (1979) [2] Das Gupta et al (1982) [10] Penn (1991) [15] Peiper et al (1994) [79] Awan et al (1996) [19]

4 3 14 1 1 1 2 1 1 1 1

Chemotherapy Resection + chemotherapy Transplantation Segmentectomy (R1) + chemotherapy Hemihepatectomy Transplantation Chemotherapy + chemotherapy Resection + chemotherapy Resection Resection (trisegmentectomy) Resection (hemihepatectomy), prophylactic chemoembolization (lipiodol + adriamycin + mitomycin) of the remnant liver Vascular ablation + chemotherapy and liver transplantation Transplantation Resection

12, 12, 7, 5 <24 NR 30 12 4 3

Gunawardena et al (1997) [11] Timaran et al (2000) [14] Rui et al (2001) [80] Ozden et al (2003) [13]

Dimashkieh et al (2004) [20]

1

Maluf et al (2005) [16] Arima-Iwasa et al (2007) [12]

7 1

Alive (follow-up in months)

2-Year survival (%)

NR

15

44 120 35 64

NR

14

NR

12 16

NR

R1,; resection with a positive margin; NR, not reported.

years without recurrence. Moreover, one case of a 10-year tumor-free survival was reported by Timaran et al [14], indicating that long-term survival is possible in individual cases. Liver transplantation has been used in some patients with angiosarcoma. The results have been disappointing and angiosarcoma is currently considered as an absolute contraindication for transplantation in most centers. Penn [15] reported 14 cases of angiosarcoma treated by liver transplantation; nine patients (64%) developed recurrence and all patients died within 27.5 months. The cause of death among patients without recurrence was not mentioned. Maluf et al [16] reviewed the United Network for Organ Sharing (UNOS) database between October 1987 and November 2003. The authors found seven patients in whom hepatic angiosarcoma was diagnosed only after histologic examination of the removed organs during liver transplantation, with a mean post-transplantation survival of 262 days [16]. Fayette et al [17] reported seven cases of hepatic angiosarcoma among 161 patients (4%) with angiosarcoma of various organs treated from 1980 to 2004 in three institutions of the French Sarcoma Group. The authors identified that angiosarcoma of the liver is associated with poor prognosis and overall survival. Decreased survival has been shown in patients with primary angiosarcoma compared with other primary liver sarcomas, even with R0 resection [18]. In the pediatric population, the first case of liver transplantation for angiosarcoma was reported in 1996 [19]. The

440

patient died 4 months after liver transplantation due to an overwhelming cytomegalovirus infection [19]. More recently, a case of hepatic angiosarcoma was reported in a 5-year-old girl who was treated by liver transplantation and who developed lung metastases 14 months later [20]. The role of systemic chemotherapy in unresectable cases remains unclear. In a report on four patients receiving systemic adriamycin, two patients demonstrated some response and were alive at 7 and 12 months, while two died after 5 and 12 months [2]. Worawattanakul et al [21] reported a case of a 34-year-old man who received systemic chemotherapy (cytoxan, adriamycin, and dacarbazine) for two hepatic lesions histologically diagnosed as angiosarcoma. Magnetic resonance imaging (MRI) showed a reduction of size in one mass and resolution of the other 17 months after initiation of therapy.

Undifferentiated sarcoma Undifferentiated sarcomas of the liver were first described by Stanley in 1973 [22]. This type of sarcoma is usually found in children under 15 years of age (see Chapter 39) and rarely in adults. This section will only describe undifferentiated sarcomas in the adult population. No etiologic factor has been described so far. Liver cirrhosis is not associated with undifferentiated sarcomas. Patients usually present with signs of advanced disease, such as weight loss, malaise, fatigue, and abdominal pain. The radiologic diagnosis of undifferentiated sarcoma is often

CHAPTER 37

difficult. CT findings show a variety of solid and cystic hypodense lesions. Peripheral enhancement may correspond to a fibrous pseudocapsule. On angiographic evaluation, the undifferentiated sarcoma appears typically avascular or hypovascular, although hypervascularity can also be present occasionally. Only a few cases of long-term survival have been reported after resection of undifferentiated sarcoma of the liver (Table 37.2). Gourgiotis et al [23] reported the case of a 20-year-old man presenting with an undifferentiated sarcoma of the left liver lobe which had been successfully resected. The patient received postoperative chemotherapy; however, he died after 9 months due to multiple metastases. Sustained remission of an hepatic undifferentiated sarcoma was achieved in a 34-year-old woman who was treated with repeated hepatectomy and chemotherapy [24]. A 22-year-old man with a large undifferentiated sarcoma involving the right lobe underwent portal vein embolization followed by trisectionectomy and bile duct resection and reconstruction. The patient received adjuvant chemotherapy with vincristine, actinomycin-D, and cyclophosphamide, and was alive without evidence of disease for 14 months [25]. This result indicates that aggressive surgical resection could improve survival. Lenze et al [24] reviewed published data on 67 patients aged 15 years or older with hepatic undifferentiated sarcoma and showed that complete resection followed by adjuvant chemotherapy provided significantly longer survival compared with resection alone. Due to the paucity of case reports, the various stages of the disease, and therapeutic regimens applied, conclusions regarding effective treatment remain difficult.

Uncommon Primary and Metastatic Liver Tumors

Epithelioid hemangioendothelioma Epithelioid hemangioendothelioma is a rare tumor of the liver first described by Weiss and Enzinger in 1982 [26]. Females are slightly more often affected (female-to-male ratio, 2:3) [27]. An association with the use of oral contraceptives has been suggested [27], but questioned by others [28]. Most patients complain of epigastric pain and weight loss. Portal hypertension with ascites has also been described in several patients with epithelioid hemangioendothelioma [28, 29]. For more details on various pathologic patterns see Chapter 3. On CT the tumor appears hypodense with an irregular outline. Focal calcifications are found in about 20% of cases. Hypervascularized areas can be detected within the tumor after administration of intravenous contrast. During the parenchymal phase, the tumor becomes isodense with the normal liver tissue, making the evaluation of the tumor extension difficult. The angiographic evaluation reveals only moderate tumoral vascularization in most cases. Epithelioid hemangioendothelioma is often diffuse at the time of diagnosis and resectability rate remains difficult to evaluate. The clinical course is often favorable, with a 2-year survival of 50% in unresectable patients [30]. However, the prognosis for an individual patient is difficult to predict since rapid progressive courses of the disease have also been documented [28, 31]. Resection remains the therapy of choice in the absence of extrahepatic disease. Unfortunately, about one-third of patients have extrahepatic metastases at the time of diagnosis [30, 32]. Whether resection has any benefit in patients with extrahepatic disease remains unclear. The available

Table 37.2 Outcome of undifferentiated sarcomas of the liver treated by various modalities in the adult population. Authors (year)

Number of patients

Treatment

Mattila et al (1974) [81] Tanner et al (1978) [82] Ellis et al (1983) [83] Wolf et al (1991) [84] Zornig et al (1992) [85] Reichel et al (1994) [86] Peiper et al (1994) [79] Johnson (1995) [87]

1 1 1 11 1 1 1 2 1

Harrison et al (1997) [1] Elias et al (1998) [50] Gourgiotis et al (2008) [23] Lenze et al (2008) [24] Pachera et al (2008) [25]

27 18 1 1 1

Extended right hemihepatectomy Hepatic artery ligation + chemotherapy Resection Resection Resection segment 5 and 6 Left lobectomy + chemotherapy Right hemihepatectomy + chemotherapy Right hemihepatectomy Left hepatectomy, resection colon transverse Resection Resection Resection + chemotherapy Repeated resection + chemotherapy Right trisectionectomy + chemotherapy

Death (months)

Alive (follow-up in months)

5 8 2 NR

36% at 2 years 30

24 7 9 of 20 3

NA 9

4% at 5 years 18% at 5 years 6 years 14

NA, not available; NR, not reported.

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data are from case reports or small series only, making comparisons of the various therapeutic regimens difficult. In early stages, resection alone can result in long-term survival. The results of epithelioid hemangioendothelioma treated by various modalities are presented in Table 37.3. Liver transplantation might be a good option in patients with unresectable tumors. In a series of 21 patients reported by Penn [15], only one-third of patients developed recurrent tumors after transplantation; however, 5-year survival was only 43% (see Chapter 23). Madariaga et al [33] reported more optimistic results in 16 patients treated by transplantation with a 71% 5-year survival. Some authors have even suggested that the presence of extrahepatic tumors should not be a contraindication for liver transplantation. For instance, Marino et al [29] reported a series of five patients who underwent liver transplantation despite the presence of extrahepatic metastases at various sites, including lung, pleura, diaphragm, hilar, and extrahepatic lymph nodes. Two patients were treated with transplantation alone and three received adjuvant adriamycin after transplantation. All five patients were alive with a follow-up of between 15 months and 11 years after the transplantation. These data suggest that extrahepatic metastases, in contrast to most other tumors, are stable even in the presence of immunosuppression. Furthermore, one patient demonstrated spontaneous regression of extrahepatic metastases after transplantation [29]. Lerut et al [34] showed good results

after liver transplantation due to hepatic epithelioid hemangioendothelioma in six patients. Two patients had extrahepatic metastases at the time of transplantation. The median disease-free survival was 77 months. The role of liver transplantation in the treatment of epithelioid hemangioendothelioma has been studied in 59 patients who were reported to the European Liver Transplant Registry (ELTR) [35]. Excellent overall results were reported with only one early (<3 months) death after liver transplantation and 22% late (>3 months) mortality. The survival rates after transplantation were 93%, 83%, and 72% after 1, 5, and 10 years, respectively. Microvascular or combined macromicrovascular invasion significantly influenced patient survival, whereas extrahepatic disease and lymph node involvement did not. Long-term survival was encouraging even in patients treated for recurrent (allograft) disease [35]. In unresectable cases, long-term survival up to 8 years has been reported with chemotherapy and radiation alone. However, less favorable courses without response to chemotherapy or radiation have also been described [27, 28]. No factors have been identified to predict response to chemotherapy.

Hepatic schwannoma Schwannomas are often associated with von Recklinghausen disease, and patients with neurofibromatoses have a 4600fold higher risk of developing schwannomas; the disease in

Table 37.3 Outcome of epithelioid hemangioendothelioma of the liver treated by various modalities. Authors (year) Sugahara et al (1974) [88] Ishak et al (1984) [32]

Dean et al (1985) [27]

Clements et al (1986) [89] Scoazec et al (1988) [90] Marino et al (1988) [29] Terada et al (1989) [91] Dietze et al (1989) [28] Penn (1991) [15] Madariaga et al (1995) [33] Idilman et al (1997) [92] Lerut et al (2004) [34] Lerut et al (2007) [35] NR, not reported.

442

Number of patients 1 3 1 1 3 1 1 1 1 1 5 1 3 2 21 16 1 6 59

Treatment

Alive (follow-up)

Resection Chemotherapy

5 years

Right hemihepatectomy Liver transplantation Symptomatic Resection Radiation + chemotherapy Symptomatic Liver transplantation Chemoembolization Liver transplantation Resection Symptomatic Liver transplantation Liver transplantation Liver transplantation Chemotherapy Liver transplantation Liver transplantation

5-Year survival (%)

9 years 7 years 15 years 3 years 8 years 9 months Mean 40 months 8 months 3 months 2 months NR NR 12 months Median 77 month

NR

43 71.1

83

CHAPTER 37

these patients also tends to follow a more malignant course. On CT imaging, schwannomas appear as well-circumscribed hypodense masses with no enhancement after intravenous contrast. The angiography shows hypovascular mass within the liver. Most schwannomas are located at the extremities and the trunk. Primary malignant schwannoma of the liver is exceptional. Prognostic factors associated with short survival are tumor size greater than 5 cm and incomplete resection [36]. Although schwannomas (Figure 37.1) are associated with a 3- and 5-year survival of 62% and 43%, respectively, patients with von Recklinghausen disease have only a 16% 5-year survival. However, patients with solitary schwannomas can expect a 5- and 10-year survival of 53% and 38%, respectively.

Uncommon Primary and Metastatic Liver Tumors

Curative resection is, whenever possible, the therapy of choice. The role of adjuvant treatment in schwannomas of the extremities and the trunk is controversial. Ducatman et al [36] reported a large retrospective series of 120 patients, who received adjuvant radiotherapy (49%) and adjuvant chemotherapy (21%). No improvement in patient survival with either adjuvant modality was noted. To date, only a few cases of schwannoma of the liver have been reported in the literature (Table 37.4). Liver resection was possible in only four cases with three being alive after 10, 18, and 48 months. Of the other five reported cases, one patient died 3.5 months after orthotopic liver transplantation due to recurrent disease. The four other patients had a rapid deteriorating course and died within 4 months of diagnosis.

Primary lymphomas of the liver

Figure 37.1 CT image of a liver metastasis of a breast cancer.

Abdominal lymphomas represent less than 2% of abdominal malignancies. The most frequent locations are the stomach (62%), the small (22%) and large (15%) bowels, and the pancreas (3%) [37]. While secondary involvement of the liver is common (70%) [38], primary lymphomas of the liver are rare. The peak incidence is in the fifth decade with a male predominance of 3:1. Most frequent symptoms are fever, weight loss, and abdominal pain. Due to nonspecific symptoms the diagnosis is rarely made prior to surgery. The prognosis of these tumors mainly depends on the histologic type and grade (see Chapter 3). Different therapeutic approaches have been performed, including chemotherapy alone, or a combination of liver resection and chemotherapy. While chemotherapy remains the mainstay of treatment, recent data suggest that a multimodality approach might be preferable. The published data are shown in Table 37.5. Again, the heterogeneity in tumor stages and treatment make any conclusion regarding optimal therapy impossible.

Table 37.4 Outcome of schwannoma of the liver treated by various modalities. Authors (year)

Number of patients

Treatment

Death (months)

Young (1975) [93] Shmurun et al (1977) [94] Tuder et al (1984) [95] Lederman et al (1987) [96] Penn (1991) [15] Heffron et al (1993) [97] Borrowdale et al (1995) [98] Morikawa et al (1995) [99] Dette et al (1997) [100]

1 1 1 1 1 1 1 1 1

Symptomatic Symptomatic Subtotal hepatectomy Hepatic artery embolization for bleeding Liver transplantation Resection segment III Wedge resection Symptomatic Right hemihepatectomy

1 1 <1 <1 3.5

Alive (follow-up in months)

18* 48 4 10**

*Free of disease. **Alive with recurrence.

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Table 37.5 Outcome of primary hepatic lymphoma treated by various modalities. Authors (year)

Number of patients

Treatment

Death (months)

Torres and Bollozos (1971) [101] Talamo et al (1980) [102] Strayer et al (1980) [103] Leahy et al (1982) [104] Osborne et al (1985) [40]

1

Symptomatic

<1

1 1 2 8 2 1 1 4

Symptomatic Symptomatic Chemotherapy Chemotherapy Resection + chemotherapy Extended left hemihepatectomy Right hemihepatectomy 3x extended right hemihepatectomy+ chemotherapy; 1x right hemihepatectomy + chemotherapy Chemotherapy Right extended hemihepatectomy Chemotherapy Hemihepatectomy Prednisolone Chemotherapy Right hemihepatectomy + chemotherapy Neoadjuvant chemotherapy + resection + adjuvant chemotherapy

<1 <1

Daniel et al (1985) [105] Ryoo et al (1986) [106] Ryan et al (1988) [107]

Andreola et al (1988) [37] Anthony et al (1990) [108]

Lei et al (1995) [109] Taketomi et al (1996) [38] Eidt et al (2003) [41]

5 1 4 1 3 6 1 1

Pescovitz et al [39] analyzed the literature comparing combined treatment regimens versus chemotherapy alone and found a better long-term survival in five patients treated with chemotherapy with resection (80%) than in 13 patients treated with chemotherapy alone (54%). On the other hand, other authors [40] reported good results for chemotherapy alone. The role of neoadjuvant chemotherapy has been highlighted by Eidt et al [41] who successfully treated a case of diffuse large-cell B-cell lymphoma of the liver in a 48-year-old woman. The patient received neoadjuvant chemotherapy followed by complete tumor resection and six cycles of postoperative chemotherapy, and remained disease-free for more than 5 years.

Liver metastases of noncolorectal nonneuroendocrine origin Despite the established agreement on the advantage of liver resection for metastatic colorectal and neuroendocrine tumors, evidence of a similar role in noncolorectal nonneuroendocrine (NCRNE) cancers is still evolving. However, the results reported in a number of recent studies support a developing trend toward surgery in this setting. In a retrospective study of 1452 patients treated at 41 centers, Adam et al [42] demonstrated that liver resection for NCRNE hepatic metastases is safe and effective. The authors categorized the outcome according to the primary tumor and the

444

15

3, 13 6, 15, 27 <1 <1, 18 2, 3, 4, 5, 16

Alive (follow-up in months)

15, All: 20, 22 18 53,

90 5, 5, 10, 16, 24, 26, 28, 40 124

61, 61

18, 12, 42 62 60 36 48 45 >60 months

5-year survival after liver resection into: favorable (adrenal, testicular, ovarian, small bowel, ampullary, breast, renal, and uterine tumors); intermediate (gastric adenocarcinoma, exocrine pancreas, cutaneous melanoma, choroidal melanoma, and duodenal tumors); and poor (gastroesophageal junction, pulmonary, esophageal, and head and neck tumors). In a comparative analysis, Reddy et al [43] studied the results of liver resection for metastatic tumors in 360 consecutive patients (245 colorectal and 33 neuroendocrine versus 82 NCRNE primaries). There has been no difference in median overall survival between patients with metastases from colorectal and noncolorectal disease. The long-term outcome after resection of NCRNE was nearly equivalent to that of colorectal tumors. Nonetheless, patients with NCRNE tumors showed shorter median disease-free survival (13 months) compared with colorectal counterparts (16 months). Modern imaging techniques such as 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography(PET)/CT combined with intraoperative gamma probe tumor detection and postoperative 18F-FDG PET/CT may provide valuable real-time intraoperative information to localize and verify tumor resection [44]. Although many of the published studies have focused on metastatic colorectal tumors, this approach could have a positive impact on the outcome of resection of liver metastases from NCRNE tumors [44]. This chapter will shed some light on liver metastases from breast, melanoma, and gastric tumors, in addition to those of unknown origin.

CHAPTER 37

Uncommon Primary and Metastatic Liver Tumors

Liver metastases from breast cancer While 65% of all patients with breast cancer eventually develop liver metastases, only 3−11% have liver metastases as the only systemic location of dissemination [45−47]. On CT evaluation, calcifications are often found within the liver metastases (Figure 37.2). Metastatic breast cancer is usually associated with an unfavorable prognosis. The median survival in these patients is poor and ranges between 5 and 8 months. Seventy percent of the liver metastases are negative for hormonal receptors, so that antiestrogen therapy is not effective in most cases (Table 37.6). Encouraging results have been recently reported with liver resection for metastatic breast cancer. In 65 patients with liver resection due to metastatic breast cancer, the median survival was 42 months [48]. Other studies showed 5-year survival of 27% and 20% [49, 50]. Caralt et al [51] recently reported that the actuarial survival at 1, 3, and 5

Figure 37.2 MRI image of an intrahepatic sarcoma.

Table 37.6 Outcome of metastatic breast cancer of the liver treated by various modalities. Author (year) Foster et al (1978) [63] Szakacs et al (1990) [110] Elias et al (1991) [111] Wolf et al (1991) [84] Penn 1991 [15] Schneebaum et al (1994) [46]

Number of patients

Raab et al (1996) [112] Harrison et al (1997) [1] Elias et al (1998) [50] Seifert et al (1999) [47] Maksan et al (2000) [54] Yoshimoto et al (2000) [49] Kondo et al (2000) [113] Benevento et al (2000) [114] Pocard et al (2001) [48] Carlini et al (2002) [61]

5 1 12 1 3 6 22 12 8 19 9 30 7 35 15 9 25 6 5 65 17

Kogure et al (2003) [58] Wilson et al (2003) [57] Diaz et al (2004) [62] Vlastos et al (2004) [53]

1 1 1 31

Lorenz et al (1995) [64]

Adam et al (2006) [42] Camacho et al (2007) [59] Caralt et al (2008) [51] Lubrano et al (2008) [52]

454 10 12 16

Treatment Resection Resection Resection + chemotherapy Right hemihepatectomy Transplantation Resection + arterial chemotherapy Systemic chemotherapy Arterial chemotherapy Resection + arterial chemotherapy Arterial chemotherapy Symptomatic Resection Resection Resection Resection Resection Resection + systemic. chemotherapy Resection + systemic chemotherapy Resection Resection Resection + chemotherapy ± hormonal therapy (13), hormonal therapy (2), no adjuvant treatment (2) Preoperative arterial and oral chemotherapy Transplantation Resection + chemotherapy + hormonal therapy Resection ± radiofrequency ablation (+ perioperative chemotherapy in 27 patients) Resection (± chemotherapy) Intra-arterial chemotherapy (+ resection in 1 patient) Resection (± perioperative chemotherapy) Resection chemotherapy ± hormonal therapy

5-Year survival (%)

NR NR NR NR NR NR 22 14 20 25 51 27 40 NR NR 46 Alive at 12 year Alive at 33 months Alive at 54 months 61

NA 33 33

NA, not available; NR, not reported.

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years was 100%, 79%, and 33%, respectively in a group of 12 patients with metastatic breast cancer. In a retrospective study on 16 patients, the survival rate was 33% after 5 years [52]. More encouraging results showed that aggressive surgical resection of metastatic breast cancer results in 5-year overall and disease-free survival of 61% and 31%, respectively [53]. Of 454 patients operated on for metastatic breast cancer, Adam et al [42] reported that 41% and 22% of these patients remain alive at 5 and 10 years, respectively. Today, liver resection should be considered as the therapy of choice for liver metastases from breast cancer if no extrahepatic disease is present. Interestingly, two prognostic factors have been identified by several authors [54−56]. First, a prolonged tumor-free interval (1−2 years) between breast cancer surgery and the appearance of liver metastases; and second, no lymph node involvement at the time of breast surgery. On the other hand, the number of metastases had no impact on survival in one series [49]. Despite the consensus of “no liver transplantation for a metastatic disease,” Wilson et al [57] reported an interesting case of a 25-yearold woman with bilateral breast cancer with metastases to the liver, which were mistakenly interpreted as cholangiocarcinoma. The management entailed liver transplantation, bilateral mastectomy, and chemotherapy. The patient was free of recurrence and leading a normal life 33 months after transplantation. Reports on preoperative chemotherapy before resection of metastatic liver lesions are few; such a strategy could provide a new treatment modality to prolong survival. Kogure et al [58] reported a 49-year-old woman with a large, solitary right lobe liver metastasis which was not amenable to resection. A combination of intra-arterial mitomycin C and 5-fluorouracil (5-FU) and systemic 5-FU and medroxyprogesterone acetate resulted in notable shrinkage of the metastasis, which was safely resected. The authors reported that the patient was alive 12 years after metastasectomy. Camacho et al [59] reported a patient with metastatic breast cancer who was successfully treated with liver resection after receiving hepatic arterial infusions of paclitaxel, and who remained disease free for 48 months. Adjuvant chemotherapy following liver resection has been advocated by some authors. Schneebaum et al [46] reported a 42-month mean survival in five patients treated with resection and adjuvant arterial chemotherapy containing 5-FU, methotrexate, adriamycin, and cyclophosphamide, compared with only 5 months in 22 patients treated with systemic chemotherapy alone. Similar data were reported for nine patients treated with resection plus chemotherapy when compared with 62 patients receiving chemotherapy alone (mean survival 28 and 5 months, respectively) [60]. Carlini et al [61] studied the survival rate after liver resection due to metastatic breast cancer in 17 patients. Fifteen patients with solitary lesions underwent wedge resection while two had either bisegmentectomy or right

446

lobectomy due to multiple metastases. Postoperatively, 13 patients received systemic chemotherapy (combined with hormonal therapy in two). Overall, the actuarial 5-year survival was 46%. Diaz et al [62] successfully treated a 34-yearold woman who developed a single liver metastasis 47 months after diagnosis of the primary tumor, which had been managed by conservative surgery, locoregional radiotherapy, and chemotherapy. The patient underwent subsegmentectomy followed by postoperative chemotherapy with doxorubicin and paclitaxel in addition to tamoxifen, and was disease-free 54 months after diagnosis of the liver metastasis. Others [63] have failed to show prolonged survival after liver resection for breast metastases with a mean survival of only 6 months. In a series of 36 patients, no benefit was found in using an aggressive approach combining intra-arterial chemotherapy and resection when compared to supportive care only [64]. Liver transplantation is considered a poor option for these patients. Penn [15] reported three cases of liver transplantation for metastatic breast cancer. All patients developed recurrence and two patients died within a year. Of interest, however, one patient survived for more than 4 years.

Liver metastases from melanoma Metastatic melanoma with hepatic involvement usually indicates widely disseminated disease and poor outcome, with mean survival ranging between 2 and 6 months [65]. Single metastases to the liver are rare and only a small series are available (Table 37.7). Series including 10 patients were reported by Elias et al [50] and Lang et al [66]. Both groups found similar 5-year survival of 20% and 22%, respectively, after liver resection for metastatic melanoma. Rose et al [67] compared 24 patients with liver resection for metastatic melanoma with 10 patients who were surgically explored but not resected. Patients after liver resection had a median survival of 28 months with a 5-year survival of 29%, while exploration alone resulted in a median survival of only 4 months with no 5-year survivors. Furthermore, Wood et al [68] studied the impact of liver resection on survival in 15 patients with metastatic melanoma compared with 639 patients who were managed nonoperatively. The authors reported 5-year survival of 20% in the resection group compared with only 6% among patients who did not undergo metastasectomy. Within the resection group, the 5-year survival was 33% when curative resection was accomplished (nine patients), compared with 0% in the subgroup undergoing palliative resection (six patients). In an American study on patients from four centers, Pawlik et al [69] showed that the location of the primary tumor substantially impacts on the recurrence and survival after resection of secondary liver tumors. Among 40 patients (24 with cutaneous and 16 with ocular melanoma) who underwent liver resection, the rate of recurrent hepatic metastases was higher among patients

CHAPTER 37

Uncommon Primary and Metastatic Liver Tumors

ficult to evaluate due to the paucity of data comparing surgery with other modalities. Stehlin et al [60] reported improved survival in four patients after liver resection (mean 14 months) compared with 17 patients treated with chemotherapy only (melphalan and doxorubicin; mean survival 4 months). Taken together, it appears that curative resection with tumor-free margins of at least 1 cm offers the only chance for prolonged survival, since reports of subtotal resection have failed to show any benefit. For instance, six patients treated with subtotal resection had a mean survival of only 6 months [70].

Liver metastases from gastric cancer (a)

Hepatic metastases from gastric cancer often indicate advanced disease with a mean survival of less than 5 months. Although the role of liver resection for metastatic gastric cancer was controversial, many recent reports support the trend toward liver resection in selected patients. Several studies demonstrated increased survival benefit with a 5-year survival between 20% and 42% (Table 37.8). A period of more than 1 year between gastric cancer resection and liver metastasis, metastasis of less than 5 cm, no lymph node involvement, and tumor-free margins of more than 1 cm have been identified as positive prognostic factors [71−74]. The impact of synchronous versus metachronous metastases remains controversial [73, 74]. We recommend liver resection for gastric cancer metastasis if no extrahepatic disease is present. The preoperative work-up should include a negative PET scan.

Liver tumors of unknown origin (b) Figure 37.3 Metastasis of a melanoma: (a) PET/CT and (b) intraoperative (laparoscopic) view.

with ocular (53.3%) compared to those with cutaneous tumors (17.4%); the latter subgroup tended to have more extrahepatic recurrence. The 5-year survival rate was 20.5% within the group with ocular melanoma compared to 0% for patients with cutaneous tumors. However, in a large European multicenter study, Adam et al [42] identified 148 patients treated by liver resection for metastatic melanoma. The primary tumor was cutaneous in 44 patients and choroidal in 104, and these two groups had a 5-year survival of 22% and 21%, respectively, indicating that the location of the primary tumor has almost no influence on survival. Cases of long-term survival after complete resection have been reported. Two patients with melanoma that was metastatic to the liver (3.5 and 14 cm in diameter) were reported to be alive and disease free 12 and 24 months after complete resection without adjuvant chemotherapy [65]. Whether chemotherapy alone can provide comparable results is dif-

The liver is the most common site of presentation of tumors of unknown origin [75]. Patients usually present with abdominal pain in the right upper quadrant, weight loss, and hepatomegaly. The most common histologic types are adenocarcinomas and undifferentiated carcinomas. In rare cases, small cell carcinomas, squamous cell carcinomas or melanomas are present [76, 77]. The primary tumor can often not be found, even after extensive evaluation. Reports on tumors of unknown origin located in the liver are summarized in Table 37.9. Indications for resection of liver tumors of unknown origin remain controversial because they may represent widely metastatic disease even if the primary tumor cannot be found. Foster et al [63] reported three patients who died within 2 years after surgery. The combination of resection with intra-arterial chemotherapy (selective intra-arterial pump device with 5-FU) has been used in six patients with a mean survival of only 2 months [60]. Hawksworth et al [78] reported seven patients who were treated for metastatic adenocarcinoma of unknown primary tumor by radiofrequency ablation and/or liver resection. After a median follow-up of 9 months, five patients were alive (one with no

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Table 37.7 Outcome for metastatic melanoma to the liver treated by various modalities. Author (year)

Number of patients

Treatment

Survival as presented by the authors

Overett et al (1985) [70] Ekberg et al (1986) [115] Szakacs et al (1990) [110] Wolf et al (1991) [84] Karakousis et al (1994) [116] Stoelben et al (1995) [65]

6 3 1 4 2 1 1 1 7 10 1 10 24

Partial resection Resection Resection Left hemihepatectomy Resection Resection Resection, IL-2 Resection Resection Resection Resection Resection Resection

NR NR

10

Exploration

15 639 16 ocular 24 cutaneous 44 cutaneous 104 choroidal

Resection Nonoperative Resection Resection Resection (±chemotherapy) Resection (±chemotherapy)

Krause et al (1995) [117] Harrison et al (1997) [1] Elias et al (1998) [50] Mondragon-Sanchez et al (1999) [118] Lang et al (1999) [66] Rose et al (2001) [67]

Wood et al (2001) [68] Pawlik et al (2006) [69] Adam et al (2006) [42]

Median 31 months 74 and 78 months 144 months 24 months 72 months 29% at 5years 20% at 5 years 48 months 22% at 5 years Median 28 months 29% at 5 years Median 4 months 0% at 5 years 20% at 5 years 6% at 5 years 20.5% at 5 years 0% at 5 years 22% at 5 years 21% at 5 years

NR, not reported; IL-2, interleukin-2.

Table 37.8 Outcome for metastatic gastric cancer of the liver treated by various modalities. Author

Number of patients

Treatment

Survival as presented by the authors

Foster (1978) [63] Morrow et al (1982) [119] Funovics et al (1986) [120] Stehlin et al (1988) [60] Wolf et al (1991) [84] Ochiai et al (1994) [71] Miyazaki et al (1996) [121]

7 11 12 5 19 21 16 5 5 11 5 8 10 19 22 64 42 22 19

Resection Resection Resection Resection Resection Resection + chemotherapy Resection + chemotherapy Resection Resection Resection Resection Resection Resection Resection (±chemotherapy) Resection Resection (±chemotherapy) Resection Curative resection Noncurative treatment

NR 13% at 5 years NR NR 39% at 5 years 19% at 5 years NR

Harrison et al (1997) [1] Elias et al 1998 [50] Benevento et al (2000) [114] Takada et al (2001) [122] Fujii et al (2001) [72] Okano et al (2002) [73] Sakamoto et al (2003) [74] Adam et al (2006) [42] Koga et al (2007) [123] Cheon et al (2008) [124]

NR, not reported.

448

0% 20% at 5 years 0% 13% at 5 years 20% at 3 years 34% actuarial 5-year survival 38% at 5 years 27% 42% at 5 years 20.8% 0%

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Uncommon Primary and Metastatic Liver Tumors

Table 37.9 Outcome for tumors of unknown origin of the liver treated by various modalities Authors (year)

Number of patients

Treatment

Alive (follow up months)

5-years survival (%)

Foster (1978) [63] Stehlin et al (1988) [60] Harrison et al (1997) [1] Elias et al 1998 [50] Hawksworth et al (2004) [78] Adam et al (2006) [42]

3 6 8 5 7 28

Resection Resection + chemotherapy Resection Resection Radiofrequency ablation ± resection Resection

NR NR NR NR 5 (median 9 months) NR

NR NR 0 0 NR 38

NR, not reported.

evidence of disease and four with disease), while two patients died. In the largest report on resection of liver metastasis from an unknown primary tumor, Adam et al [42] showed that the 5-year survival among 28 patients was 38%. We would continue to recommend resection if an extrahepatic tumor is not found after a total body CT, PET scan, and evaluation of various tumor markers.

Self-assessment questions 1 Which of the following statements regarding sarcoma are true? (more than one answer is possible) A Angiosarcoma is the most common type of sarcoma in adults B Hepatomegaly is a typical symptom in cases of hepatic angiosarcoma C Normally the progression of angiosarcoma in the liver is slow D The role of systemic chemotherapy is unclear 2 Which one of the following statements regarding epithelioid hemangioepithelioma is true? A Liver transplantation might be an option in patients with unresectable tumors B Extrahepatic disease is a contraindication for surgery C Response rate on systemic chemotherapy is high D Long-term survival is very rare 3 Which one of the following statements regarding resection of noncolorectal non-neuroendocrine liver metastasis is true? A 5-Year survival rates are similar to those for resection of colorectal metastasis B Should be routinely recommended C Is associated with survival benefit according to the location of the primary tumor D A and B

4 Which of the following statements regarding liver metastases from breast cancer are true? (more than one answer is possible) A Majority of liver metastases are negative for hormonal receptors B Number of metastases in the liver has an impact on survival C Interval between breast cancer surgery and the appearance of liver metastases is a prognostic factor D Liver transplantation is a therapeutic option in rare cases 5 Which one of the following statements regarding the survival rate after resection of metastatic melanoma to the liver is true? A Not increased compared with no metastasectomy B Definitely improves with adjuvant chemotherapy C Never influenced by the location of the primary tumor (cutaneous versus choroidal) D None of the above 6 Which of the following statements regarding resection of metastatic liver tumors of an unknown primary are true? (more than one answer is possible) A Can be combined with other ablative procedures to improve survival B May result in a high 5-year survival rate C Should be preceded by preoperative work-up, including PET-CT D None of the above

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94 Shmurun RI, Chibisov VN. [Malignant neurinoma of the liver]. Arkh Patol 1977;39:69–71. 95 Tuder RM, Moraes CF.Primary semimalignant Schwannoma of the liver. Light and electron microscopic studies. Pathol Res Pract 1984;178:345–8. 96 Lederman SM, Martin EC, Laffey KT, Lefkowitch JH. Hepatic neurofibromatosis, malignant schwannoma, and angiosarcoma in von Recklinghausen’s disease. Gastroenterology 1987;92: 234–9. 97 Heffron TG, Coventry S, Bedendo F, Baker A. Resection of primary schwannoma of the liver not associated with neurofibromatosis. Arch Surg 1993;128:1396–8. 98 Borrowdale RC, Rees M. Repeated liver resection for metastatic malignant schwannoma. Br J Surg 1995;82:990. 99 Morikawa Y, Ishihara Y, Matsuura N, Miyamoto H, Kakudo K. Malignant schwannoma of the liver. Dig Dis Sci 1995;40: 1279–82. 100 Dette K, Bechstein WO, Lobeck H, Vogl T, Neuhaus P. [Intraabdominal schwannoma. Diagnosis and surgical therapy]. Chirurg 1997;68:159–67. 101 Torres A, Bollozos GD. Primary reticulum cell sarcoma of liver. Cancer 1971;27:1489–92. 102 Talamo TS, Dekker A, Gurecki J, Singh G. Primary hepatic malignant lymphoma: its occurrence in a patient with chronic active hepatitis, cirrhosis, and hepatocellular carcinoma associated with hepatitis B viral infection. Cancer 1980;46:336–9. 103 Strayer DS, Reppun TS, Levin M, Deschryver-Kecskemeti K. Primary lymphoma of the liver. Gastroenterology 1980;78: 1571–6. 104 Leahy MF, Ibrahim EM, Worth AJ. Primary hepatic lymphoma: two case reports and a review of the literature. Med Pediatr Oncol 1982;10:575–81. 105 Daniel SJ, Attiyeh FF, Dire JJ, Pyun HJ, Carroll DS, Attia A. Primary lymphoma of the liver treated with extended left hepatic lobectomy. Cancer 1985;55:206–9. 106 Ryoo JW, Manaligod JR, Walker MJ. Primary lymphoma of the liver. J Clin Gastroenterol 1986;8:308–11. 107 Ryan J, Straus DJ, Lange C, et al. Primary lymphoma of the liver. Cancer 1988;61:370–5. 108 Anthony PP, Sarsfield P, Clarke T. Primary lymphoma of the liver: clinical and pathological features of 10 patients. J Clin Pathol 1990;43:1007–13. 109 Lei KI, Chow JH, Johnson PJ. Aggressive primary hepatic lymphoma in Chinese patients. Presentation, pathologic features, and outcome. Cancer 1995;76:1336–43. 110 Szakacs JG, Szakacs JE, Karl RC. Surgical resection versus perfusion in the treatment of metastatic and primary liver tumors. Ann Clin Lab Sci 1990;20:245–57. 111 Elias D, Lasser P, Spielmann M, et al. Surgical and chemotherapeutic treatment of hepatic metastases from carcinoma of the breast. Surg Gynecol Obstet 1991;172:461–4. 112 Raab R, Nussbaum KT, Werner U, Pichlmayr R. [Liver metastases in breast carcinoma. Results of partial liver resection]. Chirurg 1996;67:234–7. 113 Kondo S, Katoh H, Omi M, et al. Hepatectomy for metastases from breast cancer offers the survival benefit similar to that in hepatic metastases from colorectal cancer. Hepatogastroenterology 2000;47:1501–3.

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114 Benevento A, Boni L, Frediani L, Ferrari A, Dionigi R. Result of liver resection as treatment for metastases from noncolorectal cancer. J Surg Oncol 2000;74:24–9. 115 Ekberg H, Tranberg KG, Andersson R, Jeppsson B, Bengmark S. Major liver resection: perioperative course and management. Surgery 1986;100:1–8. 116 Karakousis CP, Velez A, Driscoll DL, Takita H. Metastasectomy in malignant melanoma. Surgery 1994;115:295–302. 117 Krause U, Eigler FW. [Resection of solitary liver metastases in malignant melanoma]. Chirurg 1995;66:545–6. 118 Mondragon-Sanchez R, Barrera-Franco JL, Cordoba-Gutierrez H, Meneses-Garcia A. Repeat hepatic resection for recurrent metastatic melanoma. Hepatogastroenterology 1999;46:459–61. 119 Morrow CE, Grage TB, Sutherland DE, Najarian JS. Hepatic resection for secondary neoplasms. Surgery 1982;92:610–4. 120 Funovics JM, Wenzl E, Függer R, Schemper M. [Liver resection of hematogenous and infiltrating metastases]. Wien Klin Wochenschr 1986;98:813–20. 121 Miyazaki M, Itoh H, Ambiru S, et al. Radical surgery for advanced gallbladder carcinoma. Br J Surg 1996;83:478–81.

Uncommon Primary and Metastatic Liver Tumors

122 Takada Y, Otsuka M, Seino K, et al. Hepatic resection for metastatic tumors from noncolorectal carcinoma. Hepatogastroenterology 2001;48:83–6. 123 Koga R, Yamamoto J, Ohyama S, et al. Liver resection for metastatic gastric cancer: experience with 42 patients including eight long-term survivors. Jpn J Clin Oncol 2007;37:836–42. 124 Cheon SH, Rha SY, Jeung HC, et al. Survival benefit of combined curative resection of the stomach (D2 resection) and liver in gastric cancer patients with liver metastases. Ann Oncol 2008;19:1146–53.

Self-assessment answers 1 2 3 4 5 6

A, B, D A C A, C D A, B, C

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38

Liver Tumors in Special Populations Tadahiro Uemura, Akhtar Khan, and Zakiyah Kadry Division of Transplantation, Department of Surgery, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA

Therapeutic strategies for dealing with liver tumor pathology entail an overall assessment of the patient. This chapter will focus on the epidemiology and treatment of liver tumors in specific complex patient situations that carry unique physiologic characteristics and risk factors.

Liver tumors in nonalcoholic steatohepatitis Cases of fatty liver disease similar to alcohol related steatohepatitis but in nondrinkers have been reported for at least 30 years. The term nonalcoholic steatohepatitis (NASH) was initially introduced by Ludwig et al in 1980 [1, 2]. The descriptive terminology of nonalcoholic fatty liver disease (NAFLD) was then further developed to include a wider spectrum of disease ranging from simple hepatic steatosis to NASH to the extreme of liver fibrosis and cirrhosis. NAFLD is fast becoming one of the most common causes of chronic liver disease, to which a significant contribution is thought to be related to an increasing prevalence of weight gain, poor dietary choices, and a sedentary life style, especially in Western and developed societies. There is a very high incidence of NAFLD/NASH in North America, South America, the Asia-Pacific (including Australia and New Zealand), the Middle East, and Europe [2]. In the United States, 45% of Hispanics and 32% of Caucasians have hepatic steatosis [3, 4]. In the third National Health & Nutritional Examination Survey (NHANES III), which was conducted from 1988 to 1994 by the Centers for Disease Control, there was complete information on 12 241 adults, including liver function test values and causes of liver disease [2, 5–7]. The data were analyzed and a diagnosis of NAFLD was made based on one or more elevated liver function tests in subjects lacking an explanation for the abnormal laboratory value (i.e. no hepa-

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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titis B or C, transferrin saturation < 50%, and consumption of fewer than two alcoholic drinks for men and fewer than one for women). In the NHANES III study, men were significantly more likely to develop NAFLD than women, and after adjusting for body mass index (BMI) and age, nonHispanic blacks as well as Mexican–Americans were also significantly more likely to have NAFLD than non-Hispanic whites. The prevalence of NAFLD increased with increasing BMI, even with adjustment for age and ethnicity, and both type 2 diabetes mellitus and an increased waist circumference with central adiposity were important risk factors. Overall, the estimated prevalence of NAFLD in North America and similar regions is thought to range between 3% and 23%. The main drawback to the NHANES III study relates to the fact that there was no supporting histology or tests to exclude other unusual causes of chronic hepatitis such as α1-antitrypsin deficiency, Wilson disease, and autoimmune hepatitis. A more recent study, looking at proton magnetic resonance spectrometry, estimated that approximately 30% of the United States population has increased hepatic triglycerides (45% Hispanics, 33% whites, 21% blacks, 42% white males, and 24% white females) [2, 4]. Additionally, surveys based on hepatic ultrasonography indicate a prevalence of NAFLD of 22% (16% in lean individuals and 76% in the obese) [2, 8, 9], while autopsy and liver biopsy studies show that at least 20% of obese patients have NASH [2, 10–16]. The importance of NAFLD lies in the fact that it is a slowly progressive liver disease process that can ultimately lead to cirrhosis. It has been linked to the development of hepatocellular cancer (HCC) through published case reports, retrospective studies, and prospective studies. NASH is believed to progress to cirrhosis in up to 20% of cases [3, 17] and NAFLD is estimated to account for at least 70% of “cryptogenic” chronic hepatitis in the general population. This is thought to be even higher in select obese and diabetic populations where liver biopsies show NAFLD in 90% of cases of cryptogenic hepatitis [5, 18–20]. The Nonalcoholic Steatohepatitis Clinical Research Network proposed a histologic scoring system based on an anonymized study of 50 NAFLD cases. The scoring system

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included 14 different histologic features, of which four were given a severity score (degree of steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis), while the rest were marked as either present or absent. Through multiple logistic regression analysis, five features were independently associated with NASH: steatosis, lobular inflammation, hepatocellular ballooning, fibrosis, and absence of lipogranulomas [21]. The unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning was proposed as the final elements of the new NAFLD activity score, and this is presently being used to classify biopsies as “NASH,” “borderline,” or not “NASH.” Regardless of biopsy sampling errors, the definitive diagnosis of NASH is based on its histologic features, which remain the “gold standard.” NASH is not considered to be a benign process. Progression of fibrosis has been noted histologically in 32–37% of cases, although regression of fibrosis has been described in 18–29% of cases [2, 22–24]. The latter again brings up the question of sampling error and its potential impact on estimates of progression of fibrosis. However, progression of fibrosis does seem to occur slowly and to be particularly associated with the initial fibrosis severity, obesity, and the presence of diabetes [2, 22–25]. Three studies have estimated rates of cirrhosis development over 10 years to be 5% within a community-based epidemiology project [2, 26] and 20% in patients studied within a hospital setting [2, 6, 25, 27]. Since the advent of serologic testing for hepatitis C, the number of cases of cirrhosis, defined as cryptogenic, has declined from 30% in the 1980s to 5% in the 1990s. At present cryptogenic cirrhosis forms at least 7–14% of cases requiring liver transplantation [28, 29] and NASH is considered to be the major cause of cryptogenic cirrhosis. The difficulty with the hypothesis that cryptogenic cirrhosis represents “burned out NASH” lies in the fact that steatosis may diminish significantly or disappear completely with the onset of cirrhosis. However, two studies from tertiary referral care centers offering liver transplantation have reported that the prevalences of older age, obesity, and diabetes mellitus in cryptogenic cirrhosis are similar to those in NASH [4, 30, 31]. Also, NAFLD has been reported to occur more frequently after liver transplantation in patients whose primary liver disease was classified as cryptogenic cirrhosis [4, 30, 31]. Several studies have also shown a higher prevalence of diabetes mellitus and obesity in patients suffering from cryptogenic cirrhosis [32–35]. In one retrospective study with long-term follow-up, liver-related mortality was higher in patients with histologically advanced NASH [34].

Hepatocellular carcinoma in nonalcoholic steatohepatitis Several case reports suggest a potential association between NASH and the development of HCC [36–42]. Most of these cases had the metabolic syndrome associated with NASH, in particular obesity and diabetes. Prospective studies looking

Liver Tumors in Special Populations

at the association between NASH and HCC have been limited by the prolonged follow-up needed and the relatively asymptomatic course of these patients during that time period. One study by Hui et al followed 23 patients with a strictly defined diagnosis of NASH-related cirrhosis based on clinical and histopathologic criteria, including an earlier biopsy demonstrating NASH in the majority (20 of 23 patients) [27, 41]. The study group was compared to a matched cohort of patients suffering from hepatitis C virus (HCV)-related cirrhosis. During the median follow-up of 5 years, 17% of the HCV-related cirrhosis cases developed HCC, while no tumor developed in the NASH group. In a retrospective study by Bugianesi et al, 46 cases of cryptogenic cirrhosis were identified from a registry of 641 patients dating back to 1990 and consisting of cases of cirrhosis associated with HCC. Of these patients, 23 were being actively followed and they were compared to age- and sex-matched controls suffering from HCC associated with either alcohol or virus-related cirrhosis. The prevalence of HCC in cryptogenic cirrhosis within the registry of 641 patients was 6.9%, which was lower than that associated with viral (54.9% HCV- and 16.2% with HBV-related associated cirrhosis) or alcohol-induced cirrhosis (12.9%), but higher than that associated with primary biliary cirrhosis (1.4%) [42, 43]. Also, patients with cryptogenic cirrhosis and HCC were older when compared to other patients in the same registry. This was considered to be due to a slower time to progression to cirrhosis, emphasizing the relatively indolent course of hepatic disease with the NASH-related metabolic disorder (14 ± 6 years in the cryptogenic cirrhosis group compared with 12 ± 5 years in the control patients). Univariate analysis also showed that the patients with cryptogenic cirrhosis and HCC were more likely to have type 2 diabetes mellitus, hypercholesterolemia, hypertriglyceridemia, and higher fasting blood glucose, cholesterol, and triglyceride levels, as well as a significant association with insulin resistance. Epidemiologic studies seem to suggest that diabetes mellitus may play a role in the development of HCC. However, a recent study by El Serag et al seems to indicate that this is only significant in the presence of HCV-, HBV- or alcohol-related cirrhosis [44, 45]. As a result, the presence of diabetes mellitus could instead be interpreted as a marker of more advanced liver disease which has a higher likelihood and risk of developing HCC [43]. In spite of the fact that the evidence for the association between NASH and the development of cryptogenic cirrhosis is indirect, studies such as the one by Bugianesi et al and others seem to suggest that HCC should be considered as a complicating risk factor in the natural progression of NAFLD. Surgical treatment of HCC in the setting of hepatic steatosis and/or cirrhosis is dealt with in detail in other sections of this book. It is important, however, to note that transplantation should be included as a treatment option in the setting of cryptogenic cirrhosis [46, 47], and resection should

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be given serious consideration, when possible, in the noncirrhotic setting. Hepatic steatosis has been shown to be a significant risk factor when a major hepatic resection is performed and its presence should be taken into account in the preoperative planning prior to surgical resection in that setting [48, 49].

Liver tumors in high cardiovascular risk patients: cardiac stratification for hepatic resection Hepatic resection is being performed more frequently in higher risk patients with a significant improvement in outcomes, mainly due to advances in diagnostic and surgical techniques as well as enhanced perioperative management of such patients [50]. Many high volume centers report mortality rates less than 5% after liver resection [51, 52], although the morbidity rates have remained high, ranging from 20% to 50% [51–53]. Cardiac complications pose one of the most significant risks to patients undergoing liver surgery. The risk of perioperative cardiac complications in an individual patient can be assessed by the presence or absence of clinical predictors of increased perioperative cardiovascular risk, the patient’s level of cardiac functional status, and the underlying risk of the surgical procedure. The initial clinical assessment consists of clinical history, physical examination, and electrocardiogram (ECG).

Initial clinical evaluation

Table 38.1 Active cardiac conditions for which the patient should undergo evaluation and treatment before noncardiac surgery. Condition

Examples

Unstable coronary syndromes

Unstable or severe angina* (CCS class III or IV)† Recent MI‡ High-grade atrioventricular block Mobitz II atrioventricular block Third-degree atrioventricular heart block Symptomatic ventricular arrhythmias Supraventricular arrhythmias (including atrial fibrillation) with uncontrolled ventricular rate (HR > 100 beats per min at rest) Symptomatic bradycardia Newly recognized ventricular tachycardia Severe aortic stenosis (mean pressure gradient > 40 mmHg, aortic valve area < 1.0 cm2, or symptomatic) Symptomatic mitral stenosis (progressive dyspnea on exertion, exertional presyncope, or HF)

Decompensated HF (NYHA functional class IV; worsening or new-onset HF) Significant arrhythmias

Severe valvular disease

*According to Campeau [184]. Data from the ACC/AHA 2007 perioperative guideline [54]. †May include stable angina in patients who are unusually sedentary. ‡The American College of Cardiology National Database Library defines recent MI as > 7 days but less than or equal to 1 month (within 30 days). CCS, Canadian Cardiovascular Society; HF, heart failure; HR, heart rate; MI, myocardial infarction; NYHA, New York Heart Association.

Clinical history A careful history is crucial to the discovery of cardiac and/ or comorbid disease that could place the patient in a high surgical risk category. The American College of Cardiology/ American Heart Association (ACC/AHA) 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery patients listed four categories where evaluation and treatment are recommended: unstable coronary syndrome, decompensated heart failure, significant arrhythmias, and severe valvular disease (Table 38.1). Concomitantly, it should also be determined whether the patient has a history of a pacemaker or implantable cardioverter defibrillator (ICD), or of orthostatic intolerance and risk factors associated with an increased perioperative cardiovascular risk. Patients with established cardiac disease should be asked about any recent changes in symptoms [54]. The history can also determine the patient’s functional status. If the patient has not had a recent exercise test, a functional status can usually be estimated from their ability to perform the activities of daily living. For this purpose, functional capacity has been classified as excellent (>10 metabolic equivalents or [METs]), good (7–10 METs), moderate (4–7 METs), poor (<4 METs), or unknown. The Duke Activ-

456

ity Status Index contains questions that can be used to estimate the patient’s functional capacity (Table 38.2) [55].

Physical examination The physical examination should include blood pressure measurement in both arms, an analysis of carotid artery and jugular venous pulsations for the quality of the pulse contour and the presence of bruits, auscultation of the lungs, precordial palpation and auscultation, abdominal palpation, and examination of the extremities for edema and vascular integrity. Anemia imposes a stress on the cardiovascular system that may exacerbate myocardial ischemia and aggravate heart failure [56].

12-Lead echocardiogram New or unexplained ECG changes consistent with undiagnosed ischemia or infarction should be assessed. Although the optimal time interval between obtaining a 12-lead ECG and elective surgery is unknown, general consensus suggests

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Table 38.2 Estimated energy requirement for various activities (Data from the ACC/AHA 2007 perioperative guideline [54].)

Liver Tumors in Special Populations

Table 38.3 Revised Goldman cardiac risk index (RCRI). Six independent predictors of major cardiac complications

Can you …

1 MET

• High-risk type of surgery (includes any intraperitoneal, intrathoracic, or suprainguinal vascular procedures) • History of ischemic heart disease (history of myocardial infarction or a positive exercise test, current complaint of chest pain considered to be secondary to myocardial ischemia, use of nitrate therapy, or ECG with pathological Q waves; do not count prior coronary revascularization procedure unless one of the other criteria for ischemic heart disease is present) • History of congestive heart failure • History of cerebrovascular disease • Diabetes mellitus requiring treatment with insulin • Preoperative serum creatinine > 2.0 mg/dL (177 μmol/L)

Take care of your self? Eat, dress, or use the toilet? Walk indoors around the house? Walk a block or two on level ground at 2−3 mph (3.2−4.8 kph)? Do light work around the house like dusting or washing dishes?

4 MET

Climb a flight of stairs or walk up a hill? Walk on level ground at 4 mph (6.4 kph)? Run a short distance? Do heavy work around the house like scrubbing floors or lifting or moving heavy furniture? Participate in moderate recreational activities like golf, bowling, dancing, double tennis, or throwing a baseball or football?

Table 38.4 Cardiac risk* stratification for noncardiac surgical procedures. (Data from the ACC/AHA 2007 perioperative guideline [54].)

Participate in strenuous sports like swimming, singles tennis, football, basketball, or skiing?

10 MET

Risk stratification

Procedure examples

Vascular (reported cardiac risk often > 5%)

Aortic and other major vascular surgery Peripheral vascular surgery Intraperitoneal and intrathoracic surgery Carotid endarterectomy Head and neck surgery Orthopedic surgery Prostate surgery Endoscopic procedures Superficial procedure Cataract surgery Breast surgery Ambulatory surgery

Intermediate (reported cardiac risk generally 1–5%)

kph, kilometers per hour; MET, metabolic equivalent; mph, miles per hour.

Low (reported cardiac risk generally < 1%)†

that an ECG within 30 days of surgery is adequate for those with stable disease in whom a preoperative ECG is indicated. Recently, the predictive value of an ECG abnormality was questioned, and the additional value of the preoperative ECG compared to clinical characteristics was evaluated in a retrospective study of 2422 noncardiac surgery patients (54% referred for high-risk surgery). Although right or left bundle branch block was associated with perioperative myocardial infarction (MI) and left bundle branch block was associated with perioperative mortality, no single ECG abnormality provided an additional predictive value for perioperative MI or death on multivariate analysis [57].

Prediction of preoperative cardiac morbidity Revised Goldman cardiac risk index To simplify the prediction of risk, Goldman and coworkers monitored 2893 patients (mean age 66) undergoing elective major noncardiac procedures and identified six independent predictors of major cardiac complications (Table 38.3). Devereaux et al. estimated the rate of cardiac death, nonfatal MI, and nonfatal cardiac arrest using the revised cardiac risk index (RCRI) [58]:

*Combined incidence of cardiac death and nonfatal myocardial infarction. †These procedures do not generally require further preoperative cardiac testing.

• • • •

No risk factors: 0.4% (95% CI 0.1–0.8) One risk factor: 1.0% (95% CI 0.5–1.4) Two risk factors: 2.4% (95% CI 1.3–3.5) Three or more risk factors: 5.4% (95% CI 2.8–7.9) The RCRI has become one of the most widely used risk indices [59].

Surgery-specific risk The type and timing of surgery significantly affects the patient’s risk of perioperative cardiac complications. The 2007 ACC/AHA guidelines listed the cardiac risk stratification for noncardiac surgical procedures (Table 38.4) [54]. By definition, the reported rate of cardiac death or nonfatal MI

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was more than 5% in high-risk procedures, between 1% and 5% in intermediate-risk procedures, and less than 1% in low-risk procedures. There are insufficient data published regarding hepatobiliary surgery. Most hepatobiliary procedures appear to fall into the intermediate risk category (1–5% cardiac risk) according to the 2007 ACC/AHA guidelines. Virani et al, using multicenter data, reported 0% MI and 0.4% cardiac arrest requiring cardiopulmonary resuscitation in 783 liver resections [53].

Perioperative cardiac assessment A number of algorithms have been proposed for the assessment of patients prior to noncardiac surgery, including those from the ACC/AHA [54], the American College of Physicians [60], and Fleisher and Eagle [61]. The 2007 ACC/AHA perioperative guidelines recently revised the original algorithm, which can determine the need for additional cardiac testing prior to surgery [54]. According to the 2007 ACC/ AHA perioperative guidelines, cardiac evaluation and care for patients undergoing hepatic resections are approached using the algorithm shown in Figure 38.1.

Need for emergent liver surgery

Yes

• Step 1: The urgency of the case should be determined. In emergent cases, perioperative surveillance, postoperative risk stratification, and risk factor management should be provided. • Step 2: In elective surgery, the presence of unstable coronary disease, decompensated heart failure, severe arrhythmia, or valvular heart disease usually leads to cancellation or delay of surgery until the cardiac problem has been clarified and treated appropriately. Many patients in these circumstances are referred for coronary angiography to assess further therapeutic options. Depending upon the results of the test or interventions and the risk of delaying surgery, it may be appropriate to proceed with the planned surgery with maximal medical therapy. • Step 3: In highly functional, asymptomatic patients, management will rarely be changed on the basis of the results of any further cardiovascular testing. It is appropriate to proceed with the planned surgery. If the patient has poor or unknown functional capacity, clinical risk factors should be considered. If there is no risk, it is appropriate to proceed with the planned the surgery. If there are one or two risk

Operating room

Perioperative surveillance and postoperative risk stratification and risk factor management

No

Active cardiac condition (Table 38.1)*

Yes

Evaluate and treat as per ACC/AHA guidelines

Consider operating room

No

Good functional capacity (MET level ≥ 4) without symptoms†

Yes

Proceed with planned surgery

No or unknown

Three or more risk factors‡

Consider noninvasive testing if it will change management

One or two risk factors‡

Proceed with planned surgery with HR control or consider noninvasive testing if it will change management

No clinical risk factors‡

Proceed with planned surgery

Figure 38.1 Cardiac evaluation and care algorithm based on active clinical conditions, known cardiovascular disease, or cardiac risk factors for patients 50 years of age or older. Modified ACC/AHA 2007 perioperative guideline. HR, heart rate; MET, metabolic equivalent. (Modified from Fleisher et al [54].) *See Table 38.1 for active clinical conditions † See Table 38.2 for estimated MET level equivalent ‡ Clinical risk factors form revised Goldman cardiac risk index (RCRI) include ischemic heart disease, compensated or prior heart failure, diabetes mellitus, renal insufficiency, and cerebrovascular disease

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factors, it is reasonable either to proceed with the planned surgery with heart rate control, or to consider noninvasive testing if it will change the decision process. If there are more than three risk factors, noninvasive testing should be considered if it will change management.

Perioperative medical therapy Perioperative beta-blocker therapy Current studies suggest that beta-blockers reduce perioperative ischemia and may reduce the risk of MI and death in patients with known coronary artery disease [62, 63]. A multicenter retrospective cohort study from nearly 700 000 patients suggested that perioperative beta-blockade provided a protective benefit only in higher-risk (RCRI ≥ 2) patients. In those at lower risk, beta-blockade appeared to increase the risk for complications, even if the patient’s one risk factor was diabetes or coronary disease [62]. There are insufficient data to support perioperative beta-blocker therapy in patients at low to intermediate risk (RCRI ≤ 1). However, given the risk of sudden cessation of beta-blockers, beta-blockers should be continued in patients already being treated with them [63]. Accumulating evidence suggests that effective heart rate control with beta-blockers should be targeted at less than 65 beats per min [64, 65]. It is also suggested that long-acting beta-blockade may be superior to short-acting beta-blockade [66].

Perioperative statin therapy It is suggested that the perioperative use of statins can protect from cardiac complications. A meta-analysis has shown that perioperative statin therapy provided a 44% reduction in mortality [67]. Studies in the perioperative

Liver Tumors in Special Populations

period are generally consistent in showing the benefit of statins in acute coronary syndromes [68], but current evidence does not support starting statins preoperatively in patients without a long-term indication. Nevertheless, based on established guidelines, the perioperative period provides an excellent opportunity to begin or titrate statins in patients. Statin therapy should be continued after surgery in patients who are already being treated.

Preoperative coronary revascularization Perioperative management of patients undergoing surgery with prior percutaneous coronary intervention For patients who have undergone successful percutaneous coronary intervention (PCI), there is uncertainty regarding how much time should elapse before surgery can be performed. Figure 38.2 is an approach based on expert opinion from the ACC/AHA 2007 perioperative guidelines [54]. The risk of stopping antiplatelet therapy should be weighed against the benefit of reduction in bleeding. If thienopyridines (ticlopidine or clopidogrel) must be discontinued before major surgery, aspirin should be continued and the thienopyridine restarted as soon as possible. There is no evidence that warfarin, antithrombotics, or glycoprotein IIb/IIIa will reduce the risk of stent thrombosis after discontinuation of oral antiplatelet agents [69].

Percutaneous revascularization in patients needing urgent liver surgery Patients who require percutaneous coronary revascularization in whom near-term hepatobiliary surgery is necessary require special consideration. A potential approach is given

Previous PCI

Balloon angioplasty

Time since PCI

< 14 days

Delay elective or nonurgent surgery

Bare-metal stent

> 14 days > 30–45 days

Proceed to the operating room with aspirin

Drug-eluting stent

< 30–45 days < 365 days

> 365 days

Delay elective or nonurgent surgery

Proceed to the operating room with aspirin

Figure 38.2 Proposed approach to the management of patients with previous percutaneous coronary intervention (PCI), based on expert opinion. (Adapted from the ACC/AHA 2007 perioperative guideline, Fleisher et al [54].)

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Acute MI, high-risk ACS, or high-risk cardiac anatomy

Bleeding risk of surgery

Low

Stent and continue dual-antiplatelet therapy

Not low

14–29 days

Balloon angioplasty

30–365 days

Bare-metal stent

> 365 days

Timing of surgery

Drug-eluting stent

Figure 38.3 Treatment for patients requiring percutaneous coronary intervention who need subsequent surgery. MI, myocardial infarction. (Adapted from the ACC/AHA 2007 perioperative guideline, Fleisher et al [54].)

in the ACC/AHA 2007 perioperative guidelines (Figure 38.3) [54]. If the hepatobiliary surgery is imminent (within 2–6 weeks) and the risk of bleeding is high, angioplasty and provisional bare-metal stenting plus continued aspirin antiplatelet monotherapy can be considered with restenosis being dealt with by repeat PCI if necessary [54].

Hepatic resection in elderly patients In recent years, the number of elderly patients who have undergone hepatic resection has increased because of advances in surgical technique, postsurgical management, and a prolongation in life-expectancy. Certain issues have been raised in elderly patients regarding the appropriateness and extent of surgical resection due to a presumed impaired ability of the remaining hepatic mass to regenerate after resection. During aging, the liver undergoes physiologic changes, such as decreased size and blood flow [70]. These factors may reduce the functional reserve of the organ. Unexpected liver failure can occur post resection in some patients who were expected preoperatively to have sufficient hepatic functional reserve for postoperative recovery. Liver regeneration after hepatectomy has been clinically studied with evidence of impaired regeneration in older patients [71, 72]. Based on computed tomography (CT) scan estimates of hepatic volume, older patients have been found to have a smaller regenerative volume increase than agematched controls following similar hepatic resections [71]. On the other hand, other studies have shown that the volu-

460

metric recovery is similar despite age, but hepatocyte synthetic function is impaired in elderly patients post resection. In a review of 56 patients with HCC who had undergone a right hemihepatectomy, Yamamoto et al found that there was a marked decline in postoperative protein synthesis in the older group over 70 years of age. Although specific correlations between degree of synthetic dysfunction and hepatic failure could not be proven, postoperative hepatic failure occurred more frequently in patients over 65 years of age. Of note, this group of patients was the only group in the review with concomitant diseases such as diabetes, hypertension, and ischemic heart and pulmonary disease [72]. Conversely, other studies have shown that age is not a significant independent variable for prediction of survival despite the concerns about regeneration [73]. There also studies that have shown that livers with cirrhosis or chronic hepatitis regenerate less effectively than normal liver parenchyma after similar resections, independent of the age of the patient. The ethical issues of decisions regarding palliative versus curative therapy must be approached with care and individualized for each patient. To date, sufficient evidence exists that hepatic resection can be safely performed in selected aged patients [74–76], although old age (70 years or older) used to be recognized as an adverse factor for hepatic resection [77, 78]. Hanazaki et al reported on 87 liver resections for HCC in patients over 70 years of age, comparing them with 237 liver resections in patients younger than 70 years. There were no significant differences in postoperative complications, operative mortality, and overall hospital death rate between the two groups.

CHAPTER 38

Liver Tumors in Special Populations

Table 38.5 Results of hepatic resection for colorectal liver metastasis in elderly patients. Authors

Year

Number. of patients

Age

Mortality (%)

Preoperative morbidity (%)

Complications (%)

1-Year survival (%)

3-Year survival (%)

5-Year survival (%)

p value*

Fong et al [79] Brand et al [185] Zacharias et al [80] Nagano et al [76]

1995 2000 2004 2005

128 41 56 62

≥70 ≥70 ≥70 ≥71

4 7 0 0

55 NA NA 34.50

42 39 41 19.70

85 NA 86 79.40

NA 29 44 46.50

35% 16% 21% 34.10%

NS NS NA p < 0.01

*p value compares elderly patients with younger patient in their study. NA, not available, NS, not significant.

Overall 3- and 5-year survival rates for the older and younger groups were similar: 51.0% versus 55.2%, and 42.2% versus 40.0%, respectively (p = 0.95) [79]. They concluded that selected elderly patients with HCC benefited from resection as much as younger patients, and age by itself may not be a contraindication to surgery. Similar results have been reported in hepatic resections for colorectal metastases [76, 80]. Table 38.5 lists recent studies involving hepatic resections for colorectal liver metastases in advanced age. All the reports conclude that advanced chronologic age is not a contraindication for hepatic resection for colorectal liver metastases. Furthermore, the most recent reports from Zacharias et al [81] and Nagano et al [76] showed 0% mortality, although the latter study showed significantly lower survival rates in older patients, possibly due to a higher rate of nontreatment for hepatic recurrence. The majority of reports that address the outcome of liver resection in the elderly relate to HCC, which behaves very differently from colorectal liver metastasis. Hepatic resection for HCC involves the additional risk factors of hepatitis and cirrhosis, whereas most colorectal liver metastases occur on a noncirrhotic liver background. Questions also arise about the feasibility of major hepatectomies in elderly patients. Cescon et al studied the outcome of 23 right hepatectomies in patients older than 70 years [82]. They showed excellent 1- and 3-year survival rates of 84.4% and 64.2%, respectively, and there were no differences compared to the group younger than 70 years of age. They concluded that advanced age should not be a contraindication for major hepatectomies, but a careful preoperative evaluation to exclude liver cirrhosis and severe comorbid medical conditions is necessary. There are scarce data about hepatic resection for cholangiocarcinoma in elderly patients. One report from Yeh et al studied 33 hepatic resections for peripheral cholangiocarcinoma in patients older than 70 years of age, comparing them to 185 patients younger than 70 years [83]. Excluding

patients who died within the first postoperative month, the 1-, 2-, 3-, and 5-year actuarial survival rates were 59.6%, 34.8%, 0%, and 0%, respectively, which were not significantly different from those for patients younger than 70 years (52.6%, 31.6%, 22.7%, and 13.9%, respectively; p = 0.827). A low carcinoembryonic antigen (CEA) was an independent factor for favorable survival. They concluded that hepatic resection for peripheral cholangiocarcinoma is feasible for selected elderly patients. Most reports conclude that advanced age is not a contraindication for hepatic resection. However, the data should be reviewed carefully as many of the studies suffer from significant patient selection bias, and the excellent results reported are the culmination of careful patient selection as well as specialized surgical expertise and anesthetic care. It is clear that not all elderly patients with malignant disease of the liver are candidates for aggressive and extensive liver resections. However, the data also suggest that denying patients access to surgical therapy based upon chronologic age alone is unwarranted.

Hepatic tumors in immunosuppressed patients In this section two groups of patients are discussed: patients infected with human immunodeficiency virus (HIV) and solid organ transplant recipients. Both these groups share a common underlying characteristic: a profound decrease in cell-mediated immunity. Improvements in drug therapy and better monitoring techniques for response to therapy have resulted in an increase in life-expectancy in both these groups. However, a deficiency in cell-mediated immunity still places the patients in these groups at a higher risk for the development of malignancies. This section will focus on the development of hepatic malignancies in these two specific immune-deficient populations.

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Special Tumors, Population, and Special Considerations

Human immunodeficiency virus infectionassociated liver tumors According to the joint United Nations program on HIV/ AIDS in the 2007 AIDS epidemic update, the worldwide prevalence of HIV/acquired immunodeficiency syndrome (AIDS) is 33.2 million with 2.5 million new cases occurring in 2007, as well as 2.1 million AIDS-related deaths. The advent of highly active antiretroviral therapy (HAART) has resulted in an immunologic response (defined as sustained elevations in CD4 lymphocyte counts) after 6 months of HAART, indicating a favorable clinical outcome in HIV-infected patients regardless of the virologic response (defined as near complete suppression of the HIV viral load) [84]. However, despite significant advances in treatment, complete eradication of HIV has not been achieved due to the persistence of the virus in the lymphatic tissue. The use of HAART is associated with a decreased risk of non-Hodgkin lymphoma, whereas uncontrolled HIV RNA load may be associated with an increased risk [85]. The rates of the most common opportunistic infections are markedly reduced after the initiation of antiretroviral therapy, but a similar reduction has not been observed in the incidence of other infections and lymphomas, suggesting that the T-cell repertoire is not completely restored and that long treatment periods are needed. Liver tumors in an HIV/AIDS patient can be considered under two categories: HIV/AIDS- and non-HIV/AIDS-defining malignancies. HIV/AIDS-defining malignancies include Kaposi sarcoma and non-Hodgkin lymphoma. These are systemic diseases in which the role of surgery is limited to the occasional diagnostic biopsy. Non-HIV/AIDS-defining malignancies, which are on the rise in this patient population, include HCC. In such cases, surgical treatment may improve survival and palliate symptoms.

Kaposi sarcoma At one point in the AIDS epidemic, Kaposi sarcoma was the most common gastrointestinal tumor diagnosed. Although the proportion of AIDS patients developing this neoplasm during the course of their disease is declining due to HAART therapy [86], the actual number of Kaposi sarcoma cases is increasing due to the overall rise in the total number of patient suffering from AIDS. A strong association has been described between human herpes virus 8 infection and Kaposi sarcoma, with a 95% occurrence of the virus in the tumors in one study [87]. The patient population consisted of a combination of AIDS-associated, classic Kaposi sarcoma, and Kaposi sarcoma occurring in HIV-seronegative homosexual men. Kaposi sarcoma is predominantly a cutaneous disease and the prognosis is based upon the AIDS Clinical Trials Group (ACTG) staging classification, which includes the tumor stage (T), the state of the immune system (I),

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Table 38.6 AIDS Clinical Trials Group staging classification for Kaposi sarcoma. Good risk

Poor risk

Tumor (T)

T0: Localized to skin and/or lymph nodes

Immune status (I) Systemic disease (S)

I0: CD4 count > 150/μL

T1: Tumor-related local complications (edema or ulceration) Oral or visceral involvement I1: CD4 count < 150/μL

S0: No AIDS-related opportunistic infections No constitutional symptoms Karnofsky performance scale > 70

S1: AIDS-related opportunistic infections Constitutional symptoms: fevers, night sweats, chronic diarrhea Karnofsky performance scale < 70 Other HIV/AIDS-related illnesses

and the presence of concurrent systemic illnesses [88] (Table 38.6). There are cases where Kaposi sarcoma may present as a widespread, aggressive tumor with visceral involvement. The liver is usually involved in these cases. It is very rare to have a symptomatic liver lesion without any other manifestation of the tumor [89], Isolated Kaposi sarcoma of the liver has not been described in the medical literature to this date. Kaposi sarcoma lesions are nests of endothelial cells forming channels intercalated with red blood cells that are responsible for their characteristic red and purple gross appearance. The diagnosis of hepatic Kaposi sarcoma is usually made clinically and in the majority of cases can be confirmed by a skin biopsy. Visceral involvement can be confirmed by direct visualization, i.e. endoscopy or laparoscopy. The radiologic diagnosis is characterized by visualization of low attenuation lesions on a CT scan. Percutaneous liver biopsy has a low yield in terms of obtaining tissue for a diagnosis of hepatic Kaposi sarcoma due to the fibrous and stromal nature of the tumor [90]. The utility of liver biopsies is also questionable due to the obvious presence of extrahepatic disease and the low accuracy of the biopsy result. Additionally, it has been reported that liver biopsies in patients with AIDS is associated with an increased risk of postbiopsy hemorrhage despite normal clotting studies. If a tissue diagnosis of hepatic Kaposi sarcoma is mandatory for proposed treatment, the biopsy can be performed in the operating room under direct laparoscopic visualization. If bleeding occurs, cautery or application of hemostatic agents can be implemented on the biopsy site for control of hemorrhage.

CHAPTER 38

Treatment of the HIV/AIDS-related Kaposi sarcoma is dependent upon the factors outlined in the ACTG staging system (see Table 38.6). The mainstay of treatment is highly active antiretroviral therapy, which has been shown to decrease the incidence of Kaposi sarcoma due to the immune restoration [91]. There is evidence to suggest that protease inhibitor-based and reverse transcriptase-based antiretroviral treatments may lead to an undetectable Kaposi sarcomaassociated herpes virus (KSHV) load and regression of the lesions [90]. In widespread Kaposi sarcoma with visceral involvement, chemotherapy is effective in inducing tumor regression, reduction of edema, and control of symptoms. The mainstay of therapy consists of a combination of pegylated-liposomal doxorubicin, liposomal daunorubicin, and paclitaxel [92, 93]. Moderate response rates (up to half of the treated patients) are described; although the side effects and toxicities, especially bone marrow suppression, may limit their use. It is recommended that chemotherapy be used in conjunction with antiretroviral therapy, prophylaxis for opportunistic infections, and hematopoietic growth factors [94]. Interferon-alpha in combination with antiretroviral therapy has been shown to cause complete or partial tumor regression in approximately 31–55% of patients studied, and both response and toxicities are dose dependent [95]. Matrix metalloproteinase inhibitors (COL-3) have a response rate of 41%, with major side effects being rash and photosensitivity [96]. Surgery has no current role in the management of Kaposi sarcoma. Before undertaking treatment of advanced disease with visceral involvement, clear goals of therapy should be identified. Patient involvement at each step of the way is necessary to maximize improvement in the quality of life as there is no cure for the disease.

Hepatic non-Hodgkin lymphoma Non-Hodgkin lymphoma (NHL) is the second most common malignancy in patients with AIDS/HIV, and hepatic involvement in NHL is usually a sign of disseminated disease. Survival amongst HIV/AIDS patients with generalized lymphoma is poor. There have been sporadic reports of isolated hepatic NHL in the literature [97]. It seems to be a rare occurrence. The majority of these lymphomas originate from B cells. Epstein-Barr virus (EBV) has been detected in 80% of B-cell NHLs associated with HIV when polymerase chain reaction (PCR)-based techniques were used [98]. There seems to be no direct role of HIV in the development of NHL. HIVinduced immune depression and EBV infection present in these cases can favor the expansion of B-cell clones, which in turn may increase the probability of occurrence of lymphoma carrying activated c-Myc rearrangements, thus leading to malignant transformation [99]. Mean age at presentation in the 15 cases of hepatic NHL reported in the literature was 40 years. Clinical symptoms

Liver Tumors in Special Populations

included fever, weight loss, right upper quadrant pain, and hepatomegaly. All patients had abnormal liver enzymes, including a markedly elevated lactate dehydrogenase, but normal routine tumor markers, such as CEA and alphafetoprotein (AFP). Unlike in patients with primary hepatic lymphoma but no HIV infection, the majority of these patients had multiple lesions detected on abdominal CT scan or abdominal ultrasound. On needle biopsy, the lymphomas were most commonly high-grade, B-cell type. Diffuse hepatic infiltration by a NHL has also been reported in patients with AIDS, leading to jaundice and biliary obstruction [100]. The clinical presentation of HIV/AIDS-related NHL has not changed since the introduction of HAART. There have been some reports of improvement in survival in these patients when chemotherapy and HAART are combined [101]. The chemotherapeutic regimen used in one report consisted of cyclophosphamide, doxorubicin, vincristine, and prednisolone. This approach has led to a more aggressive treatment of these lymphomas. Local therapy of lesions in isolated involvement of liver has not been studied. There are only a few case reports of surgical resection in such cases [102, 103]. Due to the lack of data, surgical resection of isolated NHL of the liver in HIV/AIDS patient cannot be recommended except within a study protocol.

Hepatocellular carcinoma in HIV/AIDS patients Due to advances in the treatment of HIV, patients are living longer and often have concomitant complications of liver disease due to coinfection with HBV and HCV. HIV coinfection has been shown to increase the progression of fibrosis in the liver [104, 105]. In the study performed by the HIV HCC Cooperative Italian–Spanish Group, an association between HIV and HCV infections along with infiltrating tumors and/or extra nodal metastasis at presentation was identified. They also found an independent association between HIV infection and a shorter survival period [106]. A study of HCC patients with HIV infection in six United States and Canadian centers found HIV-infected patients to be younger and more likely to have symptomatic lesions, although there was no significant difference in tumor staging and survival when compared to non-infected patients with HCC [107]. Upon diagnosis of cirrhosis in HIV patients coinfected with HCV or HBV, early initiation and more frequent screening for HCC is recommended. This is due to an observed early occurrence of HCC with a more aggressive course in this patient population. We recommend screening with an AFP level in combination with helical triphasic CT scan every 6 months. Treatment options are similar to those for patients suffering from HCC in the presence of viral hepatitis without HIV coinfection. The modality of treatment depends upon the extent of underlying liver disease, stage of the tumor, associated comorbidities, and immune status of the patient. These factors determine the suitability for curative resection versus

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Special Tumors, Population, and Special Considerations

liver transplantation. A detailed discussion of these modalities can be found elsewhere in Section 4. In our opinion, curative resection should be considered in HIV-infected patients suffering from early HCC in the absence of comorbidities and without significant synthetic dysfunction of the liver and portal hypertension, particularly since the results may be similar to those for patients not infected with HIV undergoing liver resection [107]. Patients who are not candidates for resection due to underlying cirrhosis and portal hypertension should be referred to a transplant center with experience in transplantation in HIV-infected patients who are early in their course. There have been multiple reports of successful orthotopic liver transplantation (OLT) in carefully selected patients, with survival data approaching those of cirrhotic patients without HIV coinfection [106, 108]. In HIV patients, the selection criteria are similar to those for non-HIV patients, and the Milan criteria for OLT in HCC (one HCC < 5 cm or three HCCs, each less than 3 cm) should be strictly adhered to. Liver transplant candidates with an HIV infection should have immune reconstitution with CD4 counts greater than 100/mL and an undetectable viral load that has been previously responsive to a HAART regimen. Patients who are not candidates for curative therapies should be considered for radiofrequency ablation (RFA) or transarterial chemoembolization (TACE). The goals of therapy for advanced disease should be directed by full participation of the patient and through a multidisciplinary approach.

Hepatobiliary tumors in solid organ transplant recipients Over the past three decades there has been a significant increase in solid organ transplantation with associated immune deficiencies induced by immunosuppressive regimens, which appear to place transplant recipients at a higher risk of developing malignancies. In the Cincinnati Transplant Tumor Registry (CTTR, initiated by Israel Penn), of the 10 151 organ allograft recipients who developed 10 813 de novo malignancies after transplantation, 755 involved the hepato-biliarypancreatico-duodenal (HBPD) area, forming approximately 10% of this population. Many of the tumors encountered were uncommon in the general population [109]. The largest group of neoplasms consisted of 474 lymphomas, which comprised 63% of the total. Other major malignancies were HCCs (15%), pancreatic carcinomas (11%), cholangiocarcinomas (3%), Kaposi sarcomas (3%), and other sarcomas (1%).

Post-transplant lymphomas In contrast to the general population where lymphomas form only 3–4% of all neoplasms, in post-transplant patients, lymphomas and lymphoproliferations comprise 22% of all

464

tumors. There is a strong association between EBV and posttransplant lymphoproliferative disorders (PTLD). The majority of these disorders originate from B cells. There are reports of T-cell-origin lymphomas but these are not a common occurrence [110]. They are characterized by a heterogeneous spectrum, starting from acute infectious mononucleosis that results in a benign polyclonal B-cell hyperplasia with normal cytogenetics and no evidence of immunoglobulin gene rearrangements. This accounts for approximately 50% of cases. If unresolved, these cases may progress to a polyclonal B-cell proliferation with evidence of early malignant transformation, including clonal cytogenetic abnormalities and immunoglobulin gene rearrangements. One-third of the patients may present with this disorder, which may then turn into a monoclonal B-cell proliferation. These can involve extranodal sites and represent up to 15% of cases. These findings are similar to those found in AIDSrelated lymphomas described in the previous section [111, 112].The main risk factors for the development of PTLD include increased intensity of induction and maintenance immunosuppression, recipient EBV seronegativity, and a younger age group [113, 114]. Exceptions are intestinal transplant recipients, where the incidence of EBV disease has been observed to be equal in both pretransplant seronegative and seropositive EBV intestinal allograft recipients [115]. The EBV-negative lymphomas occur later in the posttransplant course. These can be considered to be an entity distinct from early EBV-positive lymphomas. They are similar to lymphomas found in immunocompetent patients with a monoclonal nature and frequent m-Myc rearrangement. They have a poor prognosis as compared to EBVpositive lymphomas [116]. The presentation usually involves an insidious onset. A low threshold of suspicion is needed for early diagnosis and treatment. The usual presentation includes constitutional symptoms such as fever, lethargy, and malaise, associated with weight loss and diarrhea that can be positive for occult blood. Clinical signs may include palpable enlarged lymph nodes, ulceration, and an increased size of the oropharyngeal tonsils, as well as a palpably enlarged spleen and/or liver. The gastrointestinal system is the most commonly affected extranodal site, with involvement of the liver in up to threequarters of patients with multiorgan disease. Involvement of the liver but no other organ is less frequent, but not uncommon, as it can occur in up to 16% of nonhepatic transplant recipients. Isolated involvement of the allograft can be present in 21% of liver transplant recipients [117, 118]. In such cases, examination may reveal only mildly elevated liver function tests or, at the extreme of the spectrum, there may be diffuse infiltration of the allograft resulting in acute liver failure. Sometimes an incidental lesion can be discovered on ultrasound or CT scan of the abdomen. Such lesions usually appear hypodense on

CHAPTER 38

contrast enhancement. The diagnosis can be confirmed by excisional biopsy of the associated enlarged lymph nodes. In cases where isolated hepatic involvement is encountered, percutaneous ultrasound or CT-guided biopsy can be performed. Rapid processing of the biopsy, including viral stains, is the key, as the lymphomatous infiltrates seen can sometimes be confused with acute rejection, which may result in an increased intensity of immunosuppression with worsening of the underlying PTLD [119]. In cases where the lesions are not accessible to percutaneous biopsy due to a difficult location or a previously failed attempt, laparoscopic or open biopsy may be required to confirm the diagnosis. The majority of the post-transplant lymphomas are of host (recipient) origin. There are, however, multiple reports of donor-origin PTLD [120–122]. One report found that two of three isolated PTLD were of donor origin, and the author also noted, upon review of reported cases, that a high proportion were of donor lymphocyte origin [119]. The mainstay of treatment in PTLD is a reduction in immunosuppression. This allows cell-mediated immunity to stop proliferation of EBV-infected cells. The response to a reduction in immunosuppression is dependent on the number of poor prognostic indicators (older age, elevated lactate dehydrogenase [LDH], organ dysfunction, multiorgan involvement with PTLD, and the presence of constitutional symptoms). An 89% response rate has been reported in patients without a negative prognostic indicator, while patients with at least one such indicator showed only a 60% response rate [123]. There was no response in patients who had two or more poor prognostic indicators. Median time to response was less than 4 weeks. Ganciclovir and intravenous immunoglobulin has not been effective in randomized control trials [124]. In monoclonal lymphomas and other PTLD nonresponsive to a reduction in immunosuppression, rituximab has been used. There are retrospective data evaluating rituximab and/or chemotherapy in patients with PTLD who failed to respond to a reduction in immunosuppression. Patients treated with rituximab had an overall response rate of 68% with an overall survival of 31 months, compared to 74% and 42 months, respectively, for those who underwent chemotherapy. Treatment-related deaths were 0% in the rituximab group and 26% in the chemotherapy group [125]. The efficacy and safety of rituximab has been studied in a prospective manner and an overall response rate and patient survival of 68% and 56%, respectively, have been reported at 1 year [126]. It is a reasonable approach to use rituximab early in patients unresponsive to a reduction or discontinuation of immunosuppression. In patients unresponsive to a reduction in immunosuppression and rituximab, chemotherapy is usually recommended. There are no controlled randomized trials comparing these modalities. Due to treatment-related mortality and the significant side effect profile of current chemo-

Liver Tumors in Special Populations

therapeutic regimens, it may be prudent to treat these patients with rituximab first. The standard chemotherapy for NHL is cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP), with reported complete remission rates of 70% [127]. Another option is dose-adjusted doxorubicin, cyclophosphamide, vincristine, bleomycin, and prednisolone (ACVBP), which has been reported to result in a survival of 60% at 5 years [128]. Local therapy is reserved for either a solitary hepatic lesion without systemic involvement, or small residual or symptomatic lesions not responsive to systemic therapy. The options available are radiation, surgical resection, and RFA. The need for local treatment should be weighed against the potential risks of these procedures [129]. The treatment plan in such cases is best served by a multidisciplinary approach.

Nonlymphoma post-transplant hepatobiliary tumors The most common nonlymphoma hepatobiliary malignancy in recipients of a previous solid organ transplant is HCC. This can be categorized as either recurrent HCC or a de novo lesion in recipients of hepatic allografts. Liver transplant recipients have the highest risk of developing HCC post transplant. Among recipients who received an organ other than liver, renal transplants are at a substantial risk of developing HCC due to a higher prevalence of hepatitis in dialysis patients. In patients receiving chronic dialysis, reports suggest that hepatitis C is present in up to 10% in the United States, up to 15% in Italy, 42% in France, and 49% in Syria [130–133]. Also, the incidence of hepatitis B surface antigen positivity was 1% in the United States, 13% in Italy, 1.6% in Japan, 10% in Hong Kong, 12% in Brazil, and 16.8% Taiwan [130, 134–138]. In the presence of immunosuppression and cirrhosis, this group of patients should undergo aggressive screening with ultrasound, triphasic CT scan of the abdomen, and AFP monitoring every 6 months. The surveillance data in transplant recipients have not been reported in large cohorts and there are no studies on the cost-effectiveness of such an approach in these patients. This is a recommendation based on our experience and surveillance studies in HIV/AIDS patients with HBV and HCV coinfection showing the aggressive nature of the tumor. The initial results of liver transplantation for HCC were very poor with unacceptable recurrence rates and mortality post transplantation in the early reported data. After the Milan criteria for transplantation in cirrhotics with HCC were adopted (one lesion less than 5 cm or three lesions each less than 3 cm in the absence of extrahepatic spread), there was a better patient selection, which resulted in a reduction of HCC recurrence to ∼ 8% [46]. Post-transplantation surveillance in these patients has not been studied. The majority of recurrences post liver transplantation are extrahepatic and not amenable to local therapy [46, 139]. The majority

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SECTION 7

Special Tumors, Population, and Special Considerations

of these tumors recurred within the first 2 years after liver transplantation [139]. De novo occurrence of HCC in patients who have undergone liver transplantation has been reported. These are usually associated with recurrent hepatitis B and C with cirrhosis of the liver allograft [140]. The treatment of HCC arising in a transplant recipient of an organ other than liver is dictated by the stage of the tumor, the underlying liver disease, and the presence of comorbidities. Patients who have a resectable tumor and are good operative candidates should undergo liver resection with curative intent. In a series of 18 patients with previous kidney transplantation who developed HCC, liver resection resulted in an actuarial 5-year survival of 59%. Two patients in that series lost the kidney allograft 3 and 8 years after resection, and treatment-related mortality was 5% [141]. In patients with underlying cirrhosis with tumors within the Milan criteria, liver transplantation can be an option, although no reports pertaining to this are available in the literature. HCC in transplant recipients who are not candidates for a potentially curative therapy due to advanced underlying liver disease or comorbidities can be managed with RFA, and there are some reports of a short-term increase in survival of patients with advanced HCC [142]. If TACE is being considered in advanced HCC in renal transplant recipients, special attention should be paid to the fact that this can result in kidney allograft failure and a return to dialysis. Such a complication can in turn negatively impact on the patient’s quality of life with only a short-term gain in survival. In liver transplant recipients who have recurrent HCC, only 1–2% will be localized in the absence of significant underlying liver disease and comorbidities and warrant potential cure by liver resection [46, 139, 143]. Retransplantation in a patient has been reported [144]. It is unlikely that studies in this population will result in any definitive guidelines due to the small numbers involved. Every case has to be individually evaluated for possible curative therapy in a multidisciplinary fashion. Advanced disease is treated to palliate symptoms as prognosis for these patients is very poor [46, 139, 143]. De novo HCC in the setting of a previous liver transplant is usually associated with significant underlying liver disease, preventing curative resection. Bridge therapy with RFA and retransplantation has been reported [140]. Other malignant tumors reported in the CTTR registry in solid organ transplant recipients include sarcomas and cholangiocarcinomas. Kaposi sarcoma was dominant with 24 cases reported, only one of which was localized to the liver, while the remaining 23 patients had multiorgan involvement. The incidence of Kaposi sarcoma in the transplant population is reported to range between 2% and 3.5%. The other sarcomas in the CTTR registry were five leiomy-

466

osarcomas, one angiosarcoma, one fibrosarcoma, one mesothelioma, and one spindle cell sarcoma. Leiomyosarcoma was predominantly present in pediatric solid organ transplant recipients [145]. Human herpes simplex virus 8 (HHSV 8) has been detected in virtually all patients with Kaposi sarcoma. The presence of viral DNA as well as serum antibodies to HHSV 8 seems to be predictive for the future development of Kaposi sarcoma, especially in immunocompromised patients [146, 147]. Treatment of Kaposi sarcoma in the transplant recipient consists of a reduction in immunosuppression, when it can be done safely, and early lesions may show a favorable response to this approach [148]. Close surveillance of the transplanted organ for rejection should be performed. There are reports of regression of Kaposi sarcoma when sirolimus was used, replacing other immunosuppressive agents [149– 151]. The outcome of advanced and disseminated disease is poor, and surgery has no role. Cholangiocarcinoma in transplantation can recur in patients who have undergone liver transplantation for primary sclerosing cholangitis (PSC). The recurrence rate for cholangiocarcinoma is documented as 51% in the CTTR, with most of the recurrences occurring within 2 years of transplantation. Survival after recurrence was rarely more than a year. Half of the recurrent tumors were in liver allografts and one-third in the lungs. It was concluded that due to the high rate of recurrence and the lack of positive prognostic factors, liver transplantation should seldom be used as a treatment for cholangiocarcinoma [152]. This is corroborated by the Canadian experience which concluded that early survival appears to be good for incidental cholangiocarcinoma but intermediate and longterms result are poor in liver transplantation for known cholangiocarcinoma [153]. The Mayo Clinic group, on the other hand, found improved 5-year survival and fewer recurrences using neoadjuvant therapy and liver transplantation (82% and 13%, respectively) when compared to bile duct resection with lymphadenectomy and liver resection (21% and 27%, respectively). The patients were highly selected in this study and the protocol used consisted of external beam radiotherapy (4500 cGy in 30 fractions) with concurrent, intravenous 5-fluorouracil (5-FU) given at 500 mg/m2 as a daily bolus for the first 3 days of radiation. Two to 3 weeks after the completion of external beam radiotherapy, a transluminal boost of radiation was delivered using a transcatheter iridium-192 brachytherapy wire, with a target dose of 2000–3000 cGy. Following brachytherapy, patients initially continued to receive 5-FU at the same dose through an ambulatory infusion pump. During the last 4 years, patients have been treated with oral capecitabine (2000 mg/m2 per day in two divided doses, 2 in every 3 weeks) as tolerated until transplantation [154].

CHAPTER 38

De novo cholangiocarcinoma in a patient with liver transplant and recurrent PSC has been described. This was treated with retransplantation of the liver [155]. De novo cholangiocarcinoma has also been reported in one patient 10 years after receiving a kidney transplant [156]. In general, recurrence of cholangiocarcinoma after liver transplantation carries a poor prognosis and surgical resection is seldom indicated. We do not recommend liver transplantation for known cholangiocarcinoma outside a study protocol.

Liver tumors during pregnancy Liver tumors during pregnancy are rare [157] and the diagnosis, management, and treatment of such tumors during pregnancy is challenging. Maternal and fetal wellbeing must be continuously assessed at all stages of the disease course. Hepatic adenoma, focal nodular hyperplasia (FNH), and hemangioma appear to be the more common tumors during pregnancy, but the actual incidence of each in this particular population of patients is unknown [158]. The clinical presentation of a liver mass during pregnancy is similar to that in a nonpregnant patient; however, the diagnosis may be delayed because symptoms may initially be attributed to the pregnancy.

Hemangioma Hemangiomas are the most common benign tumors of the liver. Their incidence is estimated to be 0.4–7.3% in autopsy studies and has been reported to reach 2% with imaging studies [159–161]. The majority of hemangiomas in nonpregnant patients are asymptomatic, but they can present with pain, distention, or vague symptoms related to pressure on neighboring viscera [160]. The presentation of hemangiomas in pregnancy includes vomiting, epigastric pain radiating to the back, difficulty eating, and an awareness of an intra-abdominal mass. Tumors may be mistaken for cholecystitis, twin pregnancy, and an ovarian tumor [158]. Presentation can also include a consumptive coagulopathy and thrombocytopenia (Kasabach–Merritt phenomenon). There are several case reports of hemangiomas that have ruptured or shown a rapid increase in size during pregnancy [162, 163]. Estrogen has been suggested to play a role in the development of hemangiomas [164], but there are no reports to support the presence of estrogen receptors in hepatic hemangiomas. The concern relating to hepatic hemangiomas is the remote risk of possible spontaneous hemorrhage. In nonpregnant patients, complications from lesions of less than 10 cm in diameter are generally rare, and only 5% of symptomatic lesions are at risk for rupture [165]. The risk of rupture during pregnancy does not appear to differ between pregnant and nonpregnant women [166]. If a hemangioma ruptures during pregnancy, bleeding may be controlled by

Liver Tumors in Special Populations

arterial embolization [161, 162]. In general, hemangiomas during pregnancy are conservatively managed with serial monitoring using ultrasound, unless there is evidence of rapid growth.

Focal nodular hyperplasia FNH of the liver is the second most common benign lesion that can occur in the liver [167]. FNH is considered to be a local hyperplastic response of hepatocytes to a vascular abnormality. Most FNH lesions are asymptomatic and are discovered incidentally during liver ultrasound examination. Cobey et al reviewed 41 pregnancies associated with FNH [158]. The majority of the FNH lesions were asymptomatic in this study, but five cases had complaints of upper abdominal pain and six had a sensation of a mass. There was no occurrence of FNH rupture in association with pregnancy, although one case showed an increase in size of the lesion [158]. A 9-year study involving 216 women with FNH also suggested that pregnancy was not associated with FNH changes or complications [168]. It is therefore recommended that FNH in pregnancy be closely observed and monitored, unless there is rapid growth, in which case surgical resection should be considered [158].

Hepatocellular adenoma Hepatocellular adenoma was a rare tumor before oral contraceptives were introduced. The relationship between hepatic adenomas and oral contraceptives was reported in 1973 [169], and they have been described to regress with discontinuation of oral contraceptives [170]. The risk of development of an adenoma increases with the duration and the estrogen content of the oral contraceptive used [171]. A review of a series of hepatic adenomas has shown that the risk of spontaneous bleeding is 20–40% [172]. This risk is increased in women taking oral contraceptives, during pregnancy, and when adenomas are greater than 5 cm in diameter [173, 174]. The rupture of a hepatic adenoma is associated with a high maternal and fetal mortality of 44–59% and 38–63%, respectively [158]. Unlike hemangiomas and FNH, the presentation of a hepatic adenoma is frequently catastrophic in pregnancy, as it has been known to grow and rupture in that setting. A recent review of adenomas during pregnancy has shown that 16 of 26 cases presented with rupture [158]. In nonpregnant patients, it is recommended that adenomas greater than 5 cm should be resected, whereas those less than 5 cm should be closely followed up [173, 175]. This approach can also be applied for pregnant patients as there are no reports of rupture with adenomas less than 6.5 cm in diameter. However, because hepatic adenoma rupture is associated with a high maternal and fetal mortality [158], liver adenomas in pregnancy that are greater than 5 cm show rapid growth or become symptomatic should be resected [158].

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Hepatocellular carcinoma HCC is rare in pregnancy. In general, HCC is less common in women than in men, and, with the exception of Africans, it is rare in females of reproductive age [176]. Liver cirrhosis is also associated with infertility, particularly at an advanced stage [177]. HCC in pregnancy has been associated with poor maternal and fetal outcome. Lau et al. analyzed 28 patient with HCC in pregnancy: only two patients survived up to 1 year from diagnosis and live infants were delivered in only half of the cases [177]. Pregnancy appears to have an adverse effect on prognosis with HCC [158] because it is an aggressive tumor that has been reported to have a median survival of only 8 weeks in inoperable cases [178]. Lau et al showed a much shorter survival when pregnant patients were compared to nonpregnant women with inoperable HCC [177]. It has been suggested that estrogen may accelerate the evolution of HCC in gestation [179]. Additionally, AFP and placental steroids have been implicated as being responsible for the suppression of the immune response during pregnancy [177], and gestational immune suppression may be an enabling factor in tumor progression. However, the actual mechanism of the effect of pregnancy on HCC remains unclear. In the majority of reported cases, the pregnancy was terminated once the HCC was diagnosed [180]. Considering the frequent rapid tumor growth during pregnancy and the near universal poor outcome, early termination of pregnancy should be offered, followed by tumor resection when possible [158, 180].

Hepatobiliary surgery during pregnancy If surgery during pregnancy is chosen as the method of definitive treatment, it is crucial to consider a reduction of the risks to both mother and fetus. The timing of surgery in pregnant patients is also a controversial issue. It has been shown that surgery performed in the second trimester has a significantly lower abortion and preterm birth rate than surgery in the first or third trimesters [181]. A review of reports of cholecystectomy performed during pregnancy showed a miscarriage rate of only 5.6% in the second trimester compared to 12% in the first trimester. The rate of preterm labor was also low for surgery performed during the second trimester, but 40% for surgery in the third trimester [182]. Other advantages of surgery in the second trimester relate to the fact that the potential risk of teratogenesis is very small and the uterus is of an adequate size, but it does not obliterate the operative field, as it may during the third trimester. Therefore, the second trimester is the safest period to schedule surgery if possible [182, 183]. Intraoperative precautions should be undertaken to promote safety of the mother and fetus. The patient should be placed slightly to her left side in order to reduce compression of the vena cava. Intraoperative fetal monitoring is indicated as the supine position increases the risk of hypotension and ultimate uter-

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oplacental insufficiency [183]. Obstetricians should be consulted before the surgery, and preoperative, intraoperative, and postoperative fetal monitoring should be performed based on their recommendation. Epidural anesthesia can be used in higher risk patients in order to minimize fetal drug exposure and decrease the overall risk of general anesthesia. Postoperative antiembolic precautions are also important as the risk of thromboembolic complications is increased during pregnancy. In summary, a successful maternal and fetal outcome is dependent on multidisciplinary expertise and collaboration (the surgeons, anesthesiologists, and obstetricians) for optimal perioperative management.

Self-assessment questions 1 The prevalence of hepatocellular cancer is highest in cirrhosis due to which one of the following? A Nonalcoholic steatohepatitis B Hepatitis C C Alcohol-related liver cirrhosis D Primary biliary cirrhosis 2 Beta-blockers should be perioperatively discontinued in patients already being treated, because beta-blockade appears to increase the risk for complications in low-risk patients. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 3 Advanced age is not a contraindication for hepatic resection, because older patients appear to have the same regenerative volume and protein synthesis after liver resection as in younger patients. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 4 With regard to hepatic malignancies in HIV/AIDS patients, which one of the following statements is false? A Decreased incidence of non-Hodgkin lymphoma in HAART era is because of partial or near complete restoration of immune response B Kaposi sarcoma regression is associated with decreasing loads of human herpes simplex virus 8

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C HIV infection is an absolute contraindication to liver transplantation because of the need for immunosuppression D Hepatocellular carcinoma tends to occur earlier due to hepatitis C coinfection E Poor risk for Kaposi sarcoma is associated with high HIV PCR 5 The recommended treatment strategies for posttransplant lymphoproliferative disorder include which of the following? (more than one answer is possible) A Surgical debulking of the tumor mass B Reduction in immunosuppression C Administration of intravenous immunoglobulins D Anti CD-20 monoclonal antibody (rituximab) E Doxorubicin-based chemotherapy 6 Regarding nonlymphoma hepatobiliary tumors in solid organ transplant recipients, which one of the following statements is true? A Recurrence risk is highest for hepatocellular carcinoma in liver transplant recipients within 2 years B Kidney transplant recipients who develop hepatocellular carcinoma are not candidates for surgical resection C Most common site of recurrence of hepatocellular carcinoma is the lung D Primary treatment modality of Kaposi sarcoma in solid organ transplant recipients is pegylated daunorubicin E Incidental cholangiocarcinoma at the time of liver transplantation has no adverse effects on outcome 7 Which one of the following liver tumors mostly grows and ruptures in pregnancy? A Focal nodular hyperplasia B Hepatocellular carcinoma C Cyst D Adenoma E Hemangioma

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104 Brau N, Salvatore M, Rios-Bedoya CF, et al. Slower fibrosis progression in HIV/HCV-coinfected patients with successful HIV suppression using antiretroviral therapy. J Hepatol 2006;44:47–55. 105 Benhamou Y, Bochet M, Di Martino V, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology (Baltimore) 1999;30:1054–8. 106 Schreibman I, Gaynor JJ, Jayaweera D, et al. Outcomes after orthotopic liver transplantation in 15 HIV-infected patients. Transplantation 2007;84:697–705. 107 Brau N, Fox RK, Xiao P, et al. Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: a U.S.Canadian multicenter study. J Hepatol 2007;47:527–37. 108 Duclos-Vallee JC, Feray C, Sebagh M, et al. Survival and recurrence of hepatitis C after liver transplantation in patients coinfected with human immunodeficiency virus and hepatitis C virus. Hepatology (Baltimore) 2008;47:407–17. 109 Penn I. Primary malignancies of the hepato-biliary-pancreatic system in organ allograft recipients. J HBP Surg 1998;5:157–64. 110 Hanson MN, Morrison VA, Peterson BA, et al. Posttransplant T-cell lymphoproliferative disorders–an aggressive, late complication of solid-organ transplantation. Blood 1996;88:3626–33. 111 Capello D, Cerri M, Muti G, et al. Molecular histogenesis of posttransplantation lymphoproliferative disorders. Blood 2003; 102:3775–85. 112 Nalesnik MA, Jaffe R, Starzl TE, et al. The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression. Am J Pathol 1988;133:173–92. 113 Caillard S, Lelong C, Pessione F, Moulin B. Post-transplant lymphoproliferative disorders occurring after renal transplantation in adults: report of 230 cases from the French Registry. Am J Transplant 2006;6:2735–42. 114 Cockfield SM, Preiksaitis JK, Jewell LD, Parfrey NA. Post-transplant lymphoproliferative disorder in renal allograft recipients. Clinical experience and risk factor analysis in a single center. Transplantation 1993;56:88–96. 115 Green M. Management of Epstein-Barr virus-induced posttransplant lymphoproliferative disease in recipients of solid organ transplantation. Am J Transplant 2001;1:103–8. 116 Dotti G, Fiocchi R, Motta T, et al. Epstein-Barr virus-negative lymphoproliferate disorders in long-term survivors after heart, kidney, and liver transplant. Transplantation 2000;69:827–33. 117 Allen U, Hebert D, Moore D, Dror Y, Wasfy S. Epstein-Barr virus-related post-transplant lymphoproliferative disease in solid organ transplant recipients, 1988-97: a Canadian multicentre experience. Pediatr Transplant 2001;5:198–203. 118 Nuckols JD, Baron PW, Stenzel TT, et al. The pathology of liverlocalized post-transplant lymphoproliferative disease: a report of three cases and a review of the literature. Am J Surg Pathol 2000;24:733–41. 119 Nalesnik MA. The diverse pathology of post-transplant lymphoproliferative disorders: the importance of a standardized approach. Transpl Infect Dis 2001;3:88–96. 120 Petit B, Le Meur Y, Jaccard A, et al. Influence of host-recipient origin on clinical aspects of posttransplantation lymphoproliferative disorders in kidney transplantation. Transplantation 2002;73:265–71.

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121 Weissmann DJ, Ferry JA, Harris NL, Louis DN, Delmonico F, Spiro I. Posttransplantation lymphoproliferative disorders in solid organ recipients are predominantly aggressive tumors of host origin. Am J Clin Pathol 1995;103:748–55. 122 Cheung AN, Chan AC, Chung LP, Chan TM, Cheng IK, Chan KW. Post-transplantation lymphoproliferative disorder of donor origin in a sex-mismatched renal allograft as proven by chromosome in situ hybridization. Mod Pathol 1998;11: 99–102. 123 Tsai DE, Hardy CL, Tomaszewski JE, et al. Reduction in immunosuppression as initial therapy for posttransplant lymphoproliferative disorder: analysis of prognostic variables and long-term follow-up of 42 adult patients. Transplantation 2001; 71:1076–88. 124 Humar A, Hebert D, Davies HD, et al. A randomized trial of ganciclovir versus ganciclovir plus immune globulin for prophylaxis against Epstein-Barr virus related posttransplant lymphoproliferative disorder. Transplantation 2006;81:856–61. 125 Elstrom RL, Andreadis C, Aqui NA, et al. Treatment of PTLD with rituximab or chemotherapy. Am J Transplant 2006; 6:569–76. 126 Choquet S, Leblond V, Herbrecht R, et al. Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study. Blood 2006;107:3053–7. 127 Taylor AL, Bowles KM, Callaghan CJ, et al. Anthracyclinebased chemotherapy as first-line treatment in adults with malignant posttransplant lymphoproliferative disorder after solid organ transplantation. Transplantation 2006;82: 375–81. 128 Fohrer C, Caillard S, Koumarianou A, et al. Long-term survival in post-transplant lymphoproliferative disorders with a doseadjusted ACVBP regimen. Br J Haematol 2006;134:602–12. 129 Sudheendra D, Barth MM, Hegde U, Wilson WH, Wood BJ. Radiofrequency ablation of lymphoma. Blood 2006;107: 1624–6. 130 Finelli L, Miller JT, Tokars JI, Alter MJ, Arduino MJ. National surveillance of dialysis-associated diseases in the United States, 2002. Semin Dial 2005;18:52–61. 131 Di Napoli A, Pezzotti P, Di Lallo D, Petrosillo N, Trivelloni C, Di Giulio S. Epidemiology of hepatitis C virus among long-term dialysis patients: a 9-year study in an Italian region. Am J Kidney Dis 2006;48:629–37. 132 Courouce AM, Bouchardeau F, Chauveau P, et al. Hepatitis C virus (HCV) infection in haemodialysed patients: HCV-RNA and anti-HCV antibodies (third-generation assays). Nephrol Dial Transplant 1995;10:234–9. 133 Othman B, Monem F. Prevalence of antibodies to hepatitis C virus among hemodialysis patients in Damascus, Syria. Infection 2001;29:262–5. 134 Mioli VA, Balestra E, Bibiano L, et al. Epidemiology of viral hepatitis in dialysis centers: a national survey. Nephron 1992; 61:278–83. 135 Teles SA, Martins RM, Gomes SA, et al. Hepatitis B virus transmission in Brazilian hemodialysis units: serological and molecular follow-up. J Med Virol 2002;68:41–9. 136 Oguchi H, Miyasaka M, Tokunaga S, et al. Hepatitis virus infection (HBV and HCV) in eleven Japanese hemodialysis units. Clin Nephrol 1992;38:36–43.

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137 Chan TM, Lok AS, Cheng IK. Hepatitis C infection among dialysis patients: a comparison between patients on maintenance haemodialysis and continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 1991;6:944–7. 138 Chen KS, Lo SK, Lee N, Leu ML, Huang CC, Fang KM. Superinfection with hepatitis C virus in hemodialysis patients with hepatitis B surface antigenemia: its prevalence and clinical significance in Taiwan. Nephron 1996;73:158–64. 139 Roayaie S, Schwartz JD, Sung MW, et al. Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis. Liver Transpl 2004;10:534–40. 140 Croitoru A, Schiano TD, Schwartz M, et al. De novo hepatocellular carcinoma occurring in a transplanted liver: case report and review of the literature. Dig Dis Sci 2006;51: 1780–2. 141 Cheng SB, Yeh DC, Shu KH, et al. Liver resection for hepatocellular carcinoma in patients who have undergone prior renal transplantation. J Surg Oncol 2006;93:273–8. 142 Chok KS, Lam CM, Li FK, et al. Management of hepatocellular carcinoma in renal transplant recipients. J Surg Oncol 2004;87:139–42. 143 Schlitt HJ, Neipp M, Weimann A, et al. Recurrence patterns of hepatocellular and fibrolamellar carcinoma after liver transplantation. J Clin Oncol 1999;17:324–31. 144 Kita Y, Klintmalm G, Kobayashi S, Yanaga K. Retransplantation for de novo hepatocellular carcinoma in a liver allograft with recurrent hepatitis B cirrhosis 14 years after primary liver transplantation. Dig Dis Sci 2007;52:3392–3. 145 Aseni P, Vertemati M, Minola E, et al. Kaposi’s sarcoma in liver transplant recipients: morphological and clinical description. Liver Transpl 2001;7:816–23. 146 Cattani P, Capuano M, Graffeo R, et al. Kaposi’s sarcoma associated with previous human herpesvirus 8 infection in kidney transplant recipients. J Clin Microbiol 2001;39:506–8. 147 Chang Y, Moore PS. Kaposi’s Sarcoma (KS)-associated herpesvirus and its role in KS. Infect Agents Dis 1996;5:215–22. 148 Moosa MR. Kaposi’s sarcoma in kidney transplant recipients: a 23-year experience. Q J Med 2005;98:205–14. 149 Gheith O, Bakr A, Wafa E, et al. Sirolimus for visceral and cutaneous Kaposi’s sarcoma in a renal-transplant recipient. Clin Exp Nephrol 2007;11:251–4. 150 Iaria G, Anselmo A, De Luca L, et al. Conversion to rapamycin immunosuppression for malignancy after kidney transplantation: case reports. Transplant Proc 2007;39:2036–7. 151 Di Paolo S, Teutonico A, Ranieri E, Gesualdo L, Schena PF. Monitoring antitumor efficacy of rapamycin in Kaposi sarcoma. Am J Kidney Dis 2007;49:462–70. 152 Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation 2000;69: 1633–7. 153 Ghali P, Marotta PJ, Yoshida EM, et al. Liver transplantation for incidental cholangiocarcinoma: analysis of the Canadian experience. Liver Transpl 2005;11:1412–16. 154 Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 2005;242:451–8; discussion 8–61. 155 Heneghan MA, Tuttle-Newhall JE, Suhocki PV, et al. De-novo cholangiocarcinoma in the setting of recurrent primary

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156

157 158

159 160 161 162

163

164

165

166

167

168

169

170

171 172

474

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sclerosing cholangitis following liver transplant. Am J Transplant 2003;3:634–8. Storms P, Ramli Y. Cholangiocarcinoma in an immunosuppressed kidney transplant patient. A case report and review of literature. Acta Chirurg Belgica 1990;90:24–6. Athanassiou AM, Craigo SD. Liver masses in pregnancy. Semin Perinatol 1998;22:166–77. Cobey FC, Salem RR. A review of liver masses in pregnancy and a proposed algorithm for their diagnosis and management. Am J Surg 2004;187:181–91. Ochsner JL, Halpert B. Cavernous hemangioma of the liver. Surgery 1958;43:577–82. Ishak KG, Rabin L. Benign tumors of the liver. Med Clin N Am 1975;59:995–1013. Itai Y. Liver haemangioma and pregnancy. Lancet 1996; 347:1693–4. Itzchak Y, Adar R, Bogokowski H, Mozes M, Deutsch V. Intrahepatic arterial portal communications: angiographic study. AJR Am J Roentgenol 1974;121:384–7. Martin B, Roche A, Radice L, Aguilar K, Kraiem C. [Does arterial embolization have a role in the treatment of cavernous hemangioma of the liver in adults?] Presse Med 1986;15: 1073–6. Saegusa T, Ito K, Oba N, et al. Enlargement of multiple cavernous hemangioma of the liver in association with pregnancy. Intern Med (Tokyo) 1995;34:207–11. Creasy GW, Flickinger F, Kraus RE. Maternal liver hemangioma in pregnancy as an incidental finding. Obstet Gynecol 1985;66 (3 Suppl ):10S–3S. Schwartz SI, Husser WC. Cavernous hemangioma of the liver. A single institution report of 16 resections. Ann Surg 1987;205:456–65. Lee MJ, Saini S, Hamm B, et al. Focal nodular hyperplasia of the liver: MR findings in 35 proved cases. AJR Am J Roentgenol 1991;156:317–20. Mathieu D, Kobeiter H, Maison P, et al. Oral contraceptive use and focal nodular hyperplasia of the liver. Gastroenterology 2000;118:560–4. Baum JK, Bookstein JJ, Holtz F, Klein EW. Possible association between benign hepatomas and oral contraceptives. Lancet 1973;2:926–9. Steinbrecher UP, Lisbona R, Huang SN, Mishkin S. Complete regression of hepatocellular adenoma after withdrawal of oral contraceptives. Dig Dis Sci 1981;26:1045–50. Rosenberg L. The risk of liver neoplasia in relation to combined oral contraceptive use. Contraception 1991;43:643–52. Barthelmes L, Tait IS. Liver cell adenoma and liver cell adenomatosis. HPB (Oxford) 2005;7:186–96.

173 Terkivatan T, de Wilt JH, de Man RA, Ijzermans JN. Management of hepatocellular adenoma during pregnancy. Liver 2000;20:186–7. 174 Terkivatan T, de Wilt JH, de Man RA, van Rijn RR, Tilanus HW, IJzermans JN. Treatment of ruptured hepatocellular adenoma. Br J Surg 2001;88:207–9. 175 Ault GT, Wren SM, Ralls PW, Reynolds TB, Stain SC. Selective management of hepatic adenomas. Am Surgeon 1996;62: 825–9. 176 El-Serag HB. Hepatocellular carcinoma: an epidemiologic view. J Clin Gastroenterol 2002;35 (5 Suppl 2):S72–8. 177 Lau WY, Leung WT, Ho S, et al. Hepatocellular carcinoma during pregnancy and its comparison with other pregnancyassociated malignancies. Cancer 1995;75:2669–76. 178 Shiu W, Dewar G, Leung N, et al. Hepatocellular carcinoma in Hong Kong: clinical study on 340 cases. Oncology 1990;47: 241–5. 179 Erfling W. Effect of estrogens on the liver. Case presentation. Gastroenterology 1978;75:512. 180 Alvarez de la Rosa M, Nicolas-Perez D, Muniz-Montes JR, Trujillo-Carrillo JL. Evolution and management of a hepatocellular carcinoma during pregnancy. J Obstet Gynaecol Res 2006; 32:437–9. 181 Goodman S. Anesthesia for nonobstetric surgery in the pregnant patient. Semin Perinatol 2002;26:136–45. 182 Fatum M, Rojansky N. Laparoscopic surgery during pregnancy. Obstet Gynecol Surv 2001;56:50–9. 183 Jabbour N, Brenner M, Gagandeep S, et al. Major hepatobiliary surgery during pregnancy: safety and timing. Am Surgeon 2005;71:354–8. 184 Campeau L. Letter: Grading of angina pectoris. Circulation 1976;54:522–3. 185 Brand MI, Saclarides TJ, Dobson HD, Millikan KW. Liver resection for colorectal cancer: liver metastases in the aged. Am Surg 2000;66:412–15.

Self-assessment answers 1 2 3 4 5 6 7

B C B C B, D, E A D

39

Malignant Liver Tumors in Children Xavier Rogiers1 and Ruth De Bruyne2 1 Department of General and Hepatobiliary Surgery, Transplantation Center, University Medical Center Ghent, Ghent, Belgium 2 Department of Pediatrics, Section of Pediatric Gastroenterology, University Medical Center Ghent, Ghent, Belgium

Malignant tumors of the liver or bile ducts during childhood are rare, with an incidence of 1.6–2 per million children [1–3] or 1–2% of childhood cancer. There is some suggestion of a higher incidence in the literature, but this may relate to greater diagnostic accuracy. Hepatoblastoma and hepatocellular carcinoma (HCC) are the most important malignant liver tumors in children, with hepatoblastoma accounting for more than half of the cases. Other, very rare tumors can also develop in children. There has been significant progress in the treatment of hepatic tumors in children in the past decades. The tools to diagnose and evaluate these tumors have improved dramatically, and are largely the same as for adult patients. The development of specialized liver surgery generally, and for children in particular, and the possibility of liver transplantation in children have contributed to higher resectability rates and a more radical treatment of these diseases. Furthermore, prospective multicenter interdisciplinary protocol designed strategies, seeking to optimally combine chemotherapy and surgery, have led to significant improvements in results, especially for hepatoblastoma. Staging of pediatric liver tumors can either be based on the pretreatment extent of the disease or on the surgical resectability [4] (Table 39.1). In North America, a staging system similar to that for other solid tumors, based on surgical resectability and presence of metastases, is used. The European staging system, called PRETEXT (PRETreatment EXTent of disease scoring system) only considers the pretreatment extent of disease (Figure 39.1). Liver surgery in children essentially follows the same rules as in adult patients. Children are mainly otherwise healthy, and the remaining liver usually has a normal aspect; they therefore tend to tolerate more extensive resections than adult patients. Intraoperative ultrasound plays a vital role in making the final intraoperative decision of resectability. In cases of nonresectability, total hepatectomy and orthotopic liver transplantation may be a valuable option [5].

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

In this chapter, we review the most common pediatric malignant tumors and their treatment.

Hepatoblastoma Epidemiology Hepatoblastomas represent 80% of all malignant hepatic tumors [6]. Hepatoblastoma is an embryonal tumor occurring predominantly in early childhood. According to a report from the Automated Childhood Cancer Information System (ACCIS) project, 42% of cases occurred in the first year of life, and 91% by the age of 5 years [7]. A male predominance for hepatoblastoma is reported in several epidemiologic studies [1, 6]. Data from the Surveillance, Epidemiology and End Result (SEER) program in the United States showed an important increase in hepatoblastoma incidence between the periods 1973–1977 and 1993–1997 from 0.6 to 1.2 per million [4]. However, no significant increase in incidence was seen in the European ACCIS study from 1978 to 1997 [7]. Most cases of hepatoblastoma are sporadic and the etiology of hepatoblastoma is not well understood. Nevertheless, hepatoblastoma is associated with several congenital or genetic syndromes. Beckwith–Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by macrosomia, macroglossia, abdominal wall defects, ear anomalies, and neonatal hypoglycemia. BWS is caused by genetic abnormalities in chromosome 11p15 and children with BWS are at an increased risk of developing intra-abdominal embryonal tumors, particularly hepatoblastoma and Wilms tumor. The relative risk for hepatoblastoma is as high as 2280 [8]. Tumor surveillance by serial abdominal ultrasound and serum alpha-fetoprotein (AFP) measurements is therefore recommended in these patients [9, 10]. Children with isolated hemihypertrophy and other overgrowth syndromes are also at a higher risk of developing hepatoblastoma [11, 12]. Additionally, the risk of hepatoblastoma is approximately 800-fold higher in children with a family history of familial adenomatous polyposis (FAP) [13, 14]. FAP is an autosomal dominant condition causing

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Special Tumors, Population, and Special Considerations

Stage 1: Three adjoining sectors free Right lobe of liver

Right lobe of liver

Left lobe of liver

Left lobe of liver

colonic polyp growth and ultimately colon cancer, and is due to a genetic mutation in the adenomatous polyposis coli (APC) gene. When 50 cases of apparently sporadic hepatoblastoma were examined for APC germline mutations, 10% was found to be positive. These findings raise the issue of screening children of FAP patients for hepatoblastoma, as well as routine APC mutation screening in patients diagnosed with sporadic hepatoblastoma. De novo FAP in a spo-

Stage 2: Two adjoining sectors free Right lobe of liver

Left lobe of liver

Right lobe of liver

Left lobe of liver

Table 39.1 Staging systems for pediatric liver tumors. (Modified from Litten & Tomlinson [4].)

Stage 1

Right lobe of liver

Left lobe of liver Stage 2

European staging SIOPEL/PRETEXT (presurgical staging)

North American staging (postsurgical staging)

Tumor involves only one quadrant; three adjoining quadrants are free of tumor Tumor involves two adjoining quadrants; two adjoining quadrants are free of tumor

No metastases; tumor completely resected

Stage 3: One sector free Right lobe of liver

Left lobe of liver

Right lobe of liver

Left lobe of liver

Stage 3

Stage 4

Right lobe of liver

Left lobe of liver

Right lobe of liver

Left lobe of liver

Tumor involves three adjoining quadrants or two nonadjoining quadrants; one quadrant or two nonadjoining quadrants are free of tumor Tumor involves all four quadrants; there is no quadrant free of tumor

No metastases; tumor grossly resected with microscopic residual diseases (i.e. positive margins, tumor rupture, or tumor spill at the time of surgery) No distant metastases; tumor unresectable or resected with gross residual tumor, or positive nodes

Distant regardless of the extent of liver involvement

PRETEXT, PRETreatment EXTent of disease scoring system; SIOPEL, Childhood Liver Tumor Strategy Group of the Société Internationale d’Oncologie Pédiatrique.

Stage 4: No free sector Right lobe of liver

476

Left lobe of liver

Right lobe of liver

Left lobe of liver

Figure 39.1 PRETEXT scoring system [4]. The PRETreatment EXTent of disease scoring system involves classification of liver tumors by dividing the liver on imaging into four sectors and determining how many sectors are involved by tumors. Extension of the tumor is also included in the staging as follows: V indicates extension into the vena cava and/or all three hepatic veins; P indicates extension into the main branch and/or both the left and right branches of the portal vein; E indicates extrahepatic disease, and unlike P and V is rare and must be biopsy proven; M indicates the presence of distant metastases. (Reproduced from Litten & Tomlinson [4], with permission.)

CHAPTER 39

radic hepatoblastoma patient should warrant colorectal surveillance [15]. Low birthweight (1500–2500 g) and particularly very low birthweight (VLBW; <1500 g) are important risk factors for hepatoblastoma. In a large case–control study, the odds ratio for hepatoblastoma in VLBW infants was 51 times higher than in those of normal birthweight [16]. The reason for this high risk is unclear. In addition, parental cigarette smoking has also been reported as a risk factor for hepatoblastoma, with a doubling of risk if both parents smoke relative to neither parent smoking [17].

Clinical presentation An asymptomatic, enlarging abdominal mass is usually the predominant symptom. Anorexia and weight loss, abdominal pain, nausea, vomiting, and fever can be seen, generally in more advanced disease [18]. Jaundice is rare and mostly due to compression of larger bile ducts. Tumor rupture due to rapid growth is only seen in exceptional cases. Human β-chorionic gonadotropin or testosterone secretion by hepatoblastoma cells can occasionally give rise to precocious puberty and virilizing symptoms [19, 20].

Diagnosis Liver enzymes and bilirubin are usually normal or mildly elevated. A mild normochromic, normocytic anemia can be seen. Marked thrombocytosis is common and is probably related to thrombopoietin production by the tumor [21, 22]. The serum AFP concentration is markedly elevated in most patients at diagnosis, but unexpectedly low or even normal AFP is reported in around 5–10% of cases. These patients with low serum AFP exhibit more extensive disease and treatment failure, and therefore are classified as “high risk” in the International Childhood Liver Tumor Strategy (SIOPEL) 3 protocol [23]. Additionally, AFP is also a good marker to monitor the effect of treatment and disease recurrence. Abdominal ultrasound is the best first imaging test in a child with a suspected abdominal mass. It provides real-time evaluation of vascular anatomy, which is very useful to determine the intrahepatic extent of disease and to assess venous involvement. Doppler flow studies may contribute to the evaluation of intravascular tumor extension [24, 25]. In general, magnetic resonance imaging (MRI) is preferred over computed tomography (CT), but the choice depends on the equipment available and the radiologist’s expertise. If CT is performed, this should be done by a radiologist familiar with dose-reduction techniques. The abdomen and pelvis should be scanned following intravenous contrast injection (portal venous phase) [24]. The most common site for metastasis is the lung; therefore, a chest CT is essential. Compared to CT, MRI with enhancement may give additional information and reduces radiation exposure of the young child. Angiography is usually not performed, but

Malignant Liver Tumors in Children

occasionally it can be helpful in the planning of complicated surgery or hepatic artery embolization [26]. Bone marrow involvement and bone metastases are rare, and the latter are difficult to differentiate from paraneoplastic osteopenia. Hence, bone scintigraphy is not recommended, as falsepositive results are often seen [27]. As brain metastases are also rare at diagnosis, brain imaging is also not recommended unless the patient has neurologic symptoms or signs [26]. Scintigraphy utilizing 99mTc-labeled monoclonal anti-AFP Fab′ fragments has been used successfully in the staging of a child with hepatoblastoma; further studies are needed to prove their clinical usefulness [28]. The value of positron emission tomography using 18F-fluorodeoxyglucose (FDGPET) is also unclear. It has been proven to be more sensitive than conventional imaging (CT or MRI) in cases of recurrent hepatoblastoma or metastatic disease [29].

Staging Different treatment protocols for hepatoblastoma have varying staging approaches. Risk stratification in the treatment protocol, developed by the SIOPEL group, is almost completely based on imaging findings. The PRETEXT staging system for primary malignant liver tumors developed by the SIOPEL group describes tumor extent before any therapy, allowing effective comparison between different groups. The PRETEXT staging is based on Couinaud’s system of segmentation of the liver (see Figure 39.1). The liver segments are grouped into four sections: segments 2 and 3 (left lateral section), segment 4 (left medial section), segments 5 and 8 (right anterior section), and segments 6 and 7 (right posterior section). The PRETEXT group number equals four minus the maximum number of contiguous liver sections that are not affected by tumor (Table 39.2) [30, 31]. Additional criteria for PRETEXT staging are shown in (Table 39.3) [30, 31]. Resection of segment 1 is possible but technically difficult; involvement of the caudate lobe is therefore a potential predictor of poor outcome. Hence, if any tumor is present in segment 1 on imaging at diagnosis, the patient will be at least PRETEXT II.

Table 39.2 Definitions of PRETEXT number. (Modified from Roebuck et al [30].) PRETEXT number

Definition

I

One section is involved and three adjoining sections are free One or two sections are involved, but two adjoining sections are free Two or three sections are involved, and no two adjoining sections are free All four sections are involved

II III IV

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Table 39.3 2005 PRETEXT staging: additional criteria. (Modified from Roebuck et al [30].) Caudate lobe involvement

C

Extrahepatic abdominal disease

E

Tumor focality

F

Tumor rupture or intraperitoneal haemorrhage

H

Distant metastases

M

Lymph node metastases

N

Portal vein involvement

P

Involvement of the inferior vena cava (IVC) and/or hepatic veins

V

C1 C0 E0

Tumor involving the caudate lobe All other patients No evidence of tumor spread in the abdomen (except M or N)

E1 E2 F0 F1 H1

Direct extension of tumor into adjacent organs or diaphragm Peritoneal nodules Patient with solitary tumor Patient with two or more discrete tumors Imaging and clinical findings of intraperitoneal hemorrhage

H0 M0 M1 N0 N1 N2

P2 V0

All other patients No metastases Any metastasis (except E and N) No nodal metastases Abdominal lymph node metastases only Extra-abdominal lymph node metastases (with or without abdominal lymph node mestastases) No involvement of the portal vein or its left or right branches Involvement of either the left or the right branch of the portal vein Involvement of the main portal vein No involvement of the hepatic veins or IVC

V1 V2 V3

Involvement of one hepatic vein but not the IVC Involvement of two hepatic veins but not the IVC Involvement of all three hepatic veins and/or the IVC

P0 P1

Direct extension of tumor into other abdominal organs or through the diaphragm is uncommon, but can be coded as E1 without biopsy proof (based on imaging: CT, MRI). Peritoneal nodules are assumed to be metastases and are coded E2. Metastases are predominantly found in the lungs. A single rounded lung lesion with a diameter of greater than 5 mm in a child with hepatoblastoma is very likely to be a metastasis and can be classified as M1 without biopsy. The imaging of brain metastases, although very uncommon, is usually characteristic and biopsy is not required. Abnormal calcium metabolism is common in hepatoblastoma and may cause abnormal uptake on bone scintigraphy. Biopsy proof is necessary for suspected bone metastases. To indicate the major sites of metastasis, suffixes are added to M1: pulmonary (p), skeletal (s), central nervous system (c), bone marrow (m), and other sites (x). Lymph node metastases (porta hepatis, abdominal) are quite unusual and benign enlargement can occur. In the past, SIOPEL trials required this form of tumor spread to be histologically proven. Due to the associated risks of lymph node biopsy, SIOPEL currently discourages this. However, it may be required if there is significant nodal enlargement (i.e. >15 mm short axis) in a child with no other criteria for high-risk hepatoblastoma.

478

All C1 patients are at least PRETEXT II Add suffix “a” if ascites is present, e.g. E0a

Add suffix or suffixes to indicate location (see text)

Add suffix “a” if intravascular tumor is present, e.g. P1a

Add suffix “a” if intravascular tumor is present, e.g. V3a

Venous involvement (portal vein, hepatic veins, inferior vena cava [IVC]) is defined as imaging evidence of obstruction, circumferential encasement or invasion of the vein. When the tumor only abuts or displaces the vein, this is not considered to be venous involvement as there may be shrinkage away from the vein following preoperative chemotherapy [30, 31]. Table 39.4 shows the criteria required for patients to be stratified as high risk [30, 31]. The staging system used by the United States Children’s Oncology Group (COG) is based on postoperative evaluation: stage I is defined as tumor completely resected at diagnosis; stage II as grossly resected tumor with microscopic residual disease; stage III as unresectable tumor, tumor resected with gross residual disease, involvement of local lymph nodes or tumor spill; and stage IV as tumor with distant metastases [32, 33]. The TNM system for liver tumors was mainly developed for use in adults with HCC and is not widely used for hepatoblastoma.

Histopathology Macroscopically, hepatoblastoma presents as a wellcircumscribed single mass which can be very large at diagnosis, up to 25 cm and weighing over 1 kg. The appearance

CHAPTER 39

Table 39.4 Risk stratification in hepatoblastoma for current SIOPEL studies. (Modified from Roebuck et al [30].) High risk

Standard risk

Patients with any of the following: Serum alpha-fetoprotein 100 μg/L PRETEXT IV Additional PRETEXT criteria: • E1, E1a, E2, E2a • H1 • M1 (any site) • N1, N2 • P2, P2a • V3, V3a

All other patients

varies according to the proportion of histologic components, i.e. brown to green, fibrous or calcified, and often showing areas of necrosis, cystic change, and hemorrhage. Vascularity is usually prominent, a thin capsule may be present, and the rest of the liver is normal [34]. Hepatoblastomas are probably derived from a stem cell precursor and most tumors contain many histologic patterns reflecting diverse stages of differentiation. The most recent all-embracing classification recognizes six main histologic patterns: epithelial (56%) (pure fetal, 31%; embryonal and fetal, 19%; macrotrabecular, 3%; small cell, 3%) and mixed epithelial/mesenchymal (44%) with (10%) or without (34%) teratoid features [35]. In completely resected hepatoblastoma, pure fetal histology has been associated with improved survival, while small cell undifferentiated histology is associated with a poor prognosis [36].

Treatment As only complete tumor resection can definitely cure a patient, surgery is the mainstay of treatment for hepatoblastoma. Modern treatment protocols combine surgery with chemotherapy as most hepatoblastomas respond to cytotoxic drugs. In a large number of cases the tumor is unresectable at diagnosis, requiring chemotherapy in order to reduce its size. The approach in the approximately 30– 50% of patients with a resectable tumor varies between the different study groups. The SIOPEL study group recommends no attempt at primary surgery and preoperative chemotherapy in all patients, while the United States COG has a primary surgical approach when possible, without induction chemotherapy. Following the protocol of the German Pediatric Oncology and Hematology (GPOH) group, primary resection with a wide margin in small localized tumors is done when this does not exceed hepatic lobectomy. More extensive surgery is discouraged. This approach results in 20% primary resections [37–39].

Malignant Liver Tumors in Children

Following the SIOPEL protocol, a diagnostic biopsy is necessary regardless of the size and the apparent resectability of the tumor. Traditionally an open biopsy was performed, but currently an image-guided needle biopsy is recommended. The COG and the GPOH group recommend laparotomy with a view to primary resection of tumor when this appears possible on the basis of preoperative imaging. Following the COG protocol, all other children have a diagnostic biopsy. The GPOH group regards biopsy as unnecessary in patients aged 6 months to 3 years with unequivocal clinical findings, imaging, and elevated AFP [40, 41]. An accurate preoperative assessment of resectability is crucial. This should be done by high-quality cross-sectional imaging with contrast-enhanced CT and/or MRI. Ultrasound with Doppler studies is also extremely informative (as discussed above); however, it requires the surgeon to be present during the examination. In selective cases, intraoperative ultrasound is useful for adequate planning of the surgical strategy, particularly in cases of segmental resection [40]. Conventional liver resections are recommended as atypical resections carry a much higher risk for incomplete tumor removal and postoperative complications. Hence, the most commonly performed surgical techniques are anatomic liver resections, such as left lateral sectionectomy, left and right hemihepatectomy, and extended left and right hemihepatectomy [40, 42]. The liver has extensive regenerative capacity and up to 75–85% of the parenchyma can safely be resected. Encasement or invasion of the retrohepatic IVC does not preclude radical excision, since the IVC can be resected en bloc and be replaced by either a prosthetic graft or a venous autograft. Special techniques of hepatic resection, such as tumor resection under hypothermia and extracorporal circulation, total vascular exclusion [43], and extended left atypical hepatectomy [44] are only indicated in very rare situations. These techniques have become controversial because of the excellent results with primary liver transplantation for hepatoblastoma [45]. Difficult liver resections with a high risk of residual tumor should therefore be avoided and liver transplantation performed instead [40]. It is of utmost importance that complete tumor resection is achieved. Frozen sections of the resection margin should be taken to confirm R0 resection [40]. Intra- and postoperative complications are mainly caused by severe bleeding. Other complications are postoperative bile leak or bleeding, air embolism, abdominal abscess, and bowel obstruction due to adhesions [40]. Liver transplantation is a valid treatment option and should be considered in every child presenting with unresectable hepatoblastoma. Analysis of the results for liver transplantation in the SIOPEL 1 study (12 patients) and a review of the world experience (147 patients) showed a good prognosis, with a 10-year survival of 85% for primary transplantation but only 40% for rescue transplantation in

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the SIOPEL group, and a 6-year survival of 82% and 30%, respectively, in the world experience review [45]. The following criteria are used by SIOPEL to select potential candidates for liver transplantation [46]: • Multifocal PRETEXT IV tumors • Unifocal PRETEXT IV tumors. These are relatively rare, but unless downstaging to PRETEXT III is obtained after preoperative chemotherapy, liver transplantation should be considered • PRETEXT III with proximity to major vessels, which makes adequate tumor clearance doubtful • Tumor extension into the vena cava and/or all three hepatic veins • Invasion of the main and/or both left and right branches of the portal vein • Intrahepatic recurrent or residual tumor after previous resection (“rescue” transplantation). Extension into the major vessels is not a contraindication for liver transplantation as long as all of the tumor can be excised at the time of hepatectomy. The persistence of viable extrahepatic metastases after chemotherapy not amenable to surgical resection is an absolute contraindication. Liver transplantation is an option in children presenting with lung metastases if complete clearance can be achieved by chemotherapy with or without surgical excision. Chemotherapy must be given prior to liver transplantation. The tumor should show at least a partial response to chemotherapy; stable or progressive disease is a relative contraindication to liver transplantation. The value of postoperative chemotherapy is still unclear. Optimal timing of liver transplantation is essential and it should not be delayed for more than 4 weeks after the last course of chemotherapy to avoid tumor progression. If this cannot be achieved on a cadaveric waiting list, the possibility of living related donor transplantation should be considered [45]. Careful pretransplant evaluation of the liver transplantation candidate is important, not only of the tumor but also of the fitness for transplantation. Doxorubicin is cardiotoxic, and cisplatin is nephro- and oto-toxic. A detailed echocardiography and assessment of renal function are essential prior to transplant [46]. There is some controversy as to whether the retrohepatic vena cava should always be removed en bloc with the liver during the transplant. Some authors advise doing so and reconstruct the cava with either donor iliac vein (cadaveric donor) or donor jugular vein (living related donor). Others preserve the native retrohepatic vena cava in selected patients, provided there is no evidence of direct tumor involvement [47]. In cases of incomplete tumor resection of intrahepatic recurrences after primary liver tumors, rescue liver transplantation can be done. However, the results in these patients are rather disappointing and in times of organ shortage the indication is controversial.

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Thus, liver transplantation has become an effective treatment option for hepatoblastoma. Still, several issues remain to be elucidated, such as the prognostic significance of vascular invasion, optimal timing of liver transplantation, optimal amount and timing of pre- and post-operative chemotherapy, amount of immunosuppression needed, etc. An international electronic registry, PLUTO (Pediatric Liver Unresectable Tumor Observatory), for online registration of children undergoing liver transplantation for malignant liver tumors has therefore been created by the SIOPEL study group in collaboration with COG and GPOH [40, 45]. One of the most important advances in the management of hepatoblastoma was made in the 1980s thanks to the development of effective cisplatin-based chemotherapy protocols [48, 49]. Complete surgical tumor removal is still the goal of treatment because this provides the best chance for long-term survival. However, more than 50% of tumors are considered unresectable at diagnosis [50]. About half of these cases become resectable by preoperative chemotherapy [32, 51–53]. Another reason for preoperative chemotherapy is the fact that metastases are only detectable by imaging in about 20% of patients [54, 55]. Finally, tumor recurrence occurs in most children after surgery only [24, 56]. Radiotherapy only plays a very limited role in the treatment of hepatoblastoma due to its low efficacy and a high risk of complications. It has only been used in combination with chemotherapy in selected inoperable children and in a few cases of small residual tumors after resection [57]. However, transarterial catheter chemoembolization has been used successfully in the treatment of hepatoblastoma and should be considered as an alternative for patients with unresectable liver tumors not responding to primary systemic chemotherapy [58]. Other treatment modalities, such as AFP antibody-mediated therapy, antiangiogenic treatment or molecular therapies, are still experimental and might play a role in the development of future therapies for hepatoblastoma [59–64].

Prognosis The prognosis of hepatoblastoma has improved dramatically thanks to the availability of effective chemotherapy, better surgical techniques, safer anesthesia, improved postoperative care, and liver transplantation [65]. Standard-risk hepatoblastoma is associated with a cure rate nearing 90%, but results in extended and metastatic high-risk hepatoblastoma are still poor [37]. Complete tumor resection is essential to cure hepatoblastoma, and prognosis mainly depends on disease extension at the time of diagnosis. Extrahepatic tumor extension, multifocality, and vascular invasion are poor prognostic factors and PRETEXT correlates well with overall and event-free survival [66, 67].

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In cases of complete remission, AFP should normalize. However, this process takes up to 2 months because AFP levels can be very high and the half-life of AFP is about 6 days. A minimal rise of AFP post surgery can be a sign of liver regeneration [40], while a rapid decline in AFP during chemotherapy is correlated positively with prognosis [68]. Patients with a very low (<100 ng/mL) as well as a high (>1 000 000 ng/mL) AFP at diagnosis are at an increased risk [24]. Pure fetal histology is associated with improved prognosis [66, 67]. DNA aneuploidy [69], as well as other genetic and molecular markers [70, 71], also have poor prognostic significance. Ongoing research focuses on these markers and their use as prognostic indicators and possible targets for therapy.

Hepatocellular carcinoma HCC is the most frequent primary liver tumor in older children. The incidence of HCC in children differs widely with geography, with higher incidence in regions which are endemic for hepatitis B or C viruses (HBV and HCV). In these countries, routine immunization with HBV vaccine has proven effective in reducing the incidence of childhood HCC (see below). Apart from viral origin, HCC can occur in children with metabolic liver disease (alpha-1-antitrypsin deficiency, tyrosinemia) or other liver disorders (biliary atresia, androgen therapy, aflatoxin exposure). In contrast to hepatoblastoma, HCC tends to affect children older than 4 years [72]. The fact that HCC (in contrast to hepatoblastoma) frequently occurs in diseased livers, as well as its high tendency to metastasize, not only intrahepatically, but also into the lymphatic system or to distant organs, are major limiting factors for its curative surgical treatment [72, 73]. In contrast, the fibrolamellar variant of HCC, occurring in adolescents or young adults, has a typical histologic aspect with lamellar fibrosis around the large eosinophilic tumor cells. As this variant occurs in noncirrhotic livers, it has a higher rate of respectability, but it has not been finally proven if this results in higher survival rates than for regular HCC [74–78]. Clinically, children with HCC usually have a similar presentation to those with hepatoblastoma, with abdominal pain or an abdominal mass being the most frequent symptoms. AFP levels are not always high in HCC patients. Most HCCs do not respond (well) to radiotherapy or chemotherapy. Therefore, complete surgical resection of the tumor should be the ultimate goal of therapy. Intraoperative ultrasound should be performed to detect intrahepatic metastases or multifocal disease. However, only 10–30% of the cases are amenable to curative resection at the time of diagnosis [79–

Malignant Liver Tumors in Children

81]. Neoadjuvant chemotherapy schemes are therefore attempted with the goal of increasing resectability. The SIOPEL study, a prospective study of PLADO neoadjuvant chemotherapy for pediatric HCC, reported a partial response in 49% of patients and a successful tumor excision rate of 36% [82]. Tumor regression due to neoadjuvant chemotherapy improves the prognosis [83, 84]. Another way to achieve complete resection of otherwise unresectable HCC is liver transplantation. This also has the potential to cure eventual underlying disease. Even today, the experience with liver transplantation for HCC is rather limited [85–87]. It is not clear whether the Milan criteria, used for adult patients with HCC, should also be applied to children. Beaunoyer et al reported excellent results (recurrence-free survival at 5 years 88.9%) after liver transplantation for HCC in 10 children, of whom seven were beyond the Milan criteria. Two patients with macrovascular invasion of the intrahepatic portal vein were alive and well with a follow-up of 17 and 13 years, respectively [86]. In an analysis of 59 liver transplantations for HCC and 62 for hepatoblastoma in children [87] between 1987 and 2004, the 1-, 5-, and 10-year survival rates for HCC recipients were 86%, 63%, and 58%, respectively. The primary cause of death was metastatic or recurrent disease. It should be noted that transplantation may be an important measure for preventing the occurrence of HCC in diseases with premalignant potential (e.g. tyrosinemia with nodular changes in the liver). It should also be noted that the most effective preventive measure is vaccination for HBV in endemic areas. The nationwide vaccination program in Taiwan since 1984 has reduced the annual incidence from 0.70 to 0.36 per 100 000 children [88]. In conclusion, total surgical removal should be the ultimate goal of any strategy to treat HCC in children. The precise roles of chemotherapy and transplantation in unresectable cases are still under evaluation; evidence is difficult to gather because of the small number of cases.

Angiosarcoma Most vascular liver tumors in children are of a benign nature. Cavernous hemangiomas of the liver in children are usually asymptomatic and will be found as incidental findings during childhood or later in life. Infantile hemangioendothelioma is the most common benign tumor of the liver in children. Despite its benign nature (in contrast to hepatic hemangioendothelioma in adults, from which it should be differentiated), it deserves greater attention because of its potential complications and the difficulty of differential diagnosis with angiosarcoma. Hemangioendothelioma occurs most frequently in very

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young children (87% in the first 6 months of life) and extremely rarely in patients over 3 years of age. The main symptoms are an abdominal mass or distention. Other potential symptoms are failure to thrive, jaundice, and fever. Spontaneous tumor rupture has been described. They may also lead to the Kasabach–Merritt syndrome [89]. The treatment of hemangioendothelioma depends on the presenting symptoms and the extent of the lesions. Single lesions can be resected, even in the face of congestive heart failure [90]. In cases of multiple lesions, digitalis and diuretics are used to control heart failure. Some use steroids or interferon-alpha in the hope of speeding up regression of the tumor [91, 92]. Hepatic artery ligation or embolization can also be helpful [90, 93, 94]. Exceptionally, total hepatectomy and liver transplantation may be needed [95]. Pediatric hepatic angiosarcoma, in contrast to infantile hepatic hemangioendothelioma, is a very rare but highly malignant tumor. It usually presents with a rapidly growing hepatic mass. The precise diagnosis may be difficult, even on a biopsy specimen [96, 97]; open biopsy of the tumor is therefore advisable. Chemotherapy and radiotherapy are notably inefficient in achieving tumor control. Radical hepatic resection or even liver transplantation should therefore be attempted if possible. The prognosis remains very poor, with only three survivors in 41 cases reported up to 2004 [97].

Undifferentiated (embryonal) sarcoma Undifferentiated embryonal sarcomas are highly malignant tumors of the liver [98, 99]. They usually occur in children, with half of cases occurring in children between 6 and 10 years of age. This tumor is usually large, with abdominal distention or pain at presentation. These tumors are often cystic in nature or show central necrosis. Spontaneous rupture of the tumor has been described [99]. Complete surgical removal, if necessary after neoadjuvant chemotherapy, should be aimed for. Despite the use of a variety of treatments, disease-free survival at 2 years is below 10%.

Embryonal rhabdomyosarcoma Embryonal rhabdomyosarcomas are very rare, highly malignant tumors that can occur in children of all ages, but most frequently below the age of 5 years. This tumor usually finds its origin in the common bile duct and the major hepatic ducts. The dominating clinical picture is usually one of obstructive jaundice. Ultrasound and magnetic resonance cholangiopancreatography (MRCP) are the diagnostic tools of choice to demonstrate the level of obstruction. Complete resection of the tumor should be attempted if possible. The resectability rates vary between 20% and 40% [100, 101].

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Other tumors Other liver tumors that have been reported in children are primary malignant germ cell tumors, rhabdoid tumors, malignant fibrous histiocytoma, fibrosarcoma, leiomyosarcoma, and lymphoma.

Metastatic lesions Several typical childhood tumors, like neuroblastoma or nephroblastoma, can present with liver metastasis, either present at first presentation or later in the development of the disease. Since most of these tumors are treated within cooperative trial protocols, the rules of these protocols should be followed.

Self-assessment questions 1 Which of the following are indications for transplantation in children? (more than one answer is possible) A Multifocal PRETEXT IV hepatoblastoma B Resectable hepatoblastoma C Hepatocellular carcinoma with extrahepatic metastases D Tumor invasion of major vessels 2 Which of the following statements regarding hepatoblastoma are true? (more than one answer is possible) A Represent a minority of malignant hepatic tumors B Smoking might be a risk factor C The vast majority of patients are younger than 5 years of age D Jaundice is the primary symptom 3 Which of the following statements regarding hepatocellular carcinoma are true? (more than one answer is possible) A Is the most frequent primary liver tumor in older children B The highest incidence is in regions with endemic hepatitis B or C virus C Transplantation is the only curative treatment D Respond well to radio- or chemo-therapy 4 Which of the following are poor prognostic factors for malignant liver tumors? (more than one answer is possible) A Multifocality B Vascular infiltration

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C R0 resection D Preoperative chemotherapy 5 Which one of the following statements regarding angiosarcoma is true? A Is the most common malignant liver tumor B Grows slowly C Chemotherapy is efficient D Radiotherapy is inefficient

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and angiogenesis in a hepatoblastoma xenograft model. Pediatr Res 2006;60:282–7. Davies JQ, de la Hall PM, Kaschula RO, et al. Hepatoblastoma – evolution of management and outcome and significance of histology of the resected tumor. A 31-year experience with 40 cases. J Pediatr Surg 2004;39:1321–7. von Schweinitz D, Hecker H, Schmidt-von-Arndt G, Harms D. Prognostic factors and staging systems in childhood hepatoblastoma. Int J Cancer 1997;74:593–9. Brown J PG, Shafford E, Keeling J, et al. Pretreatment prognostic factors for children with hepatoblastoma – results from the International Society of Paediatric Oncology (SIOP) study SIOPEL 1. Eur J Cancer 2000;36:1418–25. Van Tornout JM, Buckley JD, Quinn JJ, et al. Timing and magnitude of decline in alpha-fetoprotein levels in treated children with unresectable or metastatic hepatoblastoma are predictors of outcome: a report from the Children’s Cancer Group. J Clin Oncol 1997;15:1190–7. Zerbini MC, Sredni ST, Grier H, et al. Primary malignant epithelial tumors of the liver in children: a study of DNA content and oncogene expression. Pediatr Dev Pathol 1998;1: 270–80. Weber RG, Pietsch T, von Schweinitz D, Lichter P. Characterization of genomic alterations in hepatoblastomas. A role for gains on chromosomes 8q and 20 as predictors of poor outcome. Am J Pathol 2000;157:571–8. Mullarkey M, Breen CJ, McDermott M, O’Meara A, Stallings RL. Genetic abnormalities in a pre and postchemotherapy hepatoblastoma. Cytogenet Cell Genet 2001;95: 9–11. Exelby PR, Filler RM, Grossfeld JL. Liver tumors in children in the particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Survey – 1974. J Pediatr Surg 1975;10:329–37. Ni YH, Chang MH, Hsy HY, et al. Hepatocellular carcinoma in childhood. Clinical manifestations and prognosis. Cancer 1991; 68:1737–41. Haas JE, Muczynski KA, Krailo M, et al. Histopathology and prognosis in childhood hepatoblastoma and hepatocarcinoma. Cancer 1989;64:1082–95. Craig JR, Peters RL, Edmondson HA, et al. Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinicopathologic features. Cancer 1980;46: 372–9. Teitelbaum DH, Tuttle S, Carey LC, et al. Fibrolamellar carcinoma of the liver. Review of three cases and the presentation of a characteristic set of tumor markers defining this tumor. Ann Surg 1985;202:36–41. Soreide O, Czerniak A, Bradpiece H, et al. Characteristics of fibrolamellar hepatocellular carcinoma: a study of nine cases and a review of the literature. Am J Surg 1986;151:518–23. El-Sarg HB, Davilla JA. Is fibrolamellar carcinoma different from hepatocellular carcinoma? A US population-based study. Hepatology 2004;39:798–803. Chen WJ, LeeJC, Hung WT. Primary malignant tumor of liver in infants and children in Taiwan. J Pediatr Surg 1988;3:457– 61. Moore SW, Hesseling PB, Wessels G, et al. Hepatocellular carcinoma in children. Pediatr Surg Int 1997;12:266–70.

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81 Seung-Beom Y, Hyung-Young K, Hong EO, et al. Clinical characteristics and prognosis of pediatric hepatocellular carcinoma. World J Surg 2006;30:43–50. 82 Czauderna P, Mackinlay G, Perilongo G, et al. Hepatocellular carcinoma in children: results of the first prospective trial of the International Society of Pediatric Oncology group. J Clin Oncol 2002;20:2798–804. 83 Chen JC, Chen CC, Chen WJ, et al. Hepatocellular carcinoma in children: clinical review and comparison with adult cases. J Pediatr Surg 1998;33:1350–4. 84 Katzenstein HM, Krallo MD, Malogolowkin MH, et al. Hepatocellular carcinoma in children and adolescents: results from the Pediatric Oncology Group Intergroup study. J Clin Oncol 2002;20:2789–97. 85 Otte JB, Aronson D, Vraux H, et al. Preoperative chemotherapy, major liver resection and transplantation for primary liver malignancies in children. Transplant Proc 1996;28:2393– 4. 86 Beaunoyer M, Vanatta JM, Ogihara M, et al. Outcomes of transplantation in children with primary hepatic malignancy. Pediatr Transplant 2007;11:655–60. 87 Austin MT, Leys CM, Feurer ID, et al. Liver transplantation in childhood malignancy: a review of the United Network of Organ Sharing (UNOS) database. J Pediatr Surg 2006;41:182– 6. 88 Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997;336:1855–9. 89 von Schweinitz D, Glueer S, Mildenberger H. Liver tumors in neonates and very young infants: Diagnostic pitfalls and therapeutic problems. Eur J Pediatr Surg 1995;5:72–6. 90 Becker JM, Heitler MS. Hepatic hemangioendotheliomas in infancy. Surg Gynecol Obstet 1989;168:189–200. 91 Choi HY, Lee SJ. Infantile hemangioendothelioma treated with high dose methylprednisolone pulse therapy. J Korean Med Sci 2001;16:127–9. 92 Deb G, Donfrancesco A, Ilari I, et al. Hemangioendothelioma: successfull therapy with interferon alpha: a study in association with the Italian Pediatric Hematology/Oncology Society (AIEOP). Med Pediatr Oncol 2002;38:118–19. 93 Warman S, Bertram H, Kardoff R, Sasse M. Interventional treatment of infantile hepatic hemangioendothelioma. J Pediatr Surg 2003;38:1177–81. 94 Daller JA, Bueno J, Gutierrez J, et al. Hepatic hemangioendothelioma: clinical experience and management strategy. J Pediatr Surg 1999;34:98–106. 95 Kasahara M, Kiuchi T, Haga H, et al. Monosegmental living donor liver transplantation for infantile hepatic hemangioendothelioma. J Pediatr Surg 2003;38:1108–11. 96 Awan S, Davenport M, Portmann B, et al. Angiosarcoma of the liver in children. J Pediatr Surg 1996;31:1729–32. 97 Dimashkieh HH, Mo JQ, Wyatt-Ashmead J, et al. Pediatric hepatic angiosarcoma: case report and review of the literature. Pediatr Dev Pathol 2004;7:527–32. 98 Bisogno G, Pilz T, Perilongo G, et al. Undifferentiated sarcoma of the liver in childhood: a curable disiease. Cancer 2002;94: 252–7. 99 Lack EE, Schloo BL, Azumi N, et al. Undifferentiated (embryonal) angiosarcoma of the liver. Clinical and pathological study

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of 16 cases with emphasis on immunohistological features. Am J Surg Pathol 1991;15:1–16. 100 Davis GL, Kissane JM, Ishak KG. Embryonal rhabdomyosarcoma (sarcoma botryoides) of the biliary tree. Cancer 1969;24: 333–42. 101 Rhabdomyosarcoma of the biliary tree in childhood: a report from the Intergroup Rhabdomyosarcoma Study. Cancer 1985; 56:575–81.

486

Self-assessment answers 1 2 3 4 5

A, D B, C A, B A, B D

40

Liver Tumors in Asia Norihiro Kokudo1, Sumihito Tamura1, and Masatoshi Makuuchi2 1 2

Department of Surgery, Hepato-Biliary-Pancreatic Surgery Division, University of Tokyo, Tokyo, Japan Japan Red Cross Medical Center, Tokyo, Japan

Hepatocellular carcinoma (HCC) continues to be endemic in East and South-East Asia, where the three major etiologic factors – hepatitis B, hepatitis C, and aflatoxin exposure – are still prevalent. Living donor liver transplantation (LDLT) has evolved and has become an accepted component of a multimodal approach in some regions in the area. Cholangiocarcinoma, another major histologic type of primary liver cancer, is also common in some parts of Asia. Liver fluke infection is endemic in such areas. To overcome these important public health problems, a number of investigations on the prophylaxis, early detection, and treatment of liver tumors have been conducted in the region. In this chapter, we review some of the major contributions made by Asian researchers in this field.

Historical background One year before the 1952 report of Lortat-Jacob and Robert [1], who introduced the modern era of anatomic hepatic lobectomy, Honjo and Araki in Kyoto successfully performed total resection of the right lobe of the liver [2]. They performed a right trisegmentectomy, as described by Healey and Schroy [3], in a 22-year-old man with metastatic liver tumor from rectal cancer. The patient “enjoyed a useful life for more than a year before he died of recurrent carcinoma.” The first liver resection in Japan was carried out by Ohno (Osaka) in 1937 [4]. He performed a wedge resection of a quadrate lobe for a hen egg-sized HCC in a 58-year-old female, who lived for at least 7 months after the operation. Before the report of Honjo and Araki, there had been several anecdotal reports of successful resection of liver tumors in Japanese medical journals. In 1958, just after Couinaud opened the door to segmentectomy, Lin et al [5, 6] in Taiwan popularized the finger

fracture technique for hepatic parenchymal dissection. In this method, the thumb and index finger are inserted into the liver tissue, and then the surgeon “fractures and crushes the tissue between the fingers, and when resistant vessels or ducts are encountered they are tied and divided.” They modified their method and introduced “a crushing method,” which was more efficient for hepatic transection. In Hong Kong, liver resection was started in the early 1950s, and Ong and Lee published a series of 125 liver resections, including 70 cases of HCC [7]. In 1979, Makuuchi et al presented a new ultrasonographic probe and established the use of intraoperative ultrasonography to define hepatic lesions and to plan resection [8]. Making the most of intraoperative ultrasound, they established a technique for systematic subsegmentectomy [9, 10] and reported a superior outcome in patients with HCC [11]. To increase the safety of major hepatectomy and to extend the indications for hepatectomy, hemihepatic portal vein embolization (PVE) was developed by Makuuchi et al in 1982 [12]. PVE induces homolateral atrophy of the portion of the liver scheduled for resection and contralateral compensatory hypertrophy of the remnant liver, thus decreasing the risk of postoperative liver failure. Soon after the first cases were attempted in Brazil and Australia, pediatric LDLT was initiated in 1989 in Japan [13, 14]. In 1993, Makuuchi et al successfully performed the first LDLT for an adult recipient [15]. After a decade of application, experience, and refinement of surgical techniques, LDLT has become a standard treatment for Japanese patients with end-stage liver failure. Trials of LDLT for patients with HCC have been carried out in Japanese centers. Major contributions to liver surgery from Asia are listed in Table 40.1 (see also Chapter 1).

Hepatocellular carcinoma Epidemiology

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

HCC is the fifth most common cancer in the world [16] and is most endemic in East and South-East Asia, and subSaharan Africa (Figure 40.1) [17]. In southern Guangxi,

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< 4.0 < 5.8 < 8.7 < 17.7 < 93.4

Figure 40.1 Regional variation in the mortality rates of hepatocellular carcinoma categorized according to age-adjusted mortality rates. The rates are reported per 100 000 persons. (Reproduced from El-Serag & Rudolph [16], with permission from Elsevier.)

Table 40.1 Major contributions to liver surgery from Asia. Year

Authors

Contributions

1937 1955 1958 1979 1982 1987 1989

Ohno [4] Honjo & Araki [2] Lin et al [5, 6] Makuuchi et al [8] Makuuchi et al [12] Makuuchi et al [9,10] Nagasue et al [13], Makuuchi et al [14] Makuuchi et al [15]

First successful liver resection in Japan First anatomic right lobectomy Finger fracture technique Intraoperative ultrasound Preoperative portal vein embolization Systematic subsegmentectomy Living donor liver transplantation

1994

Living donor liver transplantation in adult

China, a very high-risk area, the age-standardized (world population) incidence is approximately 120 per 100 000 person-years in men and 30 per /100 000 person-years in women. HCC is the second most common cause of death from cancer in China, where the mortality rate was 18 per 100 000 person-years from 1990 to 1992. Generally, males tend to be more commonly affected, with a male-to-female ratio that varies between 4:1 and 8:1. Chronic hepatitis B virus (HBV) infection and the presence of androgen receptors in HCC cells have been suggested as reasons for this male preponderance [18]. The three major etiologic factors associated with HCC are infection by HBV or HCV, as well as exposure to aflatoxin.

488

The relative contributions of these factors to the prevalence of HCC varies between high- versus low-incidence areas for the disease. It is estimated that 80% of HCC worldwide is etiologically associated with HBV. South-East Asia is an endemic region for type B hepatitis, and HCC is thought to be closely related to this factor. In high-risk areas of China, where the population prevalence of HbsAg positivity in men can be as high as 20−25%, the incidence of HCC among HBV carriers is about 1% per year. Furthermore, Taiwanese males who acquire carrier status early in life are estimated to be at a lifetime relative risk of 100 for developing HCC [19]. Virtually all carriers acquire the infection from their carrier mothers during infancy or by horizontal passage from infectious siblings. Many high-rate Asian countries now vaccinate all newborns against HBV, and HCC incidence has begun to decline among Chinese populations in Hong Kong, Shanghai, and Singapore [16]. Chronic infection by HCV is believed to play a relatively minor role in the development of HCC in Asia, except in Japan, where approximately 70% of HCC cases are HCV related [20]. A moderately high prevalence of anti-HCV has been observed in Taiwan (9−23%) and Hong Kong (7%) [17]. There is strong epidemiologic evidence that the increase in the incidence of HCC in Japan until the mid 1990s was due to an increase in HCV-induced chronic liver disease [21]. HCV hepatitis is believed to have existed in Japan since the early 19th century. It became endemic after World War II, probably via procedures that involve penetration of the skin, such as small pox vaccination, acupuncture, tattooing,

CHAPTER 40

use of unsterilized needles, unnecessary operations, and blood transfusions. It takes more than 20 years, perhaps about 30 years, for HCC to develop in patients with chronic HCV infection from the time of acute post-transfusion hepatitis [21]. HCC develops at a rate of more than 6% per year in HCV-positive cirrhotic patients [22]. HCC incidence rates among Japanese males declined for the first time between 1993 and 1997, probably due to popularized acknowledgement of HCV transmission [16]. The relative roles of HBV and HCV infection in hepatocellular carcinogenesis vary considerably among populations. A synergistic effect on the risk for HCC has recently been reported in Southern African blacks in whom both HBV and HCV markers are present [23]. Dietary aflatoxin exposure, which is an important codeterminant of the risk of HCC in Africa, is also a risk factor in some parts of Asia. Aflatoxin is a food contaminant arising from the improper storage of grains susceptible to mold formation during spoilage. For example, a traditional Chinese vegetarian diet has been associated with an increased risk of HCC. A study from Taiwan has demonstrated a multivariate-adjusted odds ratio of developing HCC of 5.5 for patients with detectable serum levels of aflatoxin B1 [24]. Exposure to aflatoxin is known to increase the risk of HCC in men with chronic HBV hepatitis [25]. The incidence of HCC in East Asia, including Singapore and Shanghai, China, has declined over the past several decades. This decline is considered to be related to the decreasing exposure to dietary aflatoxin. Recent economic development in East Asia has greatly diminished the population exposure to mycotoxins. HCC is a highly prevalent malignancy in Taiwan, and is now the highest ranking cause of death from malignancy among men. About 5000 people die from HCC each year in Taiwan. Although this high prevalence of HCC in Taiwan is mainly thought to be related to HBV, more and more HCCs have been found to be related to HCV since the development of an assay to detect HCV infection. Seventy to 80% of patients with HCC have cirrhosis or chronic hepatitis. Hong Kong is also an endemic area for HBV infection and has a high incidence of HCC. Of these cases, 80.3% are HBV related and 7.3% are HCV related [26]. Korea has the world’s highest rate of liver cancer mortality. Both HBV and HCV are known to be the major risk factors for HCC. HCC is the most common cancer in Thailand. Sixty-five to 87% of the cases are HBV related and 8−17% are HCV related [27]. The prevalence of HCC in India is lower than that in most parts of the world. This contrasts with the widespread contamination of foods with aflatoxin and the moderately high prevalence of HBV- and HCV-related chronic liver disease in India. There has been no conclusive explanation for this discrepancy. The annual incidence of HCC in India is around 3−5 per 100 000 population [28]. In Saudi Arabia, where HBV is endemic, the

Liver Tumors in Asia

overall prevalence of antibody to HCV is low. However, the incidence of HCV is around 30% in patients with chronic liver disease, and this is considered to be related to the development of HCC. The close relationship between HCC and Budd−Chiari syndrome (obstruction of the hepatic portion of the inferior vena cava) was first pointed out by Japanese researchers. Budd−Chiari syndrome is an important etiologic factor for HCC in Japan and Nepal [29] (see also Chapter 5).

Prophylaxis and early detection The transmission of HBV from mother to infant at or soon after birth is associated with a high incidence of HCC in early life. Since the 1980s, Asian governments have conducted extensive vaccination programs for HBV. HBV vaccination was launched in Taiwan in 1984 for neonates of mothers carrying hepatitis B e antigen. This substantially reduced the prevalence of HBsAg from 10% to 1% within a 10-year period, resulting in a decreased incidence of HCC in children [18, 30]. In Singapore, short- and long-term measures for the prevention of HCC have been tried. These include the introduction of prophylactic HBV immunization, discouragement of alcohol and tobacco consumption, screening for aflatoxin in imported human food materials, and testing for HCV. Prophylactic, intermittent long-term administration of lymphoblastoid interferon-alpha has also been tried in high-risk patients with favorable results. In general, the prognosis for patients with HCC is still dismal because of the low chance of curative treatment. To increase the chance of intervention and, more importantly, to improve survival, the early detection of subclinical HCC by alpha-fetoprotein (AFP) and/or ultrasonography screening has been implemented in many countries. AFP monitoring alone is inadequate for the early diagnosis of HCC among patients with chronic HBV infection, since it can be difficult to differentiate between benign and malignant causes of AFP elevation. HCC found at the time of a sharp rise in AFP already measures 4−5 cm [31]. Reports on HCC screening in Asian populations have shown encouraging results; HCC can be detected at a surgically resectable stage in most HbsAb-positive carriers and HCV-positive patients [22, 32]. Japanese gastroenterologists have pioneered clinical programs for the early detection of HCC [33]. In countries like Japan, where medicine is highly socialized and every person is covered by health insurance, people frequently consult physicians who can perform extensive investigations with little concern about cost, and most diseases are found before an advanced stage. With various liver function tests and imaging modalities available, patients with cirrhosis are diagnosed early and closely followed. Takayama et al defined early HCC as a well-differentiated cancer containing Glisson’s triad and showed that it is a distinct clinical entity

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with a high chance of surgical cure [34]. The usefulness of ultrasonography for the early detection of HCC has also been reported from other Asian regions [35]. Figure 40.2 shows the currently recommended surveillance algorithm in Japan. It consists of: measurement of serum AFP, L3 fraction of AFP (Lens culinaris agglutinin A-reactive AFP) [36], and PIVKA-II (protein induced by vitamin K absence, or des-gamma-carboxyprothrombin) [37] levels and ultrasonography. When there is a continuous rise in AFP by 200 ng/mL or more, a rise in PIVKA-II by 40 mAU/mL or more, or a rise in the AFP-L3 fraction by 15% or more, dynamic computed tomography (CT) or magnetic resonance imaging (MRI) should be performed even if tumors cannot be detected by ultrasonography [38]. If dynamic CT or MRI does not show a typical HCC image and the patient tests negative for other malignant liver tumors, the patient should be followed up using a tumor diameter of 2 cm as a temporary index. The interval of examination is 3 months as an index. If there is a tendency for the diameter to grow significantly, the patient is eligible for treatment [38]. Yuen et al from Hong Kong also recommended a screening program for HCC by AFP and/or ultrasonography [39].

Diagnosis Recent progress in imaging techniques has facilitated the recognition of early HCC as a principal tumor in at-risk subjects who undergo regular medical check-ups for chronic viral hepatitis or cirrhosis [33]. Imaging modalities including multidetector row computed tomography (MDCT), thinsection MRI, color Doppler sonography, CT during hepatic arteriography (CTA) or arterial portography (CTAP), and CT after hepatic intra-arterial injection of iodized oil (lipiodolCT) are promising in vivo tools for the diagnosis of HCC at an early stage [28]. According to Japanese clinical practice guidelines for HCC [38], dynamic CT or dynamic MRI is recommended for the first-line diagnosis of HCC. The use of contrast medium is indispensable for diagnostic imaging (CT/MRI) of HCCs. The examination of contrast enhancement in the arterial phase and injection of contrast medium in the delayed phase of CT are considered useful. For patients with definite HCC scheduled for liver resection, lipiodol-CT is routinely performed in some Japanese centers to check for intrahepatic metastasis. Intraoperative ultrasonography (IOUS) is also highly sensitive and is routinely performed in Japan as final diagnostic imaging before resection. Despite the recent progress in the imaging modalities for HCC, IOUS is still the most sensitive. It is not uncommon to detect new hepatic nodules by IOUS during hepatic resection for HCC [40, 41]. Patients with new tumors are at high risk for recurrence so that regular check-up is important to prolong survival [41].

490

Treatment Resection has generally been considered as a first-line therapy for HCC, with transplantation being reserved for patients with tumors that are unresectable because of the location or severity of the underlying liver disease [42]. The 5-year disease-free survival rates after liver resection in Asian series have ranged from 12% to 28%. The Liver Cancer Study Group of Japan has been conducting a nationwide survey of HCC patients every 2 years since 1965 and has accumulated more than 40 000 cases [32, 43]. In their most recent analysis of 27 062 HCC resections that were performed between 1992 and 2003 [20], the overall 5-year survival rate was 53.4%. The reported significant prognostic factors were the AFP level, tumor size, number of tumors, accompanying cirrhosis, age, surgical curability, and portal involvement. The most recent operative death rate (2002–2003) has been reported to be as low as 0.8% [20]. Since cancer cells from HCC tend to spread through the portal venous system, anatomic resection is theoretically effective for the eradication of intrahepatic metastases of HCC. There have been several reports from Japanese [11, 12] and French [44] centers providing evidence that supports the superiority of anatomic resection (Figure 40.3). The natural history of untreated HCC with portal vein tumor thrombosis is extremely poor, with a median survival time of 2.7 months [45]. Chemotherapy or transarterial chemoembolization (TACE) have been tried, but with unsatisfactory results. The surgical resection of such advanced HCCs with portal vein tumor thrombosis has also been tried by Japanese surgeons. Minagawa and Makuuchi established selection criteria for performing hepatectomies in such patients and reported a 5-year survival rate of 42% after surgery [46]. Since the pioneering work by Lin, there have been several reports on surgical treatment for HCC in Taiwan. In the mid 1980s, Lee et al reported a series of 109 resected cases of HCC with an operative mortality rate of 3%. In contrast to the poor outcome of symptomatic HCC (5-year survival, 8%), asymptomatic HCC had a favorable outcome, with a 5-year survival rate of 44%. Although short-term outcomes have improved greatly with better surgical techniques, the high rate of postoperative recurrence is now an important issue. According to Chen et al, the postoperative intrahepatic remnant rate is 80% at 5 years after resection [47]. In Hong Kong, Fan et al reported a large series of 330 patients who underwent liver resection for HCC [48]. By reducing intraoperative blood loss, they achieved an inhospital mortality rate of zero in their 110 most recent consecutive patients. Since its introduction, radiation frequency ablation (RFA) has rapidly gained popularity, and is now considered as a potentially curative treatment for small HCCs. RFA achieves

CHAPTER 40

1

Very high-risk group:

Liver Tumors in Asia

Ultrasonography at intervals of 3 or 4 months Measurement of AFP/PIVKA-II/AFP-L3 at intervals of 3 or 4 months *1, 2, 3 CT or MRI at intervals of 6–12 months (optional)

High-risk group:

Ultrasonography at intervals of 6 months Measurement of AFP/PIVKA-II/AFP-L3 at intervals of 6 months *1, 2, 3 *5

Detection of a nodular lesion by ultrasonography

Continuous rise in AFP, rise in AFP by 200 ng/mL or more, rise in PIVKA-II by 40 mAU/mL or more, or rise in the AFP-L3 fraction by 15% or more

Dynamic CT or dynamic MRI*4

2 Dynamic CT or dynamic MRI*4

Image of typical HCC*6

No lesion

Image of atypical HCC

3 Is tumor diameter 2 cm or larger?

No

No lesion

Not visualized

No growth in size and Ultrasonography at intervals of 3 disappearance months of tumor

Yes Optional examinations Angiography CT-angiography SPIO-MRI Contrast ultrasonography Tumor biopsy, etc

Image of typical HCC*6

Image of atypical HCC

1

Second ultrasonography

Growth in size/ rise in tumor marker level

Disappearance of tumor

CT/MRI at intervals of 3 months

1

Can be visualized 3

2

Growth in size/ appearance of hypervascular lesion

Definite diagnosis of HCC

Treatment

Figure 40.2 Algorithm for the surveillance of hepatocellular carcinoma (HCC) [38], cited with permission: *1, Current health insurance in Japan covers the measurement of only one tumor marker level per month; *2, alpha-fetoprotein (AFP)-lectin fraction (L3) can be measured only when the patient is diagnosed as having HCC; *3, When the AFP is 10 ng/mL or less, the AFP-L fraction cannot be measured; *4, if there is renal dysfunction or the patient is suspected of being allergic to iodinated contrast media, dynamic magnetic resonance imaging (MRI) is recommended; *5, computed tomography (CT)/MRI is performed at regular intervals; *6, a tumor that is visualized as a high signal intensity area in the arterial phase and as a relatively low signal intensity area in the venous phase; *7, if a patient is suspected of having other malignant tumors, such as cholangiocellular carcinoma or metastatic liver cancer, he/she proceeds to undergo a thorough examination for that disease. PIVKA, protein induced by vitamin K absence or antagonist; SPIO, super paramagnetic iron oxide. (Reproduced from Makuuchi et al [38]; with permission from John Wiley & Sons.)

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1 Anatomic resection

0.8

(n = 156) 0.6 0.4 Nonanatomic resection 0.2

(n = 54) P = 0.01

0 0

1

2

6 3 4 5 Overall survival (years)

7

8

Figure 40.3 Impact of type of surgical resection on long-term outcome in patients with hepatocellular carcinoma. Comparison of anatomic resection (subsegmentectomy, segmentectomy or lobectomy; n = 82) with nonanatomical resection (limited resection; n = 56); p = 0.012 (log-rank test). (Reproduced from Hasegawa et al [11], with permission from Wolters Kluwer Health.)

higher total necrosis rates with fewer treatment sessions than percutaneous ethanol injection (PEI), which had been a mainstay of percutaneous local therapy until 2000. The superiority of RFA over PEI in terms of patient survival has been demonstrated by a recent randomized controlled trial conducted in Asia [49]. The therapeutic effect of percutaneous local ablative therapy and surgical resection for small HCC has been compared in a randomized controlled study conducted in China. Chen et al [50] concluded that the therapeutic effects of the two treatment options are similar; however, this study suffered from an insufficient number of enrolled patients and a high drop-out rate because a considerable number of patients who had been assigned to the ablation treatment arm wished to undergo surgery. TACE involves the administration of a chemotherapeutic agent (usually doxorubicin, mitomycin C, or cisplatin) into the hepatic artery, followed by hepatic artery embolization (usually with a gelatin sponge). Since liver tumors preferentially receive their blood supply from the hepatic artery, the occlusion of this artery causes selective ischemia of the tumor and enhances the cytotoxicity of the chemotherapeutic agent. A Japanese radiologist was the first physician to use TACE for the treatment of patients with unresectable HCC [51]. TACE has also been used as an adjunctive therapy with liver resection or liver transplantation in an attempt to shrink the tumor or to control its growth before transplantation (see Chapter 13). Takayasu et al accumulated 8150 TACE-treated patients with unresectable HCC from the database of the Liver Cancer Study Group of Japan [52]. They concluded that TACE is a safe therapeutic modality with 0.5% treatment-related mortality and a 5-year overall

492

survival rate as high as 26%. The degree of liver damage, TNM stage, and AFP value were independent risk factors for patient survival. Chemotherapy is usually given to patients with metastatic disease or for persistent recurrent disease. No single drug or combination of drugs given systemically leads to a reproducible response rate of more than 25% or adds any survival benefit. Based on favorable preliminary data for sorafenib in Western countries, a prospective clinical trial for this promising new agent may be conducted in Asian countries. Total hepatectomy with transplantation was expected to be the solution to HCC in cirrhotic livers when hepatic resection was not feasible. Mazzafero developed these factors further into the rules known today as the Milan criteria [53]. Mazzaferro reported that the outcomes of deceased donor liver transplantation (DDLT) for patients with single (≤5 cm) or fewer than three (≤3 cm) HCC nodules are no different from those obtained for nonmalignant indications. The cumulative excellent results based on these criteria have led to their acceptance in many regions worldwide. Currently, liver transplantation remains the most attractive option for HCC complicated by liver cirrhosis (see Chapter 23). In the era of critical organ shortage, however, the bottleneck to applying liver transplantation for HCC is the limited supply of liver grafts in a timely manner, especially in the Far East. Due to the limited numbers of organs available from deceased donors in many Asian countries, LDLT has become accepted as the mainstream treatment for endstage liver disease and HCC [54−58]. In the management of HCC with LDLT, much has been applied from the lessons learned from the published experience of DDLT for HCC, including that gained from the application of the Milan criteria. However, although the current application of the Milan criteria to LDLT for HCC represents a reasonable starting point to gain public support, a more flexible approach may be considered in LDLT for two reasons. First, unlike in DDLT, the graft supply is not dependent on a nationwide organ-sharing network. Graft availability strongly depends on the donor’s altruistic decision for the benefit of a specific recipient based on their unique relationship, allowing an act of further oncologic risk taking. Second, liver transplantation for HCC can be performed in a scheduled and timelier manner, compared to DDLT, within a short waiting period from the time of the initial diagnosis. The combination of these two factors has led to a reconsideration of the rationale for imposing the current strict Milan criteria for LDLT (Table 40.2). The registry data on LDLT for HCC surveyed by the Japanese Study Group for Liver Transplantation, summarized by Todo et al [54], show that, by the end of 2003, 316 adult patients had undergone LDLT in Japan. The median followup period was 16 months. Interestingly, a strict adoption of the Milan criteria was recognized in only one-third of the

CHAPTER 40

Liver Tumors in Asia

Table 40.2 Outcomes in the Far East of living donor liver transplantation for hepatocellular carcinoma exceeding the Milan criteria. Center

Japan* [54] Seoul, Korea [57] Kyoto, Japan [56] Tokyo, Japan [60] Kyushu, Japan [58]

Number of patients

316 237 125 78 60

Number exceeding Milan criteria (%)

172 (54) 64 (27) 55 (44) 10 (13) 40 (67)

Overall survival (%)

Recurrence-free survival (%)

1 year

3 years

5 years

1 year

3 years

5 years

75 NA NA 90 NA

60 63 NA 90 NA

NA NA 64 NA NA

65 NA NA 70 83

53 NA NA 70 74

NA NA 66 NA NA

*Multicenter nationwide survey, involving 49 centers

Cumulative recurrence rate (%)

50 40 30 20 No Yes

10

p < 0.0001 0 1 2 Years post transplant

our LDLT program in 1996, a rule designated as the “5−5 rule” has been applied to patient selection. In other words, patients with up to five HCC nodules each less than 5 cm in diameter are regarded as candidates for LDLT. When stratified according to the 5−5 rule, the recurrence-free survival rate at 3 years for patients fulfilling the criteria and those exceeding the criteria was 94% and 50%, respectively [60]. Other centers in the Far East have adopted various criteria modestly expanding the Milan criteria, with cumulative data demonstrating that a mild expansion may still provide satisfactory results in LDLT for HCC (Table 40.3) (see also Chapters 16, 26).

3

Figure 40.4 Cumulative recurrence rate of hepatocellular carcinoma following living donor liver transplantation among patients selected using the Milan criteria. (Reproduced from Todo et al [54], with permission from Wolters Kluwer Health.)

LDLT centers in Japan. The overall patient survival rates at 1 and 3 years were 78% and 69%, respectively. The recurrence-free survival rates at 1 and 3 years were 73% and 65%, respectively. When stratified according to the Milan criteria, patient survival at 3 years was 79% in patients who met the criteria, and 60% in those who presented with further advanced tumors. The cumulative HCC recurrence rate in patients meeting or exceeding the Milan criteria was 3% and 20%, respectively, at 1 year, and 3% and 37%, respectively, at 3 years (Figure 40.4). From an oncologic point of view, however, these outcomes may be considered excellent. Some Asian regions [55, 57] have adopted the rules known as the University of California San Francisco (UCSF) criteria: solitary tumor less than 6.5 cm or fewer than three nodules with the largest lesion smaller than 4.5 cm and the total tumor diameter less than 8 cm, originally based on pathologic findings [59]. In Tokyo, since the beginning of

Evidence-based practice guidelines for hepatocellular carcinoma in Japan The “clinical practice guidelines for HCC,” the first evidencebased guidelines for the treatment of HCC in Japan, were compiled by an expert panel supported by the Japanese Ministry of Health, Labor, and Welfare in 2001. A systematic review of the English medical literature on HCC was performed, and a total of 7192 publications were extracted, mainly from Medline (1966–2002). There are 58 pairs of research questions and recommendations covering six research fields: prevention, diagnosis and surveillance, surgery, chemotherapy, TACE, and percutaneous local ablation therapy. For the users’ convenience, practical algorithms for the surveillance (see Figure 40.2) and treatment of HCC (Figure 40.5) were created based on evidence from the selected articles for the guidelines, and modified according to the current status of medical practice in Japan, where liver resection for HCC is regarded as safe with less than 1% mortality, and cadaveric donors for liver transplantation are extremely difficult to obtain. These guidelines have been acknowledged by most Japanese hepatologists and liver surgeons, and algorithms for the treatment of HCC (Figure 40.5) are now widely utilized in daily practice [61] (see also Chapter 26).

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Table 40.3 Various criteria applied in living donor liver transplantation for hepatocellular carcinoma in the Far East. Center

Seoul, Korea [57] Hong Kong, China [55] Kyoto, Japan [56] Kyushu, Japan [58] Tokyo, Japan [60]

Criteria other than Milan criteria

Number of tumors

UCSF No major vessel invasion UCSF DCP ≤400, tumor number ≤10, and size ≤5 cm Any tumor number and size ≤5 cm DCP ≤300 alone Tumor number ≤5 and size ≤5 cm

Overall survival (%)

Recurrence-free survival (%)

1 year

3 years

5 years

1 year

3 years

5 years

167 197 43 78

NA NA 97 NA

91 87 80 NA

NA NA 58 87

NA NA 93 NA

NA NA 71 NA

NA NA 71 95

53 46 72

NA NA 90

NA NA 88

NA NA NA

>77* 100 97

>77* 94 94

NA NA NA

*In the cited reference, the outcome data are stratified according to the size of the tumor into four groups; ≤2 cm, 2–3 cm, 3–5 cm and >5 cm. 1- and 3-year recurrence-free survival rates of groups ≤2 cm, 2–3 cm, and 3–5 cm were 95%, 100%, and 77%, and 95%, 83%, and 77%, respectively. UCSF, the University of California San Francisco criteria; DCP, des-gamma-carboxy prothrombin value in mAU/mL.

HCC*

Degree of liver damage (Child class)

Number of tumors

A, B

Treatment

2 or 3

Single

Tumor diameter

≤ 3 cm

Resection ablation†

C

Resection ablation

4 or more

> 3 cm

Resection embolization

1–3

4 or more

≤ 3 cm**

Embolization hepatic arterial infusion chemotherapy

Transplantation

Palliative care

Figure 40.5 Treatment algorithm for hepatocellular carcinoma [38]. *Presence of vascular invasion or extrahepatic metastasis to be indicated separately; Selected when the severity of liver damage is class B and the tumor diameter is ≤2 cm; **Tumor diameter ≤5 cm, when there is only one tumor. (From Makuuchi M et al. [38]; with permission from John Wiley & Sons.)

Cholangiocellular carcinoma Epidemiology According to the Classification of Primary Liver Cancer of the Liver Cancer Study Group of Japan [62], the term

494

“intrahepatic cholangiocarcinoma (ICC)” refers to malignant epithelial tumors that originate in the intrahepatic bile ducts. ICC is classified into three types based on the macroscopic appearance of the cut surface of the tumor: mass forming, periductal infiltrating, and intraductal growth.

CHAPTER 40

Liver Tumors in Asia

Table 40.4 Distribution of microscopically verified cases with liver tumor by histologic type.* Country (city)

Total number of cases

HCC (%)

ICC (%)

Hepatoblastoma (%)

Sarcoma (%)

Others (%)

Unspecified (%)

Hong Kong India (Bombay) Japan (Osaka) Korea (Kangwha) Kuwait Philippines (Manila) Singapore (Chinese) Thailand (Chiang Mai) Thailand (Khon Kaen) Vietnam (Hanoi)

3 200 732 16 350 114 57 1 775 1 281 962 3 046 633

64.1 74.8 75.1 38.5 85.7 74.7 78.8 45.9 6.8 68.8

26.3 13.0 5.4 7.7 9.5 11.2 10.9 43.7 87.3 10.9

0.5 6.6 0.4 0.0 0.0 2.2 1.6 0.3 0.8 0.0

0.3 0.3 0.2 0.0 0.0 0.5 0.6 0.6 0.0 0.7

0.6 1.6 0.6 3.8 4.8 0.5 0.9 0.0 0.4 1.4

8.8 5.3 18.9 53.8 4.8 11.4 8.1 9.5 5.1 19.6

HCC: hepatocellular carcinoma, ICC, intrahepatic cholangiocarcinoma.

ICC is another major histologic type of primary cancer of the liver, which occurs rather less frequently than HCC. In published studies, the frequency of ICC is almost always reported based on a clinical series, as a percentage of all liver cancer (on biopsy or at autopsy). The reported frequencies range from 5% to 30% of all liver cancers (Table 40.4) [17, 63]. According to a recent report on a nationwide survey in Japan [20], ICC is the second most frequent primary liver cancer in Japan, but it constitutes only 4.1% of all liver tumors (Table 40.5). Most international comparisons of the incidence of cancer usually do not distinguish between HCC and ICC. Therefore, it has been suggested that most available descriptive data only describe primary cancer as a whole. Liver flukes, including Opisthorchis viverrini and Clonorchis sinensis, are established etiologic agents of cholangiocarcinoma [63]. In an area in north-east Thailand where O. viverrini infection is endemic (70% of the population), 90% of primary liver cancers are cholangiocarcinoma. The mechanisms of carcinogenesis in O. viverrini infection have been a subject of considerable research; the presence of parasites induces DNA damage and mutations as a consequence of the formation of carcinogens/free radicals and the cellular proliferation of intrahepatic bile duct epithelium. Cholangiocarcinoma accounts for more than 20% of liver cancer around Pusan, Korea. C. sinensis in stools and heavy drinking are reported to be associated with the risk of cholangiocarcinoma. C. sinensis was endemic in Korea, Japan, China, and Vietnam. However, it is much less prevalent than it once was, and ICC from this cause appears to have been relatively infrequent in recent years [63]. Intrahepatic stones (hepatolithiasis) are another possible etiologic factor for ICC. Such stones are observed in a fairly large proportion of ICC cases, from 5.7% to 17.5% of cases in a Japanese series [64]. Bile duct epithelium in hepatolithi-

Table 40.5 Incidence of primary liver tumors in Japan.* Histologic type

Male

Female

Total (%)

Hepatocellular carcinoma Cholangiocarcinoma Combined HCC and ICC* Cystadenocarcinoma Hepatoblastoma Sarcoma Others Total

12 481 384 74 19 9 10 57 13 034

4185 243 19 13 9 3 28 4500

16 666 627 93 32 18 13 85 17 534

(95.05) (3.58) (0.53) (0.18) (0.10) (0.07) (0.48)

*Data taken from The Liver Cancer Study Group of Japan, 2000 [74] HCC: hepatocellular carcinoma, ICC, intrahepatic cholangiocarcinoma.

asis shows chronic proliferative cholangitis and epithelial hyperplasia. Most of the cases in an ICC series in Taiwan were associated with hepatolithiasis. According to Chen et al, 106 of 162 (65.4%) patients with ICC had associated hepatolithiasis [65] (see also Chapter 6).

Treatment As is the case in HCC, surgery is currently the only treatment modality that provides a chance of cure for ICC. ICC shows variable patterns of intrahepatic invasion, including dissemination through the portal vein or lymphatic vessels and direct expansion via sinusoidal spaces. Of these, the main route of intrahepatic spread of ICC is considered to be dissemination through the portal tree. From this oncologic perspective, anatomic resection seems to be the best approach for the treatment of ICC [66]. The long-term outcome of patients with ICC who undergo liver resection is slightly worse than that for patients with

495

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Special Tumors, Population, and Special Considerations

100 90 80 Survival rate (%)

70 60 50 40 30 20 10 0

0

1

2

3

4

5

6

7

8

Years post resection

HCC. According to a recent report on a nationwide survey in Japan [20], the 5-year survival rate of 1626 patients who underwent surgery for ICC was 32.7%. Patients with lymph node metastasis had an extremely poor prognosis. Inoue and Makuuchi reported an overall 5-year survival rate of 36% in 52 patients with so-called mass-forming type ICC. Of these, there were no long-term survivors among 21 patients with lymph node metastasis (Figure 40.6). Notably, among patients with mass-forming type ICC, almost all recurrence occurred within a year and most of the patients died within 2 years after hepatic resection [66]. Chu and Fan from Hong Kong reported a series of 48 resected cases of ICC with a 5-year survival rate of 22.0% [67]. Kim et al reported a series of 28 cases of ICC in Korea. Twelve of these cases (46.2%) had associated Clonorchis sinensis infection, and their overall 3-year survival rate was 22.1% [68]. In Thailand, Uttaravichien et al reported a large series of mass-forming type ICC [69]. The 3-year survival rate in 100 patients was 16%. According to a report from Taiwan that included 138 patients with ICC [65], the 5-year survival rate was 16.5% and 7.8% in those with and without hepatolithiasis, respectively (p > 0.05). Thus, hepatolithiasis per se did not influence long-term survival (see also Chapter 16).

Other primary liver tumors According to a recent report on a nationwide survey in Japan [20], HCC and ICC are the most frequent primary liver cancers in Japan and constitute 98.3% of all liver tumors. Other histologic types, including cystadenocarcinoma, combined type, hepatoblastoma, and sarcoma, are extremely rare (Table 40.5).

496

9

10

11

12

Figure 40.6 Impact of lymph node metastasis on the survival rate of patients with mass-forming type cholangiocarcinoma who underwent resection with curative intent. Thick line, patients without lymph node metastasis (n = 21); thin line, patients with lymph node metastasis (n = 31) (p = 0.0001). (Reproduced from Inoue et al [66], with permission from Elsevier.)

Hepatoblastoma and HCC are two frequent liver cancers in childhood (see also Chapter 39). Approximately twothirds of patients with hepatoblastoma have resectable tumors, and in those undergoing complete resections, surgery alone results in a long-term survival rate of around 60%. According to the cancer registry of Taiwan (1979−1992), 43 cases of hepatoblastoma were reported among 377 young patients (0−15 years of age) suffering from liver cancer [70]. Their outcome was not favorable; only 17 of these 43 patients underwent surgical resection and the 5-year survival rate of the resected cases was 47%.

Secondary liver tumors Since the report of Foster and Berman [71], liver resection has also been utilized in Asian centers for secondary liver tumors, mainly colorectal metastasis. There have been a number of reports in the English literature from Asian centers since the early 1990s [72, 73]. The reported operative mortality and 5-year survival rate after hepatectomy ranged from 0% to 3.7%, and 25.5% to 51.0%, respectively. According to the nationwide survey conducted by the Japanese Study Group of Colorectal Cancer, a total of 2779 cases of synchronous colorectal metastasis underwent liver resection between 1995 and 1998. The 5-year survival rates in patients with unilobar metastases, bilobar metastases with fewer than five lesions, and bilobar metastases with more than five lesions were approximately 40%, 35%, and 20%, respectively. Hepatic resection for secondary liver tumors from other primaries, including gastric cancer and breast cancer, has

CHAPTER 40

also been performed by Japanese surgeons. However, the survival benefit of liver surgery in such settings has yet to be determined.

Self-assessment questions 1 Which of the following are the three major etiologic factors associated with hepatocellular carcinoma in Asia? A Infection by HIV B Infection by hepatitis B virus C Infection by hepatitis C virus D Exposure to aflatoxin E Liver fluke infection 2 Which of the following are etiologic agents for cholangiocellular carcinoma? (more than one answer is possible) A Budd−Chiari syndrome B Exposure to aflatoxin C Liver fluke infection D Infection by hepatitis B virus E Hepatolithiasis 3 Surgical resection is the best treatment for HCC when sufficient hepatic function is preserved because it rarely recurs in the remnant liver. A First and second parts are wrong B First part is correct, second part is wrong C First part is wrong, second part is correct D First and second parts are correct, but “because” is incorrect E First and second parts are correct, and “because” is correct 4 In hepatocellular carcinoma (HCC), anatomic resection with complete removal of the tumor is the treatment of first choice, when feasible, because HCC tends to spread through the portal venous system. A First and second parts are wrong B First part is correct, second part is wrong C First part is wrong, second part is correct D First and second parts are correct, but “because” is incorrect E First and second parts are correct, and “because” is correct 5 The survival benefit from liver surgery has yet to be determined for which one of the following? A Hepatocellular carcinoma B Intrahepatic cholangiocarcinoma C Hepatoblastoma D Metastasis of colorectal cancer E Metastasis of breast cancer

Liver Tumors in Asia

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22 Oka H, Kurioka N, Kim K, et al. Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis. Hepatology 1990;12:680–7. 23 Kew MC, Yu MC, Kedda M-A, et al. The relative roles of hepatitis B and C viruses in the etiology of hepatocellular carcinoma in Southern African blacks. Gastroenterology 1997;112:184–7. 24 Chen W, Wang LY, Lu SN, et al. Elevated aflatoxin exposure and increased risk of hepatocellular carcinoma. Hepatology 1994;24:38– 42. 25 Sun Z, Lu P, Gail MH, et al. Increased risk of hepatocellular carcinoma in male hepatitis B surface antigen carriers with chronic hepatitis who have detectable urinary aflatoxin metabolite M1. Hepatology 1999;30:379–83. 26 Leung NW, Tam JS, Lai JY, et al. Does hepatitis C virus infection contribute to hepatocellular carcinoma in Hong Kong? Cancer 1992;70:40–4. 27 Tangkijvanich P, Hirsch P, Theamboonlers A, et al. Association of hepatitis virus with hepatocellular carcinoma in Thailand. J Gastroenterol 1999;34:227–33. 28 Akriviadis EA, Llovet JM, Efremidis SC, et al. Hepatocellular carcinoma. Br J Surg 1998;85:1319–31. 29 Shresta S M, Okuda K, Uchida T, et al. Endemicity and clinical picture of liver disease due to obstruction of the hepatic portion of the inferior vena cava. J Gastroenterol Hepatol 1996;11:170– 9. 30 Chang MH, Shau WY, Chen CJ, et al. Hepatitis B vaccination and hepatocellular carcinoma rates in boys and girls. JAMA 2000;284:3040–2. 31 Kubo Y, Okuda K, Musha H, et al. Detection of hepatocellular carcinoma during a clinical follow-up of chronic liver disease. Observations in 31 patients. Gastroenterology 1978;74:578–82. 32 The Liver Cancer Study Group of Japan. Primary liver cancer in Japan. Clinicopathologic features and results of surgical treatment. Ann Surg 1990;211:277–87. 33 Okuda K. Early recognition of hepatocellular carcinoma. Hepatology 1986;6:729–38. 34 Takayama T, Makuuchi M, Hirohashi S, et al. Early hepatocellular carcinoma as an entity with a high rate of surgical cure. Hepatology 1998;28:1241–6. 35 Liaw Y-F, Tai D-R, Chu C-M, et al. Early detection of hepatocellular carcinoma in patients with chronic type B hepatitis. Gastroenterology 1986;90:263–7. 36 Sato Y, Nakata K, Kato Y, et al. Early recognition of hepatocellular carcinoma based on altered profiles of alpha-fetoprotein. N Engl J Med 1993;328:1802–6. 37 Liebman HA, Furie BC, Tong MJ, et al. Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N Engl J Med 1984;310:1427–31. 38 Makuuchi M, Kokudo N, Arii S, et al. Development of evidencebased clinical guidelines for the diagnosis and treatment of hepatocellular carcinoma in Japan. Hepatol Res 2008;38:37–51. 39 Yuan M-F, Cheng C-C, Lauder IJ, Lam S-K, Ooi G-CC, Lai C-L. Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience. Hepatology 2000;31:330– 5. 40 Kokudo N, Bandai Y, Imanishi H, et al. Management of new hepatic nodules detected by intraoperative ultrasonography during hepatic resection for hepatocellular carcinoma. Sugery 1996;119:634–40.

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41 Zhang K, Kokudo N, Hasegawa K, et al. Detection of new tumors by intraoperative ultrasonography during repeated hepatic resections for hepatocellular carcinoma. Arch Surg 2007;142: 1170–5. 42 Sudan D, Sudan R, Schafer D, et al. Without victory there is no survival: transarterial lipiodol chemoembolization and hepatocellular carcinoma. Hepatology 1998;28:270–1. 43 Arii S, Yamaoka Y, Futagawa S, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. Hepatology 2000;32:1224–9. 44 Belghiti J. Systematic hepatectomy for liver cancer. J Hepatobiliary Pancreat Surg 2005;12:362–4. 45 Llovet JM, Bustamante J, Castells A, et al. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology 1999;29:62–7. 46 Minagawa M, Makuuchi M, Takayama T, et al. Selection criteria for hepatectomy in patients with hepatocellular carcinoma and portal vein tumor thrombus. Ann Surg 2001;233:379–84. 47 Chen M-F, Hwang T-L, Jeng L-B, et al. Postoperative recurrence of hepatocellular carcinoma. Two hundred five consecutive patients who underwent hepatic resection in 15 years. Arch Surg 1994;129:738–42. 48 Fan S-T, Lo CM, Liu CL, et al. Hepatectomy for hepatocellular carcinoma: toward zero hospital deaths. Ann Surg 1999;229: 322–30. 49 Shiina S, Teratani T, Obi S, et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 2005;129: 122–30. 50 Chen MS, Li JQ, Zheng Y, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 2006;243: 321–8. 51 Yamada K, Sato M, Kawabata M, et al. Hepatic artery embolization in 120 patients with unresectable hepatoma. Radiology 1983;148:397–401. 52 Takayasu K, Arii S, Ikai I, et al. Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients. Gastroenterology 2006;131: 461–9. 53 Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693–9. 54 Todo S, Furukawa H; Japanese Study Group on Organ Transplantation. Living donor liver transplantation for adult patients with hepatocellular carcinoma. Experience in Japan. Ann Surg 2004;240:451–61 55 Lo CM, Fan ST, Liu CL, Chan SC, Ng IO, Wong J. Living donor versus deceased donor liver transplantation for early irresectable hepatocellular carcinoma. Br J Surg 2007;94:78–86. 56 Ito T, Takada Y, Ueda M, et al. Expansion of selection criteria for patients with hepatocellular carcinoma in living donor liver transplantation. Liver Transpl 2007;13:1637–44. 57 Hwang S, Lee SG, Joh JW, Suh KS, Kim DG. Liver transplantation for adult patients with hepatocellular carcinoma in Korea: comparison between cadaveric donor and living donor liver transplantations. Liver Transpl 2005;11:1265–72.

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58 Soejima Y, Taketomi A, Yoshizumi T, et al. Extended indication for living donor liver transplantation in patients with hepatocellular carcinoma. Transplantation 2007;83:893–9. 59 Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394–403. 60 Sugawara Y, Tamura S, Makuuchi M. Living donor liver transplantation for hepatocellular carcinoma: Tokyo University series. Dig Dis Sci 2007;25:310–12. 61 Kokudo N, Sasaki Y, Nakayama T, et al. Dissemination of evidence-based clinical practice guidelines for hepatocellular carcinoma among Japanese hepatologists, liver surgeons and primary care physicians. Gut 2007;56:1020–1. 62 Liver Cancer Study Group of Japan. Classification of Primary Liver Cancer. Tokyo: Kanehara & Co Ltd, 1997:21. 63 Parkin DM, Ohshima H, Srivatanakul P, et al. Cholangiocarcinoma: epidemiology, mechanisms of carcinogenesis and prevention. Cancer Epidemiol Biomarkers Prev 1993;2:537–44. 64 Sugihara S, Kojiro M. Pathology of cholangiocarcinoma. In: Okuda K, Ishak KG, eds. Neoplasms of the Liver. Tokyo: Springer Verlag, 1987. 65 Chen M-F, Jan Y-Y, Jeng L-B, et al. Intrahepatic cholangiocarcinoma in Taiwan. J Hepatobiliary Pancreat Surg 1999;6:136–41. 66 Inoue K, Makuuchi M, Takayama T, et al. Long-term survival and prognostic factors in the surgical treatment of mass-forming type cholangiocarcinoma. Surgery 2000;127:498–505. 67 Chu K-M, Fan S-T. Intrahepatic cholangiocarcinoma in Hong Kong. J Hepatobiliary Pancreat Surg 1999;6:149–53.

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68 Kim H-J, Yun S-S, Jung K-H, et al. Intrahepatic cholangiocarcinoma in Korea. J Hepatobiliary Pancreat Surg 1999;6:142–8. 69 Uttaravichien T, Bhudhisawasdi V, Pairojkul C, et al. Intrahepatic cholangiocarcinoma in Thailand. J Hepatobiliary Pancreat Surg 1999;6:128–35. 70 Lee CL, Ko YC. Survival and distribution pattern of childhood liver cancer in Taiwan. Eur J Cancer 1998;34:2064–7. 71 Foster JH, Berman MM. Solid Liver Tumors. Major Problems in Clinical Surgery. Philadelphia: WB Saunders, 1977:1−342. 72 Kokudo N. Seki M, Ohta H, et al. Effects of systemic and regional chemotherapy after hepatic resection for colorectal metastases. Ann Surg Oncol 1988;5:706–12. 73 Minagawa M, Makuuchi M, Torzilli G, et al. Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer. Ann Surg 2000;231:487–99. 74 The Liver Cancer Study Group of Japan. The 14th Report of the Nationwide Survey of Primary Liver Cancer in Japan (1996∼1997) [in Japanese]. Kyoto: The Liver Cancer Study Group of Japan, 2000.

Self-assessment answers 1 2 3 4 5

B, C, D C, E B E E

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41

Liver Tumors in South America Lucas McCormack1 and Eduardo de Santibañes2 1 2

General Surgery Service, Hospital Aleman, Buenos Aires, Argentina Hepatobiliopancreatic and Liver Transplant Unit, Hospital Italiano, Buenos Aires, Argentina

Medicine in South America was nurtured by the influences of the European and North American schools. The endemic pathologies conditioned health professionals to develop techniques useful for local application, using the resources at their disposal. The same occurred with hepatic surgery, where the influence of immigration and ethnic mix stimulated the creativity of surgeons who, due to lack of means or from necessity, became pioneers in the development of certain techniques of our specialty. Thus, we find reports in the medical literature at the start of the last century that describe previously unpublished procedures to approach the liver [1]. The high prevalence of hydatid disease and of gallbladder cancer in many countries of South America conditioned the early development of hepatic and biliary surgery, training surgeons in liver mobilization and parenchymal fracture to treat patients with these disorders [2–4]. The high incidence of biliary lithiasis and its complications were a constant stimulus, and Pablo Mirizzi in 1931 described his experience with intraoperative cholangiography [5, 6]. In the 1970s and 80s, South American surgeons trained at centers of liver transplant in North America and Europe, returning to their native countries to set up more than 70 specialist units. However, the lack of adequate finance, education and organization has limited the development of liver surgery and transplantation in Latin America (Table 41.1). For an estimated population of 470 million, approximately 1100 liver transplantations were performed in 2002, which represents 2.3 liver transplantations per million people per year. Compared with Europe (15 per million) or the United States (25 per million), in South America the donation rate is much lower (5–12 per million). A recent study showed that the highest transplantation rates per million were in Argentina (5.4), Brazil (4.5) and Chile (4.1). In 2001, liver transplantations were not performed in two of the 10 South American countries and in five of six Central American countries. In most Latin American coun-

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

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tries performing this procedure, living donor liver transplantation has been used for pediatric patients to compensate for the organ shortage for them. However, by 2004, only three countries had used this procedure for adult liver transplantation [7]. In this chapter we will describe the development of hepatic surgery and liver transplant in the various regions of South America.

Development of hepatic surgery and liver transplantation The River Plate school (Argentina and Uruguay) Although in 1917 Lorenzo Mérola described the technique to approach the upper aspect of the liver by means of thoraco-frenolaparotomy in studies carried out in cadavers [1], it was not until August 1931 when the Uruguayan surgeon G. Caprio practiced an anatomic left lobectomy in a case of metastasis for the first time. This pioneering experience was published that same year [8] and H. Virad and J. Sgro, in their handbook Les Hepatectomies Majeures [9], as well as H. Bismuth in the Encyclopédie Medico-Chirurgicale [10] recognized this achievement, which was carried out 8 years before the same procedure was reported by Mayer May and Tung in 1939 [11]. In turn, it should be recalled that the first right hepatectomy was performed by Lortat-Jacob in 1951, i.e. 20 years later [12]. Concurrently in Argentina, the surgeon P. Mirizzi carried out the first intraoperative cholangiography in 1931, introducing a rationale approach to the treatment of biliary tree disease and leading to the popularity of a technique that today bears his name and is employed by all liver surgeons [5, 6]. In 1961, the Uruguayan surgeon R. Praderi described “transhepatic tumoral intubation,” and in the following years diverse modifications improved the technique, which was useful not only for the treatment of neoplasms but also for benign stenosis [2–4, 13].

CHAPTER 41

Liver Tumors in South America

Table 41.1 Liver transplantation (LT) in Latin America.

Argentina Brazil Chile Peru Uruguay Mexico Colombia Cuba Costa Rica Venezuela Bolivia Ecuador

Year

Donation rate (per million population)

Population (millions)

Number of LT centers

Number of LTs

LT rate (per million population)

Cost of cadaveric LT (US$)

2005 2005 2005 2002 2002 2005 2004 2002 2002 2002 2002 2002

10.5 6.3 8.6 2 17.1 4.0 4.3 NA NA NA NA NA

38.7 186.4 16.3 27.9 4.0 107 45.6 10 4 23 8 12

14 62 7 1 1 20 3 2 1 1 1 1

1969 5258 471 20 13 546 553 59 22 19 6 1

5.4 4.5 4.1 0.2 1.0 0.7 2.2 1.6 2.5 0.1 0.3 0

27 000 21 505 28 600 37 000 NA NA NA NA NA NA NA NA

NA, not available.

Encouraged by Claude Couinaud’s work, who in 1957 published his studies on hepatic anatomy in the Presse Medicale [14], the Argentine J. M. Mainetti carried out anatomic resections, mainly to treat gallbladder neoplasias. His disciple, J. R. Defelitto, jointly with J. Viaggio, wrote in later years about their experiences as the leaders in the development of Argentine hepatic surgery at that time [15]. In January 1988, E. de Santibañes at the Hospital Italiano of Buenos Aires carried out the first liver transplant in an adult patient in Argentina [16]. His pioneering team was also the first in Argentina to perform hepatic transplant in children using the range of reduction techniques, including the “Split” technique (1992), living related donor transplantation in children (1992) and adults (1998), and using an artificial biologic support with porcine liver in a case of fulminant hepatitis (1998) [17–19]. This team contributed to surgical education in the hepato-pancreato-biliary field, developing the first Fellowship program in the region and collaborating in training members of other transplant programs, not only in Argentina but also in neighboring countries, such as Uruguay, Chile, Brazil, Peru, Paraguay, and Bolivia. Up to November 2007, in Argentina a total of 1701 liver transplants had been carried out in 18 centers, nine of them located in Buenos Aires and the others in the hinterland. Although in 1999 a team led by E. Torterolo in Uruguay performed the first liver transplant at the Armed Forces Hospital, this program is currently closed and today there is no active liver transplant program in this country.

Brazil The first hepatic resection performed in Brazil is attributed to Edmundo Vasconcelos in São Paulo at the beginning of the 1950s (unpublished data). “Extended” anatomic right lobectomy was originally reported in 1956 in Revista do Colégio Brasileiro de Cirurgiões by Oliveira Jr in a patient with a gallbladder tumor. A report of “extended” right hepatic lobectomy involving segments I and IV was first published in the same journal in 1959 by Ari Fauzino, from the National Cancer Institute of Rio de Janeiro (INCA), who had been performing resections since the early 1950s. It should be highlighted that, in the mid-1950s, Célio Diniz, a disciple of Couinaud’s, from Belo Horizonte, studied hepatic segmentation and vascularization in his doctoral thesis (Mies S, personal communication). As pioneers of hepatic resection in Brazil, Raia et al described the use of temporary clamping of the inferior vena cava below and above the liver [20]. The first successful liver transplant in Brazil was performed at the Liver Unit of the São Paulo Medical School, São Paulo University on September 1, 1985 in a patient with a hepatoblastoma [21]. This unit also performed the first liver transplant from a living related donor in December 1988. The child recipient died on the sixth postoperative day during a hemodialysis session due to an incompatible blood transfusion. The second transplant of this type was performed by the same team on July 21, 1989, and its result was published as a brief communication in the Lancet [22]. The patient survived for almost 5 months after transplantation and died due to cytomegalovirus infection. More than 5000 liver transplantations have now been performed in

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Brazil, and Brazil has performed the seventh highest number of liver transplants in the Western world and the most in Latin America (see Table 41.1). Almost 1000 procedures were performed in 2004, 19% of them involving living donors [23].

Chile There is a high prevalence of hydatid disease and of gallbladder cancer in Chile and these are the leading indications of liver surgery in this country. It is estimated that 400 hepatic resections per year (26 cases per million) are carried out for hydatid disease and 1600 new interventions per year (110 cases per million population) for gallbladder cancer, which corresponds to a hepatic resection rate of 3–5% for patients with gallbladder cancers. In Chile, there are 25 centers where these procedures are practiced (J. Hepp, personal communication). The first liver transplant was performed in 1985 at the Military Hospital in Santiago de Chile. E. Buckel at the Las Condes Clinic in the same city carried out the first successful pediatric transplant using a living related donor in 1999. Currently, there are four active centers for hepatic transplant in Chile [24].

Peru The first left hepatic resection was carried out in Peru in 1955 by A. Sabogal at the Institute of Neoplasic Disorders. The following year, V. Baracco Gandolfo performed the first right hepatectomy at the Archbishop Loayza Hospital. Currently, surgery of greater complexity is performed at the following centers: the Edgardo Rebagliati Martins and Guillermo Beacon Irigoyen Social Security Hospitals, as well as the Institute of Neoplasic Disorders. As regards liver transplant, the first attempt was carried out in 1968 at experimental level by V. Baracco’s team [25], but it was only at the end of the 1990s that J. Chaman Ortiz set up the first transplant team in humans at the Guillermo Beacon Irigoyen Social Security Hospital in Lima, and carried out its first transplant in 2001 (E. Barboza, personal communication).

Colombia The first 11 hepatic transplants in Colombia were performed at the San Vicente de Paul Hospital in 1980 by A. Velásquez. In 1988 the Santa Fe Foundation of Bogotá restarted the program with a team trained by Paul McMaster. Fourteen transplants were performed over a 6-year period [25]. In 1996, L. A. Caicedo, at the Valle el Lili Foundation (Cali), began a program of liver transplants, and since then an average of 40 interventions per year have been carried out. Recently, A. Velásquez restarted his transplant program in Medellín, and this is the second active center at the present time (L. A. Caicedo, personal communication).

502

Common hepatic tumors Worldwide surveys of the incidence, prevalence and mortality of cancer estimated that in the year 2000 mortality due to cancer in developing countries would be twice as high as in developed countries [26]. This scale of difference is also observed between South American countries, with Chile displaying the highest and Venezuela the lowest prevalence [26]. Also, the general mortality rate for cancer has been rising in Chile during the last decade [27]. The presentation of hepatic tumors in South America correlates with the demographic, social, economic, cultural, and geographic features of this region, where the mixing of races with the indigenous population, as well as widespread poverty, low educational level and peculiar feeding habits prevail. As already mentioned, certain pathologies, such as gallbladder cancer and hydatid hepatic cysts, have a high incidence in Chile. Within most South American countries, local changes in the incidence and prevalence of diverse cancer types are seen. For example, in Argentina, while the overall rate of mortality due to liver cancer is 5 per 100 000, it is 9 per 100 000 in the Southern province of Santa Cruz and 2.8 per 100 000 in the Northern province of Misiones [28]. Although the general features of hepatic tumors diagnosed in South America are similar to those reported in the international literature, there are certain marked differences and these are described below.

Gallbladder cancer The incidence of gallbladder cancer is very variable throughout South America: 5% in Colombia, 5.4% in Argentina, 5.2% in Bolivia, 3% in Brazil, 2.3% in Venezuela, 3% in Uruguay, and 1.4% in Ecuador [29–36] (Figure 41.1). In Chile, gallbladder cancer represents the leading cause of death due to cancer in women [37]. Its incidence varies according to the geographic area. Its prevalence rate of 11.5 cases per 100 000 in 1995 is among the highest in the world [38]. Presentation patterns are similar to those reported in the world literature: there is a female preponderance (3.6 : 1) and the diagnosis increases with age, being highest in the seventh decade of life [31, 39, 40]. An association with cholelithiasis is very frequent (85–95%) and cases are generally diagnosed intraoperatively at an advanced stage [41]. The predominance of gallbladder cancer in the female sex suggests the influence of estrogens in its development [42]. Moreover, multiple and early pregnancies are associated with the development of gallbladder cancer, probably due to the lithogenic effect secondary to hormonal changes [43].

Lithiasis Cholelithiasis is currently the major risk factor for gallbladder cancer. The frequency of gallbladder cancer increases in

CHAPTER 41

Venezuela (2.3%) Colombia (5%) Ecuador (1.4%) Brazil (3%) Bolivia (5.2%)

Liver Tumors in South America

nitroreductase, and glucoronidase on biliary acids. Other bacteria present in the gallbladder bile, by the same mechanism, could also be related to tumor development [49]. However, in a study of 608 gallbladders obtained by cholecystectomies from patients in high-risk populations for gallbladder cancer, which were subjected to microbiologic bile analysis and pathologic evaluation of the surgical specimen, Salmonella spp in the bile was an infrequent finding in patients with or without gallbladder cancer, thus questioning the leading pathogenic role of this bacterium in the development of gallbladder cancer [49].

Early diagnosis Uruguay (3%)

direct proportion to the patient’s age and the duration of lithiasis. In turn, in more than 80% of cases, lesions are found in the mucosa adjacent to the cancerous tumor, as well as in hyperplasic foci, atypical hyperplasia, dysplasia, and carcinoma in situ [40, 43, 44]. There is a raised frequency of gallbladder cancer in certain population groups of South America, including females, lithiasis carriers, and those aged over 50 years. It is in these groups of patients where the performance of “prophylactic cholecystectomy” has been advanced in order to reduce the incidence of gallbladder cancer [40, 45–47]. During the last decade in Chile, there has been an increase in the rate of mortality from 7.84 to 9.6 per 100 000. While the most significant risk factor was cholelithiasis, during this period there was no increase in the prevalence of lithiasic disease; on the contrary, cholecystectomy indexes dropped markedly. It is estimated that by increasing the number of cholecystectomies to 12 500 per year in a specific area of high prevalence in Chile, mortality due to gallbladder cancer could be reduced in 2 years to roughly 1 per 100 000 [48].

Even today, most diagnoses are made intraoperatively or by the pathologist. Ultrasonography and computed tomography are useful for diagnosing gallbladder cancer in advanced stages. Their low sensitivity in detecting early stages is attributable to the presence of cholelithiasis and chronic inflammatory alterations, findings that considerably hinder careful observation of the gallbladder wall [50]. However, a Japanese study detected early gallbladder tumors in 30% of cases by means of ultrasonography. This procedure in Japan would be facilitated by the high percentage of these lesions associated with alithiasic gallbladder [50]. The use of tumor markers is a poor screening method to detect this pathology, since usually positive results are only observed in advanced disease. It has been reported in highrisk populations that the highest predictive capacity for gallbladder cancer is achieved with CA 19-9 levels above 37 U/ mL and carcinoembryonic antigen (CEA) values greater than 4 ng/mL [51]. That the diagnosis of gallbladder cancer is challenging is demonstrated by the 54% incidence of flat and occult lesions not recognized even by the pathologist during examination of the cholecystectomy specimen [51]. Given the high incidence of this neoplasm in South America, it is recommended that all extirpated gallbladders should be opened in the operation room to be examined in the first instance by the surgical team. In regions displaying an incidence of gallbladder cancer greater than 5%, it is useful to subject smears of the gallbladder mucosa on a microscope slide to cytologic analysis. This highly sensitive and specific study is valuable for intraoperative diagnosis of early gallbladder cancer, thus avoiding a second surgical intervention [52].

Other etiologic factors

Staging and treatment

Other factors associated with gallbladder cancer in South American populations include a family history of neoplasia, abnormalities of the biliopancreatic junction, porcelain gallbladder, gallstone size, choledochal cyst, increased intake of fats and particularly green and red peppers, constipation, and previous infection with Salmonella spp [37]. The association between this bacterium and gallbladder cancer could be explained by the action of the enzymes azoreductase,

As in the rest of the world, only a few gallbladder cancer patients are candidates for surgical treatment, given the usually advanced stage at the time of diagnosis [30]. Treatment algorithms in South America are very similar to those reported in the worldwide medical literature [39, 53]. Consequently, T1 tumors require no more than a simple cholecystectomy as definitive therapy. For T2/T3 tumors, which have an incidence of locoregional node involvement of

Argentina (5.4%) Chile (10%)

Figure 41.1 Gallbladder cancer rates in South America.

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around 46%, simple cholecystectomy without node resection is inadequate. In T4 tumors, prognosis is poor, regardless of the treatment carried out, so the morbidity due to resection would not be justified [53]. However, good results have been achieved when treating T4 N0 tumor cases by radical resections, achieving 27% 5-year survival [54]. Radical resection in T2 and T3 tumors should include hepatic segments IVb and V, complete node resection up to the level of the celiac axis, and resection of the extrahepatic biliary duct, especially in tumors located in the vesicular infundibulum. In locally advanced tumors, an hepatic lobectomy or trisegmentectomy could be required, particularly in T4 N0 tumors. Surgical treatment for gallbladder cancer should include the resection of the parietal surgical wound at initial surgery, when recurrence would not be a contraindication provided the lesion is surgically resectable. The finding of hepatic and/ or peritoneal metastatic spread at the time of exploration is a contraindication for surgical resection. De Aretxabala considers the degree of gallbladder wall invasion to be the single factor to bear in mind when determining a patient’s likelihood of cure [50]. He believes that the invasion of structures or of lymphatic nodes is almost invariably associated with a poor prognosis, and divides patients into five categories when deciding which treatment to carry out. Before radical resection he recommends intraoperative anatomopathologic assessment of para-aortic and retropancreatic nodes, as their involvement rules out any possibility of cure. Likewise, direct infiltration of hepatic pedicle structures, such as the biliary tree or the portal vein; indicates that the lesion is unresectable. According to this author, on occasion radical surgery is indicated for resection of the biliary tree to ensure resection of the infiltrating foci. However, its role is controversial due to the presence of extensive lymphatic and perineural networks surrounding the remaining components of the hepatic pedicle [50].

Complementary therapies Radiotherapy and chemotherapy have been widely used in the management of gallbladder cancer. Regrettably, most reported studies include only a small number of poorly staged patients, making it very difficult to draw definitive conclusions [55]. As adjuvant therapy to radical surgery, radiotherapy has been studied in cases of unresectable lesions, sometimes together with 5-fluorouracyl as prior sensitizer. Chemotherapy has been preferably given for palliation in such patients, since its use as adjuvant to radical surgery has proved even more debatable. Randomized prospective studies are still lacking to clarify the role of complementary treatments in gallbladder cancer.

Laparoscopic surgery As in the rest of the world, the widespread application of laparoscopic surgery in Latin America led to controversy and

504

the appearance of diverse patterns of neoplasm dissemination. This approach is contraindicated in cases of suspected gallbladder cancer where there is curative intention, since tumor manipulation by means of specific surgical instruments may disseminate the neoplasm both locally and systemically. Studies of laparoscopic surgery in other abdominal tumors have shown there is a risk of implanting tumor cells in the suspension within the CO2-insufflated cavity at the site of surgical incision. The high concentration of this gas will also favor the growth of tumor cells [56].

Histopathologic prognostic factors Adenocarcinoma is the most common histologic type in South America (90–97.9%), particularly its differentiated forms (tubular, papillary, and mucinous) [30, 40, 46]. Prospective anatomopathologic analysis of 474 surgical specimens of gallbladder cancer, diagnosed over a 7-year period in region IX of Chile, demonstrated that unsuspected tumors (34%) displayed a lower degree of gallbladder wall infiltration and a greater index of differentiation [57]. The degree of gallbladder wall invasion indicates not only the type of resective treatment, but is also the major prognostic factor [58]. Greater gallbladder wall infiltration correlates with lesser cell differentiation, increased vascular invasion, and enhanced perineural and node infiltration, all proven factors of an unfavorable oncologic prognosis [57]. Survival rates in those with gallbladder cancer in South America are similar to those reported for the rest of the world [35, 36], with global 5-year figures around 7.5% and a better prognosis in patients operated on at early stages [46].

Hepatocellular carcinoma Epidemiology Worldwide, hepatocellular carcinoma (HCC) is the most frequent solid organ tumor, responsible for over a million deaths per year. An increased incidence has been observed during the last decade in European and American countries, due probably to higher rates of hepatitis B (HBV) and C virus (HCV) infection. The experience in Western countries differs from that reported in the Far East in several ways: the incidence of cirrhosis and HCC are much lower in the West and a significant number of HCC patients do not present with cirrhosis [59]. In order to discern the features of HCC in the Brazilian population, a national survey assembled information from 19 medical centers in eight states of Brazil. The number of HCC patients selected was 287 and HCC was more common in males (male-to-female ratio, 3.4 : 1) The incidence of HCC was very variable across the diverse geographic regions studied [60]. In 71.2% of cases, HCC was associated with hepatic cirrhosis. Interestingly, 42% of the patients studied had negative serology for HBV and HCV. A history of chronic

CHAPTER 41

alcoholism was found in 37%, indicating a possible role for other etiologic factors in the development of HCC. Given the favorable climatic conditions for fungal food contamination in most Brazilian regions, aflatoxin could be an etiologic factor [60]. A study carried out in Peru investigated the prevalence of hepatitis virus in 105 patients with a biopsy compatible with chronic liver disease, but did not find either HBV or HCV infection to be a major cause of chronic liver disease, also suggesting the possibility of other etiologic factors [61]. A Chilean study investigated the prevalence of HCV virus in three different populations: 21 000 blood donors, 133 patients with chronic nonalcoholic liver disease, and 50 cases of HCC. The prevalence of antibodies against HCV in these populations was 0.3%, 53%, and 48%, respectively. When HCC was associated with liver disease, the percentage climbed to 100%. In turn, the 1b genotype was found in 100% of HCC cases and in 86% of patients with chronic nonalcoholic liver disease. At odds with the above reports from Brazil and Peru, the authors concluded that infection with HCV is a major etiologic factor for the development of chronic liver disease in Chile where the 1b viral genotype prevails [62].

Diagnosis and treatment The algorithms for diagnosis and treatment do not differ from those used in the rest of the world [63]. At the time of diagnosis, tumors are generally at an advanced stages, which frequently means that only nonresective treatments or conservative clinical support can be implemented [64]. Recently liver transplantation has become a new therapeutic option for the treatment of HCC cases. This approach, however, is limited by the lack of cadaveric donors. In Argentina, the global procurement rate of solid cadaveric organs per million inhabitants in 2005 was 10.5 [65]. This low availability of organs is reflected in the estimated waiting list time of 17 months [65]. This has encouraged the development of new strategies, such as living donor transplant, in adult patients with HCC within and outside the accepted Milan criteria. In addition, in 2005 Argentina became the second country after the United States to implement the model for end-stage liver disease (MELD) scoring system for diseased donor liver allocation. Similar to the United States, in Argentina priority points (i.e. 22 points) are given to cirrhotic patients with T2 stage HCC to reduce mortality while on the waiting list. Preliminary results have shown a significant reduction in mortality rates in these patients compared with patients without HCC. This policy for the allocation of donor livers has so far not been adopted in other Latin America countries.

Liver metastasis Metastasis is the greatest cause of death due to cancer. Initially, the presence of hepatic metastasis was synonymous

Liver Tumors in South America

with death. This encouraged novel strategies to modify the natural history of the disease. Currently, multimodal treatment of patients with liver metastasis can offer a cure in a considerable percentage of cases. As in the rest of the world, hepatic metastases originating in the colon and rectum are the most frequent in South America. This is due to the high incidence of colorectal carcinoma, with a third of such patients developing liver metastasis during the course of their illness. The prevalence of colorectal carcinoma in Argentina has been reported to be 13.7 per 100 000 population, and it is the second most common cancer in males after lung cancer [28]. The features of the primary tumor and of its metastases are similar to those reported in the European and American medical literature, as is the influence of adverse oncologic factors on patient survival, suggesting a consistent tumor biology in the West [66]. Prevailing lines of treatment for hepatic metastases at surgery centers in South America are based on the experience reported by world reference centers, with similar results [19, 67]. One of the current lines of investigation at the Italian Hospital of Buenos Aires, Argentina, is simultaneous treatment of the primary colorectal tumor and its secondary liver involvement [68]. We showed in patients undergoing simultaneous resection of the liver and colorectal tumor, similar surgical and oncologic results when compared with those obtained by resection in two stages. Hepatic resections of noncolorectal liver metastases are low throughout the world, including South America, which hinders the reliable analysis of results due to the limited number of cases. A recent multicenter study at five HPB Centers in Argentina collected 106 patients who underwent liver resection for noncolorectal non-neuroendocrine metastases in the period 1989 to 2006 [69]. Primary tumor sites included the urogenital tract (37.7%), sarcomas (21.7%), breast (17.9%), gastrointestinal tract (6.6%), melanoma (5.7%), and others (10.4%). Although 51 major hepatectomies and 55 minor resections were performed, R0 could be achieved in only 89.6%. Perioperative mortality was 1.8%. Overall, 1-, 3-, and 5-year survival rates were 67%, 34%, and 19%, respectively. Survival was significantly longer for metastases of urogenital (p = 0.0001) and breast (p = 0.003) origin. Curative resections (p = 0.04) and metachronous disease (p = 0.0001) were predictors of better survival.

Self-assessment questions 1 Which one of the following statements regarding liver transplantation in South America is false? A Up to November 2007, in Argentina a total of 1701 liver transplants had been carried out in 18 centers B The largest liver transplant programs are located in Uruguay and Bolivia

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C When compared with Europe (15 donors per million) or the United states (25 per million), in South America the donation rate is much lower (5–12 per million) D The first liver transplant from a living related donor was performed by the Liver Unit of the São Paulo Medical School, São Paulo University, in December 1988 E In Brazil, almost 1000 procedures were performed in 2004, 19% of which involved living donors 2 In which country is gallbladder cancer the most common cause of cancer death in women? A Argentina B Chile C Bolivia D Colombia E Peru

E Only a very limited number of cases of noncolorectal non-neuroendocrine metastases have undergone liver resection in South America

References 1 2 3 4 5 6

3 Which one of the following statements regarding gallbladder cancer is false? A It is more frequent in females B The diagnosis increases with age, and has highest frequency in the seventh decade of life C An association with cholelithiasis is very common D Prognosis is very good even in the presence of lymph node metastasis E Cases are generally diagnosed in advanced stages and intraoperatively

7

4 Which one of the following is not an etiologic factor associated with gallbladder cancer in South America? A Abnormalities of the biliopancreatic junction B Porcelain gallbladder C Family history of neoplasia D Gallstone size E Increased alcohol intake

13

5 Which one of the following statements with regard to malignant liver tumors in South America is false? A Similar to the United States, in Argentina priority MELD score points are given for cirrhotic patients with T2 stage hepatocellular carcinoma waiting for liver transplantation B As in the rest of the world, hepatic metastases originating in the colon and rectum are the most frequent in South America C PET/CT scan is not widely available for staging patients with malignant liver tumors in South America D Simultaneous resection of the liver metastasis and the primary colorectal tumor is not performed in South America for cultural and socioeconomic reasons

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8 9 10 11 12

14 15 16

17

18

19

20

21 22

Mérola L. Manera de abordar la cara superior del hígado. Incisión toraco-abdominal. Ann Fac Med 1917;2:105. Praderi R. Twelve years experience with transhepatic intubation. Ann Surg 1974;179:937. Praderi L, Gomez Fossati C. Ictericia por compresión hidatídica de las vías biliares. Cir Urg 1973;43:506–9. Praderi R, Delgado B, Mazza M, et al. Drainage trans-hépatiques doubles. Lyon Chir 1974;70:294. Mirizzi P. Fisiopatología del hepato-colédoco. In: Colangiografía Operatoria. Buenos Aires: El Ateneo, 1939. Mirizzi P. La colangiografía operatoria. Ejemplos que fundamentan sus ventajas y justifican su practica sistemática. Bol Acad Arg Cir 1942;26:908–17. Hepp J, Innocenti FA. Liver transplantation in Latin America: current status. Transplant Proc 2004;36:1667–8. Caprio G. Un caso de extirpación del lóbulo izquierdo del hígado. Bol Soc Cir Montevideo 1931;2:159. Virad H, Sgro J. Les Hepatectomies Majeures. Paris: L’expansion, 1970. Bismuth H. Les hépatectomies. In: Encyclopedia Med-Chirugie. Paris: Techniques Chirurgicales, 2007. Meyer May J, Tung TT. Resection anatomique du lobe gauche pour cancer. Mem Acad Chir 1939;65:1208. Lortat-Jacob J, Robert H, Henry C. Un cas d′hepatectomie doitre reglée. Mem Acad Chir 1932;78:244. Praderi R, Estefan AET. Transhepatic intubation in the benign and malignant lesions of biliary duct. Curr Prob Surg 1985;22:1. Couinaud C. Le Foie. Etude Anatomique et Chirurgicale. Paris: La Presse Medicale, Masson, 1957. de Felitto J, Biaggio. Hepatectomías. Relato oficial. LIII Congreso Argentino de Cirugía. Rev Arg Cir, 1983. de Santibañes E, Sívori J, Ciardullo M, et al. Trasplante hepático: experiencia clínica en el Hospital Italiano de Buenos Aires. Rev Arg Cir 1990;62:60. de Santibañes E, Ciardullo M, Mattera J, Pekolj J, McCormack L. Doce anos de experiencia en transplante hepático con donante vivo relacionado en el Hospital Italiano de Buenos Aires: Evolución y resultados. Rev Argent Cirug 2006;90:132–41. Argibay P, Hyon S, Martinez G. Extracorporeal auxiliary xenoperfusion: animal model of support in fulminant liver failure. Transplant Proc 1996;28:749–50. de Santibañes E. Tumores del hígado y trasplante hepático. In: Amarillo H, Brahim A, Leon S, eds. Cirugía II. Aparato DigestivoHernias-Peritoneo. Tucumán: El Graduado, 1998:326. Raia S, Guijon P, Nogueira G, et al. Major hepatectomy with temporary clamping of the inferior vena cava below and above the liver. Rev Hosp Clin Fac Med São Paulo 1970;25:165–74. Mies S, Massarollo P, Baia C, et al. Liver transplantation in Brazil. Transplant Proc 1998;30:2880–2. Raia S, Nery J, Mies S. Liver transplantation from live donors. Lancet 1989;2:497.

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23 Mies S, Baia CE, Almeida MD, et al. Twenty years of liver transplantation in Brazil. Transplant Proc 2006;38:1909–10. 24 Buckel E, Uribe M, Brahm J, et al. Outcomes of orthotopic liver transplantation in Chile. Transplant Proc 2003;35:2509–10. 25 Delpín S, García D. The 11th report of the Latin American transplant registry: 62,000 transplants. Transplant Proc 2001; 33:1986–8. 26 Ferlay J, Bray F, Pisani P, Parkin D. Globalcan 2000: Cancer Incidence, Mortality and Prevalence Worldwide, version 1.0. IARC Cancer base no 5. Lyon: IARC Press, 2001. 27 Organization PAH. La Salud de las Américas, edición de 1998. Washington, DC: OPS, 1998-2v. (OPS. Publicación científica; 569):174. 28 Matos E, Vilensky M, García C. Atlas de mortalidad por cáncer. Argentina 1989–1992. Comité Argentino de Coordinación. Programa Latinoamérica Contra el Cáncer. Buenos Aires: Edigraf SA, 1997:16. 29 Smith S, Bermudez G. Premalignant lesions of the gallbladder. Acta Med Colomb 1982;7:115–20. 30 Gutierrez V, Gallardo H, Mateu M. Lesions associated with gallbladder carcinoma. Rev Argent Cir 1985;48:274–6. 31 Ford M, Contreras M, Buguña S. Cancer of the gallbladder, San Juan de Dios Hospital (1956–1985). Bol Hosp San Juan de Dios 1988;35:57–62. 32 Monteiro M, Freitas L, Leite A. Carcinoma of the gallbladder. Rev Col Bras Cir 1993;20:109–12. 33 Travieso C, Correa J. Gallbladder neoplasms. Rev Venez Cir 1994;47:168–72. 34 Vivas C, Ferreira C, Czarnevicz D, et al. Gallbladder cancer. Cir Urug 1995;65:121–4. 35 Acosta M, Pazmino P, Gonzalez H. Gallbladder cancer. Enrique Garces Hospital, Quito. Rev Cienc 1995;5:35–40. 36 Sívori J. Cáncer de vesícula. In: Ferraina P, Oría A, eds. Cirugía de Michans, 5th edn. Buenos Aires: El Ateneo, 2000:632–5. 37 De Aretxabala X, Riedemann P, Burgos L. Gallbladder cancer: a case control study. Rev Med Chile 1995;123:581–5. 38 Serra I, Calvo A, Maturana M, Sharp A. Biliary-tract cancer in Chile. Int J Cancer 1990;46:965–71. 39 Chijiiwa K, Noshiro H, Nakano E. Role of surgery for gallbladder carcinoma with special reference to lymph node metastasis and stage using western and Japanese classification systems. World J Surg 2000;24:1271–6. 40 Rodriguez J, Monti J, Celorio G. Clinicopathological aspects of cancer of the gallbladder. Rev Argent Cir 1988;54:42–8. 41 Roa I, Araya J, Villaseca M. Gallbladder cancer in a high risk area: morphological features and spread patterns. Hepatogastroenterology 1999;46:1540–6. 42 Roa I, Araya J, Villaseca M. Cancer of gallbladder: immunohistochemical expression of estrogen receptor related protein (p29) and estrogen induced protein (pS2). Rev Med Chile 1995;123: 1333–40. 43 Roa I, Araya J, Villaseca M. Cancer of gallbladder: study of cases and controls in Chile. Rev Chil Cir 1996;48:139–47. 44 Martinez G, de la Rosa J. Neoplasm and dysplasia of the gallbladder and their relation with lithiasis. A case-control clinicalpathological study. Rev Gastroenterol Mex 1998;63:82–8. 45 Astete G, Lynch O, Madariaga J. Upper injuries of the gallbladder. Rev Chil Cir 1999;51:159–63.

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46 Cubillos L, Duarte I, Quappe G. Gallbladder cancer: anatomoclinical study of 1000 cases. Rev Chil Cir 1987;39:201–7. 47 De Aretxabala X, Burgos L, Roa I. Early gallbladder cancer. Rev Chil Cir 1997;49:646–9. 48 Chianale J, Valdivia G, del Pino G. Gallbladder carcinoma mortality rates and their relation with cholecystectomy rates. Rev Med Chile 1990;118:1284–8. 49 Roa I, Ibacache G, Carvallo J. Microbiological study of gallbladder bile in a high risk zone for gallbladder cancer. Rev Med Chile 1999;127:1049–55. 50 De Aretxabala X. Cáncer de vesícula biliar. In: Barboza E, ed. Principios y Terapéutica Quirúrgica. Lima: Didi de Arteta SA, 1999:368–73. 51 De Aretxabala X, Riedemann J, Roa I. CA 19-9 and carcinoembryonic antigen in gallbladder cancer. Rev Med Chile 1996;124:11–20. 52 Carneiro P, Sales R, Oliveira D. Histopathological aspects in pregnancy of the gallbladder: a study of 40 cases. Folha Med 1993;106:157–63. 53 Reid KM. Ramos-De la Medina A, Donohue JH. Diagnosis and surgical management of gallbladder cancer: a review. J Gastrointest Surg 2007;11:671–81. 54 Todoroki T. Chemotherapy for gallbladder carcinoma: a surgeon’s perspective. Hepatogastroenterology 2000;47:948–55. 55 Todoroki T, Kawamoto T, Otsuka M. IORT combined with resection for stage IV gallbladder carcinoma. Front Radiat Ther Oncol 1997;31:165–72. 56 Pekolj J, Aldet A, Sendin R, et al. Cáncer de vesícula y colecistectomía laparoscópica. Rev Argent Cirug 1997;73:97–106. 57 Roa I, Araya J, Wistuba I. Gallbladder cancer in the IX region of Chile: Importance of anatomopathological study in 474 cases. Rev Med Chile 1994;122:1248–56. 58 Garrido L, Aretxabala X, Roa I. Prognostic factor analysis in gallblader cancer with subserosal infiltration. Rev Chil Cir 1996;48:483–9. 59 Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg 1999;229:790–9; discussion 799–800. 60 Goncalves C, Pereira F, Gayotto L. Hepatocellular carcinoma in Brazil: report of a national survey (Florianopolis, SC, 1995). Rev Inst Med Trop São Paulo 1997;39:165–70. 61 Barham WB, Figueroa R, Phillips IA, Hyams KC. Chronic liver disease in Peru: role of viral hepatitis. J Med Virol 1994;42: 129–32. 62 Muñoz G, Velasco M, Thiers V, et al. Prevalence and genotypes of hepatitis C virus in blood donors and in patients with chronic liver disease and hepatocarcinoma in a Chilean population. Rev Med Chile 1998;126:1035–42. 63 McCormack L, Petrowsky H, Clavien PA. Surgical therapy of hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2005;17: 497–503. 64 de Santibanes E, McCormack L, Pekolj J, et al. Multimodal treatment of hepatocellular carcinoma. Acta Gastroenterol Latinoam 2001;31:367–75. 65 INCUCAI. www.incucai.gov.ar (accessed 30th November 2007). 66 de Santibañes E, Argibay P, Campi O, et al. Results of resective surgery of liver metastases from colorectal cancer. Rev Arg Cir 1991;60:1–7.

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67 de Santibañes E. Tratamento das metástases hepáticas. In: Pereira-Lima L, ed. Conductas em Cirugia Hepatobiliopancreática. Rio de Janeiro: Medsi, 1995:71–108. 68 de Santibanes E, Lassalle FB, McCormack L, et al. Simultaneous colorectal and hepatic resections for colorectal cancer: postoperative and longterm outcomes. J Am Coll Surg 2002;195: 196–202. 69 Lendoire J, Moro M, Andriani O, et al. Liver resection for noncolorectal, non-neuroendocrine metastases: analysis of a multicenter study from Argentina. HPB (Oxford) 2007;9:435–9.

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Liver Tumors in Africa Michael C. Kew Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, and Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa

Introduction Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver, constituting 85–90% of these tumors. A number of important differences exist between HCC as it occurs in sub-Saharan Africa and as it is seen in other parts of the world. The exception is HCC in ethnic Chinese patients, which varies little from that occurring in black Africans. No obvious differences have been noted in the other primary malignant tumors of the liver or in hepatic metastases, as they occur in sub-Saharan Africa and the rest of the world. The differences between HCC in black Africans and that in other populations are reviewed in this chapter.

tration or the findings on hepatic imaging, without obtaining histologic confirmation. Underdiagnosis is compounded by underreporting. In addition, very few African countries have reliable cancer registries. The highest recorded incidence of HCC in Africa is in Mozambique, where the age-adjusted annual frequency among men is 113 per 100 000 and among women 30.8 per 100 000, and the cancer is responsible for 65% of all malignant diseases in men and 31% of those in women [3]. Annual age-adjusted frequencies of 64.6 per 100 000 in men and 25.8 per 100 000 in women have been documented in Zimbabwe [4]. In contrast, HCC occurs in less than 5, and usually less than 3, per 100 000 men per annum in most other parts of the world [1, 2, 5].

Gender and age distribution

Epidemiology Incidence HCC occurs appreciably more often in the indigenous peoples of sub-Saharan Africa than in all other regions of the world, with the exception of East and South-East Asia and some of the Western Pacific islands [1, 2]. Approximately 46 000 new cases of the tumor are diagnosed in Africa annually [1]. This figure, however, grossly underestimates the true incidence of HCC in sub-Saharan Africa because many, perhaps even most, cases are either not definitively diagnosed or are not recorded. The reasons for underdiagnosis of the cancer include inadequate medical and diagnostic facilities in rural areas, where the majority of cases occur, and a nihilistic attitude toward definitive diagnosis conditioned by the absence of effective treatment and the grave prognosis of symptomatic HCC in black Africans. Even in urban areas, the tumor is frequently diagnosed on the basis of a raised serum alpha-fetoprotein (AFP) concen-

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

Male predominance in the occurrence of HCC is more obvious in black African and ethnic Chinese populations than in other populations. The global male-to-female ratio for the occurrence of the tumor is 2.1 : 1 [1], whereas the ratio in different parts of sub-Saharan Africa ranges from 5.7 : 1 to 2.1 : 1, with an average of 3.4 : 1 [1, 2, 5]. Male predominance is even more evident in young black African patients (in one study the ratio was 8.1 : 1 in patients under 30 years of age compared with 4.2 : 1 in those over 50 years of age) [6], whereas in populations at low risk for HCC it is more obvious in older patients. In the lowrisk populations, the sex ratio may be close to parity or parity in younger patients. This difference may be partly explained by the occurrence in industrialized Western countries of the fibrolamellar variant of HCC, which affects mainly young people and has an equal sex distribution, and possibly by the greater use of oral contraceptive steroids, a minor risk factor for HCC, in these countries. In most populations HCC occurs principally in the sixth, seventh and eighth decades, with the mean age at presentation ranging from the late 50s to the early 70s. Few patients under the age of 40 years are seen [1, 2, 7, 8]. In contrast, in black Africans and in the native population of parts of the People’s Republic of China, the age distribution curves of

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patients with HCC show a distinct shift towards younger ages [9–12]. This difference is most striking in Mozambique, where 50% of the patients are younger than 30 years of age and the mean age is 33 years [3]. With the very high incidence of HCC in Mozambican men and the difference in age distribution between these patients and those in industrialized Western countries with a low incidence of the tumor, it has been estimated that the risk of a Mozambican male aged between 25 and 34 years developing this cancer is 500 times that of a Caucasian man living in North America or the United Kingdom. The difference is only 15-fold in those older than 65 years. In other Southern African blacks the mean age of the patients is 40 years and 22.5% are younger than 30 years of age [9]. The peak incidence of HCC in Uganda is between 35 and 45 years [10] and that in Kenya 30–40 years, with more than 50% of the patients being younger than 40 years of age [11]. In Qidong County and the Guanxi Autonomous Region in the People’s Republic of China, the mean age of the patients is around 40 years [4, 5], and in Taiwan most patients are aged between 41 and 50 years [12]. HCC is rarely seen in children in industrialized countries, and when it is these children generally suffer from one of the rare inherited diseases known to be complicated by this tumor (and usually cirrhosis), such as alpha-1-antitrypsin deficiency, hereditary tyrosinemia, glycogen storage disease (type 1), or ataxia telangiectasia. HCC is seen in black African (and ethnic Chinese) children, although manifestly not as often as in adults [11–13]. These children are almost invariably chronically infected with hepatitis B virus (HBV) [13]. Patients with HBV-induced HCC are generally younger than those with hepatitis C virus (HCV)-induced cancers: in sub-Saharan Africa the difference is as much as 20 years, whereas in industrialized countries it is 10 years or less [14].

Clinical presentation Symptomatic HCC is often diagnosed only when the tumor has reached an advanced stage. This applies in all geographic regions, but especially so in black African patients [9–11]. Before this late stage is reached, clinical recognition is frequently difficult. There are a number of reasons for this. HCC runs a silent course in its early stages; it produces no pathognomonic symptoms or signs; the liver is relatively inaccessible to the examining hand and its large size dictates that the tumor must reach a substantial size before it can be felt or before it invades adjacent structures; the considerable functional reserves of the liver ensure that jaundice and other evidence of hepatic failure do not appear until a large part of the organ has been replaced by the tumor; and spread of HCC to distant sites usually occurs late in the course of

510

the disease. Ease of clinical recognition of HCC also differs between populations at high or intermediate risk and those at low risk. In countries in which HCC is common, including those in sub-Saharan Africa, clinicians are especially mindful of the cancer and its many and diverse presentations. Accordingly, they recognize HCC with greater facility than do clinicians practicing in countries in which this tumor is rarely seen. Moreover, HCC commonly coexists with cirrhosis, and the effect of this associated disease on the diagnosis of HCC differs between populations with a high and a low or an intermediate incidence of the tumor [15]. In the latter countries (but also in Japan, which has a high incidence) HCC often develops as a complication of longstanding symptomatic cirrhosis and the patient has few, if any, symptoms attributable to the tumor [16, 17]. If, in addition, the cancer is small, as it often is in the presence of advanced cirrhosis, it may not be evident on physical examination. A sudden unexpected change or deterioration in the condition of these patients may alert the clinician to the possibility that HCC has supervened in the cirrhotic liver [7]. These changes include the onset of abdominal pain or weight loss, ascites may appear or become blood stained, the liver may suddenly enlarge, a hepatic arterial bruit may be heard, or hepatic failure may supervene. In contrast, in black African and ethnic Chinese populations at high risk of HCC the symptoms of the coexisting cirrhosis are usually overshadowed by those of the cancer, and its presence is then uncovered only during the diagnostic work-up for the tumor or at necropsy. Thus, in these populations the tumor usually develops in individuals who were otherwise apparently healthy [9–12, 18–20]. HCCs are commonly considerably larger in these populations [9–12,18–20]. Consequently, the symptoms and physical signs are more florid and this too facilitates diagnosis. Despite the extent of the tumor burden when black Africans with HCC are first seen, the duration of symptoms is often surprisingly short [9–11]. In an analysis of rural Southern African blacks, 30% of the patients admitted to symptoms of less than 2 weeks’ duration and 60% to less than 4 weeks’ duration [9]. The duration of symptoms is generally similar in ethnic Chinese patients with HCC, but is appreciably longer in patients in industrialized countries, where symptoms have usually been present for about 6 months [7].

Symptoms Upper abdominal pain, which is the most common symptom as well as the most frequent presenting complaint in patients with HCC, is almost invariable in black African patients [9–11, 18, 19]; 90% or more have this symptom, compared with 70% or less in industrialized countries with a low or an intermediate incidence of the tumor [20]. Surprisingly, abdominal pain is less frequent in ethnic Chinese than in

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Southern African blacks 40

30

20

10

0

black African patients [12, 20]. Not only is abdominal pain more common in black African patients, it is also more severe and more likely to become progressively worse. The severity and frequency of the pain reflect the generally far larger HCCs characteristic of black African patients (Figures 42.1 and 42.2). The average weight of the cancerous liver at necropsy in black Africans in different studies is 3914 g (ranging up to 8780 g) [21], 3387 g [22], and 3045 g [23] and in ethnic Chinese 3046 g (12), compared with 2036 g in Japanese [17], 2615 g in North Americans [24], and 2477 g in South African Caucasians [22]. The cancerous liver is especially large when HCC arises in a noncirrhotic liver: in Ugandan patients without and with cirrhosis, the cancerous liver weighed 4314 and 2786 g, respectively [23], and in Southern African blacks, it weighed 3981 and 3085 g, respectively [21] (Figure 42.2). The large tumor burden at the time of diagnosis contributes in no small measure to the limited therapeutic options and grave prognosis in black African and ethnic Chinese patients [9–12, 18–20]. Due to the often large size of the cancerous liver in black Africans and ethnic Chinese with HCC, these patients are more likely to be aware of an abdominal lump than are patients in industrialized countries [9–12, 18–20]. In contrast, abdominal swelling resulting from ascites is less likely to be present in the former patients because coexisting cirrhosis complicated by portal hypertension is less common and less advanced in these patients. Other symptoms of HCC in black African patients do not differ obviously in frequency or severity from those in other populations. However, spontaneous rupture of the tumor – or of attenuated liver tissue overlying the tumor – causing an acute and life-threatening hemoperitoneum, occurs significantly more often in black African and ethnic Chinese patients than it does in patients in industrialized countries.

Patients (%)

Figure 42.1 Example of a black African patient with massive hepatomegaly resulting from the presence of a large hepatocellular carcinoma.

1000 2000 3000 4000 5000 6000 7000 8000 Liver weight (g) 1000 2000 3000 4000 5000 6000 7000 8000 0

10

20

30

40 Japanese Figure 42.2 Comparison of the weights of the tumorous liver at necropsy in black African and Japanese patients with hepatocellular carcinoma (the data on the black African patients is obtained from [25] and from the author’s patients, and that from the Japanese patients from [17]).

This complication is occasionally the reason for admission to hospital. Far more often it occurs in patients known to have HCC, when it is commonly the terminal event. For example, tumor rupture is the terminal event in 26% of blacks in Uganda [23], 18.6% of rural blacks in Southern Africa [25], 20% of Taiwanese [12], 12% of Thais [24], and 17% of Hong Kong Chinese [20] with HCC. In an occasional patient the tumor ruptures as a result of blunt abdominal trauma [26]. Surprisingly, in these patients the prognosis may be less grave than it is with spontaneous rupture: in two of three black Africans in whom HCC ruptured as a result of abdominal trauma, the HCC found at the resulting laparotomy could be resected [26].

Physical signs An enlarged liver is the most frequent physical finding in patients with HCC in all geographic regions. Hepatomegaly

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is, however, more frequent and commonly of greater degree (Figures 42.1 and 42.2) in black African and ethnic Chinese patients (91–100%) [9–12, 18–20] than in patients in industrialized countries, such as North America (56–74%) [8, 16] and Japan [17], although 93% of patients in a series from the United Kingdom had an enlarged liver [7]. Because of the often large size of the cancer in black Africans, the enlarged liver is more likely to be tender and is not infrequently extremely tender. In general, in industrialized countries hepatic metastases cause a greater degree of hepatic enlargement than does HCC, whereas the converse is true in black African and ethnic Chinese populations. Physical evidence of chronic hepatic parenchymal disease is rarely evident in black Africans and ethnic Chinese with HCC [9–12, 18–20], but is present in 50% or more of patients in industrialized countries [7, 16, 17]. Fever appears to be more common (38%) in black African [9] and ethnic Chinese [54%] patients [12, 20] than in those from other countries (24% in the United Kingdom) [8], although it was reported to be present in only 11% of Ugandan patients [10]. If substantiated, the higher frequency of fever in these populations may reflect the greater likelihood of tumor necrosis with release of pyrogenic substances in the larger HCCs. The clinical presentation of HCC in a young black African male with a short history of right hypochondrial pain, an enlarged very tender liver, and high fever may result in the tumor being mistakenly diagnosed as an amoebic liver abscess, another common disease in parts of Africa. A large number and a wide variety of unusual clinical presentations, including paraneoplastic phenomena, have been described in black Africans with HCC [25, 27, 28], but in most of these there is no proof that they occur more often than in other populations. One exception is Pityriasis rotunda (circumscripta). This rash is seen in 10–15% of black Africans with HCC, especially in older patients [29, 30]. The only other patients in whom Pityriasis rotunda has been described were in Japan, and no indication of its frequency was given [31]. The lesions occur on the trunk, buttocks, and thighs, and are round or oval, hyperpigmented, and scaly. They vary in size from 0.5 to 25 cm, and may be single or multiple (Figure 42.3). Another exception may be the propensity for the tumor to invade and propagate along the hepatic veins. Invasion of the hepatic veins alone is responsible for a clinical presentation with the Budd–Chiari syndrome [25]. With propagation of the tumor into the lumen of the inferior vena cava (IVC) the patients develop, in addition, severe pitting edema of the lower limbs extending up to the groins. Growth of the cancer up the lumen of the IVC into the right atrium (and sometimes the right ventricle) usually causes circulatory collapse and sudden death [25]. Invasion into the hepatic veins is seen at necropsy in 14% of black Africans

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Figure 42.3 Example of Pityriasis rotunda (circumscripta) on the anterior abdominal wall in a black African with hepatocellular carcinoma.

with HCC, propagation of the tumor into the IVC in 9%, and growth into the right atrium in 2% [25]. This complication is seldom reported in patients at low risk of HCC, but when mentioned is described as being rare.

Natural history, prognosis, and causes of death The usual course of HCC in black Africans is one of rapid progression, characterized by increasingly severe muscle wasting, increasing size of the liver and depth of jaundice, and worsening pain [9–11, 18, 19]. In all parts of the world, the prognosis of patients with symptomatic untreated HCC is poor, with survival times of 6 months or less being the rule [32]. The duration of survival is, however, typically even shorter in black African and ethnic Chinese patients [9–12, 18–20]. For example, the mean survival time in untreated rural Southern African blacks is 11 weeks from the time of onset of symptoms and 6 weeks from the time of diagnosis [9]. The often fulminant course of HCC in black Africans is related, at least in part, to the rate of growth of the tumor. Tumor doubling times in most populations range from about 30 days to as much as 180 days. In black Africans, based on AFP doubling times, it has been estimated that HCC may double in size in as few as 11 days [33]. In patients in industrialized countries the presence of advanced cirrhosis has a definite influence on the prognosis as well as the nature of the terminal event in patients with HCC, with liver failure and bleeding from esophageal varices being prominent. The presence of coexisting cirrhosis has little influence on prognosis in black African patients and its complications are seldom the cause of death [34]. The most common cause of death in black Africans with HCC is

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advanced malignant disease, although rupture of the tumor or hepatic failure may be responsible.

cally raised serum values [38]. Data on the diagnostic usefulness of the marker in black African patients with small asymptomatic tumors are not available.

Diagnosis

Hepatic imaging

Biochemical tests Biochemical tests of liver function are of little use in the diagnosis of HCC in all populations, including black Africans. Although these tests are almost always slightly deranged, the changes are not specific and it is difficult to determine which of the changes are attributable to the tumor and which to the coexisting cirrhosis. As raised serum cholesterol levels are rare in the general black population and because hypercholesterolemia is a not uncommon paraneoplastic phenomenon in this population (occurring in 16% of patients in one study [35]), the finding of a raised serum cholesterol level in a black African patient suspected to have HCC provides a strong clue to the diagnosis of the cancer. This may also be true in Taiwanese patients with HCC, because a raised serum cholesterol level is found in 24% of these patients [12]. A large number and variety of putative serum markers for HCC have been reported. However, with the exception of AFP, none has been found to be more useful in black African patients than in patients from other countries.

Alpha-fetoprotein Serum AFP levels are more often raised and to appreciably higher levels in black African and ethnic Chinese patients with HCC than in patients in industrialized countries. Approximately 90% of black African patients have a raised serum level (>20 ng/mL), and in about 75% the concentration is above 500 ng/mL, the value generally considered to be diagnostic of this tumor [36]. The mean concentration of the raised levels is around 70 000 ng/mL, and values as high as several million nanograms per milliliter are seen. This contrasts with a prevalence of less than 70% of patients with HCC in industrialized countries having a raised level and less than 50% a diagnostic level [36, 37]. The mean concentration of raised AFP in these populations is around 8000 ng/ mL. In black Africans production of the tumor marker by HCC is age related. This is shown in data from Southern Africa, where 96.4% of patients under the age of 30 years have raised values compared with 83.1% of those over 50 years of age, and 89.3% of the younger patients have a diagnostic level compared with 59.7% of the older patients [6]. The mean of the raised concentrations is 87 366 ng/mL in the younger patients and 43 827 ng/mL in the older patients [6]. Serum AFP concentrations are of limited use in screening for small asymptomatic HCCs in Oriental and Mediterranean patients, less than 50% of such tumors producing diagnosti-

The images obtained with ultrasonography, computerized tomography, and magnetic resonance imaging do not show features unique to HCC in black Africans or in any other population. The fact that the tumors are frequently very large in black Africans and ethnic Chinese patients is, however, confirmed. For the same reason, a raised right hemidiaphragm on plain chest X-ray is more frequently seen in black African (30%) [39] and ethnic Chinese patients (40%) [20]. Radiologically-evident pulmonary metastases are also more common in these patients: 20% [39], compared with 7% in the United Kingdom [7].

Pathology Growth patterns of HCC may be influenced both by the etiology of the tumor and by the presence and nature of coexisting liver disease. Nevertheless, the pathologic characteristics of HCC in black Africans are, in the main, similar to those in other population groups. One exception has already been mentioned, namely, the often large size of this cancer in black Africans. Another difference concerns the nature of the growth pattern. Expanding HCCs are common in Japanese (38%) and black African patients (36%), but are less common in North American patients (17%) [40]. There are, however, two differences between Japanese and black African patients in this regard: only 23% of expanding HCCs in the former compared with 54% in the latter arise in a normal liver, and expanding HCCs with a well-defined capsule are common in Japanese patients but rare in black African (and in North American) patients [40]. Moreover, encapsulated expanding tumors in Japanese patients arise almost exclusively in cirrhotic or precirrhotic livers [40]. In most black African populations, HCC coexists with cirrhosis less often than in other populations, including ethnic Chinese patients. In these other populations, cirrhosis is present in about 80% of patients with HCC [12, 20], whereas in black Africans this figure may be as low as 35% [15, 34, 41]. When the fibrolamellar variant of HCC occurs it almost always does so in patients living in the industrialized Western world: it either does not occur or is extremely rare in black African, ethnic Chinese, and Japanese patients. Patients with fibrolamellar HCC are typically young adults, have an equal sex distribution, do not have coexisting cirrhosis, have a normal serum AFP, and are not infected with either HBV or HCV. They generally have a better prognosis than do other forms of HCC.

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Treatment The treatment of HCC in black Africans is very unrewarding. Symptomatic HCC is rarely resectable in these patients. For example, only 8% of Ugandan [42] and only 1% of Southern African blacks with HCC [43] have resectable tumors, compared with resectability rates of up to 37% in some industrialized countries with a low incidence of the cancer [44] and up to 20% in Japanese patients [45]. Ethnic Chinese patients too have low resectability rates, e.g. 3% in Hong Kong Chinese [20]. The other surgical option in patients with HCC is liver transplantation. Because of the nature of this operation, more patients with HCC would be considered to be suitable for liver transplantation than would be amenable to hepatic resection. Even so, with the often advanced stage of the disease and the poor general condition of black African patients when they seek medical attention, as well as the frequency of spread beyond the liver, few would be suitable candidates for liver transplantation. In addition, facilities for liver transplantation are extremely limited in sub-Saharan Africa and very few, if any, such operations are being performed. Accordingly, there is no information on the results of liver transplantation for HCC in sub-Saharan Africa. No stratified randomized trials have shown that radiotherapy is of value in the treatment of HCC in black Africans, or indeed in any population [32]. A large number of anticancer agents, given alone or in combination and by intravenous and intra-arterial routes, have been administered to black Africans with HCC in adequate clinical trials without achieving a significant response rate, and this is also true of biologic response modifiers [32]. These results are worse than those in other populations. The reasons for the poorer results are the lateness of presentation with very large tumor burdens and perhaps a higher incidence of multiple drug resistance genes in black Africans. The use of new targeted chemotherapeutic drugs, such as the multikinase inhibitors, that are proving useful in treating patients in industrialized countries, have yet to be tried in black African patients.

Etiology and pathogenesis The spectrum of causal associations of HCC differs in different geographic regions. In sub-Saharan Africa the important environmental risk factors are chronic HBV infection, repeated dietary exposure to the fungal toxin, aflatoxin B1, dietary iron overload, and chronic HCV infection. Membranous obstruction of the IVC is also a risk factor, and alcoholic cirrhosis may play a lesser etiologic role in older urbanized black Africans. Minor environmental risk factors implicated in other populations, namely, cigarette smoking, oral con-

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traceptive steroids, and anabolic androgenic steroids, have not been incriminated in black Africans, although the reason for this may be the difficulty in proving statistically a role for marginal risk factors in the presence of one or more major risk factors. Chronic HBV infection is also the main causal association of HCC in ethnic Chinese populations, and exposure to aflatoxin B1 contributes to the etiology of the tumor in the People’s Republic of China, Taiwan, Thailand, and perhaps other countries in the Far East. In Japan and most other industrialized countries, chronic HCV infection is the predominant causal association of HCC, often in association with alcoholic cirrhosis. Chronic HBV infection plays a secondary role in these countries.

Hepatitis B virus Chronic HBV infection is the predominant risk factor for HCC in sub-Saharan Africa. As many as 98% of black Africans (average figure 75%) are infected with this virus during their lifetime, and about 10% become chronically infected [46]. Based on case-control studies, the relative risk for a black African who is a chronic carrier of HBV developing HCC is as high as 23.3 [46–48]. The infection is largely acquired in early childhood, mainly as a result of horizontal transmission of the virus from recently infected and hence highly infectious young (under 5 years of age) siblings or playmates, with perinatal infection by HBV e antigenpositive carrier mothers playing a far lesser role [49, 50]. Fifty to 90% of children infected at this age become chronic carriers of the virus, and it is these early-onset carriers that are at very high risk for HCC development. The majority of black Africans suffering from HCC are actively infected with HBV at the time the tumor becomes clinically evident, and most of the remainder show serologic evidence of past infection with the virus [46, 47, 49]. The association between the virus and the tumor may be even closer than serologic data indicate. Studies using monoclonal rather than polyclonal antibodies to detect viral antigens have shown HBV surface antigen (HBsAg) to be present in the serum of patients testing negative for markers of current HBV infection with conventional assays [51]. Moreover, Southern hybridization and the polymerase chain reaction assays have detected HBV DNA in liver and tumor tissue of such patients [52]. Occult HBV infection has been demonstrated both in apparently healthy black African carriers of HBV [53] and in the majority of black African patients with HCC who are HBsAg-negative but positive for anti-HBc and/ or anti-HBs [54]. Individuals with occult HBV infection may progress to HCC formation [55]. The pathogenesis of HBV-induced HCC remains uncertain [56]. There is no evidence to suggest that the mechanisms involved are substantially different in black Africans from those in other populations. One possible difference is the role of specific mutations in the RNA encapsidation signal (ε) of HBV, which have been described in about 30% of

CHAPTER 42

HCCs in black Africans [57]. but not, thus far, in other populations. Mutations at nucleotide 1862 in the bulge of ε, frequently accompanied by a mutation at codon 1888 in the upper stem, may be responsible for an e antigen-negative phenotype as a result of its effect on signal peptide cleavage of the precore–core protein. The e antigen negativity favors persistence of the virus and might thus increase the likelihood of integration of HBV DNA into cellular DNA and set in motion the complex stepwise pathogenesis of HCC.

Aflatoxin B1 A hepatocarcinogenic role for aflatoxin B1, a toxin derived from the molds Aspergillus flavus and A. parasiticus, is confined to sub-Saharan Africa and parts of East and South-East Asia [58]. These fungi are ubiquitous in developing countries, particularly those with warm and humid climates, and may contaminate staple crops, either in the ground or as a result of improper storage. Aflatoxin B1 is metabolized to a highly reactive epoxide. Heavy exposure to the toxin has been shown in parts of sub-Saharan Africa and China to correlate with a specific inactivating mutation of the third base of codon 249 of the p53 tumor suppressor gene, suggesting one way in which the toxin may contribute to hepatocarcinogenesis [59–61]. Heavy exposure to aflatoxin B1 occurs in the same geographic regions as are endemic for HBV infection and a strong positive interaction between the two carcinogens has been demonstrated [62].

Hepatitis C virus With the exception of Somalia, where HBV and HCV appear to play equal causal roles in HCC [63], chronic HCV infection is implicated in the etiology of a minority only of these tumors in sub-Saharan Africa, ranging from 6.2% in Mozambique to 23.1% in Niger [14, 64, 65]. Black Africans with HCV-induced HCC are on average two decades older than those with HBV-induced tumors [14, 64, 65]. This age differential is more striking than that in industrialized countries, where the difference in average age is one decade or less [14]. Male predominance is less obvious in black Africans with HCV-related than in those with HBV-related HCC, although this difference just fails to reach statistical significance [65]. Black patients with HCV-related HCC are more likely to be urban dwellers and less likely to be rural dwellers than those with HBV-associated tumors [65]. Genotype 5a of HCV occurs almost exclusively in Southern Africa and accounts for approximately 50% of the isolates [66]. Its oncogenic potential appears to be no more or less than that of the other genotypes [66].

Liver Tumors in Africa

cally of the macronodular variety with thin fibrous septa between the nodules and very little inflammatory reaction. It is usually the result of chronic HBV infection. However, in older urban or urbanized blacks with the tumor, a small proportion of patients have coexisting cirrhosis that shows the typical features of prolonged alcohol abuse [41, 67]. These patients do not have evidence of chronic HBV or HCV infection, and alcoholic cirrhosis may be the main reason for neoplastic transformation. In contrast, in industrialized countries with a low incidence of HCC, alcoholic cirrhosis is a dominant risk factor, often together chronic HCV infection.

Iron-loading diseases The inherited iron-loading disease, hereditary hemochromatosis, which is well known to carry a high risk for HCC development, does not occur in black Africans. However, another iron-loading disease, dietary iron overload (previously called Bantu visceral siderosis), is unique to black Africans living in sub-Saharan Africa, and it too carries an increased risk for neoplastic transformation (relative risk 10.6) [68]. In some parts of sub-Saharan Africa as many as 15% of the men are iron overloaded. Generation of reactive oxygen species with resulting oxidative damage appears to play a central role in the pathogenesis of this form of HCC.

Membranous obstruction of the inferior vena cava This is a rare vascular abnormality that is either a developmental anomaly or the late result of early IVC thrombosis. In South Africa and Japan, and very occasionally elsewhere, it is often complicated by HCC development: the tumor occurs in 46% of black Africans [69, 70] with this anomaly. Malignant transformation is thought to be the result of continuous hepatocyte necrosis and regeneration secondary to the chronic hepatic venous hypertension.

Self-assessment questions 1 What are the reasons for the underdiagnosis of hepatocellular carcinoma in sub-Saharan black Africans? 2 What change in a patient’s condition may alert the clinician to the possibility that hepatocellular carcinoma has supervened in a cirrhotic liver?

Cirrhosis

3 Is a raised serum alpha-fetoprotein level a more useful test for the presence of hepatocellular carcinoma in Black African patients or in European Causcasian patients?

HCC coexists with cirrhosis in 80–90% of patients in most geographic regions. The exception is in black Africans, in whom the association is generally appreciably less common [15]. The cirrhosis found in black Africans with HCC is typi-

4 What are the two major environmental risk factors for hepatocellular carcinoma in sub-Saharan Black Africans?

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5 Which environmental risk factor for hepatocellular carcinoma causes a specific inactivating mutation of the p53 tumour suppressor gene?

References 1 Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of 25 major cancers. Int J Cancer 1999;80:827–41. 2 Bosch FX, Ribes J, Borras J. Epidemiology of primary liver cancer. Semin Liver Dis 1999;19:271–85. 3 Prates MD, Torres FO. A cancer survey in Lourenco Marques, Portugese East Africa. J Natl Cancer Inst 1965;35:729–57. 4 Parkin DM. Cancer Occurrence in Developing Countries. Scientific publications no. 75. Lyon: IARC, 1986. 5 Muir C, Waterhouse JAH, Mack T, Powell J. Cancer Incidence in Five Continents, Vol 5. Scientific publications No.15. Lyon: IARC, 1987. 6 Kew MC, Macerollo P. The effect of age on the etiologic role of the hepatitis B virus in hepatocellular carcinoma in blacks. Gastroenterology 1998;94:439–42. 7 Kew MC, Dos Santos HA, Sherlock S. The diagnosis of primary cancer of the liver. Br Med J 1971;4:408–11. 8 San Jose D, Cady A, West M, et al. Primary carcinoma of the liver. Am J Dig Dis 1965;10:657–74. 9 Kew MC, Geddes EW. Hepatocellular carcinoma in rural southern African blacks. Medicine (Balt) 1985;61:98–108. 10 Alpert ME, Hutt MSR, Davidson CS. Primary hepatoma in Uganda. A prospective clinical and epidemiological study of 46 patients. Am J Med 1969;46:794–802. 11 Bagshawe A, Cameron HM. The clinical problem of liver cell cancer in a high incidence region. In: Cameron HM, Linsell DA, Warwick GP, eds. Liver Cell Cancer. Amsterdam: Elsevier, 1976; 45–59. 12 Sung J-L, Wang T-H, Yu J-Y. Clinical study on primary carcinoma of the liver in Taiwan. Am J Dig Dis 1997;12: 1036–49. 13 Kew MC, Hodkinson J, Paterson AC, Song E. Hepatitis B virus infection in black children with hepatocellular carcinoma. J Med Virol 1982;9:201–7. 14 Kew MC. Hepatitis C virus and hepatocellular carcinoma. FEMS Microbiol Rev 1994;14:211–20. 15 Kew MC, Popper H. The relationship between hepatocellular carcinoma and cirrhosis. Semin Liver Dis 1984;4:136–46. 16 Epstein S. Primary carcinoma of the liver. Am J Med Sci 1964;48:1347–53. 17 Okuda K. Clinical presentation and natural history of hepatocellular carcinoma and other liver cancers. In: Okuda K, Tabor E, eds. Liver Cancer. New York: Churchill Livingstone, 1997: 1–12. 18 Pavlica D, Samuel I. Primary carcinoma of the liver in Ethiopia. Br J Cancer 1970;24:22–9. 19 Thomas GE, Wicks ACB, Clain DJ, et al. Hepatocellular carcinoma in the Rhodesian African. Dig Dis 1997;22:573–81. 20 Lai CL, Lam KC, Wong KP, et al. Clinical features of hepatocellular carcinoma: Review of 211 patients in Hong Kong. Cancer 1981;47:2746–55.

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21 Davies JNP. Cancer of the Liver in Trans-Saharan Africa. UICC Monograph No. 1. Berlin: Springer-Verlag, 1961. 22 Steiner PE. Cancer of the liver and cirrhosis in trans-Saharan Africa and the United States of America. Cancer 1960;13: 1085–166. 23 Anthony PP. Primary carcinoma of the liver: A study of 282 cases in Ugandan Africans. J Pathol 1973;110:37–48. 24 Chearanai O, Plengvanit U, Asavanich C, et al. Spontaneous rupture of primary hepatoma. Cancer 1983;51:1532–6. 25 Kew MC, Paterson AC. Unusual clinical presentations of hepatocellular carcinoma. Trop Gastroenterol 1985;6:10–22. 26 Kew MC, Hodkinson J. Rupture of hepatocellular carcinoma as a result of blunt abdominal trauma. Am J Gastroenterol 1991;86:1083–5. 27 Kew MC, Dusheiko GM. Paraneoplastic manifestations of hepatocellular Carcinoma. In: Berk PD, Chalmers TC, eds. Frontiers in Liver Disease. New York: Thieme-Stratton Inc, 1981: 305–19. 28 Kew MC. Clinical manifestations and paraneoplastic syndromes of hepatocellular carcinoma. In: Okuda K, Ishak KG, eds. Neoplasms of the Liver. Tokyo: Springer-Verlag, 1987:199– 211. 29 DiBisceglie AM, Hodkinson HJ, Berkowitz I, Kew MC. Pityriasis rotunda – a cutaneous marker of hepatocellular carcinoma in southern African blacks. Arch Dermatol 1986;122:802–4. 30 Berkowitz I, Hodkinson HJ, Kew MC, DiBisceglie AM. Pityriasis rotunda as a cutaneous marker of hepatocellular carcinoma: A comparison with its prevalence in other diseases. Br J Dermatol 1989;120:545–9. 31 Ito M, Tanaka T. Pseudo-ichthyose acquise en taches circulaires. Ann Dermatol et Syphil 1960;87:826–37. 32 Falkson G, Falkson CI. Current approaches in the management of patients with hepatocellular carcinoma. Oncol Res 1989; 4:87–9. 33 Purves LR. Alpha-fetoprotein and the diagnosis of liver cell cancer. In: Cameron HM, Linsell DA, Warwick GP, eds. Liver Cell Cancer. Amsterdam: Elsevier, 1976:61–80. 34 Kew MC. Hepatocellular carcinoma with and without cirrhosis: A comparison in southern African blacks. Gastroenterology 1989;97:136–9. 35 Goldberg RG, Bersohn I, Kew MC. Hypercholesterolemia in primary liver cancer. S Afr Med J 1975;49:1464–6. 36 Kew MC. Tumor markers in HCC. J Gastroenterol Hepatol 1989;4:373–84. 37 Trichopoulos D, Sizaret P, Tabor E, et al. Alpha-fetoprotein levels of liver cancer patients and controls in a European population. Cancer 1980;46:736–40. 38 Kew MC. Detection and treatment of small hepatocellular carcinomas. In: Hollinger FB, Lemon SM, Margolis HS, eds. Viral Hepatitis and Liver Disease. Baltimore: Williams and Wilkins, 1991:535–40. 39 Levy JI, Geddes EW, Kew MC. The chest radiograph in primary liver cancer: An analysis of 449 cases. S Afr Med J 1976;50: 1323–6. 40 Okuda K, Peters RL, Simson IM. Gross anatomic features of hepatocellular carcinoma from 3 disparate geographic areas. Cancer 1984;54:2165–73. 41 Paterson AC, Kew MC, Herman AAB, et al. Liver morphology in southern African blacks with hepatocellular carcinoma: A

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44 45

46 47

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49

50

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52

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study within the urban environment. Hepatology 1985;5: 72–8. Harrison NW, Dhru D, Primack A, et al. The surgical management of primary hepatocellular carcinoma in Uganda. Br J Surg 1973;60:565–9. Maraj R, Kew MC, Hyslop RJ. Resectability rate of hepatocellular carcinoma in rural southern Africans. Br J Surg 1988;75:335–8. Foster JA, Berman MM. Solid liver tumors. Major Prob Clin Surg 1977;22:1–342. Okuda K, Ohtsuki T, Obata K, et al. Natural history of hepatocellular carcinoma and relation to treatment. Cancer 1985; 56:918–28. Kew MC. Chronic hepatitis B virus infection and hepatocellular carcinoma in Africa. S Afr J Sci 1992;88:524–8. Coursaget P, Chiron JP, Barres JL, Barin F. Hepatitis B virus serological markers in Africans with liver cirrhosis and hepatocellular carcinoma. In: Williams AO, O’Conor GT, De-The GB, Johnson CA, eds. Virus-associated Cancers in Africa. No. 63. Lyon: IARC, 1984:181–98. Kew MC, Yu MC, Kedda M-A, et al. The relative roles of hepatitis B and C viruses in the etiology of hepatocellular carcinoma in southern African blacks. Gastroenterology 1997;112:184–7. Barin F, Perrin J, Chotard JD, et al. Cross-sectional and longitudinal epidemiology of hepatitis B in Senegal. Prog Med Virol 1981;27:148–62. Botha JF, Ritchie MJJ, Dusheiko GM, et al. Hepatitis B virus carrier state in black children in Ovamboland: Role of perinatal and horizontal infection. Lancet 1984;2:1210–12. Kew MC, Fujita Y, Takahashi H, et al. Comparison between first and second generation monoclonal radioimmunoassays in the detection of hepatitis B virus surface antigen in patients with hepatocellular carcinoma. Hepatology 1986;6:636–9. Paterlini P, Gerken G, Nakajima E, et al. Polymerase chain reaction to detect hepatitis B virus DNA and RNA sequences in primary liver cancers from patients negative for hepatitis B surface antigen. N Engl J Med 1990;323:80–5. Owiredu WKBA, Kramvis A, Kew MC. Hepatitis B virus DNA in serum of healthy black African adults positive for hepatitis B virus surface antibody alone: Possible association with recombination between genotypes A and D. J Med Virol 2001;64: 441–54. Kew MC, Welschinger R, Viana R. Occult hepatitis B virus infection in southern African Blacks with hepatocellular carcinoma. J Gastroenterol Hepatol 2008;23:1426–30. Shafritz DA, Shouval D, Sherman HI, et al. Assessment of hepatitis B virus DNA integration state in chronic liver disease and hepatocellular carcinoma. Studies in percutaneous biopsies and post mortem liver tissues. N Engl J Med 1981;305:1067–73. Arbuthnot P, Kew MC. Hepatitis B virus and hepatocellular carcinoma. J Exp Pathol 2001;82;77–100. Kramvis A, Kew MC, Bukofzer S. Hepatitis B virus precore mutants in serum and liver of southern African blacks with hepatocellular carcinoma. J Hepatol 1998;28:132–41. Wogan GN. Aflatoxin exposure as a risk factor in the etiology of hepatocellular carcinoma. In: Okuda K, Tabor E, eds. Liver Cancer. New York: Churchill Livingstone, 1997:51–8. Bressac B, Kew MC, Wands JR, Ozturk M. G to T mutations of p53 in hepatocellular carcinoma from southern Africa. Nature

Liver Tumors in Africa

1991;350:429–31. 60 Hsu JC, Metcalf RA, Sun T, et al. Mutational hot spot in p53 gene in human hepatocellular carcinoma. Nature 1991;350: 427–8. 61 Ozturk M, Bressac B, Pusieux A, et al. A p53 mutational hot spot in primary liver cancer is geographically localized to high aflatoxin areas of the world. Lancet 1991;338:1356–9. 62 Kew MC. Synergistic interaction between aflatoxin B1 and hepatitis B virus in hepatocarcinogenesis. Liver Int 2003;23:1–5. 63 Bile K, Aden C, Norder H, et al. Important role of hepatitis C virus infection as a cause of chronic liver disease in Somalia. Scand J Infect Dis 1993;24:559–64. 64 Kew MC. Hepatitis C virus and hepatocellular carcinoma in developing and developed countries. Viral Hepatit Rev 1998;4:259–69. 65 Kew MC. Hepatitis c virus infection in black patients with hepatocellular carcinoma in southern Africa. In: Kobayashi K, Purcell RH, Shimotohno K, Tabor E, eds. Hepatitis C Virus and its Involvement in the Development of Hepatocellular Carcinoma. New Jersey: Princeton Scientific Publishing, 1994:33–40. 66 Kedda M-A, Kew MC, Coppin A. Hepatocarcinogenic potential of genotype 5 of hepatitis C virus. Trop Gastroenterol 1998; 18:153–5. 67 Mohamed AE, Kew MC, Groeneveldt HT. Alcohol consumption as a risk factor for hepatocellular carcinoma in urban southern African blacks. Int J Cancer 1992;51:537–41. 68 Mandishona E, MacPhail AP, Gordeuk VR, et al. Dietary iron overload as a risk factor for hepatocellular carcinoma in black Africans. Hepatology 1998;27:1563–7. 69 Simson IM. Membranous obstruction of the inferior vena cava and hepatocellular carcinoma in South Africa. Gastroenterology 1982;82:171–8. 70 Kew MC, McKnight A, Hodkinson J, et al. The role of membranous obstruction of the inferior vena cava in the etiology of hepatocellular carcinoma in southern African blacks. Hepatology 1989;9:121–5.

Self-assessment answers 1 The reasons are inadequate medical and diagnostic facilities in rural areas, where the majority of cases occur, and a nihilistic attitude toward definitive diagnosis conditioned by the absence of effective treatment and the grave prognosis of symptomatic hepatocellular carcinoma in black Africans. Even in urban areas, the tumor is frequently diagnosed on the basis of a raised serum alpha-fetoprotein concentration or the findings on hepatic imaging without obtaining histologic confirmation. Underdiagnosis is compounded by underreporting. In addition, very few African countries have reliable cancer registries. 2 A sudden unexpected change or deterioration in the condition of these patients may alert the clinician to the

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possibility that hepatocellular carcinoma has supervened in the cirrhotic liver. These changes include the onset of abdominal pain or weight loss, ascites may appear or become blood stained, the liver may suddenly enlarge, a hepatic arterial bruit may be heard, or hepatic failure may supervene.

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3 It is a more useful test in Black African patients. 4 Chronic hepatitis B virus infection and dietary exposure to the fungal toxin, aflatoxin B1. 5 Aflatoxin B1.

43

Anesthetic Management of Liver Surgery Marco P. Zalunardo Institute of Anesthesiology, University Hospital of Zurich, Zurich, Switzerland

In the last two decades orthotopic liver transplantation and hepatic resection have grown into established therapies with improved outcome [1]. In specialized centers performing advanced liver surgery, the anesthesiologist is involved in the preoperative evaluation and perioperative management of patients with severe liver disease and should be able to manage the perioperative care of a patient with end-stage liver disease. This chapter will give a short overview of the anesthetic management for liver surgery, including preoperative evaluation, monitoring and instrumentation, hemodynamic and hemostatic management, perioperative complications, and special considerations, such as coagulation monitoring and transesophageal echocardiography.

Preoperative evaluation Hepatic resection and cryosurgery Not every patient who presents for liver surgery has endstage liver disease. Some are asymptomatic and their pathologic findings are limited to the hepatic tumor itself. The preoperative assessment of these patients is similar to that of otherwise healthy patients scheduled for major abdominal surgery. The recommended preoperative investigations are listed in Table 43.1. Patients with comorbid illness appear to be at increased risk for early postoperative morbidity and mortality after hepatic resection [2]. In patients with HCC and underlying liver disease, the presence of comorbid illness may lead to increased physiologic stress and may exhaust the limited liver reserve following extended hepatic resection. Patients who have significant comorbid illness may not be suitable surgical candidates for extended hepatectomy. Hypoalbuminemia, thrombocytopenia, elevated serum creatinine, major hepatic resection, and transfusion were significant predictors of mortality in a series of 1222 consecutive

patients. Concomitant extrahepatic procedure, thrombocytopenia, and transfusion were predictors of morbidity in this study [3]. Elevated serum creatinine and impaired renal function and hepatorenal syndrome may be present in patients with chronic liver disease, advanced hepatic failure, and portal hypertension. Preoperatively, renal function has to be optimized by maintaining sufficient perfusion pressure rather than by excessive volume loading. Rigorous intraoperative volume restriction and total vascular exclusion may lead to serious renal impairment, especially in cases with pre-existing renal insufficiency. The preoperative evaluation and preparation of the patient scheduled for cryosurgery should anticipate possible intraand post-operative complications, such as bleeding, thrombocytopenia, myoglobinuria, acute renal failure, freeze injuries to lung, and pleural effusion. Therefore, aside from standard evaluation, a special focus on coagulation, and renal and lung function is advantageous (see Table 43.1) [4].

Liver transplantation As a member of the interdisciplinary liver group, the anesthesiologist is involved in the pretransplant evaluation of liver transplantation candidates. The main part of their work is to interpret evaluation results and findings, to complete the evaluation with additional investigations when necessary, and to identify absolute and relative contraindications for anesthesia and surgery. Many patients have acute or chronic liver disease with multiple organ dysfunction. Depending upon the deterioration of organ function, intensive evaluation and perioperative monitoring is needed [5]. Furthermore, with adequate knowledge, the patient’s condition may be optimized significantly prior to transplantation [6].

Hepatic encephalopathy

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

The clinical manifestations of hepatic encephalopathy range from a slightly altered mental state to coma. Grade 4 encephalopathy may be complicated by the development of cytotoxic or vasogenic cerebral edema and an increase in

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Table 43.1 Preanesthetic investigations before hepatic resection, cryosurgery, and liver transplantation.* Investigation

Hepatic resection

Cryosurgery

Liver transplantation*

Hct, Hb, Lc, Plts Electrolytes, Ca, Mg Liver function tests Amylase, lipase BG, urea, creatinine PT, PTT Urine analysis ECG BGA Chest X-ray Lung function test Echocardiogram Exercise stress tests

x x

x x

x x

x

x

x

x x

x x

x x

x – x – ± x

x x x – x x

x x x x x x

± ±

± ±

x ±

*For other pretransplant evaluation (immunology, serology, gastroenterology, etc) see Chapter 23. Hct, hematocrit; Hb, hemoglobin; Lc, leukocytes; Tc, platelets; Ca, calcium; Mg, magnesium; liver function tests: aspartate aminotransferase, alanine aminotransferase, alcalic phosphatase; bilirubin; gamma-glutamyltransferase, protein; BG, blood glucose; PT, prothrombin time; PTT, partial thromboplastin time; ECG, electrocardiogram; BGA, arterial blood gas analysis; x, examined; –, not examined; ±, decision on a case-by-case basis.

intracranial pressure (ICP), which is a major cause of mortality in patients with fulminant hepatic failure. Invasive ICP monitoring is the most sensitive method for the diagnosis of raised ICP. Although there are no stringent data, the United States Acute Liver Failure Group recommends ICP monitor placement in patients with clinical signs of grade 3 or early grade 4 encephalopathy [7]. ICP monitoring is also recommended when a patient with documented encephalopathy or brain edema is mechanically ventilated [8]. ICP tends to increase during the dissection phase, decrease during the anhepatic phase, and increase again during the reperfusion phase. Complications of ICP monitoring include infection, hemorrhage, technical malfunction, and false interpretation. Bleeding related to the placement of ICP monitors occurs in 10–20% of patients with acute liver failure, but is often mild and of low clinical significance, although fatal outcomes have been described [9]. Therefore, treatment of the bleeding diathesis before insertion is recommended. Intraventricular placement should be avoided. The goals of

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perioperative ICP management are ICP below 15 mmHg, mean arterial pressure above 80 mmHg, and cerebral perfusion pressure above 65 mmHg. Treatment of intracranial hypertension includes mannitol (0.5–2.0 g/kg/day; serum osmolality is not allowed to exceed 315 mOsm/kg) and a thiopental bolus of 100–200 mg.

Central pontine myelinolysis Central pontine myelinolysis (CPM) is a demyelinating disorder that affects the central portion of the base of the pons cerebri. The clinical manifestation is characterized by irreversible postoperative coma or “locked-in” syndrome after transplantation. In most cases, CPM is a postmortem diagnosis, because the symptoms are obscured by systemic complications. There is a significant relationship between the occurrence of CPM and the increase in sodium concentration during and after liver transplantation [10, 11]. Therefore, liver transplantation in patients with a preoperative sodium concentration below 125 mEq/L is not recommended.

Cardiovascular disease In contrast to earlier studies, recent data show that the prevalence of coronary artery disease (CAD) in patients with end-stage liver disease is equal to or greater than the prevalence rate in the healthy population. Furthermore, the average age of liver transplant candidates has been rising over the years [12]. The morbidity and mortality of patients with CAD who undergo liver transplantation without treatment is very high, making its identification an important consideration. In collaboration with cardiologists, we have established a cardiac evaluation program for liver transplantation candidates at our institution (Table 43.2). Exercise stress echocardiography (ECG) is not a suitable test for most candidates. Ascites, weakness, lethargy, encephalopathy, and drug interactions prevent a successful and convincing test performance. ECG is performed in all candidates for liver transplantation at our institution. ECG is very sensitive for pulmonary hypertension, which is a major perioperative risk factor [13]. In the case series of Krowka et al, patients with a mean pulmonary arterial pressure of 50 mmHg and greater had a mortality of 100%, and patients with a mean pulmonary arterial pressure between 35 and 50 mmHg had a mortality of 50%. No mortality was reported in patients with a mean pulmonary arterial pressure below 35 mmHg [14]. Prior to exclusion of a candidate from the transplantation program, pulmonary hypertension treatment should be established. Prostacycline analogs have been shown to reduce pulmonary pressures significantly and may improve outcome after liver transplantation [15, 16]. ECG is also sensitive for cardiomyopathy in hemochromatosis and dilatative cardiomyopathy in ethylic cirrhosis. Coronary angiography is performed when angina pectoris, a history of myocardial

CHAPTER 43

Table 43.2 Cardiac evaluation of liver transplantation candidates. Examination

Indication

Cardiac history, clinical examination, ECG Screening risk factors for CAD Exercise stress test (ECG)

All patients

Echocardiography Echocardiography control on waiting list

Right heart catheterization Coronary arteriography

Dobutamine stress echocardiography or myocardial perfusion scintigraphy

Anesthetic Management of Liver Surgery

in room air. The inability to achieve a PaO2 of 200 mmHg in an inspired oxygen concentration of 100% may be a contraindication to transplantation [17]. Candidates should stop smoking before transplantation, because pulmonary infection is a major cause of morbidity and mortality after liver transplantation.

All patients

Renal function Inadequate examination for most patients (ascites, lethargy, beta-blockade) All patients All patients every 12 months Patients with pulmonary hypertension (SPAP > 30 mmHg) and/or other pathologic findings in the screening echocardiography Patients with SPAP > 50 mmHg Angina pectoris, history of myocardial infarction, coronary revascularization >5 years ago, congestive heart failure, left bundle block, pacemaker, diabetes mellitus and age >40 years, age >60 years and >2 risk factors for CAD If coronary arteriography is not indicated and one risk factor for CAD or age >60 years

ECG, electrocardiogram; CAD, coronary artery disease; SPAP; systolic pulmonary arterial pressure

infarction, coronary revascularization more than 5 years ago, congestive heart failure, left bundle block, pacemaker, diabetes mellitus and age older than 40 years, age older than 60 years, and more than two risk factors for CAD are present. The sensitivity and specificity of dobutamine stress ECG for CAD is controversial. However, it is a noninvasive investigation with significantly lower mortality and morbidity than coronary angiography. Alternatively, myocardial perfusion scintigraphy, a less invasive screening method with similar sensitivity, may be performed.

Renal function may be impaired in liver transplantation candidates. Hepatorenal syndrome (HRS) is characterized by a reduction of renal blood flow, glomerular filtration rate, urine output, and dilutional hyponatremia in the absence of histologic pathology. Renal function usually recovers after transplantation. Spontaneous recovery without transplantation is very rare. Hemodialysis and hemofiltration can serve as renal support pre-, intra-, and post-operatively [18]. The long-term outcome of patients with cirrhosis and HRS is good, although the presence of HRS is associated with increased morbidity and early mortality. Immediately after transplantation, a further impairment in renal function may be observed. Five percent of patients progress to end-stage renal disease and require long-term hemodialysis.

Coagulopathy Patients with hepatic dysfunction can develop extensive blood-clotting abnormalities. Prothrombin time and partial thromboplastin time may be prolonged. In the liver, vitamin K-dependent clotting factors, specific inhibitors of coagulation, plasminogen, and alpha-2-antiplasmin are synthesized. Malabsorption of vitamin K in patients with chronic liver disease leads to a deficit of coagulation factors II, VII, IX, and X, and the anticoagulant factors protein C and S. Administration of vitamin K may improve hepatic coagulation factor production. Thrombocytopenia is common and is due to bone marrow suppression, chronic disseminated intravascular coagulation, and hypersplenism.

Electrolyte and metabolic disorders Sodium concentration is often low in cirrhotic patients due to renal dysfunction and ascites therapy with diuretics. Deterioration in hepatic function can result in a vast array of metabolic abnormalities, including hypoglycemia, lactic acidosis, hypoproteinemia, clotting factor deficiency, and hyperammonemia. Hypoglycemia can deprive all tissues of energy substrates, most importantly the brain.

Pulmonary function Assessment of the pulmonary condition should include auscultation, chest radiograph, pulmonary function tests, and arterial blood gases. Impaired gas exchange due to ventilation–perfusion mismatch, inadequate hypoxic pulmonary vasoconstriction, atelectasis associated with ascites, and intrapulmonary shunting may result in serious hypoxemia in patients with hepatic failure. Mortality in patients with hepatopulmonary syndrome is associated with lower PaO2

Intraoperative management Hepatic resection Monitoring and instrumentation Aside from standard monitoring, including ECG, pulse oximetry, temperature, and end-tidal gas analysis, invasive arterial blood pressure measurement and central venous

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Table 43.3 Hepatic clearance of perioperative drugs and inhalational agents. (Modified and supplemented from [11, 25, 45, 54].) Flow limited

Flow limited, enzyme limited

Not flow limited, not enzyme limited

Enzyme limited, binding sensitive

Enzyme limited, binding insensitive

Inhalational, low metabolism

Morphine Lidocaine Propranolol Labetalol Nitroglycerine Midazolam Etomidate

Meperidine Metoprolol Alfentanil

Propofola Fentanylb

Diazepam Chlordiazepoxide Warfarin Phenytoin Lorazepam

Ketamine Thiopental Theophylline Succinylcholine

Isoflurane Desfluranec Sevofluranec

a, prolonged recovery; b, with accumulation (repeated doses), enzymatic biotransformation may be limiting for clearance; c, no clinical data for routine use in liver surgery.

access with a multiple lumen catheter are mandatory. Rapid infusion systems, such as Level 1 (SIMS Level 1® Inc, MA), facilitate large volume infusion in a short time, combined with air detection, air removal, and warming. They are standard equipment in cardiac, trauma, and liver transplant surgery. One or more large cannulas for peripheral venous access should be installed. Indications for further instrumentation with pulmonary artery catheter or transesophageal echocardiography depend upon the patient’s cardiovascular risk profile. Installation of thoracic epidural analgesia appears to be advantageous in terms of pain relief, mobility, and postoperative pulmonary complications [19], and is part of the standard procedure at our institution.

Anesthesia induction and maintenance Intravenous as well as inhalational anesthesia, except halothane and nitrous oxide, are appropriate for hepatic resection. However, cirrhotic patients may have prolonged recovery after propofol anesthesia. In summary, drugs with elimination properties independent of liver blood flow or protein binding are preferred (Table 43.3). If thoracic epidural analgesia and general anesthesia are combined, cardiodepressive anesthetics should be titrated cautiously, because systemic vascular resistance is lowered by epidural sympatholysis. To avoid awareness due to insufficient depth of anesthesia, especially in hemodynamically unstable patients with combined anesthesia, bispectral index (BIS) monitoring may be useful. Immediate postoperative extubation is routinely performed, if cardiopulmonary stability, temperature, and recovery of the patient are satisfactory.

Hemodynamic management Bleeding during hepatic resection may be limited by adequate surgical technique, vascular exclusion, and avoidance of venous volume overload (Table 43.4) [20–22]. In over 30

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Table 43.4 Intraoperative measures to reduce bleeding during hepatic resection. • • • • • • • •

Adequate surgical access with sufficient organ exposure Spacious mobilization of the liver Pringle maneuver Hepatic vascular exclusion Controlled dissection of liver parenchyma Ultrasonic dissection Argon-beam coagulation Avoidance of venous volume overload

years of successful hepatic resection, reduction of bleeding and blood product use has paralleled the introduction of advanced surgical techniques and novel auxiliary devices (ultrasonic dissection, argon-beam coagulation). Jones et al [21] and recently Wang et al [23] demonstrated that perioperative blood loss is also correlated with central venous pressures (CVP) above 5 mmHg. In contrast, another prospective study showed that maintaining CVP below 5 mmHg was not associated with a reduction in blood loss [24]. However, there is a direct and undamped anatomic connection between the inferior vena cava (IVC) and the sinusoids. Therefore, fluid overload causes swelling of the liver volume up to 1500 mL and significant increase in blood loss. Accordingly, fluid management should be as restrictive as possible. CVP as the right ventricular filling pressure is not reliably comparable to the filling pressures in the hepatic veins and the IVC, especially when venous return is impaired by surgical mobilization of the liver. Thus, used as sole guidance for fluid management during hepatic resection, absolute “target” values of CVP are insufficient and may be misleading [25]. Heart rate trends, arterial pressure trends, arterial pressure

CHAPTER 43

curve, blood gas analysis, urine output, and CVP trends give more information. Volume overload may be avoided by venous pooling with low-dose 1–3 μg/kg/min nitroglycerine infusion. Arterial hypotension is treated with vasoactive support. Corresponding to the low systemic vascular resistance and the high cardiac output in cirrhotic patients with thoracic epidural sympatholysis, norepinephrine infusion is recommended.

Perioperative complications and adverse events Too aggressive volume restriction may also lead to renal insufficiency. In a retrospective study of 496 patients, 3% experienced a persistent and clinically significant increase in serum creatinine [26]. Most patients with ascites have diuretic therapy, which has to be continued perioperatively. The renal protective effects of low-dose dopamine by increasing renal blood flow is seriously questioned and routine use is not recommended. The following variables are significantly related to postoperative morbidity: age above 55 years, American Society of Anesthesiologists (ASA) physical status II or more, bilirubin greater than 80 μmol/L, alkaline phosphatase activity more than double the reference range, malignant tumors, abnormal liver parenchyma, simultaneous surgical procedures, operative time above 4 h, and perioperative blood transfusion above 600 mL, whereas blood transfusion and simultaneous surgery have the strongest correlation [27].

Cryosurgery and continuous intra-arterial chemotherapy Monitoring and instrumentation for cryosurgery and continuous intra-arterial chemotherapy are similar to those for hepatic resection. Common perioperative complications are hypothermia, thrombocytopenia, fever, and basal pulmonary atelectasis, while the following are less frequent: bleeding, acute renal failure, freeze injuries to skin, lung and other tissues, pleural effusion, disseminated intravascular coagulation, prolonged prothrombin time, and hypoglycemia. Myoglobinemia and myoglobinuria develop usually after cryosurgery and may cause tubular necrosis. Urine output monitoring and aggressive therapy of oliguria and acidosis are mandatory [28].

Liver transplantation The following sections concentrate on clinically relevant issues for the anesthetic management of liver transplantation.

Anesthetic Management of Liver Surgery

pulmonary artery catheter is mandatory. Despite ECG controls, pulmonary hypertension may be undetected until the day of transplantation [16]. Continuous cardiac output and continuous mixed oxygen saturation measurement (Swan-Ganz CCOmbo SvO2, Edwards Lifesciences Corporation, CA, USA) are optional, but make perioperative data collection much easier and give useful and quick hemodynamic information in most critical situations. Following the practice guidelines of the ASA Task Force on Perioperative Transesophageal Echocardiography (TEE), TEE monitoring in liver transplantation is a recommended indication. TEE is believed to be more accurate in diagnosing the cause of hemodynamic disturbances than is CVP or pulmonary artery catheter monitoring [29]. TEE use in liver transplantation is further discussed below (see Special considerations). The installation of an autotransfusion system may be useful when augmented blood loss is expected due to compromised blood coagulation, massive portal hypertension, or extraordinary abdominal anatomy. Blood coagulation is not altered by blood salvage with cell saver.

Anesthesia induction and maintenance Drugs with elimination properties independent of liver blood flow or protein binding are preferred (see Table 43.3). There is no favourite drug set listed in most reviews on anesthetic management of liver transplantation, but a slight trend for inhalational anesthesia may be seen, especially for isoflurane [30, 31] In animal models flow velocity is enhanced with isoflurane, and hepatic arterial autoregulation and oxygen delivery are effectively maintained [32]. There is little scientific information about sevoflurane or desflurane anesthesia in liver transplantation in humans. Rapid sequence induction is recommended in patients with ascites and a history of food intake 6 h before induction of anesthesia [33]. Muscle relaxation with atracurium is advantageous in patients with known or expected renal impairment [34]. The administration of 4 μg/kg clonidine during induction of liver transplantation significantly reduced the intraoperative requirements for intravenous fluids and blood products without compromising the circulatory stability. Improvement in immediate reperfusion-induced disturbances was also observed [35]. The standard anesthetics for liver transplantation at our institution are: for the induction of anesthesia, midazolam 0.02 mg/kg (except when encephalopathy is present), etomidate 0.15–0.2 mg/kg, fentanyl 1.5–2.5 μg/kg, and succinylcholine 1.5 mg/kg or atracurium 0.6 mg/kg; for anesthesia and relaxation maintenance: atracurium, fentanyl, and isoflurane.

Monitoring and instrumentation Monitoring and instrumentation for liver transplantation significantly exceed the routine standard level for major abdominal surgery and hepatic resection. Aside from invasive arterial blood pressure measurement and central venous access with a multiple lumen catheter, the installation of a

Hemodynamic management Aside from patient-related factors, such as coagulation profile or cardiovascular status, hemodynamic management basically depends on the surgical technique and the use of venovenous bypass. Cross-clamping of the IVC results in a

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marked reduction of venous return and cardiac output. This phenomenon is less pronounced in patients with end-stage liver disease, because left ventricular preload is partially preserved by the inflow through venous collateral vessels. If the piggyback technique of caval anastomosis is used or venovenous bypass is installed prior to cross–clamping, venous return may be significantly improved and cardiac output maintained [5, 31] The decrease in cardiac output during cross-clamping without venovenous bypass may be compensated by fluid administration and vasoactive support. On condition that the function of both ventricles is normal, norepinephrine infusion is recommended to address the low systemic vascular resistance in cirrhotic patients. In case of ventricular failure, dobutamine or epinephrine infusions are indicated. Under these precautions cross-clamping of 40– 60 min duration is usually well tolerated. Dramatic changes in hemodynamic parameters may occur immediately after reperfusion of the transplanted liver and may be characterized by a decrease in arterial blood pressure, bradycardia, supraventricular and ventricular arrhythmias, and occasionally cardiac arrest. The incidence of this postreperfusion syndrome may be up to 30% [36]. Immediately after reperfusion, left ventricular function may be impaired and pulmonary capillary wedge pressure may increase, while TEE monitoring shows a stable or even decreased left ventricular end-diastolic volume. These contrary findings may be due to a period of deteriorating left ventricular compliance or “cardioplegia” on reperfusion [37, 38]. Cautious TEE-guided titration of fluids may then be beneficial.

may question the routine use of aprotinin in all liver transplant recipients [41]. Moreover, the drug has been withdrawn from the worldwide market because of serious adverse events during an ongoing study. As an alternative treatment, tranexamic and epsilon-aminocaproic acids may be used as antifibrinolytic agents during liver transplantation, but their effect on transfusion requirements is controversial [42, 43]. Calcium is an important coenzyme in the coagulation cascade. During the preanhepatic and anhepatic phases of liver transplantation, hypocalcemia may develop, especially when large amounts of fresh frozen plasma have been given. In many transplant centers, continuous calcium infusions are part of standard therapy. Fresh frozen plasma and cryoprecipitate should be indicated restrictively in recipients with a normal coagulation profile. In contrast, in patients with severely prolonged prothrombin time or a corresponding TEG or rotation thromboelastometry (ROTEM) pattern, fresh frozen plasma, cryoprecipitate, and factor concentrates are indicated.

Postoperative complications Major postoperative complications after liver transplantation may be neurologic, infectious, hematologic, renal, metabolic, cardiovascular, pulmonary, and gastrointestinal (Table 43.5). A detailed description of postoperative complications is beyond the scope of this chapter.

Special considerations Coagulation monitoring

Hemostatic management Patients with pre-existing coagulation disorders are common liver transplant recipients. Especially during hepatectomy, blood loss and concomitant hyperfibrinolysis, coagulation factor deficiency, and thrombocytopenia are not always predictable, and transfusion requirements are variable. Without prompt, efficient, and specific volume replacement therapy with blood components, massive bleeding may result. Hemostatic management with advanced monitoring techniques is mandatory for adequate substitution with blood components during liver transplantation. Thromboelastography (TEG) and other useful on-site devices have been rediscovered or developed for coagulation monitoring. They will be discussed later in this chapter. Hyperfibrinolysis contributes to bleeding during orthotopic liver transplantation. Intraoperative use of aprotinin significantly reduces blood transfusion requirements and prophylactic use of aprotinin ameliorates the postreperfusion syndrome in liver transplantation, as reflected by a significant reduction in vasopressor requirements [39, 40]. However, reports on fatal pulmonary thromboembolism

524

The documented benefits of perioperative monitoring of coagulation are reduced consumption of blood and blood products, appropriate volume replacement with blood components, and improved haemostasis management [44].

Thromboelastography TEG was introduced in 1948 by Hellmut Hartert as a research tool [45]. It did not gain widespread usage in clinical practice until Yoogoo Kang and his group used it for coagulation monitoring during liver transplantation in the early 1980s. The TEG principle is simple: a heated cup with whole blood oscillates, while a pin is suspended freely in it from a torsion wire. When the clot starts to form, the fibrin strands increase the elastic shear modulus of the sample. Electromagnetic transduction converts this signal to a TEG tracing. The TEG parameters have specific characteristics. The reaction time, r, depends on the activity of the intrinsic system and increases with factor deficiency. k Measures the speed of clot development and describes thrombin activity and fibrin formation. Alpha is the angle formed by the slope of the tracing from the r to the k value. It indicates the speed of clot strengthening and measures the activity of the intrinsic system and platelet function or count. Maximum amplitude (MA) is the

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Anesthetic Management of Liver Surgery

3500

Table 43.5 Major postoperative complications after liver transplantation.

3000

greatest amplitude of the tracing. It represents the absolute strength of the clot and the maximum dynamic properties of fibrin and platelets. The TEG index is a linear combination of the TEG parameters with specific coefficients. It increases with hypercoagulability, decreases with hypocoagulability, and shows good correlation with bleeding and the coagulation profile [46] Kang and his group demonstrated that hemostasis management with TEG decreases blood transfusion requirements during liver transplantation [47]. To illustrate the clinical impact of TEG, three consecutive TEG tracings from a 60-year-old patient are shown in Figures 43.1–43.3. The patient had chronic C hepatitis, Child class C cirrhosis, and mild renal insufficiency. Initial platelet count was only 44 000/mL and the prothrombin time 76%.

2500 Blood loss (mL)

Neurologic: • Seizures • Encephalopathy • Central pontine myelinolysis • Stroke • Intracranial hemorrhage Infectious Fungal: • Bacterial • Viral • Protozoal • HIV • Hematologic • Coagulopathy • Disseminated intravascular coagulation • Thrombosis (hepatic vessels) • Lymphoproliferative disorders • Bone marrow depression Renal: • Renal tubular necrosis Metabolic: • Protein catabolism Cardiovascular: • Cardiac failure • Hypotension • Shock • Bradycardia Pulmonary: • Pulmonary edema • Acute respiratory distress syndrome Gastrointestinal: • Hemorrhage (esophageal varices, intra-abdominal) • Pancreatitis • Liver failure • Biliary leakage

2000 1500 1000 500

0

2

6 8 10 12 4 Mean caval pressure (mmHg)

14

16

Figure 43.1 Correlation between blood loss and inferior vena caval pressure during liver resection. (Reproduced from Johnson et al. Br J Surg 1998;85:188–90, with permission.)

However, platelets were not substituted at that time because, from a clinical point of view, coagulation was good and TEG showed only a very slight decrease in MA (Figure 43.2). During the anhepatic period, coagulation deteriorated, MA decreased, and reaction time increased (Figure 43.3). In order to increase MA, 12 units of platelets and 10 units of fresh frozen plasma were given to decrease reaction time. After reperfusion, the TEG was normal, the platelet count 66 000/mL, and the prothrombin time 75% (Figure 43.4). It is likely that more units of platelets would have been given without the information from the TEG. In the last few years, the ROTEM TEG analyzer (Pentapharm GmbH, Munich, Germany) has gained widespread acceptance as the perioperative coagulation monitoring tool. The ROTEM creates similar traces to conventional TEG, but offers also the possibility to test specific coagulation components, e.g. fibrinogen concentration and function (Figure 43.5). This new coagulation monitoring method may improve hemostasis management in liver transplantation [48].

On-site prothrombin time and partial thromboplastin time devices The perioperative utility of laboratory hemostasis assays is limited by the delay in obtaining results. The hemostasis management of liver surgery still requires rapid and accurate information about the prevailing coagulation status. Therefore, on-site coagulation monitoring may be beneficial. Furthermore, Despotis et al demonstrated that the use of on-site coagulation assays can reduce the use of blood products, decrease the operating time, and minimize the chest tube drainage in cardiac surgery [49]. The portable

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Plts. 44 000/mL PT 76%

+0.60 TEG index: Normal range: –2.0 to +2.0

10 mm scale

Pt: NR:

SP (mm) R (mm) K (mm) MA (mm) Ang (deg) 5.5 6.0 4.0 66.5 49.5 10–14 3–6 59–68 54–67

LY30 (%) 3.0

LY60 (%) 7.0

Figure 43.2 Thrombelastography (TEG) tracing during hepatectomy in a 60-year-old patient with chronic C hepatitis, Child class C cirrhosis and mild renal insufficiency. MA is slightly decreased, but TEG index and all other parameters are normal. Plts, platelet count; PT, prothrombin time; NR, normal range of TEG parameters.

Plts. 35 000/mL PT 56%

TEG index: –9.27 Normal range: –2.0 to +2.0

10 mm scale

Pt: NR:

SP (mm) R (mm) K (mm) MA (mm) Ang (deg) 21.0 23.5 11.0 37.0 44.5 10–14 3–6 59–68 54–67

LY30 (%) 1.0

LY60 (%) 3.0

Figure 43.3 Thrombelastography (TEG) tracing during the anhepatic phase. MA is decreased and reaction time increased, and the lowered TEG index indicates hypocoagulability. Plts, platelet count; PT, prothrombin time; NR, normal range of TEG parameters.

Plts. 62 000/mL PT 75%

+2.23 TEG index: Normal range: –2.0 to +2.0

10 mm scale

Pt: NR:

SP (mm) R (mm) K (mm) MA (mm) Ang (deg) 6.0 7.0 3.0 69.5 62.0 10–14 3–6 59–68 54–67

LY30 (%) 0.0

LY60 (%) 1.0

Figure 43.4 Thrombelastography (TEG) tracing after reperfusion. After substitution with 12 units of platelets and 10 units of fresh frozen plasma, the TEG tracing and TEG index indicate normal coagulation. Plts, platelet count; PT, prothrombin time; NR, normal range of TEG parameters.

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EXTEM CT: 131 s A10: 34 mm

FIBTEM

INTEM

2007-02-15 13:30 2:

CFT: 219 s A15: 38 mm

α:

53°

A20: 41 mm

CT: 210 s A10: 32 mm

Anesthetic Management of Liver Surgery

2007-02-15 13:32 2:

CFT: 238 s A15: 38 mm

α:

58°

A20: 42 mm

2007-02-15 13:33 2:

CT: 482 s

CFT:

–s

A10: 3 mm

A15:

3 mm

α:

–°

A20: 3 mm

Figure 43.5 Rotation thromboelastometry (ROTEM) tracing with hypofibrinogenemia. Only FIBTEM (fibrinogen tracing) shows lack of fibrinogen, while the extrinsic (EXTEM) and intrinsic (INTEM) tracings are normal.

coagulation monitor CoaguChek-Plus (Boehringer Mannheim, Germany) has been shown to measure intraoperative on-site prothrombin time and partial thromboplastin time in less than 3 min. However, clinical evaluation under different hemostatic conditions found insufficient correlation with standard laboratory assays. The poor accuracy of the device was found equally for pre-, intra- and postoperative measurements, and for different ranges of prothrombin time [50]. The poor correlation may be caused by the high International Sensitivity Index (ISI) of the thromboplastin used, and more sensitive thromboplastins with lower ISIs should be preferred, because these show a smaller between-laboratory variability. Such new devices with lower ISIs are under investigation. On-site platelet and hemoglobin count (AC.T8 Hemocytometer, Hialeah, USA) is also very useful for hemostasis management during liver transplantation.

has been helpful in the diagnosis of many hemodynamic disturbances. As mentioned earlier in this chapter, filling pressures are not always reflective of preload because of significant fluctuations in ventricular compliance. TEE gives substantial information about preload and may help to identify hemodynamic changes during and after reperfusion of the liver [51]. TEE has also been used in the diagnosis and management of intraoperative complications, such as air embolism and thromboembolism, and in the management of patients with unrelated cardiopulmonary disease, such as CAD, valvular pathology, idiopathic hypertrophic subaortic stenosis, etc [52–54]. TEE has also proven to be an essential monitoring tool in patients with pulmonary hypertension undergoing liver transplantation. Furthermore, TEE allows for the intraoperative evaluation of the major vessels, including suprahepatic IVC anastomosis [55].

Transesophageal echocardiography In the preoperative evaluation, transthoracic echocardiography is used for patients undergoing liver transplantation. It provides information about global cardiac function, valvular function, presence of pericardial effusion, increased right ventricular pressure, and pulmonary hypertension. Due to potential damage to esophageal varices with subsequent severe bleeding, TEE initially was used very reluctantly, but this complication appears to be very uncommon, and if it occurs, it is mild and self-limiting. Today, TEE is used more commonly in patients undergoing liver transplantation, and

Self-assessment questions 1 Which of the following are the major significant predictors of mortality in candidates for extended hepatectomy? (more than one answer is possible) A Fluid overload B Thrombocytopenia C Elevated serum creatinine D Elevated serum bilirubin E Transfusion

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2 Which one of the following explains why fluid overload may be deleterious in hepatic resection? A Arterial hypertension leads to a significant increase in blood loss B Liver volume may increase up to 1500 mL C Concomitant hemodilution leads to deterioration of the coagulation profile D High central venous pressure may lead to distension and failure of the right ventricle E Blood loss is augmented by the elevation of the systemic pressure 3 Pulmonary hypertension is not an absolute contraindication for liver transplantation, because pulmonary arterial pressure between 35 and 50 mmHg has a mortality of 50%. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 4 Preoperative sodium concentration below 125 mEq/L may be fatal, because central pontine myelinolysis is caused by low sodium concentrations. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 5 Echocardiography may be helpful for the risk stratification of liver transplant candidates, because it reveals which one of the following? A Congenital heart disease B Coronary heart disease C Diastolic dysfunction D Pulmonary hypertension E Atrial septum defect 6 Thromboelastography is used in the perioperative setting of liver transplantation, because it is an established test for chronic coagulation disorders. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct

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7 Which of the following are perioperative complications in cryosurgery? (more than one answer is possible) A Hypothermia B Fever C Hyperglycemia D Renal failure E Liver failure 8 In contrast to patients with end-stage liver disease, cross-clamping of the vena cava during liver transplantation results in a marked reduction of venous return and cardiac output in liver transplant recipients without cirrhosis, because left ventricular preload is not preserved by the inflow through venous collateral vessels. A First part wrong, second part wrong B First part correct, second part wrong C First part wrong, second part correct D First part correct, second part correct, “because” incorrect E First part correct, second part correct, “because” correct 9 Which one of the following symptoms is not characteristic for the postreperfusion syndrome? A Ventricular fibrillation B Atrial fibrillation C Low output syndrome D Increase of the plasma potassium concentration E Hypothermia (blood flush of the cold liver) 10 Which one of the following is not a complication of intracranial pressure monitoring? A Bleeding B Infection C Malfunction D Misinterpretation E Intracranial hypertension

References 1 Clavien PA, Petrowsky H, DeOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 2007;356:1545–59. 2 Wei AC, Tung-Ping Poon R, Fan ST, Wong J. Risk factors for perioperative morbidity and mortality after extended hepatectomy for hepatocellular carcinoma. Br J Surg 2003;90:33–41. 3 Poon RT, Fan ST, Lo CM, et al. Improving perioperative outcome expands the role of hepatectomy in management of benign and malignant hepatobiliary diseases: analysis of 1222 consecutive patients from a prospective database. Ann Surg 2004;240:698– 708; discussion 708–10. 4 Littlewood K. Anesthetic considerations for hepatic cryotherapy. Semin Surg Oncol 1998;14:116–21.

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5 Merritt WT. An International View of Perioperative Issues in Liver Transplantion, parts 1 and 2, vol 44. Hagerstown: Lippincott Williams and Wilkins, 2006. 6 De Wolf AM. Preoperative optimization of patients with liver disease. Curr Opin Anaesthesiol 2005;18:325–31. 7 Stravitz RT, Kramer AH, Davern T, et al. Intensive care of patients with acute liver failure: Recommendations of the U.S. Acute Liver Failure Study Group. Crit Care Med 2007;35: 2498–508. 8 Bass NM. Monitoring and treatment of intracranial hypertension. Liver Transpl 2000;6:S21–6. 9 Vaquero J, Fontana RJ, Larson AM, et al. Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy. Liver Transpl 2005;11: 1581–9. 10 Yu J, Liang TB, Zheng SS, Shen Y, Wang WL, Ke QH. [The possible causes of central pontine myelinolysis after liver transplantation.] Zhonghua wai ke za zhi 2004;42:1048–51. 11 Heng AE, Vacher P, Aublet-Cuvelier B, et al. Centropontine myelinolysis after correction of hyponatremia: role of associated hypokalemia. Clin Nephrol 2007;67:345–51. 12 Tiukinhoy-Laing SD, Rossi JS, Bayram M, et al. Cardiac hemodynamic and coronary angiographic characteristics of patients being evaluated for liver transplantation. Am J Cardiol 2006;98:178–81. 13 Torregrosa M, Genesca J, Gonzalez A, et al. Role of Doppler echocardiography in the assessment of portopulmonary hypertension in liver transplantation candidates. Transplantation 2001;71:572–4. 14 Krowka MJ, Plevak DJ, Findlay JY, Rosen CB, Wiesner RH, Krom RA. Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transpl 2000;6:443–50. 15 Ashfaq M, Chinnakotla S, Rogers L, et al. The impact of treatment of portopulmonary hypertension on survival following liver transplantation. Am J Transplant 2007;7: 1258–64. 16 Minder S, Fischler M, Muellhaupt B, et al. Intravenous iloprost bridging to orthotopic liver transplantation in portopulmonary hypertension. Eur Respir J 2004;24:703–7. 17 Krowka MJ, Wiseman GA, Burnett OL, et al. Hepatopulmonary syndrome: a prospective study of relationships between severity of liver disease, PaO(2) response to 100% oxygen, and brain uptake after (99 m)Tc MAA lung scanning. Chest 2000;118: 615–24. 18 Cardenas A, Uriz J, Gines P, Arroyo V. Hepatorenal syndrome. Liver Transpl 2000;6:S63–71. 19 Ballantyne JC, Carr DB, deFerranti S, et al. The comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized, controlled trials. Anesth Analg 1998;86:598–612. 20 Bechstein WO, Neuhaus P. Bleeding problems in liver surgery and liver transplantation. Chirurg 2000;71:363–8. 21 Jones RM, Moulton CE, Hardy KJ. Central venous pressure and its effect on blood loss during liver resection. Br J Surg 1998;85: 1058–60. 22 Chen H, Merchant NB, Didolkar MS. Hepatic resection using intermittent vascular inflow occlusion and low central venous

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39 Porte RJ, Molenaar IQ, Begliomini B, et al. Aprotinin and transfusion requirements in orthotopic liver transplantation: a multicentre randomised double-blind study. EMSALT Study Group. Lancet 2000;355:1303–9. 40 Molenaar IQ, Begliomini B, Martinelli G, Putter H, Terpstra OT, Porte RJ. Reduced need for vasopressors in patients receiving aprotinin during orthotopic liver transplantation. Anesthesiology 2001;94:433–8. 41 Fitzsimons MG, Peterfreund RA, Raines DE. Aprotinin administration and pulmonary thromboembolism during orthotopic liver transplantation: report of two cases. Anesth Analg 2001;92:1418–21. 42 Dalmau A, Sabate A, Acosta F, et al. Tranexamic acid reduces red cell transfusion better than epsilon-aminocaproic acid or placebo in liver transplantation Anesth Analg 2000;91:29–34. 43 Kaspar M, Ramsay MA, Nguyen AT, Cogswell M, Hurst G, Ramsay KJ. Continuous small-dose tranexamic acid reduces fibrinolysis but not transfusion requirements during orthotopic liver transplantation. Anesth Analg 1997;85:281–5. 44 Nuttall GA, Oliver WC, Ereth MH, Santrach PJ. Coagulation tests predict bleeding after cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1997;11:815–23. 45 Hartert H. Blutgerinnungsstudien mit der Thrombelastographie, einem neuen Untersuchungsverfahren. Klinische Wochenschrift 1948;26:577–83. 46 Mallett SV, Cox DJ. Thrombelastography. Br J Anaesth 1992;69:307–13. 47 Kang Y. Transfusion based on clinical coagulation monitoring does reduce hemorrhage during liver transplantation. Liver Transpl Surg 1997;3:655–9. 48 Coakley M, Reddy K, Mackie I, Mallett S. Transfusion triggers in orthotopic liver transplantation: a comparison of the thromboelastometry analyzer, the thromboelastogram, and conventional coagulation tests. J Cardiothorac Vasc Anesth 2006;20: 548–53. 49 Despotis GJ, Santoro SA, Spitznagel E, et al. Prospective evaluation and clinical utility of on-site monitoring of coagulation in

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patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1994;107:271–9. Zalunardo MP, Zollinger A, Seifert B, Patti M, Pasch T. Perioperative reliability of an on-site prothrombin time assay under different haemostatic conditions. Br J Anaesth 1998;81:533–6. Cheung AT, Savino JS, Weiss SJ, Aukburg SJ, Berlin JA. Echocardiographic and hemodynamic indexes of left ventricular preload in patients with normal and abnormal ventricular function. Anesthesiology 1994;81:376–87. Prager MC, Gregory GA, Ascher NL, Roberts JP. Massive venous air embolism during orthotopic liver transplantation. Anesthesiology 1990;72:198–200. De Wolf A. Monitoring and handling of reperfusion. Liver Transpl Surg 1997;3:459–61. Navalgund AA, Kang Y, Sarner JB, Jahr JS, Gieraerts R. Massive pulmonary thromboembolism during liver transplantation. Anesth Analg 1988;67:400–2. Bjerke RJ, Mieles LA, Borsky BJ, Todo S. The use of transesophageal ultrasonography for the diagnosis of inferior vena caval outflow obstruction during liver transplantation. Transplantation 1992;54:939–41.

Self-assessment answers 1 2 3 4 5 6 7 8 9 10

B, C, E B D B D B A, B, D E E E

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Qualitative and Economic Aspects of Liver Surgery René Vonlanthen1, Ksenija Slankamenac1, and Christian Ernst2 1 Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland 2 Economics and Management of Social Services, University Hohenheim, Stuttgart, Germany

Patients requiring elective surgery are often faced with a choice between a variety of public and private hospitals. They make their choice based on their insurance status and the reputation of the hospital, as well as its vicinity and convenience, and often also for irrational or intuitive reasons. For many procedures, particularly the more complex ones, the patient’s choice of provider/treating physician may have a profound impact on postoperative morbidity or even mortality. To help the patient and/or referring physician to make the right choice of hospital, it is therefore crucial to establish evidence-based outcome measures and quality assessment of the respective procedures. Unfortunately, there is little agreement among health economists on how these data should be used. A much debated issue is whether the publication of such data leads to overall quality improvements. As with most economic choices, such a proposal has benefits as well as possible detrimental effects. A positive effect is that publication of outcome data, such as mortality or complication rates, may lead to a better match between severity of illness and provider capability. A possible negative effect is that such data may affect provider reputation, especially if they are tied to reimbursement, leading to the most capable providers avoiding the most severely-ill patients because there is a high probability that these patients will negatively affect measures of their performance. In one of the best studies to date, Dranove et al [1] showed that for report cards on cardiac surgery, the detrimental effect of patient selection dominated the beneficial effect of a better matching between illness severity and provider experience. Based on this finding, the authors conclude that report cards did in fact reduce both patient welfare and overall welfare for society. This trade-off should be borne in mind in the following discussion, but it does not detract from the general desirability of establishing such objective quality performance measures, because they may help surgeons to improve

Malignant Liver Tumors: Current and Emerging Therapies, 3rd edition. Edited by Pierre-Alain Clavien. © 2010 by Blackwell Publishing

performance even if they are not made publicly available. An example of this approach is the use of the data of the “Bundesgeschäftsstelle Qualitätssicherung GmbH” (BQS) in the German healthcare system. These data are not published, but if a provider’s scores are consistently below average, peer visits and a structural dialogue with the reporting institution ensue.

Quality measurement in surgical care Surgical outcomes vary quite considerably with healthcare provider. Debate is ongoing about which parameters should be used to reflect surgical quality. Birkmeyer et al proposed quality measurement in three domains: structure, process, and outcome − adopted from the Donabedian paradigm [2]. Though a very helpful framework, it should be borne in mind that many open questions remain as to the exact relationship between these three dimensions of quality. Structural measures (capabilities) are represented by variables reflecting the setting or system in which surgical care is provided. Procedure volume is the most commonly used surrogate for surgical quality. Other important structural variables are, for example, subspecialty training by the operating surgeon, “closed” intensive care units, high nurse-to-bed ratios, and resource availability. All these parameters seem to be important predictors of surgical outcome. Process measures reflect the care that patients receive and are strongly associated with improved patient outcomes. Examples of process measures associated with surgical outcomes are: venous thromboembolism prophylaxis, early nutritional support in critically ill patients, and procedures related to central venous line management. Another example is the use of institution-specific clinical pathways developed from national or international evidence-based guidelines. At the same time, procedure-specific processes of care, individually and in combination, may sometimes explain apparent associations between structural variables and outcomes. Outcome measures are represented, amongst others, by morbidity and mortality rates, patient satisfaction, and

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functional health. In the face of ever increasing healthcare expenditures, treatment costs have also been suggested as a possible outcome measure from a society perspective. The problem here is that the objective of low treatment costs often conflicts with the other outcome measures (the socalled cost–quality trade-off). The most effective approach to quality measurement is to look at the baseline risk of the procedure and how commonly it is performed at individual hospitals. According to these parameters, recommendations exist for when particular variables should be the focus [2]. There are several scenarios for a given surgical procedure. For example, most procedures in liver surgery carry a high baseline risk for complications. If a hospital has a high caseload for liver surgery, structural and outcome variables are recommended for quality assessment, but if the caseload is low, only structural variables should be applied. This applies particularly for complex liver resections, pancreatic resections, and esophagectomies.

Table 44.1 Clavien–Dindo classification of surgical complication [9, 10]. Grade

Definition

Grade 1

Any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic, and radiological interventions Allowed therapeutic regimens are: drugs as antiemetics, antipyretics, analgesics, diuretics and electrolytes, and physiotherapy. This grade also includes wound infections opened at the bedside

Grade 2

Requiring pharmacological treatment with drugs other than those allowed for grade 1 complications Blood transfusions and total parenteral nutrition are also included

Grade 3

Requiring surgical, endoscopic or radiological intervention Intervention not under general anesthesia Intervention under general anesthesia

Structural and outcome measures in hepatic surgery

Grade 3a Grade 3b

Hospital volume is defined as the average number of surgical procedures per year [3]. Many studies have shown better results for cardiovascular surgery, cancer resections, and other high-risk procedures in high-volume centers [4, 5]. Definitions of what is a low- or high-volume center still lack standardization. The Leapfrog Group [6] has made some efforts to implement a minimum number of operations for a center to qualify as a high-volume center. In visceral surgery, this group suggests a minimum of 11 pancreatic resections and 13 esophagectomies per year, while for liver surgery consensus is still lacking. In Germany, explicit minimum procedure volumes for hepato-pancreatico-biliary (HPB) surgery are: partial liver resections and hepatectomies, 20 per hospital/year; liver transplantations, 20 per hospital/year, and pancreatic procedures, 10 per hospital/ year. Hospitals will only receive a diagnosis-related group (DRG)-reimbursement if these minimum-volume thresholds are met (situation in 2009). Mortality is clearly defined, but the terms complication or morbidity lack standardization. Martin et al showed that complications are routinely reported in the surgical literature [7] and are often used to show improvements over time or to assess the impact of therapeutic changes on patient outcome. However, because of the inconsistency of reporting and the lack of accepted standards in assessment of complications, these data do not qualify as indicators of quality in surgery. Efforts to change this situation were first reported by Clavien et al in 1992 who proposed a new classification. They defined negative outcome by differentiating complications, sequelae, and failures to cure [8]. Using this definition, Dindo et al proposed a five-scale classification based on the therapy needed to correct the complication [9] (Table 44.1). This

Grade 4

532

Grade 4a Grade 4b

Life-threatening complication (including CNS complications*) requiring intermediate care/ intensive care unit management Single organ dysfunction (including dialysis) Multiorgan dysfunction

Grade 5

Death of a patient

Suffix “d”

If the patient suffers from a complication at the time of discharge, the suffix “d” (for “disability”) is added to the respective grade of complication. This label indicates the need for follow-up to fully evaluate the complication

*Brain hemorrhage, ischemic stroke, subarachnoid bleeding, but not transient ischemic attacks

classification system has recently found wide acceptance in the literature. Despite the lack of definitions and widely accepted standards, in 1998 Choti et al [11] in an overview of 606 liver resections conducted in 36 hospitals (data obtained from the Maryland Health Services Cost Review Commission) addressed the question, Does hospital or surgical volume have an impact on mortality and postoperative complications in hepatic surgery?. Of these resections, 43.6% were performed in one high-volume center (average 40.6 cases/ year) and the remaining 56.4% of resections at 35 lowvolume hospitals (average 1.5 cases/year). The mortality rate for all procedures in the low-volume group was 7.9% compared to 1.5% for the high-volume provider (p < 0.01, relative risk = 5.2). This lower mortality rate was seen for all

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types of resection. No overall differences were observed between the low- and high-volume providers in total hospital charges. Improved results at high-volume centers probably have multifactorial explanations: they may reflect the increased surgical and perioperative management (including anesthesia, intensive care management, nursing and other supportive care), expertise that is gained when larger numbers of procedures are performed. These experienced teams may avert adverse events through earlier recognition of problems. Furthermore, a better infrastructure, newer surgical techniques and equipment (intraoperative ultrasonography, argon beam coagulation, ultrasonic dissection, and anatomic resection techniques) may positively influence outcome. A generally accepted but unproven finding was the recognition that liver resections in patients with primary hepatic malignancies (often associated with cirrhosis) were associated with a worse overall outcome than that for those undergoing resection for metastatic disease. Although this study has provided first evidence of the high volume–low complication paradigm, it suffers from several limitations: only a single hospital was included in the high-volume group and only inhospital clinical outcomes were measured [11]. Further publications support the conclusion of Choti et al and emphasize the importance of the centralization of hepatic resections [12–14]. In 1999, Glasgow et al showed an up to four-fold higher mortality rate for low-volume centers in a series of 507 patients undergoing hepatectomy for hepatocellular carcinoma (HCC) [13]. Crude operative mortality rates decreased with increasing hospital volume, from 24.4% in the lowest-volume centers to 6.2% in the highest-volume centers. High-volume centers were found to have shorter average lengths of hospital stay. The lowestvolume providers had a mean length of stay of 14.7 days compared with 10.8 days in the high-volume providers. Overall, high-volume centers required lower resources. Dimick et al compared the mortality and morbidity rates for 569 hepatic resections conducted in high- and low-volume centers [12]. The overall inhospital mortality rate was 4.8%, and this was significantly lower in the high-volume centers (2.8%) than in low-volume centers (10.2%). In the lowvolume centers, increased rates of complications were observed, e.g. significantly higher rates of reintubation (RR, 2.5; 95% CI, 1.8–3.4), pulmonary failure (RR, 2.3; 95% CI, 1.6–3.5), acute renal failure (RR, 2.0; 95% CI, 1.1–3.7), acute myocardial infarction (RR, 2.6; 95% CI, 1.2–5.9), and aspiration (RR, 1.4; 95% CI, 0.9–2.0). The difference in outcome between the low- and high-volume centers seems to rely on a variation and a summation in postoperative complications. A recent study by McKay et al investigated the effects of an individual surgeon’s volume and training on the outcome after hepatic resections [14]. In total, 1107 hepatic resections performed by 72 surgeons were analyzed. The inhospital mortality rate was 6% and the overall complication rate 46%. Statistically significant predictors of

Qualitative and Economic Aspects of Liver Surgery

operative mortality were: urgency of admission, diagnosis of primary hepatic malignancy, extent of resection, and an increasing burden of comorbidities. The surgeon’s training was predictive of postoperative complications, along with patient’s gender, urgency of admission, diagnosis of primary hepatic malignancy, extent of resection, and the number of comorbidities.

Is long-term survival in high-volume centers superior after resection for cancer? The question of whether there is a correlation between the volume and experience of the surgeon, and outcome cannot be answered in general as some of the simpler procedures may be performed well in low-volume hospitals. Each procedure has to be evaluated separately. A series of publications has looked at outcome after oncologic procedures [15–17]. Killeen et al showed that high-volume providers have a significantly better outcome for complex cancer surgery, specifically for pancreatectomy, esophagectomy, gastrectomy, and rectal resections. Absolute differences in 5-year survival rates between low- and high-volume hospitals range from 17% for esophageal cancer resection, 6% for gastric cancer, and 5% for pancreatic cancer resection [15, 16]. Fong et al showed in their study of long-term survival after resection of hepatic malignancies that hospital volume lost its significance with time, indicating that in this group, the major effect of volume was on the perioperative outcome [17].

Summary Hospital volume, surgical experience, and training have an important impact on mortality and morbidity in hepatic surgery. These data underline the importance of centralization of complex hepatic surgery in high-volume centers and a specialized training for HPB surgery. Decreasing morbidity and mortality rates along with improving surgical quality may also have important economic consequences. However, it has to be emphasized that no single quality measurement will be appropriate for all operations. Policy-makers should consider sample size in selecting the best quality measure for specific procedures, particularly when data are used for public reporting. We are convinced that a broad implementation of a standardized classification into the surgical literature may facilitate the evaluation and comparison of surgical outcomes among different surgeons, centers, and therapies. An interesting related question concerns also the “optimal” center size. The German Institute for Quality and Efficiency in the Healthcare System (IQWIG) has shown worsening outcomes (post-surgical mobility of joint) for knee-replacement surgery if the number of cases is increased beyond a certain level [18]. This question has not yet been investigated for liver surgery.

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Economic aspects of hepato-pancreatobiliary surgery Cost-effectiveness analysis can help inform policy-makers on better ways to allocate limited resources. Based on these analyses, a diagnostic test or a treatment may be adopted or excluded. However, up to now interpreting the results of cost-effectiveness analysis remains a challenge. Whereas it is generally possible to compare the results of effectiveness studies between countries, economic evaluations require cost measures which are expressed in monetary terms and these tend to differ considerably internationally. For instance, a therapy that shows prohibitive costs per life year gained for the very expensive United States healthcare system (high drug prices) may nevertheless prove efficient for a healthcare system with price caps on important resources. Additional problems occur because of the low number of published data, a lack of standardization, and publication bias. In the following section we will provide a systematic review of the few cost-effectiveness studies in HPB surgery. To better understand the issues, definitions of frequently used terms are given initially.

Definitions: cost-effectiveness, cost-utility, and cost-benefit analysis The cost-effectiveness (CEA) of a therapeutic or preventive intervention is the ratio of the costs of the intervention to a relevant measure of its effect (costs per measure of effect). A special form of CEA is cost-utility analysis (CUA). The purpose of CUA is to estimate the ratio between costs of a health-related intervention and the benefit. CUA is often given in quality adjusted life-years gained (QALY). Consequently, a QALY takes into account both the quantity and the quality of life generated by healthcare interventions. It is the arithmetic product of life-expectancy and a measure of the quality of the remaining life-years. Using the CUA, it is possible to compare different interventions. To understand the value of CEA and CUA it is essential to appreciate that both methods can only achieve a relative, and not an absolute, ranking of alternatives [19]. The idea is to spend a given budget (usually for a given disease or indication) efficiently, so that only those measures are undertaken that require the least amount of Euros or US dollars expended per life-year gained, or QALY. Two important problems result from this. One is the fact that the often cited threshold levels of US$50 000/QALY (£30 000/QALY in the UK) cannot be endogenously derived from the model. Second, there is a risk that alternatives are compared that are inefficient in absolute terms. To see this, consider a therapy that costs US$ 10 000/QALY (CUA). If individuals attach a monetary value of only US$ 8000 to one QALY gained, the net benefit of the therapy would be “$8000 − $10 000 = − $2000”! Clearly,

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society and individuals would be better off without that therapy but both CEA and CUA fail to show this because no monetary value is attached to the outcome measures. The only evaluation method that can rank alternatives in absolute terms is therefore cost-benefit analysis (CBA), where a monetary value is attached to both the resources used (costs) and the benefits or consequences. Needless to say, this is also the most challenging technique in terms of data input and methodology, and it is not surprising that we have been unable to identify a single cost–benefit analysis for the treatment options considered here. Despite these limitations, below we follow the often suggested practice of considering a CEA ratio below US$50 000 per life-year gained as cost-effective. For some studies we also considered the incremental cost-effectiveness ratio (ICER), defined as the ratio of the change in costs of a therapeutic intervention (compared to the alternative, such as doing nothing or using the best available alternative treatment) to the change in effects of the intervention.

Cost-effectiveness studies in hepato-pancreatobiliary diseases and surgery Surveillance of cirrhosis for hepatocellular carcinoma In a systematic review and economic analysis, Thompson Coon et al showed in a cohort of liver cirrhosis patients with mixed etiology (alcohol, hepatitis B and C) that the most effective surveillance strategy is to screen each patient with an alpha-fetoprotein (AFP) assay and ultrasound imaging on a 6-monthly basis [20]. However, when costs are taken into account it is doubtful whether ultrasound should be routinely offered to those with a blood AFP level of less than 20 ng/mL, as the costs are over US$88 275/QALY gained. At an acceptable threshold of US$50 000, the most costeffective strategy would be an AFP measurement every 6 months (ICER, US$40 600 US/QALY gained). Furthermore, the cost-effectiveness of surveillance for HCC depends on the etiology of cirrhosis. It is much more cost-effective in those with HBV-related cirrhosis than in those with alcoholic liver disease-related cirrhosis.

Cost–effectiveness studies in liver surgery for (colorectal) liver metastases The first cost-effectiveness analysis for hepatic resection for colorectal liver metastases was published by Beard et al in 2000 [21]. They compared the surgical procedure with standard chemotherapeutic treatment. A simple decisionanalysis model based on published and locally derived data was presented. In this study hepatic resection for colorectal liver metastases provides an estimated marginal benefit of 1.6 life-years. Further, surgical resection of the liver for colorectal metastases was highly cost-effective compared with nonsurgical treatment, with a cost per life year gain

CHAPTER 44

(LYG) of US$2160–13 285. Univariate sensitivity analysis of key model parameters showed the cost per LYG to be consistently less than US$22 000. In this model, hepatic resection appears highly costeffective compared with nonsurgical treatment for colorectal-related liver metastases. However, to unambiguously establish this result with the highest possible evidence level would require a double-blind randomized controlled trial, since the current data only consider the relative economic merits of resection on modeled case series data. However, such a randomized controlled trial of liver resection versus conservative therapy would probably never be approved for ethical reasons, given that conventional nonsurgical treatments show only modest survival benefits for these patients. An indepth analysis of cost-effectiveness is particularly useful for multistage procedures where additional steps might increase cost with limited benefit to the patient. One such study looked at the cost-effectiveness of hepatic resection in patients with metachronous liver metastases from colorectal carcinoma and investigated the impact of operative and follow-up strategies on outcomes, cost, and costeffectiveness [22]. The study considered a treatment strategy comprising resection of up to six metastases and one repeat resection, with computed tomography (CT) follow-up every 6 months. With this approach, a gain of 2.63 QALYs relative to the no-test/no-treat strategy, at an incremental cost of US$18 100/QALY, was achieved. When additional surgical strategies were considered, the ICER (relative to the next least effective strategy) was US$31 700 QALY. More aggressive treatment strategies (i.e. resection of more metastases or resection of recurrent metastases) were superior to less aggressive strategies and had ICERs below US$35 000/ QALY. It was concluded that hepatic resection of metastases appears to be a cost-effective option for selected patients with metachronous colorectal liver metastases limited to the liver. The study provides a first and interesting insight into the economic aspects of complex liver disease, with the caveat that it is based on a heterogeneous patient population and assumptions for the model parameters may have to be re-evaluated. A similar study compared the cost-effectiveness of percutaneous radiofrequency ablation (RFA) versus that of hepatic resection. The authors concluded that RFA is a cost-effective treatment option for patients with colorectal liver metastases [23]. However, in most scenarios, hepatic resection is a more successful therapy than RFA in terms of QALYs gained, and it has an ICER of less than US$35 000/QALY. Colorectal liver metastasis are a very common disease with variable presentation, including in tumor size, and the number and localization of these metastasis. Therefore, several therapeutic options have been developed to best fit the individual patient’s need. Since economic aspects may conflict with pure outcome studies, the latter have

Qualitative and Economic Aspects of Liver Surgery

received more attention. In a prospective, nonrandomized pilot study, four different treatment options for colorectal liver metastases were assessed in 40 patients with the goal of identifying the optimal cost-utility ratio. The four options were hepatic resection, RFA, systemic chemotherapy, and symptom control alone. Hepatic surgery appeared to be the most effective approach, with an average benefit of 2.58 QALYs compared with 1.95 QALYs for RFA, 1.18 QALYs for chemotherapy, and 0.82 QALYs for symptom control alone, giving cost-utility ratios of US$7792, US$8056, US$12 571, and US$4788/QALY, respectively [24]. The cost-utility of hepatic resection and RFA are not dissimilar, although with the limited number of cases assessed, it is not clear whether the conclusions drawn can be generalized.

Cost-effectiveness studies comparing partial hepatectomy with orthotopic liver transplantation for the treatment of resectable hepatocellular carcinoma The treatment of patients with compensated liver cirrhosis and small HCCs is still being debated [25–29]. While partial hepatectomy for HCC in cirrhotic liver is widely recommended, another option, orthotopic liver transplantation (OLT), has become more and more attractive [30]. Excellent 5-year patient survivals of greater than 70% after liver transplantation have been reported from many centers using criteria for OLT in patients with HCC similar to or slightly exceeding the Milan criteria (single lesion of ≤5 cm, or two to three lesions of ≤3 cm) [31]. Cost studies in hepatic surgery exist mainly for liver transplantation. Charges for liver transplantation range from US$60 000 to US$200 000 and are higher in the United States than in Europe. As we have already argued above, this difference is explained by the different healthcare systems, in particular the costs of inputs such as drugs and personnel. In general, the risk factors associated with higher costs vary widely for liver transplantation, except for renal insufficiency [32]. In 1997 Sarasin et al showed that there was a substantial survival benefit for patients with HCC treated with OLT compared with liver resection. A minimum of 1 year to a maximum of 4.7 years were gained with OLT, depending on the treatment-related survival rates [33]. However, the magnitude of this benefit depended on the availability of organ donors. Currently, the waiting time for cadaveric organs is long, increasing the risk for tumor growth and dissemination during this time. When this constraint is included in the calculations, the predicted marginal cost-effectiveness ratios of transplantation compared with resection range between US$44 454 and US$183 840/QALY, depending on the time delay before receiving a transplant. Obviously, this range comprises values below and above the often-used US$50 000/ QALY threshold. This documents a need for multiway sen-

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sitivity analyses, preferably using probabilistic methods so that a probability distribution can be assigned to the respective extreme possible realizations of the ratio. Ideally this would yield probability assessments such as “the probability that the threshold of $50 000/QALY is exceeded is 10%.”

Cost-utility analysis of living donor living transplantation for hepatocellular carcinoma As the results of cadaveric liver transplantation (CLT) for HCC depend on the waiting time, as shown by Llovet et al [34], a solution to this dilemma can be provided by living donor liver transplantation (LDLT), which allows patients to be transplanted before they develop tumor progression or show metastasis. Sarasin et al showed that LDLT in early HCC offered substantial gain in life-expectancy with acceptable cost-effectiveness ratios [35]. LDLT was cost-effective (10%) and provided gains in life-expectancy of 4.8–6.1 months at an acceptable cost (US$40 000/QALY) for patients waiting for 1 year or more, while for shorter waiting periods it was not cost-effective (US$74 000/QALY). In the same study, the cost-effectiveness of percutaneous treatment, which increases the life-expectancy by 5.2–6.7 months, was shown to be associated with a marginal cost of approximately US$20 000/QALY in all cases and for all waiting periods. These conclusions were confirmed more recently in another institution by Gores et al [37].

Cost-effectiveness of adjuvant therapy strategies after liver resection Adjuvant interferon therapy after surgical resection of hepatitis C-related HCC is a promising therapeutic option. The cost-effectiveness and life-expectancy benefit were investigated in a retrospective analysis by Hoshida et al [38]. They concluded that adjuvant interferon after surgical resection of primary hepatitis C-related HCC improved life-expectancy through suppression of recurrent cancer. The costeffectiveness of US$15 700/QALY compared with no interferon therapy was quite acceptable.

Impact of complications on costs following major hepato-pancreato-biliary surgery The growing demand for quality in healthcare has triggered interest in measuring clinical outcome and costs. Complications have become quantifiable using severity-oriented complication scores. The question remains how complications impact on costs after major HPB surgery. 536

To answer this question our group looked at postoperative outcome and costs (calculated according to the “bottom up” methodology) of 519 consecutive patients undergoing major HPB- surgery in a single interdisciplinary center. Data were prospectively analyzed over a 4-year period (2005–2008) for 404 major liver/bile duct and 115 pancreatic operations. Postoperative complications were evaluated according to a standardized severity-oriented complication score [9], and their impact on inhospital costs was assessed using linear regression models. Cost drivers (independent variables) used for calculation of costs of complications were severity and number of complications, age, Charlson index, American Society of Anesthesiologists (ASA) score, nutrition risk factor, operating time, and hospital stay. Overall mortality was 4.4%, while morbidity was 59.3%. Patients with uneventful courses incurred median costs of US$24 918 (interquartile range (IQR) US$19 598–32 425) per case. Costs increased with the severity of complications and reached US$83 360 (range US$40 794–122 826) for grade 4 complications. For all types of surgery, costs increased with severity of complications. Complications after pancreatic surgery incurred significantly higher costs than liver/bile duct surgery. ASA and type of surgery appeared to be independent risk factors for costs. Additionally, operating time and number of complications correlated with increased cost. This study demonstrates the dramatic impact of severe complications on total inhospital costs, which can increase more than three times. It highlights a relevant savings capacity for HPB procedures, and supports efforts to lower complications, e.g. by treatment in a high-volume centre. Consequently, the severity of complications could be used as an additional cost-determining variable in a DRG system.

Cost comparison of endoscopic stenting versus surgical treatment for unresectable cholangiocarcinoma The limited therapeutic options for unresectable cholangiocarcinomas were analyzed in a retrospective study by Martin et al [39]. They compared the total costs of endoscopic stenting versus surgical therapy in a study including only 20 patients. The median total lifetime costs for surgical therapy was US$60 986 (mean survival 16.5 months) versus US$24 251 (mean survival 19 months) for endoscopic therapy. Consequently, endoscopic therapy is an effective palliative therapy for unresectable cholangiocarcinoma with significantly lower costs and higher life-expectancy compared with surgical treatment.

Summary Only a small number of cost-effectiveness analyses in HPB surgery exist, making recommendations and conclusions difficult. The value of these analyses is very limited mainly because of the study designs (e.g. retrospective analysis,

CHAPTER 44

small case numbers, heterogeneity of patients, lack of standardization, varying country-specific costs, etc). However, results do suggest that both liver resection for colorectal liver metastasis and liver transplantation for HCC are costeffective. Additionally, severe complications dramatically increase costs in liver surgery. Though in countries like the United Kingdom resource allocation is based on QALYs, more consistent empirical evidence is required before this approach can be universally justified. Due to the rising cost of healthcare, economic and cost-effectiveness aspects will probably tend to become more and more important in liver surgery. Ideally, data should be collected prospectively to serve as a base for discussions that may impact on the decision to choose a specific therapeutic option. This discussion may also spawn an ethical debate in view of financial restrictions influencing medical decisions.

Self-assessment questions 1 Quality measurement in surgery, based on the Donabedian paradigm, can be done using which of the following? (more than one answer is possible) A Structure variables B Process variables C Baseline risk of a procedure complication D Outcome variables E Grade of complication 2 Where there is a high baseline risk for a complication for a surgical procedure and a low caseload per hospital, which one of the following variables should be measured? A Process variable B Process and outcome variables C Outcome variables D Structure variables 3 In health economics which one of the following is the only evaluation method that can rank alternatives in absolute terms? A Cost-utility analysis B Cost-benefit analysis C Cost-effectiveness analysis D None of the above 4 What is the often cited threshold level for a QALY? A US$20 000 B US$30 000 C US$40 000 D US$50 000 E US$60 000

Qualitative and Economic Aspects of Liver Surgery

References 1 Dranove D, Kessler D, McClellan M, Satterthwaite M. Is more information better? The effects of “report cards” on health care providers. J Political Economy 2003;111:555–86. 2 Birkmeyer JD, Dimick JB, Birkmeyer NJ. Measuring the quality of surgical care: structure, process, or outcomes? J Am Coll Surg 2004;198:626–32. 3 Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States. N Engl J Med 2002;346:1128–37. 4 Luft HS, Bunker JP, Enthoven AC. Should operations be regionalized? The empirical relation between surgical volume and mortality. N Engl J Med 1979;301:1364–9. 5 Begg CB, Cramer LD, Hoskins WJ, Brennan MF. Impact of hospital volume on operative mortality for major cancer surgery. JAMA 1998;280:1747–51. 6 The Leapfrog Group. Evidence-based Hospital Referral (EBHR), 2007. Available at: www.Leapfroggroup.org 7 Martin RC 2nd, Brennan MF, Jaques DP. Quality of complication reporting in the surgical literature. Ann Surg 2002;235: 803–13. 8 Clavien PA, Sanabria JR, Strasberg SM. Proposed classification of complications of surgery with examples of utility in cholecystectomy. Surgery 1992;111:518–26. 9 Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien–Dindo Classification of Surgical Complications. Five-Year Experience. Ann Surg 2009;250:187–96. 10 Clavien PA, Strasberg SM. Severity Grading of Surgical Complications. Editorial. Ann Surg 2009;250:197–8. 11 Choti MA, Bowman HM, Pitt HA, et al. Should hepatic resections be performed at high-volume referral centers? J Gastrointest Surg 1998;2:11–20. 12 Dimick JB, Pronovost PJ, Cowan JA Jr, Lipsett PA. Postoperative complication rates after hepatic resection in Maryland hospitals. Arch Surg 2003;138:41–6. 13 Glasgow RE, Showstack JA, Katz PP, Corvera CU, Warren RS, Mulvihill SJ. The relationship between hospital volume and outcomes of hepatic resection for hepatocellular carcinoma. Arch Surg 1999;134:30–5. 14 McKay A, You I, Bigam D, et al. Impact of surgeon training on outcomes after resective hepatic surgery. Ann Surg Oncol 2008;15:1348–55. 15 Killeen SD, O’Sullivan MJ, Coffey JC, Kirwan WO, Redmond HP. Provider volume and outcomes for oncological procedures. Br J Surg 2005;92:389–402. 16 Birkmeyer JD, Sun Y, Goldfaden A, Birkmeyer NJ, Stukel TA. Volume and process of care in high-risk cancer surgery. Cancer 2006;106:2476–81. 17 Fong Y, Gonen M, Rubin D, Radzyner M, Brennan MF. Long-term survival is superior after resection for cancer in high-volume centers. Ann Surg 2005;242:540–4; discussion 4–7. 18 (IQWIG) IfQuWiG. Entwicklung und Anwednungen von Modellen zur Entwicklung von Schwellenwerten für die Knie Total-Endoprothese, Abschlussbericht B05/01a. 2005. 19 Drummond M, Sculpher, M., Torrance, G. Methods for the Economic Evaluation of Health Care Programs, 3rd edn. Oxford: Oxford University Press, 2005. 537

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Special Tumors, Population, and Special Considerations

20 Thompson Coon J, Rogers G, Hewson P, et al. Surveillance of cirrhosis for hepatocellular carcinoma: systematic review and economic analysis. Health Technol Assess 2007;11:1–206. 21 Beard SM, Holmes M, Price C, Majeed AW. Hepatic resection for colorectal liver metastases: A cost-effectiveness analysis. Ann Surg 2000;232:763–76. 22 Gazelle GS, Hunink MG, Kuntz KM, et al. Cost-effectiveness of hepatic metastasectomy in patients with metastatic colorectal carcinoma: a state-transition Monte Carlo decision analysis. Ann Surg 2003;237:544–55. 23 Gazelle GS, McMahon PM, Beinfeld MT, Halpern EF, Weinstein MC. Metastatic colorectal carcinoma: cost-effectiveness of percutaneous radiofrequency ablation versus that of hepatic resection. Radiology 2004;233:729–39. 24 McKay A, Kutnikoff T, Taylor M. A cost-utility analysis of treatments for malignant liver tumours: a pilot project. HPB (Oxford) 2007;9:42–51. 25 Vargas V, Castells L, Balsells J, et al. Hepatic resection or orthotopic liver transplant in cirrhotic patients with small hepatocellular carcinoma. Transplant Proc 1995;27:1243–4. 26 Iwatsuki S, Starzl TE, Sheahan DG, et al. Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg 1991; 214:221–8; discussion 8–9. 27 Bismuth H, Chiche L, Adam R, Castaing D, Diamond T, Dennison A. Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg 1993;218: 145–51. 28 Moreno P, Jaurrieta E, Figueras J, et al. Orthotopic liver transplantation: treatment of choice in cirrhotic patients with hepatocellular carcinoma? Transplant Proc 1995;27:2296–8. 29 Bruix J. Treatment of hepatocellular carcinoma. Hepatology 1997;25:259–62. 30 McPeake J, Williams R. Liver transplantation for hepatocellular carcinoma. Gut 1995;36:644–6. 31 Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693–9.

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32 Sagmeister M, Mullhaupt B. Is living donor liver transplantation cost-effective? J Hepatol 2005;43:27–32. 33 Sarasin FP, Giostra E, Mentha G, Hadengue A. Partial hepatectomy or orthotopic liver transplantation for the treatment of resectable hepatocellular carcinoma? A cost-effectiveness perspective. Hepatology 1998;28:436–42. 34 Llovet JM, Mas X, Aponte JJ, et al. Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation. Gut 2002;50:123–8. 35 Sarasin FP, Majno PE, Llovet JM, Bruix J, Mentha G, Hadengue A. Living donor liver transplantation for early hepatocellular carcinoma: A life-expectancy and cost-effectiveness perspective. Hepatology 2001;33:1073–9. 36 Sagmeister M, Mullhaupt B, Kadry Z, et al. Cost-effectiveness of cadaveric and living-donor liver transplantation. Transplantation 2002;73:616–22. 37 Gores GJ. Hepatocellular carcinoma: gardening strategies and bridges to transplantation. Liver Transpl 2003;9:199–200. 38 Hoshida Y, Shiratori Y, Omata M. Cost-effectiveness of adjuvant interferon therapy after surgical resection of Hepatitis C-related hepatocellular carcinoma. Liver 2002;22:479–85. 39 Martin RC, 2nd, Vitale GC, Reed DN, Larson GM, Edwards MJ, McMasters KM. Cost comparison of endoscopic stenting vs surgical treatment for unresectable cholangiocarcinoma. Surg Endosc 2002;16:667–70.

Self-assessment answers 1 2 3 4

A, B, D D B D

Index

73T strain, Newcastle disease virus 356 “aberrant” arteries 14 abscesses, cryoablation and 228, 235 (Table) “accessory” arteries 14–15, 80 (Fig.) acetic acid ablation 127, 267 clinical results 272 dosage 268 acini 30 acquired immune deficiency syndrome see human immunodeficiency virus infection activated clotting time, isolated hepatic perfusion 164 activated partial thromboplastin time (APTT) on-site monitoring 525–7 for percutaneous ethanol injection 269 acupoints 415 acupuncture 417 acute cholinergic syndrome 107 ACVBP (chemotherapy regimen), post-transplant lymphoproliferative disorders 465 adenoma, hepatic computed tomography 81 magnetic resonance imaging 94 (Fig.) pregnancy 467 transplantation and 285–6 adenovirus 354 (Table), 356–60, 408 adhesions, repeat liver resection 216 adjuvant therapy chemotherapy breast carcinoma metastases 446 cholangiocarcinoma 187 colorectal carcinoma metastases 110–11, 158, 159 (Table), 196, 344–5 see also preoperative chemotherapy HCC 296–303 cost-effectiveness 536 retinoids 297 (Table), 299–300, 387–8 transarterial chemoembolization as 147 see also bridging therapy adoptive transfer, lymphocytes 300 Adriamycin see doxorubicin aflatoxin HCC 54, 489, 515 p53 gene mutations 371, 515 Africa 509–18 afterloading, radionuclide therapy 126 age cholangiocarcinoma incidence 57 colorectal carcinoma metastases 193–4

HCC 52 Africa 509–10 China 510 hepatitis B and C viruses, Africa 510 hepatitis C virus vs hepatitis B virus infections 510, 515 liver resection 310 see also elderly people agenesis of gallbladder 22 AIDS see human immunodeficiency virus infection Akt (protein) 374, 386–7 alcohol cholangiocarcinoma 58, 59, 60, 72 HCC 53–4 Africa 515 Brazil 505 see also ethanol ablation alcoholic steatohepatitis 30–1, 32 algorithms 307 for assessment HCC detection, Japan 490, 491 (Fig.) perioperative cardiac 458–9 for treatment Barcelona Clinic Liver Cancer staging system 319 (Fig.) cholangiocarcinoma 325 (Fig.), 327 (Fig.), 329 (Fig.) colorectal carcinoma metastases 343 (Fig.) gallbladder carcinoma 338–9 Japan 320 (Fig.) HCC 494 (Fig.) liver resection in cirrhosis 309 (Fig.) percutaneous coronary intervention and 459 (Table), 460 (Table) see also clustering algorithms alkali therapy, percutaneous 277 alkaline phosphatase see liver function allocation policies, transplantation for HCC 288–9 alpha-1-antitrypsin deficiency, cholangiocarcinoma 60 fibrolamellar HCC 41 alpha-fetoprotein 43, 69–71 diagnosis 70 HCC 71 Africa 513 Asia 489–90 cost-effectiveness of screening 534 postoperative follow-up 222

hepatoblastoma 477, 481 L3 fraction, HCC surveillance 490 prognosis 127 promoters for gene therapy 354–5, 357 treatment monitoring 70–1 alpha-L-fucosidase 71 alternating current, heating by 244–6 alternative medicine 414–17, 419 altitude, implantable infusion pump flow rates 151 American Joint Committee on Cancer, staging of gallbladder carcinoma 335–6 amplicons, herpes simplex type 1 virus 360–3 amplifications, chromosomal, HCC 370 anatomic resections 181 colorectal carcinoma metastases 194 segment 1 183 anatomy 11–26, 177–8 blood supply 131 see also specific blood vessels historical aspects 4 nomenclature 5, 177–8 pathological distortions 22 regeneration of liver on 216 anesthesia liver surgery 519–30 induction and maintenance 522, 523 percutaneous ethanol injection 268 anesthetic agents, hepatic clearance 522 (Table) angiogenesis 400–4 inhibitors 349, 376–8, 388–9, 400–13 conventional treatment combined with 409 see also specific drugs liver as environment for 402 tumor growth 401–2 angiogenic barrier concept 410 angiogenic switch 400 angiography 93–5, 97 (Fig.) angiosarcoma 439 computed tomography 79–80 internal radiotherapy 132 percutaneous hepatic perfusion 169 selective continuous intra-arterial chemotherapy 152 transarterial embolization 142 angiopoietin-2, HCC 402 angiosarcoma 46, 439–41, 482 chemotherapy 116, 440 transplantation for 291, 440

539

Index angiostatin 407–8 doxorubicin with 409 animal models, molecular targeted therapies 374 anomalies bile ducts 15–16 extrahepatic 23–4 gallbladder carcinoma 333–4 left hemiliver drainage 16 right hemiliver drainage 15–16 cystic artery 23 gallbladder 22 hepatic artery 24, 152 of origin 14 (Fig.) portal vein 18 antennae, microwave thermal ablation 254, 255, 257 anterior approach, liver resection 195 anti-VEGF antibody 404–5 antiangiogenic compounds endogenous 407–8 see also angiogenesis, inhibitors; specific drugs antibody-mediated vascular targeting 409 anticoagulants herbal remedies interacting with 416 isolated hepatic perfusion 164 antineoplastons (Burzynski) 415 antioxidants, dietary 416 antiplatelet therapy 459 antisense oligonucleotides Bcl-2 397 IGF-2 383–4 apoptosis 393–4, 395 (Fig.) induction 393–9 see also TRAIL apoptosis protease activating factor-1 394 appendix, primary neuroendocrine tumors 425 aprotinin 524 arantian plate 21 Aretxabala, Xabier de, on gallbladder carcinoma invasion 504 Argentina metastases 505 colorectal carcinoma 505 transplantation 501, 505 see also River Plate school arginine deiminase 404 (Table) argon, for cryoablation 230 argon beam coagulation, gas embolism 204 Arrow implantable infusion pumps 151, 153 arterialization 33 arteries see blood vessels; named arteries ascites hemorrhagic 97 (Fig.) liver resection planning 179 open vs laparoscopic liver resection 210 Asia 487–99 interferon side-effects 298–9 living donor liver transplantation 492–3 HCC and 288 sorafenib trial 385–6 aspartate, thrombocytopenia 233 atelectasis, cryoablation 233 atracurium, liver transplantation 523 atrophic gastritis, chronic 425

540

autopsy, liver weight, Africa 511 autotransfusion, liver transplantation 523 awareness, anesthesia 522 AXIN1 mutations 388 Ayurveda 414–15 AZD2171 (Recentin) 110, 404 (Table) B4 (bile duct), anomalies 16 bacteria, gallbladder carcinoma 503 Bad (protein), underexpression 396 Bantu visceral siderosis 515 Barcelona Clinic Liver Cancer staging system 139, 140 (Fig.), 317, 318 Japanese guidelines vs 320–1 treatment algorithm 319 (Fig.) bare area 21 bare crease 21 basic fibroblast growth factor, HCC 402 batimastat 408 Bax (protein), underexpression 396 BAY12–9566 (selective MMPI) 408–9 Bcl-2 (protein) antisense oligonucleotides 397 overexpression 396 Beckwith–Wiedemann syndrome 475 Berchtold system, radiofrequency ablation 247 Bernardino needle 268 beta-blockers, perioperative 459 beta-catenin cholangiocarcinoma 61 HCC 388 see also Wnt signaling pathway beta emission, radioconjugates 132 (Table) bevacizumab 404 (Table), 405–6 biliary tract carcinoma 115 breast carcinoma metastases 406 colorectal carcinoma metastases 108–9, 197, 405 neoadjuvant 344 HCC 112, 113, 349, 376, 377 (Table), 388 erlotinib with 376, 389 liver resection and 115, 310, 406 pancreatic endocrine tumors 115 renal cell carcinoma metastases 406 bile duct system (biliary tract) anastomosis, high biliary-enteric 16 anatomy 15–16 extrahepatic 23–4 intrahepatic 11 liver regeneration on 216 anomalies 15–16 extrahepatic 23–4 gallbladder carcinoma 333–4 left hemiliver drainage 16 right hemiliver drainage 15–16 blood supply 24–5 bypass, segment 3 bile duct 16 carcinoma systemic therapy 113–15 see also cholangiocarcinoma; gallbladder, carcinoma caudate lobe 16–17 colorectal carcinoma metastases 48, 111 cystadenocarcinoma 45–6

cysts, cholangiocarcinoma and 57 (Table), 58 excision 337 fibrosis of liver due to diseases of 33 fistula, after cryoablation 235 (Table) preoperative catheterization, cholangiocarcinoma resection 186, 312, 328 radioembolization toxicity 134 strictures gelfoam embolization 142 radiofrequency ablation and 252 see also cholangiography; common bile duct bile salt transporter proteins, cholangiocarcinoma 61 biliary cystadenocarcinoma 45–6 biliary-enteric anastomosis, high 16 biliary fistula, after cryoablation 235 (Table) biliary intraepithelial neoplasia (BilIN) 61 biliary papillomatosis cholangiocarcinoma and 57 (Table), 60 see also intraductal cholangiocarcinoma biliary tract see bile duct system bilirubin, liver resection planning 179 bilomas 23 at cryosites 240 biopsy 474 angiosarcoma 439 fatty liver disease 31 HCC 282 hepatoblastoma 479 hilar cholangiocarcinoma 326 Kaposi sarcoma 462 neuroendocrine tumors 427 post-transplant lymphoproliferative disorders 465 seeding and 282 biotherapy, neuroendocrine tumors 427–8 Bismuth classification, hilar cholangiocarcinoma 326 Bismuth, Henri 6 “blind” instruments, laparoscopic liver transection 206–7 blood loss inferior vena cava pressure 525 (Fig.) resection of liver 180 laparoscopic 208 blood salvage, liver transplantation 523 blood supply 131 bile ducts 24–5 by hepatic artery 11–12 see also vascularity of tumors blood vessels cryotherapy 228 as heat sinks 228, 245–6 sealing system, laparoscopic liver transection 206 see also vascularity of tumors body mass index, HCC mortality 54 body surface area, total liver volume vs 198 boiling carboplatin 275 bone marrow hepatoblastoma 477 radiation dose limitation 134

Index bortezomib 378–9 bracketed technique, microwave thermal ablation 255 Bragg peak 124 Brazil HCC 504–5 liver surgery 501–2 breast carcinoma metastases 48, 443 (Fig.), 445–6 bevacizumab 406 internal radiotherapy 136 MRI contrast agents 95 (Fig.) tumor marker 73 molecular targeted therapies, hazard ratios 379 (Table) breath tests, microsomal hepatic function 310 (Table) breathing motion, external beam radiotherapy 122, 123 bridge of liver tissue (in umbilical fissure), division at hilar cholangiocarcinoma surgery 18 bridging therapy 286–7 chemoembolization, transarterial 286, 287 cost-effectiveness 536 embolization 147 radioembolization 135 radiofrequency ablation 251–2, 286, 287 resection of liver 286–7 cost-effectiveness 536 transarterial chemoembolization 286, 287 Brisbane nomenclature, liver anatomy 5, 11–12, 178, 194 brivanib 404 (Table) Broelsch, Christoph E., split liver transplantation 6 bubbles, after transarterial embolization 143 Budd–Chiari syndrome 489 bystander effect, suicide gene prodrug therapy 353 c-MET/hepatocyte growth factor signaling pathway 350, 384 CA 15-3 (tumor marker) 73 CA 19-9 (tumor marker) 72 colorectal carcinoma metastases 192 gallbladder carcinoma 503 CA 27-29 (tumor marker) 73 “cage” configuration, microwave thermal ablation 255, 257 calcification patterns, gallbladder carcinoma 49 (Fig.), 334 calcineurin inhibitors 287 calcium infusion, liver transplantation 524 Calne, Sir Roy (surgeon) 6 Cancell (biologic remedy) 415 Cancer of the Liver Italian Program score 317, 318 (Table) Cantlie, James, Rex–Cantlie line 4 capabilities see structural measures capecitabine colorectal carcinoma metastases 108 mitomycin with, biliary carcinoma 114 capillarization, sinusoids 33

CAPIRI regimen, colorectal carcinoma metastases 108 CAPOX regimen, colorectal carcinoma metastases 108 bevacizumab with 109 capsule of liver 21–2 11 C-ethanol, dynamic PET 267 11 C-labeled 3,4-dihydroxyphenylalanine PET, neuroendocrine tumors 427 carbon dioxide pneumoperitoneum 204, 504 carboplatin, boiling 275 carcinoembryonic antigen 42, 72 colorectal carcinoma metastases 192, 342 postoperative follow-up 219 cryoablation follow-up 232, 239 gallbladder carcinoma 503 carcinogenesis, cholangiocarcinoma 60–1 carcinogens 59, 60 carcinoid syndrome heart 427, 429 interferon 115–16 carcinoid tumors 424–5 imaging 428 (Fig.) systemic therapy 115–16 tumor markers 73 cardiac assessment, perioperative 458–9 see also electrocardiography cardiac output, liver transplantation 523 cardiac risk 456–60 liver transplantation 520–1 surgery-specific 457–8 cardiotrophin-1 314 Carell, Alexis (surgeon) 6 Caroli syndrome, cholangiocarcinoma and 57 (Table), 58 carriers, hepatitis B virus 488, 514 caseloads, quality assessment methods and 532 caspases 393–4, 395 (Fig.) downregulation in tumors 396 catheter(s) biliary, cholangiocarcinoma resection 186 radionuclides, radiotherapy 126 catheter-assisted angiography 93–5, 97 (Fig.) catheter-assisted arterial portography, CT with 95–6 catheterization pulmonary artery 523 right heart 521 (Table) caudate lobe 12 biliary drainage 16–17 systemic venous drainage 19 caudate veins 12 division 21 cautery, saline-linked 195, 246 cavernous hemangioma 481 Cavitron ultrasonic surgical aspiration (CUSA) 180 CD gene 357 CD34 antigen, angiosarcoma 46 celecoxib 388 cell death temperature 244 see also apoptosis; necrosis Celon system, radiofrequency ablation 247

central fibrosis 33 central pontine myelinolysis 520 central venous pressure, hemostasis and 195, 522 ceramides, apoptosis 394, 397 cerebral edema 519, 520 cetuximab as antiangiogenic agent 404 (Table) biliary tract carcinoma 115 colorectal carcinoma metastases 109, 157, 160, 197, 376, 406–7 HCC 377 (Table), 383 models 373 charged particle radiotherapy 124–5 charring 245 chemical shift imaging, MRI 85 chemicals, industrial 60 chemoembolic therapy 93–4, 127 as control arm for clinical trials 375 neuroendocrine tumors 433–5 see also transarterial chemoembolization chemotherapy 105, 107–21 alpha-fetoprotein 71 angiosarcoma 116, 440 bevacizumab with 405 carcinoembryonic antigen 72 colorectal carcinoma metastases 107–12 adjuvant 110–11, 158, 159, 196, 344–5 cost-effectiveness 535 palliation 112–13 repeat resection vs 218 selective continuous intra-arterial 155–8 gallbladder carcinoma 188, 335, 337, 504 HCC, Africa 514 hepatoblastoma 116, 480 internal radiotherapy with 136 intralesional 275, 276 (Fig.) Kaposi sarcoma 463 liver changes 36, 216, 310 neuroendocrine tumors 432–3 non-Hodgkin lymphoma 463 parenchymal friability 216 post-transplant lymphoproliferative disorders 465 resection of liver, safety after 197 selective continuous intra-arterial 151–63, 523 selective portal vein occlusion and 312 transplantation for cholangiocarcinoma 289–90 see also adjuvant therapy, chemotherapy; FOLFOX; neoadjuvant chemotherapy; preoperative chemotherapy; regional chemotherapy; transarterial chemotherapy chemotherapy-associated steatohepatitis, portal hypertension, radioembolization toxicity 134 chest infections, cryoablation 235 (Table) chest X-ray, raised hemidiaphragm 513 chi (life force) 415 Chiba needle 267–8 chicken-wire fibrosis 32 children 475–86 HCC 481 Africa 510 metastases 482, 496–7 transplantation, Argentina 501

541

Index Children’s Oncology Group (USA), hepatoblastoma staging 478 Chile gallbladder carcinoma 502, 504 HCC 505 liver surgery 502 China HCC 487–8 mean age 510 microwave thermal ablation equipment 253, 254 percutaneous chemical ablation vs liver resection 492 Chinese medicine, traditional 415 Chinese University Prognostic Index 317, 318 (Table) chitosan 134 cholangiocarcinoma 56–63, 324–32 Asia 494–6 computed tomography 81–2 cost comparisons of treatment 536 epidemiology 56–7 etiology 57–60 immunohistochemistry 42 (Table) internal radiotherapy 136 liver changes 35–6 magnetic resonance cholangiopancreatography 98 magnetic resonance imaging and 92 natural history 60–1 pathology 44–5 portal vein anatomy at surgery 17–18 positron emission tomography 84–5, 86 (Fig.) post-transplant 466–7 regional chemotherapy 158–60 resection 175, 186–7 biliary drainage before 312, 328 elderly people 461 staging 43 (Table) intrahepatic 44 perihilar 45, 328 systemic treatment 113–15 transplantation 187, 289–90 hilar tumor 289–90, 328 recurrence after 466–7 tumor markers 72 cholangiography 96–8 CT with, hilar cholangiocarcinoma 82 see also magnetic resonance cholangiopancreatography cholecystectomy gallbladder carcinoma 187, 334, 336, 338–9 prophylactic 503 stopping surgery 339 pregnancy 468 at selective continuous intra-arterial chemotherapy 152 choledochal cysts, cholangiocarcinoma and 57 (Table), 58 cholelithiasis, gallbladder carcinoma 187, 333, 502–3 cholesterol see hypercholesterolemia cholinergic syndrome, acute 107

542

CHOP regimen, post-transplant lymphoproliferative disorders 465 chromogranin, neuroendocrine tumor metastases 48 chromosomes, HCC 369–70 chronic atrophic gastritis 425 CI-1042 (genetically engineered adenovirus) 357–60 cirrhosis 33 abdominal drainage and 181 alpha-fetoprotein 70 cost-effectiveness of screening 534 angiogenesis 388 cholangiocarcinoma 36, 59–60 HCC 53, 281–2 Africa 510, 512–13, 513–14, 515 repeat resection and 222 transplantation 282 nonalcoholic steatohepatitis 454, 455 portal hypertension, radioembolization toxicity 134–5 Pringle’s maneuver and 180 resection of liver 210, 308 algorithms 309 (Fig.) sorafenib and 385 transplantation 282, 284, 285 cisplatin, cholangiocarcinoma 114, 187 cisplatin/epinephrine injectable gel 275, 276 (Fig.) clamp crushing, parenchymal transection 180 clamping inferior vena cava 501, 523–4 laparoscopic liver resection 205 portal triad, intermittent 314 Clavien–Dindo classification of complications 532 clear cell adenocarcinoma, gallbladder 49 clearance (hepatic) drugs 522 (Table) tests 310 (Table) indocyanine green 179, 310–11 clearance (total body), regional drug delivery and 154–5 CLF regimen, biliary tract carcinoma 114 clinical target volume (CTV), radiotherapy 122 clinical trials chemotherapy 110 guidelines 350 molecular targeted therapies 375 CLIP (Cancer of the Liver Italian Program) score 317, 318 (Table) clonidine, liver transplantation 523 Clonorchis sinensis, cholangiocarcinoma and 58, 495 clopidogrel 459 clustering algorithms, genomics 371 CNHK500 (dual-regulated oncolytic adenovirus) 357 CoaguChek-Plus 527 coagulating current 245 coagulation (blood), monitoring 524–7 isolated hepatic perfusion 164 percutaneous ethanol injection 269

coagulopathy cryoablation 235 (Table) see also thrombocytopenia liver transplantation 521 coils, embolization with 142 coils (MRI), high-density surface coils 85–6 cold preservation, donor livers 6 colectomy, open vs laparoscopic, COST trial 207 collagen(s) 30 acetic acid on 267 collagen XVIII 408 Collins formula 154, 155 collision tumors, mixed hepatocellular/ cholangiocarcinoma 45 Colombia, transplantation 502 colorectal carcinoma, ceramide deficiency 397 colorectal carcinoma metastases 64–8, 128, 342–6 bevacizumab 108–9, 197, 405 neoadjuvant 344 bile ducts 48 cetuximab 109, 157, 160, 197, 376, 406–7 chemotherapy 107–12 adjuvant 110–11, 158, 159, 196, 344–5 cost-effectiveness 535 palliation 112–13 repeat resection vs 218 selective continuous intra-arterial 155–8 computed tomography and PET/CT 85 cost-effectiveness of treatments compared 535 cryoablation 236–9 liver resection and 219–20, 228, 236, 238 (Table) synchronous with primary resection 228 detection 65 epidemiology 64–5 epidermal growth factor inhibitors 406–7 extrahepatic 193, 219, 342 G207 virus 362 isolated hepatic perfusion 166–7 Japan 496 laparoscopic resection 212 laser thermal ablation 259–61 microvessel density 403 molecular targeted therapies, hazard ratios 379 (Table) MRI 92 (Fig.) natural history 65–7 number of 193 radioembolization 136 radiofrequency ablation see radiofrequency ablation (RFA), colorectal carcinoma metastases recurrence see recurrence, colorectal carcinoma resection see resections of liver, colorectal carcinoma metastases selective continuous intra-arterial chemotherapy 155–8 South America 505 treatment 128, 342–5 tumor markers 72–3 see also hereditary nonpolyposis colorectal carcinoma syndrome colorectal neuroendocrine tumors 425

Index common bile duct 23 blood supply 24 diameter 23 excision 337 strictures 329 common hepatic artery 13 common hepatic duct 23 blood supply 24 confluence with cystic duct 22, 23 (Fig.) comorbid illness, liver surgery 519 compensated cirrhosis, transplantation and 284, 285 complementary medicine 414, 417–18, 419 information sources 415 (Table) complications effect of staff training 533 impact on costs 536 quality of care and 532 see also specific procedures computed tomographic angiography 79–80 computed tomography 78–85 absent left portal vein 18 angiosarcomas 439 catheter-assisted arterial portography with 95–6 catheter-assisted arteriography with 95–6 colorectal carcinoma metastases 192, 219 contrast agents 98 after cryoablation 232 for cryoablation 230 epithelioid hemangioendothelioma 441 gallbladder carcinoma 334 HCC detection 490 hepatoblastoma 477 left portal vein, absent 18 lipiodol 271 percutaneous ethanol injection 268, 270 positron emission tomography with 83–5, 219 cholangiocarcinoma 86 (Fig.) radiotherapy planning 122 remnant liver volume assessment 311 TACE patients, assessment 143 without contrast agent 80–1 see also multidetector computed tomography concentrations, regional delivery 154–5 conditionally replicative adenovirus (CRAd), immunomodulation 357 conductive heating 245 conformal radiotherapy, fluorodeoxyuridine with 128 conformal treatment planning four-dimensional 123 three-dimensional 122–3, 124 (Fig.), 125 (Fig.) dose–volume histograms 126 (Fig.) Consensus Conference on CLM, statement 198–9 continuous intra-arterial chemotherapy, selective 151–63, 523 contraceptives (oral), hepatic adenoma 467 contrast agents computed tomography 78, 98 HCC detection, Japan 490 MDCT 78 MRI 89–90, 93 (Fig.) adenoma 94 (Fig.)

breast carcinoma metastases 95 (Fig.) double-contrast 90–1 focal nodular hyperplasia 92 gadolinium 88–9 liver-specific 89–90, 93 (Fig.) sonographic 77 contrast-enhanced ultrasound (CEUS) 77 clinical role 78 control arms, clinical trials 375 convective heat loss 245–6 conversion rates, laparoscopic to open liver resection 208 cooling probes for microwave thermal ablation 253, 255 radiofrequency electrodes 246 coronary angiography, for liver transplantation 520–1 coronary artery disease liver transplantation 520 see also cardiac risk coronary ligament 21 coronary revascularization, preoperative 459–60 cost(s) as outcome measures 532 percutaneous ablation therapies 275–6 see also economics cost-benefit analysis 534 cost-effectiveness 534–7 cost–quality trade-off 532 COST trial, open vs laparoscopic colectomy 207 cost-utility analysis 534 living donor liver transplantation, HCC 536 Couinaud, Claude 4, 5 (Fig.) segments of liver 4, 11, 14 (Fig.), 177–8 counter attack against T cells 396 counterstaining, segment 5 segmentectomy 182 cracking of ice ball, cryoablation 233, 235 (Table) Crown needle 267–8 crushing with clamp, parenchymal transection 180 cryoablation 227–43 colorectal carcinoma metastases 236–9 liver resection and 219–20, 228, 236, 238 (Table) synchronous with primary resection 228 complications 523 neuroendocrine tumors 431 postoperative follow-up 232, 233 (Fig.) preanesthetic investigations 520 (Table) preoperative preparation 519 prognostic factors 239–40 cryoassisted wedge excision 217 cryoprecipitate, liver transplantation 524 cryoshock 233, 234 (Table) cryptogenic cirrhosis 455 crystallization of water 227 CTL102 (adenovirus) 360 CTNNB1 gene 371, 388 cure cryoablation with liver resection 240 fibrolamellar HCC 127 repeat resection of colorectal carcinoma metastases 218

cyclooxygenase-2, cholangiocarcinoma 61 cyclophosphamide, activation by P450 2B1 transgene 362 cyclosporine A, historical aspects 6 cyst(s) choledochal, cholangiocarcinoma and 57 (Table), 58 computed tomography 81 cystadenocarcinoma, biliary 45–6 cystadenoma, biliary 46 cystic artery 23 cystic duct anatomy 22, 23 (Fig.) common bile duct mistaken for 24 cystic plate 21, 23 cystic veins 23 cytochrome c, prevention of release 396 cytochrome P450 enzymes cholangiocarcinoma 61 milk thistle and 416 cytokeratins intrahepatic cholangiocarcinoma vs metastases 45 tumor immunohistochemistry 42 (Table) cytokine genes, immunomodulation 356 cytokines, liver regeneration 311 cytology, intraoperative, gallbladder 503 cytoplasm, HCC 40 cytoreductive surgery (debulking) neuroendocrine tumors 424, 428–9, 435 see also downstaging cytosine deaminase gene, suicide gene prodrug therapy 353 cytosolic hepatic function, tests 310 (Table) dacarbazine, neuroendocrine tumors 115 DcR3 (decoy receptor) 396 de Aretxabala, Xabier, on gallbladder carcinoma invasion 504 de novo recurrences HCC 296 after liver transplantation 464, 465–6, 467 death ligands 396 death receptors 393 debulking see cytoreductive surgery decompensated cirrhosis, transplantation and 284, 285 decoy receptors 396 defective infection single-cycle HSVs (DISCs) 360, 361 des-γ-carboxy prothrombin (DCP) 71, 490 desiccation 245 “detoxification” (alternative therapy) 416 dexamethasone, selective continuous intraarterial chemotherapy with 156 (Table), 157 diabetes mellitus cholangiocarcinoma 60 nonalcoholic steatohepatitis 455 steatosis 32 dialysis patients, hepatitis C virus 465 diet alternative therapies 415 iron overload 515 for steatosis 309

543

Index differentiation, as criterion for transplantation 284 diffuse HCC 40 diffusers, laser thermal ablation 259 direct cholangiography 97, 98 (Fig.) computed tomography with, hilar cholangiocarcinoma 82 DISCs (defective infection single-cycle HSVs) 360, 361 Disse, space of 30, 31 (Fig.) disseminated intravascular coagulation, adenoviruses 360 dissemination see seeding of tumor distal cholangiocarcinoma 324, 328–30 distal intrahepatic selective embolization, hepatic artery, neuroendocrine tumors 433 dl1520 (genetically engineered adenovirus) 357–60 dlsptk (HSV mutant), oncolytic therapy 361 DNA, hepatitis B virus, HCC 53 dobutamine stress electrocardiography, for liver transplantation 521 donor livers preservation 6 steatosis 7 donor-origin post-transplant lymphoproliferative disorders 465 DOPA, 11C-labeled, PET, neuroendocrine tumors 427 dopamine, low-dose 523 Doppler ultrasound 76 dorsal resection 183, 184 (Fig.) dorsal sector of liver 177 dosage acetic acid ablation 268 isolated hepatic perfusion, maximum tolerated 165 dose calculation internal radiotherapy 133 see also radiation dose limitations dose–response curves, cytotoxic drugs 155 dose–volume histograms (DVH) 123, 126 (Fig.) safe doses 128 double-contrast MRI 90–1 double gallbladder 22 double-stranded protein kinase, oncolytic therapy 355 doubling times colorectal carcinoma metastases 65–6 HCC 54 Africa 512 downstaging 285 colorectal carcinoma metastases 111–12 see also under transplantation doxorubicin (Adriamycin) angiostatin with 409 HCC 112, 377 (Table) cetuximab with 383 isolated hepatic perfusion 167 sorafenib with 386 neuroendocrine tumors, chemoembolic therapy 434 pancreatic endocrine tumors, streptozocin with 115 RAD001 with 387

544

drainage (surgical) bile duct system, cholangiocarcinoma resection 186, 312, 328 liver resection 181, 186 dropout, transplantation waiting lists 286 see also bridging therapy drug-eluting beads (DEB) 146 drugs hepatic clearance 522 (Table) interactions with herbal remedies 416 prodrugs, suicide gene prodrug therapy 353 dual loop probes, microwave thermal ablation 255 dual-regulated oncolytic adenovirus CNHK500 357 “ducts of Luschka” 23 duodenum, primary neuroendocrine tumors 425 duration of freezing 227 dye injection, selective continuous intra-arterial chemotherapy 152 dynamic positron emission tomography, ethanol in tumors 267 dysplasia–carcinoma sequence, cholangiocarcinoma 61, 62 (Fig.) dysplastic nodules 41 e antigen negativity, hepatitis B virus 515 E1A gene, oncolytic therapy 357 E1B-55K-encoding gene 357 Eastern Cooperative Oncology Group (ECOG), performance status 132 ECF regimen, biliary tract carcinoma 114 echinococcosis, computed tomography 80–1 echocardiography 521 (Table) transesophageal 523, 527 economics 534–7 edges see margins elderly people, resection of liver 460–1 electrical heating 244 electrical stimulation, for pruritus 417 electrocardiography 456–7 liver transplantation 520 dobutamine stress 521 electrodes microwave thermal ablation 254 radiofrequency ablation 245, 246, 247, 248 ELF regimen, biliary tract carcinoma 114 embolization 127 hepatic artery colorectal carcinoma metastases, after liver resection 219–20 neuroendocrine tumors vs chemoembolic therapy 434–5 distal intrahepatic selective 433 recurrent HCC 223 for internal radiotherapy 132 radioconjugates 132 (Table) portal veins 198, 311, 312, 314, 328 after chemotherapy 344 historical aspects 487 see also chemoembolic therapy; internal radiotherapy; postembolization syndrome; transarterial chemoembolization embryonal pattern, hepatoblastoma 43 embryonal rhabdomyosarcoma 47, 482

embryonal sarcoma 47 encephalopathy 519–20 endocrine tumors see neuroendocrine tumors endogenous antiangiogenic compounds 407–8 endogenous opioids, acupuncture and 417 endoscopic stenting, cholangiocarcinoma, costs 536 endoscopic ultrasound gallbladder carcinoma 334 hilar cholangiocarcinoma 326 endostatin 408 endothelial cells 400 antibody-mediated vascular targeting 409 HCC 402 sinusoidal 404 VEGF as survival factor 405 endpoints, clinical trials 375 energy requirements, cardiovascular status 457 (Table) eosinophilic globules, embryonal sarcoma 47 epicholedochal plexus 24 epidemiology 29 cholangiocarcinoma 56–7 colorectal carcinoma metastases 64–5 HCC 52 epidermal growth factor inhibitors 406–7 epidermal growth factor receptor (EGFR) 349, 373, 376, 382–3 cetuximab on 109, 376 panitumumab and 109–10 transforming growth factor α on 374 epidural analgesia, thoracic 522 epinephrine, intralesional chemotherapy 275 epirubicin, pancreatic endocrine tumors 115 epithelial hepatoblastoma 43–4 epithelioid hemangioendothelioma 46–7, 441–2 chemotherapy 116 transplantation for 291, 442 epsilon-aminocaproic acid, liver transplantation 524 Epstein–Barr virus non-Hodgkin lymphoma 463 post-transplant lymphoproliferative disorders 464 p-ERK (MAPK pathway activation marker) 383 erlotinib as antiangiogenic agent 404 (Table) colorectal carcinoma metastases 110 HCC 113, 373, 376, 377 (Table), 383 bevacizumab with 376, 389 sorafenib with 386 Escherichia coli, lacZ gene mutation, gene therapy 362 Essiac (herbal remedy) 416 estimated total liver volume 198 ethanol ablation 127, 266–72 clinical results 271–2 colorectal carcinoma metastases, recurrence after liver resection 220 in combination therapies 274–5 complications 269–70 HCC 251, 321 recurrent 223 metastases 220, 275 in multiablation therapy 275

Index neuroendocrine tumors 432 radiofrequency ablation vs 273–4, 277, 286 costs 276 HCC 251, 321 recurrent HCC 223 technique 268–9 transportal, TACE with 274 etiology cholangiocarcinoma 57–60 HCC 52–4 genetics 52–3, 368–74 etomidate, liver transplantation 523 Europe, treatment guidelines, HCC 318 everolimus 287, 376 evidence, gallbladder carcinoma 333–5 evidence-based guidelines, HCC, Japan 493, 494 (Fig.) examination (physical), cardiovascular status 456 exenteration, transplantation for neuroendocrine tumors with 432 exercise stress testing 520, 521 (Table) experience, value of 533 expression dysregulation, genes 371–2 extended resection, gallbladder carcinoma 336, 337 external beam radiotherapy 122–30 extracellular matrix 30 angiogenesis 400 fibrosis 32–3 extracorporeal circuit isolated hepatic perfusion 164, 165 (Fig.) percutaneous hepatic perfusion 169 extraction of specimen, laparoscopic liver resection 207 incisions 210 extraction ratio, hepatic 155 extrahepatic arteries 24 extrahepatic bile ducts 23–4 extrahepatic cholangiocarcinoma 45, 56 epidemiology 56, 57 survival rates 61 extrahepatic metastases colorectal carcinoma 193, 219, 342 epithelioid hemangioendothelioma 442 exclusion for cryoablation 230 HCC 83 hepatoblastoma 480 extrinsic pathway, apoptosis 393–4, 395 (Fig.) eye melanoma, metastases from, isolated hepatic perfusion 166–7 factor VIII-related antigen, angiosarcoma 46 FADD activation, apoptosis 393 falciform ligament 22 familial adenomatous polyposis 475–6 Fas (protein) decreased in HCC 396 signaling pathway for apoptosis 393 fat, chemical shift imaging, MRI 85 fat-storing cells see hepatic stellate cells fatty liver see nonalcoholic fatty liver disease; steatosis FCU1 gene, suicide gene prodrug therapy 355–6 FELV regimen, biliary tract carcinoma 114 fentanyl, liver transplantation 523

ferumoxides see superparamagnetic iron oxide fetal pattern, hepatoblastoma 43 fever HCC, Africa 512 percutaneous ethanol injection 269 postembolization syndrome 143 fibrinogen fibrolamellar HCC 41 ROTEM TEG analysis 527 (Fig.) fibrinolysis see hyperfibrinolysis fibrolamellar HCC 35, 41, 481 curability 127 epidemiology 513 systemic therapy 113 transplantation and 285, 286 (Table) tumor markers 72 fibrosis 32–4 steatohepatitis 32 nonalcoholic 455 fiducial markers 123 finger fracture technique 487 fish, liver flukes 58 5–5 rule, liver transplantation 493 5-hydroxytryptamine, PET, neuroendocrine tumors 427 floxuridine (FUDR; fluorodeoxyuridine) 151, 154, 427 conformal radiotherapy with 128 cryoablation and 240 G207 virus with 362–3 hyperfractionated radiotherapy with 127 isolated hepatic perfusion 167 pharmacokinetics 155 transarterial chemotherapy 312 fluid management, liver surgery 522 fluorescein injection, selective continuous intraarterial chemotherapy 152, 154 (Fig.) 18 F-fluorodeoxyglucose PET 83 colorectal carcinoma metastases 192 assessment of response to radioembolization 136 computed tomography integrated with 83 cryoablation follow-up 232 neuroendocrine tumors 426, 427 radiofrequency ablation follow-up 252 on role of intraoperative ultrasound 78 see also positron emission tomography fluorodeoxyuridine see floxuridine 5-fluorouracil apoptosis and 397 cholangiocarcinoma 114, 187 colorectal carcinoma metastases 107, 111, 157, 158, 344 neuroendocrine tumors, streptozocin with 115 pharmacokinetics 155 prodrugs tegafur 110 see also capecitabine suicide gene prodrug therapy 353, 355 focal nodular hyperplasia imaging 81, 91 (Fig.) pregnancy 467 FOLFIRI regimen, colorectal carcinoma metastases 107, 108 (Table), 111 cetuximab with 109

FOLFOX regimens, colorectal carcinoma metastases 107, 108 (Table), 157, 158, 218, 220 bevacizumab with 109, 405 cetuximab with 109 neoadjuvant 344 resection with 110–11 FOLFOXIRI, colorectal carcinoma metastases 111 folinic acid 5-fluorouracil with, colorectal carcinoma metastases 107 FUDR with, isolated hepatic perfusion 167 foot massage 418 four-dimensional conformal treatment planning 123 freeze–thaw cycle, repetition 228, 231 frequency (Hz) 245 fresh frozen plasma, liver transplantation 524 friable parenchyma 216 Frizzled (transmembrane receptor) 372 FUDR see floxuridine functional capacity, cardiovascular status 456, 457 (Table) future liver remnant volume, colorectal carcinoma metastases workup 192, 193, 197–8, 199 (Fig.) G207 (multimutated virus) 362–3 gadolinium (contrast agent) lipophilic variants 90 use in MRI 88–9 galactose elimination capacity test 310 (Table) galactosyl human serum albumin, 99mTc-labeled, uptake test 310 (Table) Galen (130–200 AD) 3 gallbladder anatomy 22 anomalies 22 carcinoma 48–9, 333–41 adjuvant transarterial chemotherapy 344 Chile 502, 504 diagnosis 335 epidemiology 57 follow-up 345 PET/CT 85 prognosis 335 resection 187–8 South America 502–4 staging 49, 187, 335–6, 337–8 systemic treatment 113–15 treatment guidelines 333–41 right hepatic duct joining infundibulum 24 68 Ga-octreotide PET, neuroendocrine tumors 427 gallstones cholangiocarcinoma 57 (Table), 59, 495 gallbladder carcinoma 187, 333, 502–3 gamma emission, radioconjugates for internal radiotherapy 132 (Table) gamma probes, neuroendocrine tumors 426 ganciclovir (GCV), suicide gene prodrug therapy 353 gas embolism, laparoscopic liver resection 203–4, 208 gases, for cryoablation 230 gastrinomas 425–6

545

Index gastritis, chronic atrophic 425 gastroduodenal artery, selective continuous intraarterial chemotherapy 152 gastroenteropancreatic NETs, chemotherapy 116 gastrointestinal tract complications of radioembolization 135 post-transplant lymphoproliferative disorders 464 primary neuroendocrine tumors 424–5 gefinitib 376 gelfoam 142 hemostasis, cryoablation 231 gemcitabine cholangiocarcinoma 114 adjuvant chemotherapy 187 mitomycin with 114 gallbladder carcinoma 188 HCC, oxaliplatin with 112–13, 376, 377 (Table) pancreatic endocrine tumors and 115 gender cholangiocarcinoma incidence 57 gallbladder carcinoma 333, 502 HCC incidence 52, 488 Africa 509 gene expression dysregulation 371–2 gene expression profiling, selection criterion for transplantation 284 gene therapy HCC, adjuvant 297 (Table), 300 viral-based 352–67 angiostatin 408 generators microwave thermal ablation 254 radiofrequency ablation 245, 246 genetics cholangiocarcinoma 60–1 colorectal carcinoma metastases 67 HCC, etiology 52–3, 368–74 genomic analyses 349–50 clustering algorithms 371 see also microarray technologies geography HCC 52, 487–8 hepatitis C virus 514 Germany minimum procedure volumes 532 quality measurements 531 gestational immunosuppression 468 gimeracil 110 Gli (protein), Hedgehog pathway signaling on 372 Glisson, Francis (17th century) 3 glucagonomas 426 chemotherapy 433 glycoprotein(s), as tumor markers 72–3 glycoprotein H, cell line for DISC-HSV culture 361 gold seeds (fiducial markers) 123 Goldman cardiac risk index, revised 457 gradient recalled echo sequences, MRI adenoma 94 (Fig.) volumetric 87–8 grading, HCC (WHO) 40

546

granulocyte–macrophage colony-stimulating factor (GM-CSF), gene therapy 361, 363 gross tumor volume (GTV) 122 grounding pads, radiofrequency ablation 247–8 growth factors, liver regeneration 311 growth rates see doubling times Guangxi, China, HCC 487–8 guided imagery 418 guidelines 307 cholangiocarcinoma 325, 327 (Fig.) clinical trials 350 gallbladder carcinoma 333–41 HCC 317–23 Japan 319–21, 493, 494 (Fig.) neuroendocrine tumors 435 (Table) perioperative cardiac assessment 458–9 H2-receptor blockers 428 Haberer, Hans von (surgeon) 4 Habib Laparoscopic Sealer 4XL® 206 half-lives alpha-fetoprotein 70 18 F-fluorodeoxyglucose 83 radioconjugates for internal radiotherapy 132 (Table) hamartoma, mesenchymal 47 hand-assisted laparoscopic liver resection 204, 205 (Fig.), 206, 208, 210 “hanging maneuver,” right hepatectomy 19, 181, 195 harmonic imaging, ultrasound 76–7 harmonic scalpels 206 hazard ratios, molecular targeted therapies 378–9 HB signature see “hepatoblast signature, HB” HCC Healey, John E. 4 nomenclature 177–8 heart carcinoid syndrome 427, 429 catheterization, liver transplantation 521 (Table) HCC invasion 512 toxicity, sorafenib and doxorubicin 386 see also cardiac assessment; cardiac risk heat sinks, blood vessels as 228, 245–6 heating by alternating current 244–6 by microwave energy 253 heavy-ion radiotherapy 125 Hedgehog signaling pathway 372 helical computed tomography see spiral computed tomography hemangioendothelioma infantile 481–2 see also epithelioid hemangioendothelioma hemangioma angiosarcoma vs 439 cavernous 481 computed tomography 81 contrast-enhanced ultrasound 77 pregnancy 467–8 hemidiaphragm, raised on chest X-ray 513 hemihepatectomy 12, 181 see also hepatectomy

hemihypertrophy (overgrowth syndrome) 475 hemilivers 177 biliary drainage anomalies 15–16 inflow occlusion 180 hemochromatosis, HCC 54 hemodynamics contrast-enhanced ultrasound 77 management liver surgery 522–3 liver transplantation 523–4 hemoperitoneum, ruptured HCC 140 hemorrhage biopsy, Kaposi sarcoma 462 hemangioma 467 intracranial pressure monitor placement 520 hemorrhagic ascites 97 (Fig.) hemostasis cryoablation 231, 235 (Table), 240 liver resection 180–1, 522–3 historical aspects 4 laparoscopic 206, 208 two-surgeon technique 195, 196 (Fig.) liver transplantation 524 hepatectomy 12 cost-effectiveness 535 elderly people 461 laparoscopic, transplantation after 212 left hepatic veins 20 laparoscopic 211 (Table) right 19–20, 177 laparoscopic 205–6, 210, 211 (Table) two-stage, metastases 194–5, 312, 313 (Fig.), 342 virtual 80 see also resections of liver hepatic arteries anatomy 11–12 surgical 13–15 see also angiography anomalies 24, 152 of origin 14 (Fig.) chemoembolization (HACE) neuroendocrine tumors 433–5 see also transarterial chemoembolization (TACE) CT angiography 80 (Fig.) distal intrahepatic selective embolization, neuroendocrine tumors 433 infusion (HAI) 105 see also regional chemotherapy; entries beginning transarterial . . . ligation 140 neuroendocrine tumors 433 supply to tumors 131 surgical anatomy 13–15 see also embolization hepatic ducts anomalies 15–16 right, anomalies 23–4 see also common hepatic duct hepatic encephalopathy 519–20 hepatic stellate cells 30, 31 (Fig.) liver fibrosis 33, 34 (Fig.)

Index hepatic veins 178 (Fig.), 183 (Fig.), 184 (Fig.) HCC involvement 512 hemihepatectomy 181 hepatoblastoma involvement 478 liver resection 18–20 hemostasis 195 middle hepatic vein 18–20, 181 (Fig.) hepatico-jejunostomy, bile duct transection 24 hepatico-pancreatico-biliary centers 7 hepatitis, fibrosis 33 hepatitis B virus Africa 514–15 age 510 angiogenesis in infection 388 on apoptosis 395–6 cholangiocarcinoma 59 HCC 52, 53 adjuvant immunotherapy 296–9 Asia 488, 489 children 481 incidence 34–5 radiation-induced liver disease 128 on Raf/MEK/ERK signaling pathway 385 hepatitis C virus Africa 515 age 510 angiogenesis in infection 388 Asia 488–9 Chile 505 cholangiocarcinoma 59 cirrhosis 455 dialysis patients 465 geography 514 HCC 52, 53 adjuvant immunotherapy 296–9 incidence 34 HIV co-infection 463 on Raf/MEK/ERK signaling pathway 385 “hepatoblast signature, HB” HCC 372 hepatoblastoma 43–4, 475–81 Asia 495 (Table) chemotherapy 116, 480 Japan 496 hepatocellular adenoma see adenoma hepatocellular carcinoma adjuvant therapy 296–303 cost-effectiveness 536 retinoids 297 (Table), 299–300, 387–8 Africa 509–18 angiogenesis 402–3 Asia 487–94, 495 (Table) children 481 Africa 510 cirrhosis 53, 281–2 Africa 510, 513–14, 515 repeat resection and 222 transplantation 282 clinical trial design 375 computed tomography 81 contrast-enhanced ultrasound 77 cryoablation 233–4, 236 (Table) diagnosis 282 endogenous antiangiogenic compounds 407–8

epidemiology 52 etiology 52–4 genetics 52–3, 368–74 external beam radiotherapy 126–8 guidelines for treatment 317–23 HIV/AIDS patients 463–4 immunohistochemistry 42–3 isolated hepatic perfusion 167 Japan detection 489–90, 491 (Fig.) evidence-based guidelines 493, 494 (Fig.) resection 490 treatment guidelines 319–21 laparoscopic resection of liver 211–12 liver changes 34–5 microwave thermal ablation 254–5, 257 Milan criteria 135, 283 molecular targeted therapies, hazard ratios 379 (Table) multicentric 220–1 natural history 54 nonalcoholic steatohepatitis 455–6 pathology 40–3 percutaneous ethanol injection 271–2 PET/CT 83–4 post-transplant 465 pregnancy 468 PTEN/MMAC mutations 387 radioembolization 135–6 radiofrequency ablation 251–2, 257 ethanol ablation vs 251, 321 recurrent 223 receptor tyrosine kinases 382–4 see also tyrosine kinase inhibitors recurrence see recurrence, HCC regional chemotherapy 158–60 resection of liver laparoscopic 211–12 see also resections of liver, HCC sarcomatoid 47 screening 54, 71, 184, 463, 465 Asia 489–90 cost-effectiveness 534 signaling pathways 368–81 softness 266 South America 504–5 staging 43, 317, 318 (Table) systemic therapy unresectable tumor 112–13 see also specific drugs transarterial embolization 139–50 as adjuvant therapy 147 efficacy 143–6 transplantation see transplantation of liver, for HCC tumor markers 69–72 vascularity 139, 266 hepatocellular/cholangiocarcinoma, mixed 45 hepatocystic triangle 22 hepatocyte growth factor 350, 374, 384 hepatocytes 30 elderly people 460 mass, tests 310 (Table) preconditioning 180

hepatolithiasis, cholangiocarcinoma 57 (Table), 59, 495 hepatomegaly, Africa 512 hepatoprotection, liver resection 308–16 hepatorenal syndrome gadolinium contrast agents and 89 liver transplantation 521 hepatotoxicity herbal remedies 416 irinotecan 197, 310 HepPar-1 (antibody) 42 Her2/neu (receptor) 373 herbal remedies 416 Chinese medicine 415 hereditary nonpolyposis colorectal carcinoma syndrome 60 Herophilus (330–280 BC) 3 herpes simplex type 1 virus (HSV-1) 360–3 see also thymidine kinase gene (HSV-tk) herpesviruses 359 (Table) multimutated, rRp450 362 safety 363 see also human herpes simplex virus 8 high biliary-enteric anastomosis 16 high-density surface coils, MRI 85–6 high dorsal resection 183, 184 (Fig.) high-dose chemotherapy 155 high-frequency alternating currents 245 high-volume vs low-volume centers 532–3 highly active antiretroviral therapy 462 hilar cholangiocarcinoma 45, 56, 324, 326–8 computed tomography 81–2 resection 175 biliary drainage before 312, 328 with chemotherapy 187 portal vein anatomy 17–18 transplantation 289–90, 328 treatment guidelines 327 (Fig.) hilar communicating artery 24 hilar plate 21 hilar plexus 24 histology HCC 40 liver 467–76 tumor markers 69 historical aspects 3–10, 177 Asia 487, 488 (Table) cryotherapy 227 HCC stage at diagnosis 369 (Fig.) internal radiotherapy 131 microwave thermal ablation 253 radiofrequency ablation 244 South America 500–2 viral therapy 352 history-taking, cardiovascular risk 456 Hjorstjo, Carl-Herman 4 Hjorstjo’s crook 16 holmium-166 132 (Table), 134 Hong Kong liver resection 487, 490 viral hepatitis 488, 489 Honjo, Ichio, liver resection 5 hospital volume 532 hot carboplatin 275

547

Index hot saline injection 272–3 hrR3 (HSV mutant), oncolytic therapy 361–2 human herpes simplex virus 8, 466 human immunodeficiency virus infection cholangiocarcinoma 60 liver tumors associated 462–4 steatosis 32 human macrophage elastase 407–8 human telomerase reverse transcriptase promoter (hTERT), oncolytic therapy 357 hydatid disease, Chile 502 hydrochloric acid, percutaneous injection therapy 277 5-hydroxytryptamine, PET, neuroendocrine tumors 427 hypercalcemia, sclerosing HCC and 42 hypercholesterolemia, paraneoplastic 513 hyperfibrinolysis 524 hyperfractionated radiotherapy 127 hyperthermia 244 hot carboplatin 275 hot saline injection 272–3 isolated hepatic perfusion 164 melanoma metastases 166 hypnotherapy 418 hypocalcemia, liver transplantation 524 hypoglycemia, insulinomas 426 hypotension, liver surgery 523 hypothermia, cryoablation 233 hypoxia-inducible VEGF receptor, gene therapy 361 hypoxia response promoter, oncolytic therapy 357 ice crystallization 227 ICG-001 (molecular agent), on Wnt signaling pathway 378 ICP6 region deletion, rRp450 (multimutated herpesvirus) 362 ideal tumor marker 69, 70 (Table) IFL chemotherapy regimen, colorectal carcinoma metastases 107 ileum, primary neuroendocrine tumors 425 image-guided radiotherapy 123–4 imagery, guided 418 imaging 76–102 carcinoid tumors 428 (Fig.) cryoablation 232 gallbladder carcinoma suspected 339 HCC detection 490 hepatoblastoma 477 neuroendocrine tumors 426–7 percutaneous ethanol injection 268 follow-up 270–1 pretransplant 283 radiofrequency ablation 247 follow-up 252 see also specific modalities imatinib, HCC 376, 377 (Table) immunohistochemistry angiosarcoma 46 embryonal sarcoma 47 liver fibrosis 33, 34 (Fig.) malignant liver tumors 42–3

548

metastases 42 (Table), 48 intrahepatic cholangiocarcinoma vs 45 neuroendocrine tumors 48, 427 immunomodulation adenovirus 357–60 gene therapy 353 retroviruses 355 vaccinia virus 356 HSV amplicons 360–1 Newcastle disease virus 356 immunosuppression 461–7 extrahepatic metastases, epithelioid hemangioendothelioma 442 gestational 468 HCC recurrence 283, 287 historical aspects 6 for viral therapy 352 immunotherapy 300 colorectal carcinoma metastases 108–10 HCC 113 interferon 296–9 see also immunomodulation impedance 245, 246–7 implantable infusion pumps 151–63, 523 failure rates 152–3 incidental discovery, gallbladder carcinoma 338–9 incidental HCC 286 incisions cryoablation 230–1 laparoscopic liver resection hand-assisted 205 (Fig.) specimen extraction 210 open liver resection 210 selective continuous intra-arterial chemotherapy 152 incremental cost-effectiveness ratio (ICER) 534 resection of colorectal carcinoma metastases 535 India, HCC 489 indirect cholangiography 97–8 111 In-octreotide scintigraphy, neuroendocrine tumors 426, 427 111 In-somatostatin analog radiotherapy, neuroendocrine tumors 433 indocyanine green clearance test 179, 310–11 industrial chemicals 60 infantile hemangioendothelioma 481–2 infections chest, cryoablation 235 (Table) drainage tubes 181 implantable pump pockets 154 see also specific viruses infectious mononucleosis 464 inferior vena cava clamping 501, 523–4 drainage of caudate veins 12 HCC involvement 512 hepatoblastoma involvement 478 resection 479, 480 isolation at hepatic resection 20 membranous obstruction 515 pressure, blood loss at surgery 525 (Fig.) venography, percutaneous hepatic perfusion 169

“inferior vena caval ligament” 19 inflammation colorectal carcinoma metastases 67 HCC 53 inflammatory bowel disease, cholangiocarcinoma 60 inflow occlusion 180, 314 by cryotherapy 227 for cryotherapy 228 laser thermal ablation with 261 for radiofrequency ablation 246, 248 see also Pringle’s maneuver infusion pumps see implantable infusion pumps inhalational anesthetic agents hepatic clearance 522 (Table) liver transplantation 523 inhibitor of apoptosis proteins (IAPs) 397 insulin-like growth factor, signaling 374, 383–4 insulin-like growth factor-1 receptor, humanized antibodies 384 insulin-like growth factor-2 and receptor 383–4 insulin-like growth factor receptor-1, signaling pathway 350 insulinomas 426 111 In-octreotide scintigraphy 426 integrative oncology 414–20 intensity-modulated radiotherapy (IMRT) 123 intention-to-treat analyses, transplantation 284–5 interferon adjuvant to liver resection 296–9 cost-effectiveness 536 carcinoid syndrome 115–16 Kaposi sarcoma 463 neuroendocrine tumors 427–8 interleukin-2 HSV amplicon 360 immunomodulation 357 interleukin-6, cholangiocarcinoma 60–1 interleukin-12 HSV amplicon 360 multimutated virus NV1042 363 interleukin-18, immunomodulation 357 intermittent clamping of portal triad 314 intermittent hepatic artery occlusion, neuroendocrine tumors 433 internal radiotherapy 105, 131–8 complications 134–5 gallbladder carcinoma, salvage 345 131 I-lipiodol, adjuvant therapy, HCC 297 (Table), 299 neuroendocrine tumors 433, 435 post-treatment assessment 133 pretreatment assessment 132 technique 133 internal target volume (ITV), radiotherapy 123 International Hepatobiliary Pancreatic Association (IHBPA), Brisbane nomenclature 5, 11–12, 178, 194 international normalized ratio (INR), for percutaneous ethanol injection 269

Index intersectional planes 11, 13 (Fig.) intersegmental planes 11 interstitial electrodes 245 interventional oncology see embolization; internal radiotherapy intra-arterial chemotherapy, selective continuous 151–63, 523 intra-arterial therapy percutaneous, ethanol 274 see also entries beginning transarterial . . . intracellular signaling pathways 384–8 intracranial pressure, liver transplantation 520 intraductal cholangiocarcinoma 324 intraductal papillary neoplasia of bile duct 61 intrahepatic cholangiocarcinoma 44–5, 56, 324–5 Asia 494–6 choledochal cysts 58 epidemiology 56–7 hepatolithiasis 59 internal radiotherapy 136 regional chemotherapy 158–60 resection 186–7 elderly people 461 survival rates 61 transplantation 289 treatment guidelines 325 intrahepatic selective embolization, hepatic artery, neuroendocrine tumors 433 intralesional chemotherapy 275, 276 (Fig.) intraoperative cytology, gallbladder 503 intraoperative management 521–4 intraoperative staging laparoscopy, colorectal carcinoma metastases 192 intraoperative ultrasound 78, 490 cryoablation 230, 232 historical aspects 487 liver resection planning 180, 181 neuroendocrine tumors 426 for radiofrequency ablation 247, 248 (Fig.) intraoperative use of gamma probes, neuroendocrine tumors 426 intravenous access liver surgery 522 liver transplantation 523 intravital microscopy 404 intrinsic pathway, apoptosis 394 invasion cholangiocarcinoma 324 intrahepatic 44 gallbladder carcinoma 337–8, 504 portal veins HCC 222, 283, 490 hepatoblastoma 478 see also vascular invasion 131 I-lipiodol 132 (Table), 133 adjuvant therapy, HCC 297 (Table), 299 131 I-meta-iodobenzylguanidine scintigraphy, neuroendocrine tumors 426–7 ionic friction 244 irinotecan colorectal carcinoma metastases 107, 111, 196 capecitabine with 108 cetuximab with 109

neoadjuvant 344 regional chemotherapy with 158 friable parenchyma 216 liver toxicity 197, 310 iron overload disorders, HCC 54 Africa 515 iron oxide see superparamagnetic iron oxide Iscador (herbal remedy) 416 ischemia, inflow occlusion 180, 314 islet cell tumors 425–6 chemotherapy 432–3 isoflurane, liver transplantation 523 isolated hepatic perfusion (IHP) 105, 164–8, 170 isolated limb perfusion 409 IsoMed implantable infusion pumps 151, 152 (Fig.), 153 Ito cells see hepatic stellate cells Japan colorectal carcinoma metastases 496 HCC detection 489–90, 491 (Fig.) evidence-based guidelines 493, 494 (Fig.) resection 490 treatment guidelines 319–21 hepatitis C virus infection 59 hepatoblastoma 496 liver resection 487 liver weight at necropsy 511 living donor liver transplantation 487, 492–3 microwave thermal ablation, equipment 253 tumor incidence by type 495 (Table) Japan Integrated Staging score 317, 318 (Table) jaundice, gallbladder carcinoma suspected 339 K-ras mutation colorectal carcinoma metastases, on therapy response 160 on EGFR blockade 109 Kaposi sarcoma 462–3, 466 Kasabach–Merritt phenomenon 467 Keen, William W. (surgeon) 3 Klatskin tumor see hilar cholangiocarcinoma Kupffer cells 30 L3 fraction of alpha-fetoprotein, HCC surveillance 490 lacZ gene mutation (Escherichia coli), gene therapy 362 Langenbuch, Carl, surgery, historical aspects 3, 4 (Fig.) “laparoscopic segments” 207, 210 laparoscopy ablative therapies 229 cryoablation 231 ethanol injection therapy 269 neuroendocrine tumors 431 radiofrequency ablation 247, 431 gallbladder carcinoma 334, 336, 339, 504 hilar cholangiocarcinoma, staging 328 intraoperative staging, colorectal carcinoma metastases 192 resection of liver by 203–15 colorectal carcinoma metastases 212

HCC 211–12 open resection vs 208–10 outcomes 207–12 laparotomy, for isolated hepatic perfusion 164 lapatinib 376, 383 large cell change, dysplastic nodules 41 large regenerative nodules 40–1 laser thermal ablation 257–61 late recurrences see de novo recurrences lateral decubitus position, laparoscopic liver resection 203 left hepatectomy hepatic veins 20 laparoscopic 211 (Table) left hepatic duct 16 left hepatic vein 18–20 left lateral decubitus position, laparoscopic liver resection 203 left lateral sectionectomy, laparoscopic 205, 206 (Fig.), 210 left portal vein 17 absence 18 umbilical portion 17, 22 left ventricular dysfunction, sorafenib and doxorubicin 386 leucovorin see folinic acid ligamentum teres 22 ligamentum venosum 17, 22 ligation of hepatic arteries 140 neuroendocrine tumors 433 limited resections see nonanatomic resections Lindbergh, Charles A. 6 linear accelerators, image-guided radiotherapy 123 lipiodol follow-up imaging and 271 188 Re HDD-lipiodol 132 (Table), 134 transarterial chemotherapy 141 see also 131I-lipiodol lipocytes see hepatic stellate cells lipophilic gadolinium variants 90 liquid nitrogen 230 lithiasis cholangiocarcinoma 57 (Table), 59, 495 gallbladder carcinoma 187, 333, 502–3 liver flukes, cholangiocarcinoma and 58–9, 495 liver function colorectal carcinoma metastases workup 192 after cryoablation 233 HCC 221, 222 after preconditioning therapy 314 protection strategies 312–14 radiation-induced liver disease 134 sorafenib on 385 tests before surgery 310–11 see also decompensated cirrhosis “liver kampo” (Chinese botanical) 416–17 liver toxicity herbal remedies 416 irinotecan 197, 310 liver transplantation see transplantation of liver and also bridging therapy; living donor liver transplantation liver tumors of unknown origin 447–9

549

Index living donor liver transplantation 6, 186 Asia 492–3 HCC and 288 hepatocellular carcinoma 287–8 cost-utility analysis 536 historical aspects 487 laparoscopic liver procurement 210–11 Pringle’s maneuver 180 South America 500 lobules 30, 31 (Fig.) loop antennae, microwave thermal ablation 254, 255, 257 Lortat-Jacob, Jean-Louis, liver resection 5 loss of heterozygosity, colorectal carcinoma 73 low birthweight, hepatoblastoma 477 low-concentration alkali therapy, percutaneous 277 low-dose dopamine 523 low-dose nitroglycerine infusion 523 low-volume vs high-volume centers 532–3 lung colorectal carcinoma metastases 110, 193, 219, 342 injury from cryoablation 233 radiation dose limitation 134, 135 lung cancer, molecular targeted therapies, hazard ratios 379 (Table) lung shunt fraction (LSF), internal radiotherapy 132 177 Lu-somatostatin analogs, neuroendocrine tumors 433 lymph nodes aspiration 328 colorectal carcinoma metastases 342 gallbladder carcinoma involvement 337 pedicle, colorectal carcinoma 193 lymphocytes, adoptive transfer 300 lymphoma AIDS 463 liver transplantation for 291–2 post-transplant 464–5 primary hepatic 47, 443–4 Lynch syndrome 60 macroaggregated albumin, 99mTc-labeled, scanning for internal radiotherapy 132 macrobiotic diet 415 macroregenerative nodules 40–1 macrosteatosis, liver resection 308–9 macrotrabecular pattern, hepatoblastoma 43–4 macrovesicular steatosis 31 magnetic field strength, MRI 86–7 magnetic resonance cholangiopancreatography, cholangiocarcinoma 98 magnetic resonance imaging and 92 magnetic resonance imaging 85–93 adenoma 94 (Fig.) clinical role 90–3 contraindications 90 cryoablation 232 gallbladder carcinoma 334 hepatoblastoma 477 hilar cholangiocarcinoma resectability 326

550

laser thermal ablation guidance 259 percutaneous ethanol injection 270 for radiofrequency ablation 247 remnant liver volume assessment 311 magnetic resonance spectrometry, nonalcoholic steatohepatitis prevalence 454 Makuuchi, M., developments in liver tumor management 487 Makuuchi’s criteria 179 Makuuchi’s maneuver 180 Makuuchi’s segmentectomy 181, 182 (Fig.) malignant melanoma see melanoma Mallory bodies 31 (Fig.), 32 mammalian target of rapamycin (mTOR) 374 inhibitors 287, 376 sorafenib with 386 signaling pathway see PI3K/Akt/mTOR signaling pathway mangafodipir trisodium 90 MAPK signaling pathway, HCC 113, 385–6 margins cryotherapy 240 resection of colorectal carcinoma metastases 195–6, 249 marimastat 408 markers see tumor markers mass-forming intrahepatic cholangiocarcinoma 324–5, 496 massage therapy 418 massive HCC 40 mathematics, number of overlapping ablations 248–9 matrix metalloproteinase inhibitors, Kaposi sarcoma 463 matrix metalloproteinases, cholangiocarcinoma 61 maximum intensity projection, MDCT 80 (Fig.) maximum tolerated dose, isolated hepatic perfusion 165 Mayo Clinic protocol, hilar cholangiocarcinoma 328 Medline searches, gallbladder carcinoma 333 Medtronic implantable infusion pumps 151, 152 (Fig.) melanoma, metastases 446–7, 448 (Table) immunohistochemistry of 48 isolated hepatic perfusion 166–7 percutaneous hepatic perfusion 170 MELD score see model for end-stage liver disease (MELD), score melphalan isolated hepatic perfusion 165–7, 168 percutaneous hepatic perfusion 169 membranous obstruction of inferior vena cava 515 Memorial Sloan-Kettering Cancer Center, adjuvant chemotherapy trials 158, 159 (Table) mental imagery see guided imagery meridians (Chinese medicine) 415 mesenchymal hamartoma 47 MET (protein) 384 c-MET/hepatocyte growth factor signaling pathway 350, 384

metabolic syndrome 31 metabolic therapies (alternative medicine) 416 metachronous metastases, colorectal carcinoma 65 metachronous primaries, HCC 221 metallic coils 142 metalloproteinase inhibitors 408–9 metastases Africa, hepatomegaly 512 angiogenesis 403–4 Asia 496–7 bevacizumab 405–6 breast carcinoma see breast carcinoma, metastases children 482, 496–7 cholangiocarcinoma vs 44–5 colorectal carcinoma see colorectal carcinoma metastases computed tomography 82–3 cryoablation 239 HCC, genetics 371 hepatoblastoma 478 immunohistochemistry 42 (Table), 48 intrahepatic cholangiocarcinoma vs 45 intrahepatic cholangiocarcinoma vs 44–5 laser thermal ablation 259–61 liver changes 36 magnetic resonance imaging 92–3 neuroendocrine tumors see neuroendocrine tumors, metastases noncolorectal non-neuroendocrine 444–9 pathology 48 percutaneous ethanol injection 275 radioembolization 136–7 selective portal vein occlusion and 312 South America 505 transplantation for 292 tumor markers 72–3 two-stage hepatectomy 194–5, 312, 313 (Fig.), 342 ultrasound, contrast-enhanced 77 see also extrahepatic metastases metastatic mixed neoplasia, radioembolization 136–7 METAVIR scoring system, liver fibrosis 33, 34 (Fig.) methylation of tumor suppressor genes, cholangiocarcinoma 61 MIBG scintigraphy, neuroendocrine tumors 426–7 microarray technologies angiogenic factors in blood 403 gene expression dysregulation 371 microbubble contrast agents 77 microsatellite instability, colorectal carcinoma 73 microsomal hepatic function, tests 310 (Table) microspheres starch 142 yttrium-90 131–3 microvesicular steatosis 31, 32 microvessel density (MVD) HCC 402–3 metastases 403

Index microwave thermal ablation 253–7 in multiablation therapy 275 radiofrequency ablation vs 255–7, 258 (Table) mid-plane of liver 11, 12 (Fig.) midazolam, liver transplantation 523 middle cholangiocarcinoma 328–9 middle hepatic vein 18–20, 181 (Fig.) Milan criteria HCC 135, 283 liver transplantation 492, 493 Milican (radioconjugate) 132 (Table), 134 milk thistle 416 mind–body therapies 418 see also traditional alternative medical systems mindfulness-based stress reduction (MBSR) 418 minimum procedure volumes 532 Mirizzi, Pablo 500 Mirizzi syndrome, right hepatic duct anomaly 24 Mirizzi technique 500 mitochondrial membrane proteins apoptosis regulation 394 overexpression 396 mitogen-activated protein kinase signaling pathway, HCC 113, 385–6 mitomycin, biliary carcinoma capecitabine with 114 gemcitabine with 114 mixed epithelial/mesenchymal hepatoblastoma 44 mixed hepatocellular/cholangiocarcinoma 45 mixed metastatic neoplasia, radioembolization 136–7 MOC-31 (antibody) 42–3 model for end-stage liver disease (MELD), score 179, 288 HCC 288 Argentina 505 modified vaccinia virus (MVA) 355–6 molecular pathogenesis HCC 368–74 see also signaling pathways molecular targeted therapies 374–9 monoclonal antibodies colorectal carcinoma metastases 196 see also specific drugs mortality cholangiocarcinoma extrahepatic 57 intrahepatic 57 colorectal carcinoma 64 HCC body mass index 54 from treatment 368 high-volume vs low-volume centers 532–3 mosaic vessels 409 Mozambique, HCC 510 age distribution 510 MTH68 strain, Newcastle disease virus 356 mTOR see mammalian target of rapamycin; PI3K/ Akt/mTOR signaling pathway mucins, intrahepatic cholangiocarcinoma 44

multiablation therapy 275 multicentric HCC 220–1 multidetector computed tomography (MDCT) 78–9 gallbladder carcinoma 334 hilar cholangiocarcinoma resectability 326 magnetic resonance imaging compared with 90 multikinase inhibitors see sorafenib; sunitinib multimutated herpesviruses 362–3 multiple endocrine neoplasia type 1, pancreatic neuroendocrine tumors 426 multiple repeat liver resections colorectal carcinoma metastases 219 HCC 222 multistage procedures, colorectal carcinoma metastases, cost-effectiveness 535 multivisceral transplantation, neuroendocrine tumors 432 muscularis propria, gallbladder carcinoma invasion 337 music therapy 417–18 mutations hepatitis B virus 515 see also specific mutations myelinolysis, central pontine 520 myoglobin release, cryoablation 233, 235 (Table) National Comprehensive Cancer Network Guidelines Panel for HCC 318–19 natural history cholangiocarcinoma 60–1 colorectal carcinoma metastases 65–7 HCC 54 nausea acupuncture 417 mind–body therapies 418 necropsy, liver weight, Africa 511 necrosis apoptosis vs 394, 395 effect of ethanol 267 radiofrequency ablation 245 transarterial embolization response 143 needle guidance, cryoablation 231 needles percutaneous ethanol injection 267–8 see also biopsy neoadjuvant chemotherapy colorectal carcinoma metastases 110–11, 112, 344 HCC, children 481 primary lymphoma 444 transplantation for cholangiocarcinoma 289–90 see also preoperative chemotherapy neodymium:YAG laser 259 nephrogenic systemic sclerosis 89 neuroendocrine tumors computed tomography 82 (Fig.) metastases 48, 424–38 cryoablation 230, 234–6 isolated hepatic perfusion 167, 168 (Fig.) percutaneous hepatic perfusion 169–70 radioembolization 136

radiofrequency ablation 249 transplantation for 290–1 systemic therapy 115–16 neurofibromatosis, schwannomas 442–3 neuropathy, oxaliplatin 108 neurotensin, fibrolamellar HCC 72 Newcastle disease virus 354 (Table), 356, 358 (Table) NHANES III (survey), nonalcoholic steatohepatitis 454 nitric oxide, cholangiocarcinoma 61 nitrogen, liquid 230 nitroglycerine, low-dose infusion 523 nitrosoamines, cholangiocarcinoma 59 “no-touch technique,” hilar cholangiocarcinoma resection 328 nodular HCC 40 nodules, precursor lesions of HCC 40–1 nolatrexed, HCC 377 (Table) nomenclature 11–26 liver anatomy 5, 177–8 Brisbane nomenclature 5, 11–12, 178, 194 neuroendocrine tumors 424 non-Hodgkin lymphoma, AIDS 463 nonalcoholic fatty liver disease 454–5 HCC 35 nonalcoholic steatohepatitis 31, 32, 310, 454–6 HCC 455–6 nonanatomic resections 181, 183 colorectal carcinoma metastases 194 noncolorectal non-neuroendocrine metastases 444–9 nonsmall cell lung cancer, molecular targeted therapies, hazard ratios 379 (Table) norepinephrine infusion, liver surgery 523, 524 North American staging, children 476 (Table) nuclear medicine imaging hepatoblastoma 477 for internal radiotherapy 132 neuroendocrine tumors 426–7 see also positron emission tomography 99m Tc-galactosyl HSA uptake test 310 (Table) see also internal radiotherapy NV1020, NV1034, NV1042 (multimutated viruses) 363 obesity gallbladder carcinoma 333 HCC 54 nonalcoholic steatohepatitis 454, 455 steatosis 31 occlusion, vascular see inflow occlusion octreotide 427–8 68 Ga-labeled, PET, neuroendocrine tumors 427 HCC 112 adjuvant therapy 297 (Table), 300 111 In-labeled, scintigraphy of neuroendocrine tumors 426, 427 ocular melanoma metastases, isolated hepatic perfusion 166–7 Okuda staging system 317, 318 (Table) omega-3 fatty acids, for steatosis 309 oncogenes, cholangiocarcinoma 61

551

Index oncolytic therapy 353–4 adenovirus 357–60 hrR3 (HSV mutant) 361–2 HSV-1 361 Newcastle disease virus 356 reovirus 355 ribonucleotide reductase 361–2 Onyx-015 see dl1520 (genetically engineered adenovirus) open colectomy, vs laparoscopic 207 open liver resection incisions 210 vs laparoscopic 208–10 conversion rates 208 open surgery, radiofrequency ablation 247 opioids, endogenous, acupuncture and 417 Opisthorchis viverrini, cholangiocarcinoma and 58–9, 495 optimal center size 533 oral contraceptives, hepatic adenoma 467 osteopontin 372 oteracil 110 outcome measures, quality of care 531–2 oval cells, hepatitis C virus infection 59 overlapping ablations, number of 248–9 oxaliplatin in biliary tract carcinoma regimens 114 colorectal carcinoma metastases 107–8, 111, 157, 196–7 neoadjuvant 344 regional therapy 158 friable parenchyma 216 HCC, gemcitabine with 112–13, 376, 377 (Table) isolated hepatic perfusion 170 liver toxicity 197, 310 oxygen saturation measurement, liver transplantation 521, 523 p-ERK (MAPK pathway activation marker) 383 p53 (protein), apoptosis 394 p53 gene mutations 370–1, 396, 515 replacement 353 P450 2B1 transgene, rRp450 (multimutated herpesvirus) 362 packaging genes 354 pain HCC, Africa 510–11 music therapy 417 percutaneous ethanol injection 269 “pale bodies,” fibrolamellar HCC 41 palliation chemotherapy, colorectal carcinoma metastases 112–13 gallbladder carcinoma 337 neuroendocrine tumor metastases, resection 429, 430, 435 percutaneous ethanol injection 267 see also complementary medicine pancreas distal cholangiocarcinoma 324, 328–30 endocrine tumors 425–6 systemic therapy 115, 116

552

pancreaticobiliary duct anomalies, gallbladder carcinoma 333–4 pancreaticoduodenectomy, distal cholangiocarcinoma 330 panitumumab, colorectal carcinoma metastases 109–10 papillomatosis, biliary cholangiocarcinoma and 57 (Table), 60 see also intraductal cholangiocarcinoma parallel imaging, MRI 87 paraneoplastic phenomena 512, 513 parenchyma friable 216 transection 180–1 laparoscopic 205–7 parenteral nutrition, steatosis 32 partial thromboplastin time see activated partial thromboplastin time particle size, radioconjugates for internal radiotherapy 132 (Table) Patched (receptor) 372 pathology liver 467–76 malignant liver tumors 40–51 pathway addiction 373 pazopanib 404 (Table) pedicle lymph nodes, colorectal carcinoma 193 pedicles, portal 21 clamping in laparoscopic liver resection 205 division 21 see also inflow occlusion; Pringle’s maneuver pedicular cholangiocarcinoma 328–9 pentoxifylline 314 percutaneous chemical ablation 127, 266–80 China 492 clinical results 271–2 colorectal carcinoma metastases 219–20 in combination therapies 274–5 complications 269–70 guidelines, West vs East 321 HCC radiofrequency ablation vs 251 recurrent 223 metastases 275 in multiablation therapy 275 neuroendocrine tumors 432 technique 268–9 percutaneous coronary intervention 459–60 percutaneous cryoablation 231 percutaneous hepatic perfusion (PHP) 168–70 percutaneous hot water injection see hot saline injection percutaneous radiofrequency ablation 247 perfusion isolated hepatic (IHP) 105, 164–8, 170 isolated limb 409 percutaneous hepatic (PHP) 168–70 tests 310 (Table) see also implantable infusion pumps periductal infiltrating intrahepatic cholangiocarcinoma 324–5 perihilar cholangiocarcinoma see hilar cholangiocarcinoma

perioperative cardiac assessment 458–9 see also electrocardiography peripheral cholangiocarcinoma see intrahepatic cholangiocarcinoma peritoneal carcinomatosis 193 see also seeding of tumor Peru HCC 505 liver surgery 502 pharmacokinetics, selective continuous intraarterial chemotherapy 154–5 pheochromocytoma, duodenal neuroendocrine tumors and 425 phosphatidylinositol-3-kinase pathway 349, 374, 386–7 phospholipase C-gamma 382 32 P-GMS 132 (Table), 134 physical examination, cardiovascular status 456 physical signs, HCC, Africa 511–12 PI3K/Akt/mTOR signaling pathway 349, 374, 386–7 PIAF regimen, HCC 112 Pichlmayr, Rudolf, split graft transplantation 6 PIP3 phosphatases 387 pityriasis rotunda 512 PIVKA-II (protein induced by vitamin K absence; des-γ-carboxyprothrombin), HCC surveillance 71, 490 PKI116 (epidermal growth factor inhibitor) 406 planning target volume (PTV), radiotherapy 123 plasminogen 402 plate/sheath system 20–1 platelet counts hepatoblastoma 477 for percutaneous ethanol injection 269 see also thrombocytopenia pleural effusions, cryoablation 233, 235 (Table) PLUTO (Pediatric Liver Unresectable Tumor Observatory) 480 pneumonitis, radiation-induced 135 pneumoperitoneum 203–4, 504 polyprenoic acid 300, 387–8 polyps, gallbladder, malignancy 334 polyvinyl alcohol 142, 144–5 pontine myelinolysis, central 520 populations, for clinical trials 375 port sites laparoscopic liver resection 204 resection of 337 portal fibrosis 33 portal hypertension liver resection and 221 radioembolization toxicity 134–5 portal pedicles 21 clamping in laparoscopic liver resection 205 division 21 see also inflow occlusion; Pringle’s maneuver portal veins anatomy 17–18, 178 liver regeneration on 216 catheter-assisted arterial portography, CT with 95–6

Index embolization 198, 311, 312, 314, 328 after chemotherapy 344 historical aspects 487 ethanol injection TACE with 274 thrombolysis 267 invasion HCC 222, 283, 490 hepatoblastoma 478 MDCT venography 80 selective occlusion 311–12, 313 (Fig.) thrombosis (PVT) 142 internal radiotherapy suitability 135 see also left portal vein portography, catheter-assisted arterial, CT with 95–6 positioning of patient, laparoscopic liver resection 203 positron emission tomography cholangiocarcinoma 84–5, 86 (Fig.) colorectal carcinoma metastases 342 computed tomography with 83–5, 219 cholangiocarcinoma 86 (Fig.) dynamic, ethanol in tumors 267 extrahepatic disease 230 gallbladder carcinoma 334 neuroendocrine tumors 427 before radiofrequency ablation 249 see also 18F-fluorodeoxyglucose PET postembolization syndrome 134, 143 postoperative complications impact on costs 536 liver transplantation 524, 524 (Table) postoperative morbidity, factors 523 postreperfusion syndrome 524 power Doppler ultrasound 76 pravastatin, HCC 297 (Table), 300 preclinical models, molecular targeted therapies 374 precocious puberty 477 preconditioning inflow occlusion 180, 314 pharmacologic 314 precursor lesions, HCC 40–1 pregnancy alpha-fetoprotein 70 gallbladder carcinoma 502 liver tumors 467–8 magnetic resonance imaging and 90 preload, transesophageal echocardiography 527 preoperative assessment 519–21 pregnancy 468 see also electrocardiography; perioperative cardiac assessment preoperative catheterization of biliary tract, cholangiocarcinoma resection 186, 312, 328 preoperative chemotherapy breast carcinoma metastases 446 colorectal carcinoma metastases 196–7 Consensus Conference on 198–9 hepatoblastoma 480 see also neoadjuvant chemotherapy preoperative coronary revascularization 459–60

preoperative observation period, repeat resection of colorectal carcinoma metastases 219 presentation, gallbladder carcinoma, basis for therapeutic algorithm 338–9 PRETEXT system, staging in children 476, 477–8, 479 (Table) pretransplant imaging 283 primary colorectal carcinoma, resection 342 primary sclerosing cholangitis cholangiocarcinoma 57 (Table), 58 perihilar 45 tumor markers and 72 transplantation 289 Pringle’s maneuver 180, 195, 314 laser thermal ablation with 261 radiofrequency ablation 248 see also inflow occlusion prioritization, transplantation for HCC 288–9 probes cryoablation 230, 231 gamma-emitting, neuroendocrine tumors 426 intraoperative ultrasound 78 radiofrequency ablation 246, 248 process measures, quality of care 531 prodrugs, suicide gene prodrug therapy 353 proliferation index, neuroendocrine tumor metastases 290 Prometheus 3, 4 (Fig.) promoter hypermethylation, cholangiocarcinoma 61 proper hepatic artery 13, 131 left hepatic artery mistaken for 15 (Fig.) prophylactic cholecystectomy, gallbladder carcinoma 503 propofol 522 prostacycline analogs, pulmonary hypertension 520 prostate specific antigen, metastases 48 protease inhibitors 408–9 proteasome activation, drugs inhibiting 378–9 protective techniques, liver resection 308–16 protein kinase(s) 384–5 double-stranded, oncolytic therapy 355 protein kinase C 382 prothrombin induced by vitamin K absence or antagonist-11 (PIVKA-11) 71, 490 prothrombin time, on-site monitoring 525–7 proton magnetic resonance spectrometry, nonalcoholic steatohepatitis prevalence 454 proton pump inhibitors 428 proton radiotherapy 125 pruritus acupuncture 417 gallbladder carcinoma 337 PTEN/MMAC mutations, HCC 387 PTEN mutation 374 publication of quality measurements 531 pulmonary artery catheterization, liver transplantation 523 pulmonary function, liver transplantation 521 pulmonary hypertension 520 pulse diagnosis (Chinese medicine) 415 pulsed current, radiofrequency ablation 246 pumps see implantable infusion pumps

quality adjusted life years 534 quality of care, measurement 531–3 Quattlebaum, Julian K., liver resection 5 R7020 (multimutated virus) 363 RAD001, doxorubicin with 387 radiation dose limitations lung 135 188 Re HDD-lipiodol 134 radiation exposure liver tolerance 122, 127–8 reduction technology, MDCT 80 radiation-induced liver disease (RILD) 127, 128, 134 radiation pneumonitis 135 radiation therapy see radiotherapy radioembolization see internal radiotherapy radiofrequency ablation (RFA) 127, 244–53, 490–1 clinical studies 249–52 colorectal carcinoma metastases 249–51 cost-effectiveness 535 after liver resection 220 liver resection vs 251 synchronous with primary resection 228 compensated cirrhosis 284 complications 252 cryoablation vs 229, 240 ethanol ablation vs 273–4, 277, 286 costs 276 HCC 251, 321 HCC ethanol ablation vs 251, 321 recurrent 223 liver resection vs 185 metastases 275 microwave thermal ablation vs 255–7, 258 (Table) in multiablation therapy 275 neuroendocrine tumors 431–2, 435 transplantation, bridging therapy 251–2, 286, 287 radiofrequency-assisted hepatic resection 206 Radionics/Valleylab system, radiofrequency ablation 247 radionuclides radiotherapy 126 neuroendocrine tumors 433 transarterial therapy (TART), 188Re HDD-lipiodol 134 see also nuclear medicine radiosurgery see stereotactic body radiotherapy Radiotherapeutics system, radiofrequency ablation 246–7 radiotherapy 105 colorectal carcinoma metastases 128 external beam 122–30 gallbladder carcinoma 504 HCC 126–8 hepatoblastoma 480 planning 122–6 transplantation for cholangiocarcinoma 289–90 see also internal radiotherapy

553

Index Raf/MEK/ERK signaling pathway, HCC 113, 385–6 randomized clinical trials 375 rapamycin (sirolimus) 374, 376 Kaposi sarcoma 466 transplantation for epithelioid hemangioendothelioma 291 rapid infusion systems 522 rapid sequence induction of anesthesia 523 Ras signaling pathway 387–8 oncolytic therapy 355 see also K-ras mutation real-time tumor tracking, radiotherapy 123 receptor tyrosine kinases, HCC 382–4 see also tyrosine kinase inhibitors rectum carcinoma 116 primary neuroendocrine tumors 425 recurrence cholangiocarcinoma, post-transplant 466 colorectal carcinoma 158 after cryoablation 239 CT and PET/CT 85 detection 219 prevention 220 radiofrequency ablation vs resection 251 HCC 175, 185 de novo 296 prediction by molecular studies 372 after resection 220–1, 222–3, 252, 296–303 after transplantation 283, 287, 465–6 after liver transplantation 464, 465–6, 467 after microwave thermal ablation 257 after percutaneous ethanol injection 271 see also repeat resection, liver reflexology 418 regeneration of liver 3, 5, 311 bevacizumab on 197 elderly people 460 friable parenchyma 216 portal vein embolization 198 see also macroregenerative nodules regenerative nodular hyperplasia, chemotherapy 36 regional chemotherapy 105, 158–60 colorectal carcinoma metastases 158, 159 (Table) cryoablation with 238 (Table) see also transarterial chemoembolization (TACE); transarterial chemotherapy regional delivery, concentrations 154–5 remnant liver volume assessment 311 see also future liver remnant volume renal cell carcinoma bevacizumab for metastases 406 clear cell adenocarcinoma vs, gallbladder 49 renal failure cryoablation and 233 gadolinium contrast agents and 89 liver surgery 523 renal function, liver surgery 519, 521 renal transplantation HCC 465 transarterial chemoembolization and 466

554

reovirus 355 repeat resection gallbladder carcinoma 334–5 liver 185, 216–26 repeat transplantation for HCC 466 reperfusion liver transplants 524 thromboelastography 526 (Fig.) preconditioning 314 “replaced” arteries 13–14, 14–15 replication, liver cells 311 resectability colorectal carcinoma metastases 65, 111–12, 175, 193–4, 344 vs chemotherapy response 156 factors precluding 67 gallbladder carcinoma (de Aretxabala) 504 HCC Africa 514 children 481 hepatoblastoma 479 hilar cholangiocarcinoma 326 resection of port sites 337 resection of wounds, gallbladder carcinoma surgery 503 resections of liver 175, 177–91 anatomy 13–15, 177–8 Asia 487, 490, 492 bevacizumab and 115, 310, 406 Brazil 501 breast carcinoma metastases 445–6 as bridging therapy for transplantation 286–7 cost-effectiveness 536 Chile 502 cholangiocarcinoma hilar 326 intrahepatic 495–6 colorectal carcinoma metastases 110–11, 175, 192–202, 342–4 cost-effectiveness 534–5 cryoablation and 219–20, 228, 236, 238 (Table) margin status 195–6, 249 radiofrequency ablation previously 220 radiofrequency ablation vs 251 repeat 217–20 compensated cirrhosis 284 contraindications 179 cryoablation and 236, 238 (Table), 240 elderly people 460–1 gallbladder carcinoma 335, 336, 337 HCC 175, 183–6, 490 cost-effectiveness 535 elderly people 461 HIV/AIDS patients 464 post-transplant 466 radiofrequency ablation vs 251 recurrence 220–1, 222–3, 252, 296–303 repeat surgery 220–3 hemihepatectomy 12, 181 hepatic veins 18–20 hemostasis 195 hepatoblastoma 479, 480

historical aspects 3–5 inferior vena cava isolation 20 intraoperative management 521–3 melanoma metastases 446–7 neuroendocrine tumors 428–31, 435 Peru 502 portal veins 17–18 preanesthetic investigations 520 (Table) preoperative biliary drainage 312, 328 protective techniques 308–16 repeat 216–26 gallbladder carcinoma 334–5 HCC 185 River Plate school 500–1 safety after chemotherapy 197 steatosis 308–10, 456 surgical anatomy 13–15, 177–8 terminology 12, 13 (Fig.), 14 (Fig.) two-stage hepatectomy, metastases 194–5, 312, 313 (Fig.), 342 virtual 80 see also cardiac risk; hepatectomy; laparoscopy, resection of liver by resistance (electrical) 245 resistive heating 244 respiratory motion, external beam radiotherapy 122, 123 response rates, as clinical trial endpoints 375 retinoids, HCC, adjuvant therapy 297 (Table), 299–300, 387–8 retroviruses 358 (Table) gene therapy 354–5 Rex–Cantlie line 4 RFA see radiofrequency ablation rhabdomyosarcoma, embryonal 47, 482 188 Re HDD-lipiodol 132 (Table), 134 ribonucleotide reductase, oncolytic therapy 361–2 right heart catheterization, liver transplantation 521 (Table) right hemiliver drainage, biliary anomalies 15–16 right hepatectomy 19–20, 177 laparoscopic 205–6, 210, 211 (Table) right hepatic artery accessory 80 (Fig.) anomaly 24 right hepatic ducts, anomalies 23–4 right hepatic veins 19 right portal vein, absence 18 RILD (radiation-induced liver disease) 127, 128, 134 RITA system, radiofrequency ablation 246, 248 rituximab, post-transplant lymphoproliferative disorders 465 River Plate school 500–1 RNA encapsidation signal, hepatitis B virus 514–15 Rokitansky Aschoff sinuses, gallbladder carcinoma invasion 337 “rolloff,” radiofrequency ablation programs 247 ROTEM TEG analyzer 525, 527 (Fig.) rRp450 (multimutated herpesvirus) 362

Index rupture adenoma 467 HCC Africa 511 hemoperitoneum 140 hemangioma 467 S-1 (fluoropyrimidine) 110 safety adenoviruses 360 herpesviruses 363 liver resection after chemotherapy 197 protective techniques 308–16 saline, hot 272–3 saline-linked cautery 195, 246 Salmonella spp., gallbladder carcinoma 503 salvage chemotherapy, gallbladder carcinoma 345 salvage of blood, liver transplantation 523 salvage transplantation, HCC 222, 285 sarcomas Asia 495 (Table) post-transplant 466 primary hepatic 46–7, 439–41 undifferentiated 47, 440–1, 482 sarcomatoid HCC 47 Saudi Arabia, viral hepatitis 489 schwannoma, hepatic 442–3 scintigraphy see nuclear medicine sclerosing cholangitis see primary sclerosing cholangitis sclerosing HCC 42 scoring systems liver fibrosis 33, 34 (Fig.) tumor marker grading 69 see also model for end-stage liver disease; staging screening, HCC 54, 71, 184, 463, 465 Asia 489–90 cost-effectiveness 534 second primaries, HCC 221 sectional arteries, hepatic 11 sectional bile ducts, anomalies 16 sectionectomies 12, 13 (Fig.), 194 laparoscopic 205, 206 (Fig.), 210 sectors, liver 177 sedation, percutaneous ethanol injection 268 seeding of tumor biopsy 282 gallbladder carcinoma 334, 337, 504 radiofrequency ablation and 252, 286 see also peritoneal carcinomatosis SEER Registry, cholangiocarcinoma 56 segment 3 bile duct, biliary bypass 16 segmental arteries 11 segmentectomies 12, 177, 181–3, 194 segment 1 183, 184 (Fig.) segment 4, 3 and 2 183 segment 5 182–3 segment 6 183 segment 7 183 segment 8 181–2 segments (Couinaud) 4, 11, 14 (Fig.), 177–8 segments (Healey) 177–8

segments (‘laparoscopic’) 207, 210 selection effect, publication of quality measurements 531 selective continuous intra-arterial chemotherapy 151–63, 523 selective embolization via hepatic artery, neuroendocrine tumors 433 selective internal radiotherapy see internal radiotherapy sepsis, cholangiocarcinoma 61 septa, in tumors 267 seroma, implantable pump pocket 153–4 serotonin acupuncture and 417 liver regeneration 311 see also carcinoid syndrome 73T strain, Newcastle disease virus 356 sevoflurane 314 shaft antennae, microwave thermal ablation 253, 255 shape of liver 22 shark cartilage 415 SHARP trial, sorafenib 113, 378 (Fig.) sheaths, plate/sheath system 20–1 Sho-Saiko-To (Chinese botanical) 416–17 “shrunken” gallbladder 22 sialic acid, as tumor marker 72–3 signaling pathways 349–50 for apoptosis 393 HCC 368–81 Raf/MEK/ERK 113, 385–6 Ras 387–8 oncolytic therapy 355 see also K-ras mutation targeted therapies 376–8, 382–92 Wnt 61, 350, 371, 372 drugs targeting 378–9, 388 signs, HCC, Africa 511–12 simulation, external beam radiotherapy 122 Singapore, HCC prevention 489 single photon emission computed tomography, neuroendocrine tumors 426 sinusoids 30 endothelial cells 404 liver fibrosis 33 obstruction, cytotoxic drugs 197, 310 SIOPEL/PRETEXT system, staging in children 476, 477–8, 479 (Table) SIR-Spheres® (radioconjugate) 132 dose calculation 133 sirolimus (rapamycin) 287, 289 Kaposi sarcoma 466 transplantation for epithelioid hemangioendothelioma 291 skin, cetuximab toxicity 109 slice thickness, MDCT 78–9 small cell change, dysplastic nodules 41 small cell undifferentiated pattern, hepatoblastoma 44 small intestine, primary neuroendocrine tumors 425 smoking cholangiocarcinoma 58 hepatoblastoma 477

Smoothened (receptor) 372 sodium, central pontine myelinolysis 520 sodium hydroxide, percutaneous 277 softness, HCC 266 somatostatin HCC 112 neuroendocrine tumors 427 somatostatin analogs 427–8 radiolabeled, radiotherapy with 433 see also octreotide somatostatinomas 426 sorafenib 404 (Table) on angiogenesis 389 control arm for clinical trials 375 HCC 113, 135, 140, 287, 349, 377 (Table), 378, 385–6, 407 adjuvant therapy 300 adverse events 113 unresectable 287 South America 500–8 space of Disse 30, 31 (Fig.) specimen extraction, laparoscopic liver resection 207 incisions 210 sphere, volume of 268 spherical ablations 246 maximum size 248 sphingomyelin transport molecules 397 Spiegelian lobe 11 spiral computed tomography 78, 83 see also multidetector computed tomography splenic artery, selective continuous intra-arterial chemotherapy 152 split liver transplantation 6 Src (non-receptor tyrosine kinase) 383 staging 127 children 475, 476 PRETEXT system 476, 477–8, 479 (Table) cholangiocarcinoma 43 (Table) intrahepatic 44 perihilar 45, 328 colorectal carcinoma metastases, intraoperative laparoscopy 192 gallbladder carcinoma 49, 187, 335–6, 337–8 HCC 43, 317, 318 (Table) hepatoblastoma 44, 477–8 Kaposi sarcoma 462 liver fibrosis 33 malignant liver tumors 43 see also Barcelona Clinic Liver Cancer staging system staining, segmentectomy 182 standardized future liver remnant volume 198 stapler hepatectomy 206 starch microspheres 142 Starzl, Thomas E., liver transplant 5 statins, perioperative 459 steatosis 30–2 chemical shift imaging, MRI 85 cytotoxic agents causing 197, 344 donors for transplantation 7 liver resection 308–10, 456 see also nonalcoholic fatty liver disease

555

Index stellate cells, hepatic 30, 31 (Fig.) liver fibrosis 33, 34 (Fig.) stents cholangiocarcinoma, costs 536 gallbladder carcinoma 335, 337 stereotactic body radiotherapy (SBRT) 123, 124 (Fig.), 125 (Fig.) dose–volume histogram 126 (Fig.) stomach carcinoma, metastases from 447, 448 (Table) primary neuroendocrine tumors 425 streptozocin, neuroendocrine tumors 115 structural measures, quality of care 531, 532–3 subserosa, gallbladder carcinoma invasion 337–8 succinylcholine, liver transplantation 523 suicide gene prodrug therapy 352–3 adenovirus 356–60 retroviruses 354 vaccinia virus 355–6 sunitinib 404 (Table) HCC 113, 376–8, 388–9 superior mesenteric artery, catheter-assisted arterial portography 95 superparamagnetic iron oxide (SPIO) 90 MRI 93 (Fig.), 96 (Fig.) double-contrast 90–1 supine position, laparoscopic liver resection 203 surface tumors, percutaneous ethanol injection contraindicated 267 surgery historical aspects 3–5 pregnancy 468 surgery-specific cardiac risk 457–8 survivin 397 Swedish massage 418 symptoms, HCC, Africa 510–11 SynchroMed EL implantable infusion pumps 153 (Table) synchronous metastases, colorectal carcinoma 64–5 synergism G207 virus 362–3 HSV amplicons 360 systemic therapy 107–21 preoperative, colorectal carcinoma metastases 196–7 regional chemotherapy with 157 T-cell lymphoma, primary hepatic 47 T1-weighted images, MRI 85 cryoablation 232 T2-weighted images, MRI 85 TACE see chemoembolic therapy; hepatic arteries, chemoembolization (HACE); transarterial chemoembolization (TACE) Taiwan finger fracture technique 487 HCC 489 resection 490 hepatitis B virus vaccination 481 tamoxifen, HCC 112 tape, “hanging maneuver,” right hepatectomy 195

556

tattooing, segmentectomy 182 taxanes, pancreatic endocrine tumors and 115 99m Tc-galactosyl HSA, uptake test 310 (Table) 99m Tc-macroaggregated albumin, scanning for internal radiotherapy 132 TEG (thromboelastography) 524–5, 526 (Fig.), 527 (Fig.) tegafur 110 telomerase reverse transcriptase (TERT) immunization 379 see also human telomerase reverse transcriptase promoter (hTERT) temozolomide, pancreatic endocrine tumors 115 temperature (body), infusion pump flow rates 151–2 temperature (tissues) cell death 244 cryotherapy 227 temsirolimus 376 termination of pregnancy, HCC 468 terminology see nomenclature testosterone, HCC and 52 tetracycline, VEGF inhibition 405 Thailand, cholangiocarcinoma 56, 58–9 thalassemia, HCC 54 thalidomide 404 (Table), 408 pancreatic endocrine tumors 115 thawing, cryotherapy 227–8, 231 TheraSphere® (radioconjugate) 132 dose calculation 133 thermal ablation 244–65 see also microwave thermal ablation; radiofrequency ablation thermocouples cryoablation monitoring 232 laser ablation monitoring 259 thin slices, MDCT 78–9 thoracic epidural analgesia 522 thoracic route, percutaneous ethanol injection 268 thoracoscopy, hand-assisted laparoscopic liver resection with 210 Thorotrast 59 angiosarcoma 46 cholangiocarcinoma 57 (Table) three-dimensional conformal treatment planning 122–3, 124 (Fig.), 125 (Fig.) dose–volume histograms 126 (Fig.) three-dimensional images MDCT 78 volumetric MRI 87–8 threshold levels, quality adjusted life years 534 thrombocytopenia 521 cryoablation 233 see also coagulopathy thromboelastography 524–5, 526 (Fig.), 527 (Fig.) thrombolysis, percutaneous ethanol injection 267 thromboplastins coagulation monitoring 527 see also activated partial thromboplastin time thrombosis, portal veins (PVT) 142 internal radiotherapy suitability 135

thymidine kinase gene (HSV-tk) oncolytic therapy 361 suicide gene prodrug therapy 353, 354, 356–60 thyroid gland, 131I-lipiodol and 133 Tibetan yoga 418 ticlodipine 459 Tijuana, Mexico, metabolic therapies 416 time to progression as clinical trial endpoint 375 sorafenib on 385 tines, radiofrequency ablation 246 TMUGS (Tumor Marker Utility Grading Scheme) 69 worksheet 70 (Fig.) total body clearance, regional drug delivery and 154–5 total liver volume 197–8 total vascular exclusion 180 toxicity heart, sorafenib and doxorubicin 386 herbal remedies 416 irinotecan 197, 310 radioembolization 134–5 skin, cetuximab 109 TRADD activation, apoptosis 393 traditional alternative medical systems 414–15 TRAIL (TNF-related apoptosis-inducing ligand), immunomodulation 357 training of staff effect on complications 533 laparoscopic liver resection 212 tranexamic acid, liver transplantation 524 transabdominal ultrasound 76–8 transaminases see liver function transarterial chemoembolization (TACE) 105, 127, 139–40, 141, 492 as adjuvant therapy 147 efficacy 143–6 follow-up imaging 271 HCC before cryoablation 234 recurrent tumor 223 hepatoblastoma 480 131 I-lipiodol therapy vs 133 laser thermal ablation after 261 percutaneous ethanol injection with 274 portal vein occlusion with 312 radiotherapy with 128 renal transplant patients 466 transplantation of liver, bridging therapy 286, 287 see also chemoembolic therapy transarterial chemotherapy cryoablation with 240 gallbladder carcinoma, adjuvant 344 lipiodol as carrier 141 selective portal vein occlusion with 312 see also selective continuous intra-arterial chemotherapy transarterial embolization (TAE) HCC 139–50 as adjuvant therapy 147 efficacy 143–6

Index laser thermal ablation after 261 percutaneous ethanol injection with 266, 274 transarterial radionuclide therapy (TART), 188Re HDD-lipiodol 134 transcatheter arterial embolization see transarterial embolization transcatheter radioembolization see internal radiotherapy transducers, intraoperative ultrasound 78 transection bile ducts, hepatico-jejunostomy 24 parenchymal 180–1 laparoscopic 205–7 transection line, intraoperative ultrasound 180 transesophageal echocardiography, liver transplantation 523, 527 transforming growth factor α, HCC models 373–4 transforming growth factor β hepatitis C virus, HCC 53 after portal vein embolization 198 radiation-induced liver disease 127 transforming growth factor β1 71 type II receptor gene mutation 73 transhepatic tumoral intubation (Praderi) 500 transition tumors, mixed hepatocellular/ cholangiocarcinoma 45 transplantation of kidney HCC 465 transarterial chemoembolization and 466 transplantation of liver 175, 281–95, 492 anesthesiology 519–21, 523–4 for angiosarcoma 291, 440 Argentina 501, 505 Brazil 501–2 for breast carcinoma metastases 446 children 481 Chile 502 for cholangiocarcinoma 187, 289–90 hilar 289–90, 328 Colombia 502 cryptogenic cirrhosis 455 for epithelioid hemangioendothelioma 291, 442 guidelines, West vs East 321 for HCC 167, 185–6, 281–9, 292 children 481 cost-effectiveness 535 HIV/AIDS patients 464 noncirrhotic patients 285–6 recurrence after 283, 287, 465–6 repeat 466 “salvage” 222, 285 for hepatoblastoma 479–80 historical aspects 5–7 after laparoscopic hepatectomy 212 for neuroendocrine tumors 432 Peru 502 preanesthetic investigations 520 (Table) South America 500, 501–2, 505 steatosis and 32 thromboelastography 525, 526 (Fig.) transesophageal echocardiography 523, 527 tumors developing after 464–7

see also bridging therapy; living donor liver transplantation transportal ethanol injection, TACE with 274 transthoracic route, percutaneous ethanol injection 268 transverse portion, left portal vein 17 trastuzumab 373, 376 trauma, rupture of HCC, Africa 511 triple loop antenna, microwave thermal ablation 255 trisectionectomy 12 trocars, laparoscopic liver resection 204 TroVax (MVA virus carrying tumor antigen 5T4 gene) 356 tumor-associated markers 69 tumor growth angiogenesis 401–2 selective portal vein occlusion 312 tumor markers 69–75 gallbladder carcinoma 503 neuroendocrine tumors 427 see also CA 19–9 tumor necrosis factor (TNF), isolated hepatic perfusion 166–7 tumor necrosis factor alpha signaling pathway for apoptosis 393 as therapy 397 tumor-specific markers 69 tumor suppressor genes cholangiocarcinoma 61 replacement 353 adenovirus 357 retroviruses 354–5 tumorectomies see nonanatomic resections two-dimensional treatment planning, external beam radiotherapy 122 two-stage hepatectomy, metastases 194–5, 312, 313 (Fig.), 342 two-surgeon techniques, liver resection hemostasis 195, 196 (Fig.) laparoscopic 212 tyrosine kinase inhibitors 376, 407 see also receptor tyrosine kinases ulcers, gastrointestinal, after radioembolization 135 Ulex europaeus, angiosarcoma 46 Ulster strain, Newcastle disease virus 356 ultrasonic dissectors 195 Cavitron ultrasonic surgical aspiration 180 laparoscopic surgery 206 ultrasonic scalpels, laparoscopic surgery 206 ultrasound 76–8 gallbladder carcinoma 334, 503 hepatoblastoma 477 laparoscopic 205 liver resection planning 180 nonalcoholic steatohepatitis prevalence 454 percutaneous ethanol injection 268, 270 postoperative follow-up 219 see also echocardiography; endoscopic ultrasound; intraoperative ultrasound umbilical plate 21 umbilical portion, left portal vein 17, 22

“umbilical vein” 18 United States of America Children’s Oncology Group, hepatoblastoma staging 478 microwave thermal ablation 253, 254, 255 treatment guidelines, HCC 318 University of California, San Francisco-expanded criteria for liver transplantation 283, 493 University of Wisconsin solution 6 unknown origin, liver tumors of 447–9 unsaturated vitamin B12-binding capacity, fibrolamellar HCC 72 upper abdominal exenteration, transplantation for neuroendocrine tumors with 432 urokinase-type plasminogen activator 71 Uruguay, River Plate school 500–1 vaccination, hepatitis B virus 53, 481, 489 vaccinia virus 354 (Table), 355–6, 358 (Table) vandetanib 404 (Table) variants see anomalies vascular endothelial growth factor 376 blood levels 403 factor A (VEGF-A) 349 HCC 402 hypoxia-inducible receptor, gene therapy 361 inhibition 404–6 metastases 403–4 receptor binding AZD2171 110 bevacizumab 108–9 vascular exclusion, total 180 vascular injury, radioembolization 135 vascular invasion HCC 283 portal veins HCC 222, 283, 490 hepatoblastoma 478 vascular occlusion see inflow occlusion vascular status of tumors 409 vascular targeting 409 vascularity of tumors contrast-enhanced ultrasound 77 HCC 139, 266 vessels supplying 131 see also blood vessels vasoactive intestinal peptide 426 VEGF factor A (VEGF-A) 349 vena cava see inferior vena cava venography inferior vena cava, percutaneous hepatic perfusion 169 portal veins (by MDCT) 80 venous access liver surgery 522 liver transplantation 523 venovenous bypass isolated hepatic perfusion 164 liver transplantation 524 total vascular exclusion of liver 180 Verner–Morrison syndrome 426 very low birthweight, hepatoblastoma 477 vessel sealing system, laparoscopic liver transection 206

557

Index VIPomas 426 viral-based gene therapy 352–67 angiostatin 408 virilization 477 virtual hepatectomy 80 visualization (guided imagery) 418 vitamin A derivatives, HCC, adjuvant therapy 297 (Table), 299–300, 387–8 vitamin B12-binding capacity, fibrolamellar HCC 72 vitamin K 521 Vivant Medical system, microwave thermal ablation 255 volume of liver 80, 197–8 remnant 198, 311 volume of sphere 268 volume of tumor, gross (GTV) 122 volume overload, liver surgery 523 volume-rendered MDCT 80 (Fig.) volumetric MRI 87–8 von Recklinghausen disease, schwannomas 442–3

558

waiting lists for transplantation 288 on cost-effectiveness 535 dropout 286 see also bridging therapy watersheds blood supply to bile ducts 24 hepatic blood supply 11 wave distortion, ultrasound 76–7 WDHA syndrome (Verner–Morrison syndrome) 426 websites complementary and alternative medicine 415 (Table) guidelines on HCC 318, 319 wedge resections 194 repeat 216–17 see also nonanatomic resections Weibel-Palade bodies 46 Wendell, Walter, liver resections 4 Wnt signaling pathway 61, 350, 371, 372 drugs targeting 378–9, 388 World Health Organization, grading of HCC 40

wound resection, gallbladder carcinoma surgery 503 XELIRI regimen, colorectal carcinoma metastases 108 cetuximab with 109 XELOX regimen, colorectal carcinoma metastases 108 cetuximab with 109 xenografts, drug evaluation 374 yoga 418 yttrium-90 historical aspects 131 microspheres 131–3 90 Y-somatostatin analogs, neuroendocrine tumors 433 ZD 6126 (vascular targeting agent) 409 Zollinger–Ellison syndrome 425, 428 zone of necrosis, radiofrequency ablation 245

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