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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25

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 interrupt