Dx Rx: Pancreatic Cancer (Jones & Bartlett DX RX Oncology)

Dx/Rx: Pancreatic Cancer Maeve Lowery, MD Memorial Sloan-Kettering Cancer Center Department of Medicine GI Oncology Service New York, New York Eileen M. O’Reilly, MD Memorial Sloan-Kettering Cancer Center Department of Medicine GI Oncology Service New York, New York

Series Editor: Manish A. Shah, MD Memorial Sloan-Kettering Cancer Center Department of Medicine GI Oncology Service New York, New York

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Library of Congress Cataloging-in-Publication Data Lowery, Maeve Dx/Rx. Pancreatic cancer / Maeve Lowery, Eileen O’Reilly. p. ; cm. — (Dx/Rx oncology series) Other title: Pancreatic cancer Includes bibliographical references and index. ISBN-13: 978-0-7637-8065-4 (pbk.) ISBN-10: 0-7637-8065-0 (pbk.) 1. Pancreas—Cancer—Handbooks, manuals, etc. I. O’Reilly, Eileen, MD. II. Title. III. Title: Pancreatic cancer. IV. Series: Jones and Bartlett Publishers Dx/Rx oncology series. [DNLM: 1. Pancreatic Neoplasms—Handbooks. WI 810] RC280.P25L69 2012 616.99⬘437—dc22 2010029107 6048 Printed in the United States of America 14 13 12 11 10 10 9 8 7 6 5 4 3 2 1

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Contents Editor’s Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .v 1

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic Conditions Associated with Pancreatic Ductal Adenocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . Screening in High-Risk Patients . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

5 7 9

Diagnosis and Staging . . . . . . . . . . . . . . . . . . . . . . . . 11 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3

1 1

11 16 18 18

Molecular Pathogenesis. . . . . . . . . . . . . . . . . . . . . . . 21 Molecular Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

4

Localized Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Localized Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adjuvant Therapy for Localized Disease . . . . . . . . . . . . . . Adjuvant Chemotherapy: Randomized Trials . . . . . . . . . . . Adjuvant Chemoradiation: Randomized Trials . . . . . . . . . . Neoadjuvant Therapy for Resectable Disease . . . . . . . . . . Summary and Recommendations . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31 37 37 39 40 42 44

iii

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iv Contents 5

Locally Advanced Disease . . . . . . . . . . . . . . . . . . . . . 47 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Use of Radiosensitizers for Chemoradiation . . . . . . . . . . . Chemoradiation Versus Best Supportive Care . . . . . . . . . . Chemoradiation Versus Radiation Alone . . . . . . . . . . . . . . Chemoradiation Versus Chemotherapy Alone . . . . . . . . . . Outcomes for LAPC in Systemic Chemotherapy Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Induction Chemotherapy Followed by Chemoradiation Therapy . . . . . . . . . . . . . . . . . . . . . . Summary and Recommendations . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6

55 57 58

63 64 64 66 70 73 75

Uncommon Pancreatic Malignancies . . . . . . . . . . . 83 Uncommon Exocrine Pancreatic Malignancies . . . . . . . . . Giant Cell Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Resection of Metastatic Nonpancreatic Cancers . . . . . . . . Primary Pancreatic Lymphoma . . . . . . . . . . . . . . . . . . . . . Primary Pancreatic Sarcomas . . . . . . . . . . . . . . . . . . . . . . . Pancreatic Endocrine Neoplasms . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8

54

Metastatic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Metastatic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemotherapy Versus Best Supportive Care . . . . . . . . . . . Single-Agent Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . Combination Chemotherapy Regimens . . . . . . . . . . . . . . . Targeted Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Second-Line Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7

47 49 50 50 52

83 87 88 88 89 89 94

Supportive Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Supportive Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

9

Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 Future Directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

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Editor’s Preface I would like to welcome this latest addition to the Dx/Rx: Oncology series, Dx/Rx: Pancreatic Cancer by Maeve Lowery, MD, and Eileen M. O’Reilly, MD. This book represents an important contribution to the Dx/Rx family, given that cancer of the pancreas continues to be a common global illness with exceedingly poor survival. This book is wonderfully written and organized similar to other books in this series in bulleted, easy-to-read chapters divided by epidemiology, diagnosis and staging, molecular pathogenesis, and, importantly, management of both locally advanced and metastatic disease. The timing of this book could not be better, given the recent positive results of the FOLFIRINOX regimen in this disease (presented at ASCO 2010), after a series of negative phase III studies. Drs. O’Reilly and Lowery also provide important management guidance for supportive care for pancreatic cancer, as well as a look to the future with new biologic agents being explored in this disease. I am certain you will find this book both informative and an easy-to-read pocket resource as you manage this complex and difficult malignancy. Manish A. Shah, MD

v

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C H A P T E R

1

Epidemiology ■ Epidemiology ■

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■

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Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer death in the United States and is disproportionally high on this list when compared to leading causes of cancer incidence, where it ranks fourth. PDAC is the 10th most common cancer in men and women, accounting for 3% of all new cancer diagnoses; 42,470 new cases of pancreatic cancer and 35,240 pancreatic cancer–related deaths are estimated in the United States in 2009.1 In Europe, the estimated incidence in 2008 was 68,500 and mortality was 70,200.2 Median age at diagnosis is 72 years. The age-adjusted incidence rate is 11.7 per 100,000 men and women per year. The incidence in men has remained stable since 1976, while the incidence in women has increased modestly.3 The overall 5-year survival rate for all races and both sexes is 5.5%.4

■ Risk Factors Age and Gender ■ Pancreatic cancer is rare below the age of 45 years and most frequently occurs in the seventh and eighth decades of life. It is slightly more common in males than females, but does not show the significant male predominance seen in most other cancers of the gastrointestinal tract. The highest incidence worldwide is seen in New Zealand Maoris, African Americans (but not African men), and native Hawaiians, while Indian and Nigerian men have the lowest reported rates.5 (See Figure 1.1.) 1

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2 Chapter 1 Smoking Diabetes Obesity Chronic pancreatitis Male sex Increasing age Figure 1.1 Risk factors for the development of pancreatic ductal adenocarcinoma.

Type I and II Diabetes Mellitus ■ An association between type II diabetes and pancreatic cancer has been clearly demonstrated in several large population-based studies; however, a causal relationship has been more difficult to prove. A meta-analysis of 17 case-control studies and 19 cohort studies involving 9220 people found evidence of a modest causal association, with an age- and sex-adjusted odds ratio of 1.82 (95% CI: 1.66–1.89).6 The risk of pancreatic cancer was 50% higher in those diagnosed with diabetes within the previous 5 years (odds ratio 2.1 vs. 1.5, p < 0.005). ■ A subsequent population-based study looked at 2122 newly diagnosed diabetics age older than 50 years. Eighteen (0.85%) developed pancreatic cancer within 3 years, indicating that patients with a new diagnosis of diabetes are 8 times more likely than nondiabetics to develop pancreatic cancer. ■ Regarding type I or early onset diabetes and pancreatic cancer risk, a systematic review looked at 3 cohort and 6 case-control studies. The total number of patients identified was small, only 39; however, they found a similar increased risk for development of pancreatic cancer as previously seen with type II diabetes (relative risk 2.0, 95% CI 1.37–3.01).7 ■ More recently, a case-control study demonstrated a lower risk of pancreatic cancer in diabetic patients treated with metformin, compared to those who had not received it (RR 0.38, 95% CI 0.22–0.69, p ⫽ .001). There was also

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Epidemiology 3

a trend toward increased risk of pancreatic cancer among patients treated with insulin or insulin secretagogues. Cigarette Smoking ■ Cigarette smoking has been shown in several large cohort and case-control studies to approximately double the risk of developing pancreatic cancer, and it accounts for 25% of all cases diagnosed each year.8 The risk has been shown to correlate with duration and intensity of smoking, and decreases with smoking cessation. A large meta-analysis of 82 published studies found that cigarette smoking was associated with a 75% increased risk of development of pancreatic cancer, and that an increased risk persisted in former smokers for at least 10 years.9 ■ More recently, published data from the Pancreatic Cancer Cohort Consortium supported this finding.10 They again demonstrated that current smokers had a significantly elevated risk of development of pancreatic cancer (OR ⫽ 1.77, 95% CI: 1.38, 2.26). The risk increased significantly with greater intensity, duration, and cumulative smoking dose. The risk for former smokers more than 15 years after smoking cessation was similar to that for those who had never smoked. Pancreatitis ■ Chronic pancreatitis is associated with pancreatic carcinoma; however, a causal relationship has been more difficult to establish. Common risk factors for both conditions may confound the picture. While some studies have reported up to a 28-fold increased risk for development of pancreatic cancer following diagnosis with chronic pancreatitis, further large case-control studies have suggested a more modest association.11 A recently published case-control study found that a positive history of pancreatitis was associated with pancreatic cancer with an odds ratio of 4.68 (95% CI, 2.23–9.84).12 While acute pancreatitis is not a risk factor for PDAC, approximately 3% of all invasive cancers present with an episode of acute pancreatitis. Hereditary pancreatitis is

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4 Chapter 1 associated with a greatly increased risk of PDAC and is discussed below. Diet ■ An association between obesity and pancreatic cancer is biologically plausible based on the known association with type II diabetes. A meta-analysis of 21 prospective studies confirmed a 12% increase in risk of pancreatic cancer for a 5 kg/m2 increase in body mass index (BMI).13 A multicenter observational study looked at 161,808 postmenopausal women and found no association between BMI and pancreatic cancer incidence; however, an increasing waist-to-hip ratio was associated with an increasing risk of pancreatic cancer, suggesting a possible relationship to centripetal obesity and insulin resistance.14 Familial Pancreatic Adenocarcinoma ■ Approximately 7–10% of all PDAC is related to genetic factors. There are several well-defined genetic syndromes known to predispose to PDAC; however, in up to 70% of cases a significant family history with multiple family members diagnosed with PAC is seen, but no specific genetic abnormality is identified.15 ■ The familial component to pancreatic cancer etiology was established initially by several case reports and early population-based studies from the 1970s onward. The National Familial Pancreas Tumor Registry (NFPTR) was established in 1994 to prospectively observe relatives of patients with PDAC and assess their prospective risk.15 Eight hundred thirty-eight relatives of patients with PDAC were followed and their prospective risk of development of PDAC was calculated by comparing the observed to expected numbers of cases based on Surveillance Epidemiology and End Results (SEER) data. It was shown that people with 3 first-degree relatives with pancreatic cancer had a 32 times increased risk of developing PDAC. In those with 2 first-degree relatives the risk was increased by 6.4fold, and those with 1 relative with PDAC had a 4.6-fold increased risk of developing the disease. It was concluded

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Epidemiology

5

that this clustering of PDAC in families is due in part to a yet unidentified gene, in combination with shared environmental factors.

■ Genetic Conditions Associated with Pancreatic Ductal Adenocarcinoma

BRCA 1 / 2 Mutations ■ Germline BRCA 1 and 2 mutations have been clearly identified as carrying an increased lifetime risk of PDAC. A large series looking at BRCA 2 mutation-carrying families estimated an increased risk of 3.5 times the population risk.16 The risk in BRCA 1 mutation carriers has been shown to be somewhat lower, with a relative risk of 2.2 compared to the general population.17 The Ashkenazi Jewish population has an increased carrier frequency of BRCA 1 and 2 germline mutations, so a lower threshold for genetic screening in Jewish patients presenting with PDAC is appropriate. Increased sensitivity to DNA crosslinking agents such as mitomycin, cisplatin, and carboplatin has been demonstrated in other BRCA associated malignancies; anecdotal reports suggest that this may also be true for BRCA mutation–associated pancreatic cancer. Poly ADP-ribose polymerase (PARP) inhibitors have shown promising results in BRCA mutation–associated breast and ovarian cancer; ongoing clinical trials are currently evaluating the use of PARP inhibitors in the PDAC population with both a known BRCA mutation and in the sporadic population. (See Table 1.1.) Peutz-Jeghers Syndrome ■

This is an autosomal dominantly transmitted hereditary condition, characterized by hyperpigmentation of the buccal mucosae and lips, along with hamartomatous polyps of the gastrointestinal tract. Eighty percent of cases are due to a germline mutation in the STK11/LLDI gene. The condition is associated with multiple cancers of the gastrointestinal tract, lung, breast, and gynacological cancers. The estimated increased risk of PDAC is estimated at 132.18

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6 Chapter 1 Table 1.1

Hereditary Conditions Associated with Increased Risk of Pancreatic Ductal Adenocarcinoma Relative risk of PAC

Condition

Gene

BRCA 1 mutation BRCA 2 mutation

BRCA 1 / 2

2.2 3.5

Hereditary non-polyposis colorectal cancer (HNPCC)

MSH1/2, PMS1/2, and MSH6

Uncertain

Familial adenomatous polyposis (FAP)

APC gene

4.0

Familial atypical malignant mole and melanoma (FAMMM)

p16/CDKN2A

38.0

Hereditary pancreatitis

Trypsinogen / SPINK-1

53.0

Peutz-Jeghers syndrome

STK11/LLDI

132

Interestingly, in this population the development of invasive pancreatic cancer appears to arise via the Intraductal Papillary Mucinous Neoplasm (IPMN) pathway, making screening for this population an attractive concept. Hereditary Pancreatitis ■ This is a rare inherited condition characterized by recurrent episodes of acute pancreatitis. It arises due to a hereditary defect in the trypsinogen gene in the autosomal dominant form, or in the SPINK1 gene in the autosomal recessive form. It carries an estimated increased risk of pancreatic cancer of 53-fold higher compared to the general population, with 30–40% of sufferers anticipated to develop invasive pancreatic cancer by the age of 70 years.19 In this population pancreatic cancer has been shown to occur significantly earlier in smokers compared to nonsmokers.20

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Epidemiology 7

Hereditary Non-Polyposis Colorectal Cancer (HNPCC) ■ This is an autosomal dominant condition resulting from a germline mutation in genes encoding for proteins responsible for DNA repair, including the MSH1/2, PMS1/2, and MSH6 genes. It not only carries an increased risk of colon cancer but also predisposes to endometrial, ovarian, gastric, renal, and urinary tract cancers. HNPCC also has been shown to carry an increased risk of pancreatic and biliary cancers, but this risk has been difficult to quantify.21 Familial Atypical Multiple Mole and Melanoma Syndrome (FAMMM) ■ This is an autosomal dominantly inherited condition resulting from a germline mutation in the p16/CDKN2A gene. It carries an increased risk of melanoma, breast cancer, lung cancer, and sarcoma as well as pancreatic cancer. The estimated increased risk of developing PDAC compared to the general population is estimated at a 38-fold increased risk.22 Familial Adenomatous Polyposis (FAP) ■ This is an autosomal dominant condition arising from a germline mutation in the APC tumor suppressor gene. Affected individuals develop multiple colonic adenomatous polyps, resulting in an almost absolute risk of developing adenocarcinoma of the colon by age 40 years. Other associated cancers include thyroid, gastric, duodenal, and ampullary carcinomas. It also carries a 4-fold increased risk of pancreatic carcinoma.23 An association with pancreaticoblastoma has also been described, a connection between the 2 conditions being plausible via the APC/Wnt pathway. Screening in High-Risk Patients ■

The benefit of screening of patients at high risk for development of pancreatic adenocarcinoma based on family history or on known predisposing germline mutation is

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8 Chapter 1

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currently under investigation. Options include the use of endoscopic ultrasound (EUS) with FNA as indicated, or CT or MRI cross-sectional imaging. EUS allows evaluation of the pancreatic duct for areas of dilatation or focal narrowing or wall thickening and provides a useful means for obtaining histological diagnosis. The estimated diagnostic yield from screening programs published to date ranges from 3.9% to 23% for prevalent invasive cancers. However, there is considerable heterogeneity among the population screened between different institutions and also in the diagnostic tests used. The series from Johns Hopkins included patients with PeutzJeghers syndrome (screened from age 30 years onward) and familial pancreatic patients (⬎ 3 first-degree relatives with pancreatic cancer) from age 50 years onward. In this high-risk group of patients, the diagnostic yield for moderate or severe dysplasia was 95.8% and 33% for IPMN with high-grade dysplasia or PANIN 3. Surgical resection was well tolerated in these patients; long-term data regarding survival are pending. Prospective data regarding the results of large screening programs are awaited. The CAPS 5 trial is currently recruiting and will provide long-term data regarding the benefit of screening high-risk patients for pancreatic cancer. A key area of intense research at present is the search for biomarkers, both in blood and in pancreatic fluid, to incorporate into screening programs with EUS or cross-sectional imaging. For the general population at large, no routine screening has been shown to be of use and is not recommended. Young patients presenting with sporadic pancreatic cancer should be encouraged to attend a clinical geneticist for discussion regarding genetic screening; relatives of these patients and those with a known predisposing genetic mutation should be encouraged to partake in clinical trials of screening and prevention and to enroll in prospective registry studies. Smoking cessation is also of paramount importance in this population, given that it represents the only reversible risk factor.

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Epidemiology

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■ References 1. 2. 3.

4.

5. 6. 7. 8. 9. 10.

11. 12.

13. 14.

Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA. 2009;59:225–249. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. In press, corrected proof. Edwards B, Ward E, Kohler B, et al. Annual report to the nation on the status of cancer, 1975–2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer. 2010;116:544–573. Ducreux M, Boige V, Gor D, et al. The multidisciplinary management of gastrointestinal cancer. Pancreatic cancer: from pathogenesis to cure. Best Pract Res Clin Gastroenterol. 2007;21:997–1014. Ghadirian P, Lynch HT, Krewski D. Epidemiology of pancreatic cancer: an overview. Cancer Detect Prev. 2003;27: 87–93. Huxley R, Ansary-Moghaddam A, de Gonzlez AB, et al. Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer. 2005;92:2076–2083. Stevens RJ, Roddam AW, Beral V. Pancreatic cancer in type 1 and young-onset diabetes: systematic review and metaanalysis. BrJ Cancer. 2007;96:507–509. Coughlin SS, Calle EE, Patel AV, et al. Predictors of pancreatic cancer mortality among a large cohort of United States adults. Cancer Causes Control. 2000;11:915–923. Iodice S, Gandini S, Maisonneuve P, et al. Tobacco and the risk of pancreatic cancer: a review and meta-analysis. Langenbecks Arch Surg. 2008;393:535–545. Lynch SM, Vrieling A, Lubin JH, et al. Cigarette smoking and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium. Am. J. Epidemiol. 2009;170:403–413. Karlson BM, Ekbom A, Josefsson S, et al. The risk of pancreatic cancer following pancreatitis: an association due to confounding? Gastroenterology. 1997;113:587–592. Maisonneuve P, Lowenfels A, Bueno-de-Mesquita HB, et al. Past medical history and pancreatic cancer risk: results from a multicenter case-control study. Ann Epidemiol. 2010;20:92–98. Larsson SC, Orsini N, Wolk A. Body mass index and pancreatic cancer risk: a meta-analysis of prospective studies. Int J Cancer. 2007;120:1993–1998. Luo J, Margolis KL, Adami HO, et al. Obesity and risk of pancreatic cancer among postmenopausal women: the

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10 Chapter 1

15. 16. 17. 18. 19.

20. 21. 22. 23.

Women’s Health Initiative (United States). Br J Cancer. 2008;99:527–531. Klein AP, Brune KA, Petersen GM, et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res. 2004;64:2634–2638. Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. 1999;91:1310–1316. Brose MS, Rebbeck TR, Calzone KA, et al. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst. 2002;94:1365–1372. Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology. 2000;119:1447–1453. Lowenfels A, Maisonneuve P, DiMagno E, et al: Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst. 1997;89:442–446. Lowenfels AB, Maisonneuve P, Whitcomb DC, et al. Cigarette smoking as a risk factor for pancreatic cancer in patients with hereditary pancreatitis. JAMA. 2001;286:169–170. Lynch HT, Voorhees GJ, Lanspa SJ, et al. Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: a family study. Br J Cancer. 1985;52:271–273. Lynch H, Fusaro R, Lynch J, et al. Pancreatic cancer and the FAMMM syndrome. Fam Cancer. 2008;7:103–112. Giardiello FM, Offerhaus GJ, Lee DH, et al. Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut. 1993;34:1394–1396.

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C H A P T E R

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Diagnosis and Staging ■ Diagnosis Diagnostic Tests Ultrasound ■ Transabdominal ultrasound is usually the first diagnostic test obtained in a patient presenting with obstructive jaundice or elevation of liver function tests. Liver metastases, biliary dilatation, or a pancreatic mass may be appreciated on ultrasound alone. The sensitivity of ultrasound for detection of a pancreatic exocrine tumor has been reported as up to 90% in high-volume centers.1 CT Imaging ■ Computerized tomography of the pancreas remains the imaging modality of choice for detection and staging of pancreatic adenocarcinoma. Advances in imaging techniques and the development of spiral and multidetector row CT (MDCT) scanners have improved the accuracy of pancreatic CT imaging. MDCT2 and spiral CT allow for rapid image acquisition timed with administration of intravenous contrast medium, and so can selectively opacify the venous, arterial, or portal venous systems. ■ The sensitivity of MDCT for detection of pancreatic tumors in reported series ranges from 76% to 91%, but is somewhat less than this for tumors smaller than 2 cm.3 ■ Adherence to a specific technique is essential for goodquality imaging of the pancreas and surrounding vessels. High-density oral contrast agents are not given; instead, water is used to aid visualization of the duodenum and small bowel. Intravenous contrast is administered by fast injection for optimal enhancement of the pancreatic parenchyma and surrounding vasculature. Images are 11

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12 Chapter 2

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rapidly acquired during arterial, venous, and portal venous phases.4 Images obtained can now be reconstructed using 3D imaging with volume rendering software, with the ability to alter parameters, enabling optimal visualization of the pancreas parenchyma or of the vessels. Liver metastases are best seen during the portal venous phase of enhancement and usually appear as lowattenuation lesions compared to normally enhancing liver.4 The sensitivity of CT for detection of liver metastases has been reported as approximately 75%, with missed lesions commonly being those ⬍ 1cm in diameter or located on the surface of the liver.5

MRI ■ Pancreatic adenocarcinomas typically appear on MRI as hypointense tumors on T1-weighted fat-suppressed images, and as hypointense lesions on arterial phase gadolinium enhanced imaging. T2-weighted images are used for detection of liver metastases. ■ Multiple studies comparing MDCT to MRI imaging for diagnosis and staging of pancreatic adenocarcinoma have shown no benefit from MRI over MDCT. More recent studies have suggested that recent advances in MDCT techniques may render it superior to MRI for the evaluation of pancreatic lesions.6 ■ As an MRI is more costly, longer in duration of study, and offers poor visualization of the lungs when compared to CT, its use is usually reserved for evaluation of the pancreas when biliary dilatation is detected on CT with no mass visible, or for the evaluation of liver lesions indeterminate on CT imaging.6 Endoscopic Ultrasound (EUS) ■ The role of EUS in pancreatic malignancy has evolved from its initial application in diagnosis and staging to include celiac plexus block techniques for palliation of pain and radiofrequency ablation. The potential therapeutic role of endoscopic techniques in the management of inoperable pancreatic cancer is discussed in Chapter 8.

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Diagnosis and Staging ■

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■

■

13

EUS has been shown to be superior to CT imaging for the detection of pancreatic lesions and also more accurate for staging of ductal adenocarcinoma.7 It allows direct visualization of lesions as small as 2–3 mm and has the added advantage of enabling tissue diagnosis to be obtained by fine needle aspiration (FNA). EUS evaluation of the pancreas is indicated when there is a suspicion of malignancy on CT imaging but no distinct mass is identified, or to confirm the presence of locally advanced disease when CT imaging is equivocal.8 EUS-guided FNA is an efficient and cost-effective method to obtain histological diagnosis, especially for small pancreatic lesions. It has been shown to be at least equivalent to image-guided FNA of pancreatic lesions in terms of sensitivity, specificity, and diagnostic accuracy.9 It has also been shown to have a lower association with peritoneal seeding than percutaneous FNA. Given the high diagnostic yield, low risk of tumor seeding, and additional advantages in imaging and staging, EUS-guided FNA is the preferred method of obtaining histological diagnosis. It is worth noting, however, that histological diagnosis is not always mandated prior to surgical resection. In a patient who has both a typical clinical presentation and radiological features consistent with pancreatic cancer, preoperative biopsy is unlikely to alter management and is not routinely recommended.10 Pancreatic ductal carcinomas frequently have a surrounding inflammatory or desmoplastic component, which can result in a false negative biopsy result. If a patient is being considered for neoadjuvant or palliative therapy, however, tissue diagnosis is required prior to initiation of treatment.

Endoscopic Retrograde Cholangiopancreatography (ERCP) ■ ERCP is predominantly used with therapeutic intent for relief of obstructive jaundice, as discussed in Chapter 8. ERCP images may demonstrate the classical double duct sign of dilatation of the common bile duct and the pancreatic duct.

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14 Chapter 2 ■

■

Brushings obtained during ERCP may provide cytological diagnosis; however, the higher diagnostic yield and lower complication rate associated with EUS make it the diagnostic test of choice. MRI/MRCP or MDCT has typically superseded ERCP as a diagnostic imaging test in the absence of jaundice.

Positron Emission Tomography (PET) ■ FDG-PET imaging has no role in the local staging of pancreatic carcinoma due to poor spatial resolution. A benefit of PET imaging over CT for the detection of distant metastases has been difficult to prove to date, and the role of PET for staging of pancreatic malignancy remains unclear. Limitations of PET imaging include poor visualization of peritoneal metastases and the possibility of false-negative results in hyperglycemic patients. Newer tracers (e.g., FLT in lieu of FDG-PET) may overcome some of the issues related to poor sensitivity in the setting of hyperglycemia. ■ Possible applications of PET include assessment of response to treatment and tumor viability; however, these applications have not been validated in the setting of pancreas adenocarcinoma. The incorporation of CT imaging with PET increases spatial resolution, and in one study was shown to change management in 11% of patients who had previously been imaged with CT alone.11 The use of PET imaging for pancreatic cancer is an evolving field, and PET is not currently routinely recommended for staging or diagnosis. Staging Laparoscopy ■ Staging laparoscopy is particularly useful in detecting radiographically occult small peritoneal metastases and metastases on the surface of the liver; however, the routine use of staging laparoscopy for all radiographically resectable pancreatic cancers varies among institutions and is an ongoing area of debate. ■ A selective approach to the use of staging laparoscopy has been suggested, limiting its use to patients with

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Diagnosis and Staging

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15

imaging suggestive of occult disease and those at greatest risk for metastatic disease, such as patients with large primary tumors ⬎ 3 cm, systemic symptoms of advanced disease, or a high Ca 19.9.10 Tumors of the body and tail of the pancreas have been shown to have approximately double the risk of occult abdominal metastases compared to tumors located in the head of the pancreas,12 and staging laparoscopy is commonly used for tumors in these locations. A large series of ⬎ 1000 patients with radiologically resectable pancreatic or peri-pancreatic cancers identified unresectable disease in 14% of patients at laparoscopy. The authors note, however, that the proportion of patients with unresectable disease decreased with the use of high-quality CT imaging to 8%. The significance of positive peritoneal cytology in patients with otherwise resectable disease at laparoscopy has been shown to correlate with reduced overall survival compared to patients with negative cytology, and outcomes post resection approach those of patients with stage IV disease at diagnosis who do not undergo surgical resection.13 Newer techniques for examination of peritoneal fluid include the use of reverse transcriptase PCR (RT-PCR) for tumor markers and may provide a more sensitive test for detection of subclinical peritoneal metastases.14 Staging laparoscopy has been also used in patients with locally advanced disease to guide the use of radiation therapy, as up to 30–40% of patients will have radiographically occult metastases at laparoscopy. In patients with inoperable locally advanced disease, positive peritoneal washings indicate metastatic disease. With the current trend for upfront systemic treatment of locally advanced disease (see Chapter 5), this has become less of an indication for staging laparoscopy, as patients with true localized disease are selected out by lack of progression on systemic treatment. Advantages of staging laparoscopy in this population include the ability to obtain diagnostic histology and potential to perform a celiac plexus nerve block intraoperatively.

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16 Chapter 2

■ Staging ■

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The staging system for pancreatic cancer is described below, as defined by the American Joint Committee on Cancer (AJCC), version 7 (2010). (See Tables 2.1, 2.2, 2.3, and 2.4.) The sixth edition of the AJCC staging manual, published in 2003, modified the staging of pancreatic adenocarcinoma to separate T3 and T4 disease based on resectability and removed locally advanced disease from the stage IV grouping. This staging remains unchanged in the most recent AJCC staging manual, published in 2010.15 Stages IA to IIB represent resectable disease, with stage III being locally advanced, unresectable disease and stage IV distant metastases.15 The majority of patients present with unresectable disease at diagnosis, and median survival correlates with tumor stage at presentation.16 Nodal involvement is seen in over 80% of resected surgical specimens and corresponds to a reduction in median survival of 1 year compared to node negative patients.16 Increasing tumor size and positive surgical resection margins have also been shown to correlate with reduced survival in patients undergoing primary resection.

Table 2.1

TNM Staging (Primary T)

T

Primary Tumor

TX

Primary not assessable

T0

No primary

Tis

In situ carcinoma

T1

Limited to pancreas, ⬍ 2 cm in size

T2

Limited to pancreas, ⬎ 2 cm in size

T3

Extends beyond pancreas, no involvement of SMA or CA

T4

Tumor involves CA or SMA (unresectable)

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Diagnosis and Staging 17 Table 2.2

TNM Staging (Nodal)

N

Regional Lymph Nodes

Nx

Regional nodes not assessable

N0

No regional node involvement

N1

Regional node involvement

Table 2.3

TNM Staging (Metastases)

M

Distant Metastases

MX

Distant metastases not assessable

M0

No distant metastases

M1

Distant metastases present

Table 2.4

■

AJCC Stage Grouping

Stage

TNM

Stage 0

Tis, N0, M0

Stage IA

T1, N0, M0

Stage IB

T2, N0, M0

Stage IIA

T3, N1, M0

Stage IIB

T1–3, N1, M0

Stage III

T4, Any N, M0

Stage IV

Any T, Any N, M1

The median survival for patients for each stage of disease is outlined below. (See Table 2.5.) The five-year survival rate was 20% for resected disease in the United States in 2009, 8% for locally advanced disease, and 2% for metastatic disease.17

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18 Chapter 2 Table 2.5

Median Survival of Pancreatic Adenocarcinoma by Stage at Diagnosis

Stage

Median Survival

Stage I–IIB

15–22 months

Stage III

8–18 months

Stage IV

4–8 months

■ Summary ■

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■

High-quality CT imaging is the diagnostic test of choice for diagnosis and staging of pancreatic adenocarcinoma. Histological confirmation of diagnosis is not required prior to surgical resection in a patient with typical clinical and radiological features of malignancy. If a mass is not visible on CT imaging or CT findings are atypical for adenocarcinoma, EUS is the preferred method for further evaluation of the pancreas and for obtaining histology. MRI/MRCP may be useful in the evaluation of indeterminate liver lesions or to evaluate the pancreas in the setting of a ductal dilatation in the absence of a mass. Staging laparoscopy is recommended in patients with large primary tumors, tumor located in the body or tail of the pancreas, or in patients with clinical or radiological features suggestive of occult metastases. The role of PET imaging in pancreas cancer is evolving and has not been shown to date to improve accuracy of staging or diagnosis.

■ References 1. 2. 3.

Karlson BM, Ekbom A, Lindgren PG, et al. Abdominal US for diagnosis of pancreatic tumor: prospective cohort analysis. Radiology. 1999;213:107–111. Nichols M, Russ P, Chen Y. Pancreatic imaging: current and emerging technologies. Pancreas. 2006;33:211–220. Francis I. Pancreatic adenocarcinoma: diagnosis and staging using multidetector-row computed tomography (MDCT)

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Diagnosis and Staging

4. 5. 6. 7.

8. 9. 10.

11. 12. 13. 14.

15. 16. 17.

19

and magnetic resonance imaging (MRI). Cancer Imaging. 2007;7:S160–S165. Horton KM, Fishman EK. Adenocarcinoma of the pancreas: CT imaging. Radiol Clin North Am. 2002;40:1263–1272. Zeman RK, Cooper C, Zeiberg AS, et al. TNM staging of pancreatic carcinoma using helical CT. Am J Roentgenol. 1997;169:459–464. Peddu P, Quaglia A, Kane PA, et al. Role of imaging in the management of pancreatic mass. Crit Rev Oncol Hematol. 2009;70:12–23. DeWitt J, Devereaux B, Chriswell M, et al. Comparison of endoscopic ultrasonography and multidetector computed tomography for detecting and staging pancreatic cancer. Ann Intern Med. 2004;141:753–763. Wong J, Lu DSK. Staging of pancreatic adenocarcinoma by imaging studies. Clin Gastroenterol Hepatol. 2008; 6:1301–1308. Boujaoude J. Role of endoscopic ultrasound in diagnosis and therapy of pancreatic adenocarcinoma. World J Gastroenterol. 2007;13:3662–3666. Callery M, Chang K, Fishman E, et al. Pretreatment assessment of resectable and borderline resectable pancreatic cancer: expert consensus statement. Ann Surg Oncol. 2009;16:1727–1733. Farma J, Santillan A, Melis M, et al. PET/CT fusion scan enhances CT staging in patients with pancreatic neoplasms. Ann Surg Oncol. 2008;15:2465–2471. Jimenez RE, Warshaw AL, Castillo CF. Laparoscopy and peritoneal cytology in the staging of pancreatic cancer. J Hepatobiliary Pancreat Surg. 2000;7:15–20. Ferrone C, Haas B, Tang L, et al. The influence of positive peritoneal cytology on survival in patients with pancreatic adenocarcinoma. J Gastrointest Surg. 2006;10:1347–1353. Dalal K, Woo Y, Galanis C, et al. Detection of micrometastases in peritoneal washings of pancreatic cancer patients by the reverse transcriptase polymerase chain reaction. J Gastrointest Surg. 2007;11:1598–605. AJCC Cancer Staging Manual, 7th edition, 2010. Katz MHG, Hwang R, Fleming J, et al. Tumor-nodemetastasis staging of pancreatic adenocarcinoma. CA Cancer J Clin. 2008;58:111–125. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–249.

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C H A P T E R

3

Molecular Pathogenesis ■ Molecular Pathogenesis ■

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The pathophysiologic processes underlying the development of pancreatic ductal adenocarcinoma are complex and have not yet been fully elucidated. It has been suggested that exocrine organ dysfunction and pancreatitis lead to release of local growth factors, cytokines, and oxygen radicals, which induces abnormal cell proliferation and differentiation and selects for oncogenic somatic mutations.1 One theory is that the cellular damage results in an expanded population of stem cells, which are particularly susceptible to oncogenic transformation resulting from acquired genetic mutations. Three known precursor lesions to pancreatic ductal adenocarcinoma have been identified: pancreatic intraepithelial neoplasia (PANIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN). IPMN and MCN are detectable radiologically. PANIN is not visible on cross-sectional imaging and is a histologic diagnosis.

PANIN ■ Of all identified precursor lesions to pancreatic adenocarcinoma, PANIN has been most extensively studied and is best understood. The term was coined in 1999 to describe the noninvasive precursor lesion of pancreatic ductal adenocarcinoma (PDAC). It is graded as 1 to 3 with clear progression of histological and molecular changes identified during the evolution from normal pancreatic tissue through PANIN 1 to 3 to invasive carcinoma.2 21

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22 Chapter 3 ■

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Autopsy series have demonstrated a prevalence of PANIN-1 lesions of 40% in adults without evidence of invasive carcinoma, while PANIN-3 lesions are only seen in  5% of cases.3 Increased numbers of genetic alterations are seen in higher grade PANIN. The sequence and frequency of acquisition of these somatic mutations have been demonstrated by pathological examination of resected specimens. The pancreatic progression model indicates the timing and frequency of acquired somatic mutations in the development from PANIN to invasive pancreatic adenocarcinoma4 (see Figure 3.1). K-RAS mutations are found sporadically in up to 18% of normal pancreatic tissue;5 however, invasive pancreatic cancer cells carry a K-RAS mutation in up to 90% of cases, although in resected pancreas cancers the frequency of RAS mutations may be lower and may reflect

BRCA2

Pdx1 SHH Embryo

p16 K-RAS Activated 90%

Telomere Shortening

Embryo/benign ductal cells

Inactivated 95%

FANCC/FANCG Inactivated <10% MS1/MLH2

p53 SMAD4 Inactivated 55-75% Inactivated Inactivated 4% 55%

PANIN 1>3

Invasive carcinoma

Figure 3.1 Key molecular events in the development of pancreatic adenocarcinoma. Adapted from: Ghaneh P, Costello E, Neoptolemos JP: Biology and Management of Pancreatic Cancer, Gut 56(8):1134–1152, 2007.

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Molecular Pathogenesis 23

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■

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a different part of the spectra of pancreatic tumor biology. Mouse models of PANIN have demonstrated this to be one of the earliest genetic events occurring in the PANIN to PDAC sequence, and it also appears to play a key role in the maintenance of PDAC.6 The addition of K-RAS mutation analysis to cytological examination of FNA samples from suspicious pancreas masses may add to the diagnostic accuracy and is currently under evaluation. The p16/INK4A tumor suppressor gene is downregulated early in the PANIN to PAC progression model, with loss of function occurring early in 85–95% of sporadic pancreatic cancers. The SMAD4/DPC4 tumor suppressor gene is usually inactivated late in the development of PDAC and is involved in the regulation of TGF-B mediated cell growth and development. BRCA 2 nongermline mutations also occur late in the progression from PANIN to invasive PDAC. The multiple genetic alterations that occur in the development of invasive pancreatic carcinoma result in significant genomic complexity and instability of the tumor. This has been suggested as a likely contributing factor to the relative resistance of PDAC to systemic chemotherapy and radiation therapy. Comprehensive genome sequencing of 24 human pancreatic cancers has yielded important genetic information regarding the molecular signature of PAC.7 Considerable heterogeneity was seen in the genetic alterations detected between individual pancreatic tumors, with an average of 63 mutations identified per cancer. However, these genetic alterations were shown to exert their effect via 12 common signaling pathways involved in key cellular processes including cell cycle regulation, metabolism, genomic repair, and cell surface expression proteins. Novel targeted agents directed at these key signaling pathways offer the most hope for meaningful improvement in clinical outcomes for PAC over the coming decade.

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24 Chapter 3 IPMN ■ IPMNs are a subtype of mucinous cystic pancreas neoplasms characterized by mucin production, cystic dilatation of the pancreatic duct, and intraductal papillary growth. They were first formally classified as a distinct histological and clinical diagnosis in 1996 by the World Health Organization.8 The clinical significance of a diagnosis of IPMN is due to the potential for malignant transformation of these lesions, which demonstrate a range of dysplastic changes from mildly dysplastic adenoma to invasive carcinoma. As IPMN is increasingly recognized as a radiologically identifiable precursor lesion to invasive pancreatic cancer, it has become an area of considerable research interest over the last decade. ■ The key molecular alterations occurring during transformation from low-grade dysplasia to invasive malignancy in IPMN have yet to be fully elucidated. K-RAS point mutations have been demonstrated in 40–60% of IPMN, while inactivation of p53 has been estimated to occur in approximately 8%, considerably less frequently than in invasive PAC. PIK3CA mutation has been shown in 10% of IPMN, while STK11/LKB1, a tumor suppressor gene mutated in Peutz-Jeghers syndrome, has also been found in some malignant IPMN.9 Cytogenetic analysis of IPMN with varying degrees of dysplasia has demonstrated recurrent chromosomal copy number alterations in IPMN containing intermediate- to high-grade dysplasia or invasive carcinoma, while low-grade IPMN lacked these alterations. It has not yet been definitively shown that low-grade IPMN has the capability to progress to invasive carcinoma. ■ IPMN has recently been further subclassified histologically into four groups, as defined by an international consensus group in 2005.10 These include gastric, intestinal, pancreaticobiliary, and oncocytic type, as defined by morphological features and immunohistochemical reactivity for specific glycoproteins contained in mucin (see Table 3.1). Gastric type IPMN was found to occur predominantly in peripheral branch ducts with low-grade

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Molecular Pathogenesis 25 Table 3.1

Histological Subtypes of IPMN

IHC

Gastric

Low

MUC5AC

Branch duct

Intestinal

Moderate/ high

MUC-2 MUC5AC

Main duct

Colloid carcinoma

Pancreaticobiliary

Moderate/ high

MUC-1 MUC5AC

Main duct

Tubular carcinoma

Oncocytic

Moderate/ high

MUC1+ MUC5AC

—

—

■

■

Typical Location

Typical Invasive Pathology

Histological Subtype Dysplasia

—

atypia, while the other subtypes commonly involve the main duct and contain higher-grade dysplasia, which is more frequently associated with invasive cancer. It is not yet clear if these different subtypes are distinct entities or if the gastric type may be a precursor to the other types. IPMN is predominantly detected as an incidental finding on cross-sectional imaging and rarely presents with symptoms. Radiologically, IPMN is subclassified into main duct, branch duct, or combined duct, with main-duct IPMN presenting as diffuse dilatation of the main pancreatic duct. With branch duct IPMN the main duct remains of normal caliber, and cystic lesions are seen within the gland (see Figure 3.1). Combined duct IPMN demonstrates a combination of these features.11 Involvement of the main duct carries a significantly higher risk of malignancy than branch duct IPMN and more frequently corresponds to the intestinal or pancreaticobiliary histological subtype, while branch duct IPMN more frequently contains the gastric subtype of IPMN and has a lower likelihood of containing invasive malignancy. Several radiological characteristics associated with the presence of malignancy on resected IPMN specimens have been reported by institutional series. Overall,

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26 Chapter 3

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branch duct IPMN less than 3 cm with no dilatation of the main pancreatic duct and no solid component have been shown to have an incidence of malignancy of less than 3%, a figure that approximates the mortality from surgical resection.12 This provides a rational basis for observation of branch duct IPMN without radiologic features suggestive of malignancy. A caveat to this, however, is the possibility that a visible cyst may represent a retention cyst adjacent to a radiologically occult carcinoma, and so an early follow-up imaging study is recommended initially (see Figure 3.2). In lesions that have indeterminate findings on crosssectional imaging, endoscopic ultrasound (EUS) can provide further information regarding the presence of a solid component to a lesion and also sample cyst fluid endoscopically. The differentiation between small branch duct IPMN and benign cystic pancreatic neoplasms without malignant potential can prove a diagnostic challenge on

Cystic lesion Main duct dilated or solid component?

Yes

No

Surgical resection and surveillance of remnant

Size  3cm?

Yes

No

Observe: radiological follow up

No

EUS  cyst aspiration

Yes

Solid component or CEA  200?

Figure 3.2 Algorithm for management of cystic pancreatic lesions.

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Molecular Pathogenesis 27

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■

cross-sectional imaging alone. Cyst fluid CEA levels have been shown to correlate with the presence of mucinous neoplasm, with CEA level > 200 having a positive predictive value of up to 85% in identifying a mucinous neoplasm.13 Cytological cyst fluid analysis is limited by low cellular content and contamination of the fluid with mucin and is less accurate than CEA in differentiating IPMN from benign cystic pancreatic lesions. (See Figure 3.3.) In parallel with recent advances in assessing the malignant potential of a given IPMN, a more selective approach to surgical resection has been proposed. Radiological follow-up is recommended by most institutions for small, incidentally discovered branch duct IPMN without high-risk radiological features. Surgical resection is recommended in the setting of main-duct dilatation or solid component and for all main-duct or combined-duct IPMN. Following partial pancreatic resection, the risk of recurrent IPMN within the pancreatic remnant is approximately 8%, so ongoing radiological surveillance is required in all patients postoperatively.14 Total pancreatectomy is reserved for diffuse gland involvement without evidence of invasive malignancy. The prognosis for patients with surgically resected malignant IPMN remains unclear. Colloid carcinoma has been shown to arise from IPMN and carries a significantly better prognosis than regular PDAC. Outcomes for patients postresection of malignant IPMN have been reported as significantly better than for non-IPMN associated adenocarcinoma; however, the inclusion of patients with colloid carcinoma may confound these findings.11 Patients with malignancy identified in IPMN also frequently have early microinvasive or small T1 lesions with a low rate of nodal positivity, making outcome comparison with conventional PDAC difficult.

MCN ■ MCNs are cystic neoplasms of the pancreas containing mucin-producing epithelium, which do not communicate visibly with the pancreatic ductal system. They can

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28 Chapter 3

(a)

(b) Figure 3.3 Radiographic classification of IPMN. (a) Main-duct IPMN. (b) Side branch IPMN.

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Molecular Pathogenesis 29

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contain the same spectrum of dysplasia as seen with IPMN, but they have distinct clinical and radiological features.15 MCN occurs almost exclusively in postmenopausal females, predominantly in the body and tail of the pancreas. They frequently contain ovarian-type stroma and can appear morphologically very similar to MCNs of the liver, ovary, and retroperitoneum.16 Treatment is surgical resection, with the prognosis dependent on the presence and depth of invasion of invasive cancer. Completely resected MCNs without dysplasia are generally considered cured.

■ References 1. 2. 3.

4. 5.

6. 7. 8. 9.

10.

Hezel A, Kimmelman A, Stanger B, et al. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2006;20:1218–1249. Koorstra J-B, Feldmann G, Habbe N, et al. Morphogenesis of pancreatic cancer: role of pancreatic intraepithelial neoplasia (PanINs). Langenbecks Arch Surg. 2008;393:561–570. Hruban RHMD, Takaori KMDP, Klimstra DSMD, et al. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol. 2004 Aug;28(8):977–987. Ghaneh P, Costello E, Neoptolemos J: Biology and management of pancreatic cancer. Gut. 2007;56:1134–1152. Lüttges J, Reinecke-Lüthge A, Möllmann B, et al. Duct changes and K-RAS mutations in the disease-free pancreas: analysis of type, age relation and spatial distribution. Virchows Archiv. 1999;435:461–468. Hruban RH, Goggins M, Parsons J, et al. Progression model for pancreatic cancer. Clin Cancer Res. 2000;6:2969–2972. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801–1806. Klöppel G, Solicia E, Longnecker D. Histological Classification of Tumors of the Exocrine Pancreas. 2nd ed. New York: Springer Verlag; 1996. Fritz S, Castillo C, Mino-Kenudson M, et al. Global genomic analysis of intraductal papillary mucinous neoplasms of the pancreas reveals significant molecular differences compared to ductal adenocarcinoma. Ann Surg. 2009;249:440–447. Furukawa T, Kloppel G, Adsay NV, et al. Classification of types of intraductal papillary-mucinous neoplasm

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30 Chapter 3

11. 12.

13.

14. 15. 16.

of the pancreas: a consensus study. Virchows Archiv. 2005;447:794–799. Allen P. The management of intraductal papillary mucinous neoplasms of the pancreas. Surg Oncol Clin N Am. (Online) 2010;19:297–310. D’Angelica M, Brennan M, Suriawinata A, et al. Intraductal papillary mucinous neoplasms of the pancreas: an analysis of clinicopathologic features and outcome. Ann Surg. 2004;239:400–408. Brugge W, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology. 2004;126:1330–1336. White R, D’Angelica M, Katabi N, et al. Fate of the remnant pancreas after resection of noninvasive intraductal papillary mucinous neoplasm. J Am Coll Surg. 2007;204:987–993. Adsay NV. Cystic neoplasia of the pancreas: pathology and biology. J Gastrointest Surg. 2008;12:401–404. Zamboni G, Scarpa A, Bogina G, et al. Mucinous cystic tumors of the pancreas: clinicopathological features, prognosis, and relationship to other mucinous cystic tumors. Am J Surg Path. 1999;23:410–422.

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C H A P T E R

4

Localized Disease ■ Localized Disease Definition of Resectability ■ Localized resectable pancreatic adenocarcinoma is represented by AJCC stage IA to IIB disease (see Chapter 2). Patients with unequivocally resectable disease are those with no evidence of tumor extension to the superior mesenteric vein (SMV) and portal vein (PV) and clear fat planes around the celiac axis (CA), the hepatic artery (HA), and the superior mesenteric artery (SMA), in the absence of distant metastases.1 ■ Tumors located in the head of the pancreas are resected by pancreaticoduodenectomy, usually with pylorus preservation, while tumors of the body and tail of the pancreas are managed by distal pancreatectomy. Rarely, tumors in the neck or proximal body of the pancreas will be removed by a central pancreatectomy. ■ Survival following pancreatic resection for localized disease remains poor, with median survival postsurgical resection for stage IA to IIB disease being approximately 17–22 months. Along with nodal status, the strongest predictor of outcome postresection is the ability to achieve an R0 resection. A large review of the National Cancer Database confirmed the positive association between survival and negative margins, and also demonstrated that patients operated on in high-volume tertiary referral centers were more likely to undergo an R0 resection.2 ■ Standard Whipple pancreaticoduodenectomy involves resection of the gallbladder, lower common bile duct, pancreatic head, duodenum with or without the distal stomach, lymph nodes associated with the lower bile duct, pylorus, and the anterior and posterior surfaces of 31

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the pancreatic head. This operation was originally described as a two-stage operation performed over two days by Kausch and Whipple in the early twentieth century.3 Although historically it carried an extremely high rate of morbidity and mortality, in tertiary referral centers performing high volumes the associated mortality is now 0.7–3%, with morbidity 36–41%.4 Of note in patients with operable disease presenting with jaundice, preoperative biliary drainage has been shown to be associated with increased morbidity and mortality postoperatively and is not recommended in the absence of acute cholangitis or severe symptomatic jaundice.5

Extended Pancreatectomy ■ Given the poor long-term outcome following resection of localized pancreatic adenocarcinoma, several attempts at modification of the standard Whipple resection have been made. Extended pancreatectomy describes standard pancreatectomy with any of the following: extended lymphadenectomy, resection of adjacent vessels, retroperitoneal structures, or organs.4 This includes total pancreatectomy, extended lymph node resection, and vascular resection. The evidence for and recommendations regarding each of these interventions are discussed below. Pylorus Preservation Preservation of the pylorus is standard procedure for pancreaticoduodenectomy, as it has been shown to result in no difference in overall survival, postoperative morbidity, and mortality, compared to resection of the distal stomach. Gastric resection is reserved for tumors infiltrating the stomach or with lymphadenopathy along the gastric curvature.6

■

Extended Lymph Node Dissection (ELND) ■ Standard lymph node dissection for pancreaticoduodenectomy involves removal of regional lymph nodes at the duodenum and pancreas, including nodes at the right

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Localized Disease 33

side of the hepatico-duodenal ligament, the right side of the SMA, and the anterior and posterior pancreaticoduodenal lymph nodes. ELND refers to any more extensive lymph node dissection beyond a standard dissection. Several prospective studies showed no benefit in terms of outcomes from ELND; one prospective randomized Italian study indicated a survival benefit for node-positive patients only, but this conclusion was based on an unplanned subgroup analysis. A subsequent large metaanalysis concluded that the procedure made no impact on survival but was associated with increased morbidity.7 For these reasons, ELND is not recommended as part of standard resection for pancreatic head carcinoma. Total Pancreatectomy ■ The rationale for consideration of total pancreatectomy for invasive pancreatic cancer is based on a not infrequent observation of multicentric disease, along with the potential to eliminate postoperative leakage at the pancreatic anastomosis, the ability to perform more extensive lymph node dissection, and the elimination of margin positivity at the pancreatic resection margin.4 ■ The associated risks, however, include the development of diabetes mellitus, which can sometimes be difficult to control with frequent episodes of hypoglycemia, the requirement for splenectomy, and frequent postoperative complications of marginal ulceration at the gastro-jejunal anastomosis due to lack of bicarbonate secreted by the pancreas. There is also an increased incidence of hepatic steatosis. ■ There are no prospective data evaluating total pancreatectomy for routine management of ductal adenocarcinoma; however, several retrospective series failed to demonstrate a survival benefit to the procedure and in fact demonstrated reduced survival post–total pancreatectomy.6 Based on observed increased morbidity and mortality associated with the procedure, it is not routinely recommended for management of pancreatic carcinoma, even in

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34 Chapter 4 the setting of a positive distal pancreatic resection margin, as there is no evidence for improved outcomes and known increased risk of postoperative complications.8 Total pancreatectomies are occasionally undertaken in the setting of prevention for the rare patient having a high likelihood of an invasive malignancy or an extensive main-duct intraductal papillary mucinous neoplasm (IPMN). Portal/Mesenteric Vascular Resection ■ Resection of the portal vein (PV)/superior mesenteric vein (SMV) or SMV-PV confluence due to inflammatory adhesions or tumor invading the vessels is occasionally performed in order to obtain an R0 surgical resection. No prospective studies have evaluated outcomes of PV or SMV resection for pancreatic cancer; however, several retrospective series showed no significant increase in morbidity or mortality associated with the procedure. ■ Resection of the portal or mesenteric vein invaded by tumor, however, has not been shown to improve survival; this is likely due to the underlying tumor biology, as once a tumor has involved adjacent vasculature, it is likely to have already developed micrometastatic or radiographically occult disease.9 In a minority of cases, PV or SMV resection may be performed to achieve negative margins due to tumor location and is a reasonable consideration in this setting as it carries no increased risk of morbidity. Arterial Resection ■ Resection of the superior mesenteric artery (SMA), celiac artery (CA), or hepatic artery (HA) is rarely performed, as postoperative survival of patients with arterial involvement of tumor has been shown to be similar to that of unresected patients.10 The procedure is associated with a high incidence of margin positivity and significant increased mortality. Patients with arterial involvement of tumor at diagnosis are highly likely to have micrometastatic disease, with prognosis determined by the rapidity of development of systemic disease rather than the extent of surgical resection.

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Borderline Resectable Disease ■ Over recent years, in parallel with improved preoperative staging using multidetector CT (MDCT) and endoscopic ultrasound (EUS), it has become apparent that a subset of patients exists who do not fit easily into the definition of unequivocally resectable disease, yet similarly cannot be said to have absolutely unresectable disease. These patients have a high rate of margin positivity with surgical resection, even with extended surgical techniques as defined above. ■ The NCCN defined this group as borderline resectable, based on criteria depending on the location of the tumor and extent of involvement of adjacent structures11 (see Table 4.1). ■ MD Anderson reported their experience using a modified version of these criteria, including short-segment occlusion of the HA, or of the SMV/PV or SMV-PV Table 4.1

NCCN Criteria Defining Borderline Resectable Disease11

Borderline Resectable Disease Venous involvement of the SMV/portal vein demonstrating tumor abutment with or without impingement and narrowing of the lumen Encasement of the SMV/portal vein but without encasement of the nearby arteries, or short segment venous occlusion resulting from either tumor thrombus or encasement but with suitable vessel proximal and distal to the area of vessel involvement, allowing for safe resection and reconstruction Gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or direct abutment of the hepatic artery, without extension to the celiac axis Tumor abutment of the SMA ⬍ 180 degrees of the circumference of the vessel wall Source: NCCN Pancreatic Adenocarcinoma Panel recognize the work of the experts and adapt their criteria to define resectability status. Callery M, Chang K, Fishman EK, et al. Pretreatment Assessment of Resectable and Borderline Resectable Pancreatic Cancer: Expert Consensus Statement. Ann Surg Oncol 2009;16:1727–1733.

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confluence, if amenable to resection and reconstruction. They also included tumors with less than 180-degree abutment of the SMA.12 Given that it has been well established that margin positivity is a strong predictor for outcome post–pancreatic resection, and that patients with more extensive local spread of tumor have a high likelihood of either radiographically occult metastases or micrometastatic disease, there is a strong rationale for the use of preoperative therapy in these borderline patients. Given the high morbidity associated with pancreatic resection, preoperative selection of the subset of patients with more favorable tumor biology most likely to benefit from surgery is an attractive concept. The group at MD Anderson published an experience with 160 patients with borderline resectable disease as defined by their own criteria, treated with chemotherapy, chemoradiation, or a combination of both. Patients without evidence of progressive disease on therapy and of adequate performance status proceeded to surgical resection.12 Seventy-eight percent of patients completed therapy, and 41% proceeded to surgical resection. Median survival was 40 months for patients who underwent surgery and 13 months for those who did not undergo surgery. Negative margins were achieved in 94% of patients who underwent surgery. The entire cohort included 76 patients who were deemed unresectable based on a radiological suspicion of metastatic disease or reduced performance status. Thirty-eight percent of patients deemed borderline resectable on anatomical criteria alone proceeded to surgical resection. This subgroup of patients is only now being clearly recognized and reported as a separate entity, and so the management of borderline resectable pancreatic cancer remains an evolving field without prospective data to guide management decisions. There is a growing consensus overall, however, that neoadjuvant treatment is the most appropriate option for this group of patients. Further prospective data are needed to clarify the optimal sequencing or combination of chemotherapy and radiation therapy.

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■ Adjuvant Therapy for Localized Disease ■

Adjuvant chemotherapy with gemcitabine or 5-fluorouracil has been shown in several large randomized phase III clinical trials to significantly improve disease-free and overall survival post–surgical resection of pancreatic adenocarcinoma. The role and value of adjuvant chemoradiation, however, has been more difficult to discern from randomized clinical trials to date. Although it is still frequently used as standard adjuvant therapy in the United States, in Europe there has been a recent shift toward the use of adjuvant systemic therapy alone. Several ongoing large clinical trials are prospectively evaluating the potential benefit to the addition of radiation to adjuvant chemotherapy and will guide further recommendations over the coming years.

■ Adjuvant Chemotherapy: Randomized Trials ■

■

ESPAC-1 was a randomized phase III trial with a complicated randomization to one of four arms post–surgical resection: observation, 5-FU chemotherapy alone, 5-FU– based chemoradiation, and 5-FU–based chemoradiation followed by systemic 5-FU alone.13 Two hundred eightynine patients were randomized to this 2 x 2 factorial design; 147 patients received chemotherapy, either alone or with chemoradiation, while 142 patients did not receive chemotherapy (observation or chemoradiation alone arms). A significant survival benefit was seen in patients who received chemotherapy compared to those who did not (median survival 20.1 vs. 15.5 months, p ⫽ 0.09). One hundred forty-five patients received chemoradiation, either alone or with chemotherapy; the survival for this group of patients was significantly lower compared to the 144 patients treated with observation or chemotherapy alone (15.9 months vs. 17.9 months, p ⫽ 0.05). The investigators concluded that adjuvant chemotherapy prolonged median survival, while chemoradiation was associated with worse clinical outcome. The RTOG 9704 trial was a randomized phase III trial that assessed the addition of gemcitabine or 5-FU

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chemotherapy for 1 month prior to and 4 months poststandard 5-FU–based chemoradiation.14 Four hundred fifty-one patients were randomized; median overall survival for all patients was nonstatistically different in the gemcitabine and 5-FU arms (18.8 vs. 16.9 months, p ⫽ 0.34). When patients with pancreatic head tumors were evaluated separately, however, a significant overall survival benefit to the addition of gemcitabine compared to 5-FU was seen (20 vs. 16.9 months, p ⫽ 0.09). The activity seen with gemcitabine in metastatic disease led to further evaluation as adjuvant therapy, the CONKO-001 trial, reported on 368 patients with earlystage resected pancreatic adenocarcinoma randomized in a straightforward trial design to observation or gemcitabine adjuvant chemotherapy.15 A significant improvement in disease-free survival was seen with the use of adjuvant gemcitabine (13.4 vs. 6.9 months, p ⬍ 0.001), and subsequently a significant overall survival benefit in the treatment arm was confirmed (22.8 vs. 20.2 months, p ⫽ 0.05).16 This survival benefit was demonstrated even though most patients in the observation arm received gemcitabine at time of relapse, indicating a definite benefit to adjuvant systemic therapy. Most recently, results of the ESPAC-3 trial, a randomized trial comparing adjuvant gemcitabine to 5-FU chemotherapy, were presented.17 One thousand eighty-eight patients were randomized to treatment with either postoperative gemcitabine or 5-FU for 6 months. Initially the trial also contained an observation arm; however, accrual to this arm was halted following results of the ESPAC-1 trial as described above. Median survival was equivalent in both arms, 23.0 vs. 23.6 months for the 5-FU and gemcitabine arms, respectively. However, better compliance and dose intensity in the gemcitabine arm along with less observed toxicity compared to 5-FU means that most clinicians favor gemcitabine as the treatment of choice in the postoperative setting. The demonstration of a modest survival benefit to the addition of either capecitabine or erlotinib to gemcitabine

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for treatment of stage IV disease has led to the evaluation of these combination regimens as adjuvant therapy. The ESPAC-4 trial is currently recruiting in Europe, with patients randomized to 6 months of gemcitabine alone or in combination with capecitabine. CONKO-005 is also recruiting in Europe, with patients randomized to gemcitabine with or without the addition of erlotinib. The U.S. Intergroup/RTOG 0848 trial will shortly begin recruitment in the United States. This trial aims to recruit almost 1000 patients and will evaluate the benefit of the addition of erlotinib to gemcitabine. It will also address the role of adjuvant chemoradiation based on a second randomization to chemoradiation or observation. Chemoradiation will be administered following completion of adjuvant chemotherapy. (See Table 4.2.)

■ Adjuvant Chemoradiation: Randomized Trials ■

The first randomized trial to demonstrate a benefit to adjuvant chemoradiation was the GITSG trial, presented initially in 1985.18 This trial assigned patients to either observation or 5-FU–based chemoradiation postoperatively. A significant overall survival benefit was seen in the

Table 4.2

Randomized Trials of Adjuvant Chemotherapy Overall Survival (Months)

Trial

#

Regimen

RTOG 970414

451

Gemcitabine ⫹ 5-FU/RT 5-FU ⫹ 5-FU/RT

18.8 16.9

0.34*

CONKO00115

368

Gemcitabine Observation

22.8 20.2

0.05

1088

Gemcitabine 5-FU

23.6 23

NS

ESPAC-317

P-value

*Patients with pancreatic head tumors, OS 20.5 vs 16.9 months, p ⫽ 0.09 NS ⫽ Not significant

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treatment arm, with median overall survival 20 months in those receiving chemoradiation versus 11 months in patients randomized to the chemoradiation arm. Subsequently, the EORTC trial reported on 218 patients randomized to adjuvant treatment with 5-FU–based chemoradiation versus observation alone; median survival in the treatment group was 21.6 versus 19.2 months in the observation group; however, the difference was not statistically significant.19 The ESPAC-1 trial, as discussed above, suggested a negative impact on survival with the use of adjuvant chemoradiation post–surgical resection, although it is worth noting that in this trial patients randomized to chemoradiation plus chemotherapy were administered chemoradiation first, and many patients in the chemoradiation arm did not complete RT as planned. Overall, clinical trials to date evaluating adjuvant chemoradiation postresection of pancreatic adenocarcinoma have been limited by a lack of consensus regarding standard treatment, different eligibility criteria, differing rates of R0 resection between trials, and lack of statistical power. Further randomized trials are needed to adequately assess the value of adjuvant chemoradiation for pancreatic adenocarcinoma. (See Table 4.3.)

■ Neoadjuvant Therapy for Resectable Disease ■

■

Despite the use of adjuvant chemotherapy, survival post–surgical resection for pancreatic adenocarcinoma remains poor, with a high incidence of systemic relapse even following an R0, node-negative resection. There is a compelling rationale for the use of preoperative therapy, even in the setting of unequivocally operable disease; potential benefits include earlier systemic treatment of micrometastatic disease and better tolerance of therapy in the preoperative setting than post–major pancreatic resection, where it is estimated that up to 25% of patients never receive adjuvant therapy. There is also a theoretical possibility that down-staging of the primary tumor may increase the rate of R0 resections.

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Localized Disease Table 4.3

Trial GITSG

18

Randomized Trials of Adjuvant Chemoradiation Overall Survival (months) P-value

#

Treatment

N ⫽ 43

Observation 5-FU/RT_5-FU

11 20

0.035

EORTC19

219

5-FU chemoradiation Observation

21.6 19.2

NS

ESPAC-113

289

5-FU 5-FU/RT_5-FU 5-FU/RT Observation

}20.1 }15.5

0.09

■

■

41

Both the nodal yield and positive lymph node number have been reduced following preoperative chemoradiation. Most importantly, preoperative therapy may be used to select out patients who have occult distant metastases or aggressive tumor biology and so are unlikely to benefit from surgical intervention. Several single-arm institutional phase II studies have evaluated the use of neoadjuvant therapy for resectable disease; the majority of these trials incorporated preoperative chemoradiation, with early trials mainly using 5-FU and most recently published studies using gemcitabine as radiosensitizer. The percentage of patients proceeding to surgical resection ranges from 38% to 85%, with median survival ranging from 12 to 36 months; however, several of these trials included patients with borderline unresectable disease.20 One of the largest single-arm phase II trials of neoadjuvant therapy for stage I–II disease was reported by Evans et al.21 Eighty-six patients were enrolled, all of whom had unequivocally resectable disease on cross-sectional imaging. All patients received 7 weeks of gemcitabine 400 mg/m2, with EBRT 30Gy in 10 fractions. Seventy-four percent of patients were inoperable following completion of neoadjuvant therapy, either due to disease progression found intraoperatively or on post-therapy CT or

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due to a decline in performance status. Median survival in patients who proceeded to surgical resection was 34 months, compared to 7 months for unresected patients. From the same institution, Varadachary et al. reported on 90 patients with early-stage disease treated with neoadjuvant chemoradiation as described above, but with the addition of four cycles of gemcitabine and cisplatin administered prechemoradiation and only 4 weeks of gemcitabine administered with chemoradiation.22 Sixty-six percent of patients who completed all preoperative therapy proceeded to surgical resection; median survival in this group was 31 months, compared to 10.5 months in unresected patients. Comparing overall survival in the resected group from both trials, the authors concluded that the additional cycles of chemotherapy did not improve clinical outcomes compared to chemoradiation alone. Very few investigators have assessed the value of chemotherapy alone in the neoadjuvant setting. Heinrich et al. reported on 28 patients with resectable pancreatic adenocarcinoma treated with four cycles of neoadjuvant cisplatin/gemcitabine, with the primary objective being to assess for toxicity and histologic response.23 Twentyfour patients proceeded to surgical resection; histologic response was seen in 54% of resected specimens. No increase in surgical morbidity or mortality was seen. There are currently no randomized data evaluating the use of neoadjuvant therapy for pancreatic adenocarcinoma. The feasibility and safety of neoadjuvant chemotherapy or chemoradiation has been confirmed in phase II trials from academic centers. There is a compelling biologic rationale for this approach; however, neoadjuvant therapy remains experimental, except perhaps in the group of borderline resectable patients, and is the subject of ongoing and planned randomized trials.

■ Summary and Recommendations ■

Adjuvant gemcitabine chemotherapy administered over six months has been shown to significantly improve both overall and disease-free survival following resection of

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■

pancreatic adenocarcinoma and is an established standard of care. Bolus 5-FU is a reasonable alternative given equivalent efficacy demonstrated in the ESPAC-3 trial, although it may carry an increased risk of toxicity. The use of adjuvant combination regimens including capecitabine or erlotinib are currently the subject of several ongoing randomized phase III clinical trials (ESPAC-4, CONKO-005, RTOG 0848). (See Table 4.4.) Neoadjuvant chemotherapy and chemoradiation for unequivocally resectable disease is an attractive concept but remains an experimental approach and is currently under evaluation in several trials. The role of adjuvant chemoradiation remains unclear. An overall survival benefit to the addition of chemoradiation has not been supported by the weight of available data, although improved local control has been consistently

Table 4.4

Ongoing Randomized Trials of Adjuvant Therapy Planned Accrual Regimen

Primary Endpoint

Trial

Phase

ESPAC-4

III

1080

gem/ capecitabine vs. gem

Overall survival

CONKO-005

III

436

gem/erlotinib vs. gem

Relapsefree survival

JSPAC

III

360

gem vs. S1

Overall survival

RTOG 8048

III

952

gem/erlotinib vs. gem +/chemoradiation

Overall survival

ACOSOG Z05041

II Singlearm

90

Neoadjuvant gem/erlotinib

Overall survival (2-year)

*gem = gemcitabine

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44 Chapter 4 observed. A rational approach is to reserve the use of chemoradiation for patients who do not develop progressive disease on adjuvant systemic therapy, thus selecting patients with more favorable tumor biology who are most likely to benefit from loco-regional disease control. This specific concept is being evaluated in RTOG 0848.

■ References 1.

2. 3. 4. 5.

6. 7.

8. 9.

10. 11.

Callery M, Chang K, Fishman E, Talamonti M, Traverso LW, Linehan D. Pretreatment assessment of resectable and borderline resectable pancreatic cancer: expert consensus statement. Ann Surg Oncol. 2009;16(7):1727–1733. Bilimoria K, Talamonti M, Sener S, et al. Effect of hospital volume on margin status after pancreaticoduodenectomy for cancer. J Am Coll Surg. 2008;207(4):510–519. Whipple AO, Parsons WB, Mullins CR. Treatment of carcinoma of the ampulla of Vater. Ann Surg. 1935;102(4): 763–779. Reddy S, Tyler D, Pappas T, Clary B. Extended resection for pancreatic adenocarcinoma. Oncologist. 2007;12(6):654–663. Povoski SP, Karpeh MSJ, Conlon KC, Blumgart LH, Brennan MF. Association of preoperative biliary drainage with postoperative outcome following pancreaticoduodenectomy. Ann Surgery. 1999;230(2):131. Michalski C, Weitz J, Bchler M. Surgery insight: surgical management of pancreatic cancer. Nat Clin Pract Oncol. 2007;4(9):526–535. Michalski C, Kleeff J, Wente M, Diener M, Buchler M, Friess H. Systematic review and meta-analysis of standard and extended lymphadenectomy in pancreaticoduodenectomy for pancreatic cancer. Br J Surg. 2007;94(3):265–273. Karpoff HM, Klimstra DS, Brennan MF, Conlon KC. Results of total pancreatectomy for adenocarcinoma of the pancreas. Arch Surg. 2001;136(1):44–47. Siriwardana H, Siriwardena A. Systematic review of outcome of synchronous portal-superior mesenteric vein resection during pancreatectomy for cancer. Br J Surg. 2006; 93(6):662–673. Nakao A, Takeda S, Inoue S, et al. Indications and techniques of extended resection for pancreatic cancer. World J Surg. 2006;30(6):976–982. Reproduced with permission from The NCCN 1.2010 Pancreatic Adenocarcinoma Clinical Practice Guidelines in Oncology. © National Comprehensive Cancer Network,

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12. 13.

14.

15.

16.

17.

18. 19.

20.

2010. Available at: http://www.nccn.org. Accessed 06/09/ 2010. To view the most recent and complete version of the guidelines, go online to www.nccn.org. NCCN Pancreatic Adenocarcinoma Panel recognize the work of the experts and adapt their criteria to define resectability status. Callery M, Chang K, Fishman EK, et al. Pretreatment Assessment of Resectable and Borderline Resectable Pancreatic Cancer: Expert Consensus Statement. Ann Surg Oncol. 2009;16: 1727–1733. Katz MHG, Pisters PWT, Evans D, et al. Borderline resectable pancreatic cancer: the importance of this emerging stage of disease. J Am Coll Surg. 2008;206(5):833–846. Neoptolemos J, Stocken D, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350(12): 1200–1210. Regine W, Winter K, Abrams R, et al. Fluorouracil vs. gemcitabine chemotherapy before and after fluorouracilbased chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008;299(9):1019–1026. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs. observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297(3):267–277. Neuhaus P, Riess H, Post S, et al. CONKO-001: Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer (PC). J Clin Oncol (Meeting Abstracts). 2008;26(15-suppl):LBA4504–. Neoptolemos J, Buchler M, Stocken DD, et al. ESPAC3(v2): A multicenter, international, open-label, randomized, controlled phase III trial of adjuvant 5-fluorouracil/folinic acid (5-FU/FA) versus gemcitabine (GEM) in patients with resected pancreatic ductal adenocarcinoma. J Clin Oncol (Meeting Abstracts). 2009;27(18S):LBA4505–. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg. 1985;120(8):899–903. Smeenk H, van Eijck CHJ, Hop W, et al. Long-term survival and metastatic pattern of pancreatic and periampullary cancer after adjuvant chemoradiation or observation: longterm results of EORTC trial 40891. Ann Surg. 2007;246(5): 734–740. Abbott D, Baker M, Talamonti M. Neoadjuvant therapy for pancreatic cancer: a current review. J Surg Oncol. 2010;101(4):315–320.

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46 Chapter 4 21.

22.

23.

Evans D, Varadhachary G, Crane C, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clinical Oncol. 2008;26(21):3496–3502. Varadhachary G, Wolff R, Crane C, et al. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clinical Oncol. 2008;26(21):3487–3495. Heinrich S, Schfer M, Weber A, et al. Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer without increasing morbidity: results of a prospective phase II trial. Ann Surg. 2008;248(6): 1014–1022.

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C H A P T E R

5

Locally Advanced Disease ■ Background ■

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Locally advanced pancreatic cancer (LAPC) is deemed to be surgically unresectable disease due to local tumor extension, in the absence of distant metastases. The National Comprehensive Cancer Network (NCCN) criteria defining unresectable disease are outlined in Figure 5.1.1 Note that in this chapter we refer to LAPC as being unequivocally unresectable disease, as opposed to borderline resectable disease, management of which is discussed elsewhere. Unresectable disease includes patients with > 180-degree encasement of the superior mesenteric artery, abutment or encasement of the celiac axis, unreconstructable superior mesenteric vein or portal vein occlusion, and invasion or encasement of the aorta (see Figure 5.2). Patients with nodal metastases beyond the field of surgical resection or distant metastases are considered to have AJCC stage IV disease.2 In the TNM staging of pancreatic cancer, T4 disease corresponds to unresectable locally advanced stage, representing AJCC stage III disease. It is estimated that about 20–30% of patients with pancreatic adenocarcinoma present with locally advanced disease.3 Treatment goals in this setting are generally considered noncurative, with the median survival for patients remaining less than one year, although there are anecdotal long-term responders treated with nonoperative managment. SEER data report an 8.7% 5-year survival in this subgroup; however, it is likely that this figure includes a significant number of borderline resectable cases. The role of radiation for locally advanced pancreatic adenocarcinoma has proven difficult to define, mainly due 47

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48 Chapter 5 Criteria Defining Unresectable Disease ⬎180 degrees SMA encasement Celiac abutment/encasement Unreconstructible SMV/portal occlusion Aortic invasion/encasement Nodal metastases beyond the field of resection Distant metastases Figure 5.1 Definition of locally advanced pancreas adenocarcinoma. Source: Adapted from NCCN Guidelines.1 NCCN Pancreatic Adenocarcinoma Panel recognize the work of the experts and adapt their criteria to define resectability status. Callery M, Chang K, Fishman EK, et al. Pretreatment Assessment of Resectable and Borderline Resectable Pancreatic Cancer: Expert Consensus Statement. Ann Surg Oncol. 2009;16:1727–1733.

Figure 5.2 Locally advanced PDAC.

to a high incidence of systemic failure from radiographically occult or micrometastatic disease at presentation. Shoup et al. reported a series of 100 patients with locally advanced disease on cross-sectional imaging but no evidence of metastases, all of whom underwent staging

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Locally Advanced Disease 49

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laparoscopy. Laparoscopy identified metastatic disease in 37% of patients, which was not seen on preoperative imaging.4 Recently published results from the Rapid Autopsy Series at Johns Hopkins reported on autopsy findings of 76 patients with pancreatic cancer who had succumbed to their disease.5 Thirty percent of these patients died with locally destructive pancreatic cancer, while 70% died with widespread metastases, contrary to widespread belief that most patients die due to an unacceptable burden of metastases. Evaluation of DPC4 (Deleted in Pancreas Cancer -4) immunolabeling patterns demonstrated loss of DPC4 expression in only 22% of locally advanced tumors with no distant metastases, compared with a 75% rate of loss in patients with an extensive metastatic burden. This suggests that the genetic status of a pancreatic carcinoma may predict widespread systemic failure and implies that advanced pancreatic cancer may encompass several distinct molecular subtypes associated with clinically distinct patterns of spread. Although many trials of systemic therapy have enrolled patients with both locally advanced and metastatic disease, there is now a move toward designing specific trials to evaluate optimal stage-specific therapy.

■ Use of Radiosensitizers for Chemoradiation ■

■

5-fluorouracil (5-FU) remains the most commonly used radiosensitizer used in combination with radiotherapy for pancreatic cancer and is the reference agent used in all early trials of chemoradiation. More recently, newer agents gemcitabine, capecitabine, and paclitaxel have been used with comparable efficacy. Saif et al. combined capecitabine at increasing doses to 1000 mg/m2 bid with external beam radiation (EBRT) and reported a median survival of 14 months with acceptable toxicity.6 Early trials of gemcitabine in combination with EBRT had unacceptable levels of grade 3 and 4

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gastrointestinal and hematological toxicity at initial doses tested;7 however, subsequent trials using lower dose biweekly gemcitabine reported comparable outcomes to 5-FU–based chemoradiation with an acceptable toxicity profile.8 Weekly paclitaxel has also been evaluated in combination with EBRT and was found to be comparable in outcomes to gemcitabine or 5-FU–based therapy with acceptable toxicity.9

■ Chemoradiation Versus Best Supportive Care ■

A small randomized trial compared 5-FU–based chemoradiotherapy with best supportive care and demonstrated a significant survival benefit with doubling of median overall survival (p ⬍ 0.01), as would be expected from previously published data of nonrandomized chemoradiation trials.10

■ Chemoradiation Versus Radiation Alone ■

■

■

Two randomized phase III trials and a large retrospective review have evaluated chemoradiation compared to radiation alone11-13 (Table 5.1). The GITSG study group published a randomized phase III trial in 1979 comparing two doses of EBRT (40 Gy vs. 60 Gy) in combination with 5-FU to EBRT alone. There was a significant survival benefit for chemoradiation compared to radiation alone, regardless of the dose of radiation.11 In 2003 a large retrospective review by Kryzanowska et al. looked at 1696 patients treated with chemoradiotherapy (5-FU based) compared to those treated with chemotherapy alone, radiation alone, or best supportive care.13 Those treated with 5-FU–based chemoradiation had an improvement in median overall survival compared to chemotherapy or radiation alone. However, a phase III trial published in 2005 randomized 114 patients to EBRT alone versus chemoradiation with 5-FU and mitomycin C.12 While there was a trend toward increased survival in the chemoradiation arm, it

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Retrospective

Phase III

Phase III

Trial Type

Chemo/RT RT alone Chemotherapy alone No treatment

RT alone (59.4 Gy) RT (59.4 Gy) & 5-FU/ Mitomycin C

RT alone (60 Gy) 5-FU/RT (40 Gy) 5-FU/RT (60 Gy)

Regimen

10.8 6.7 6.2 3.5

7.1 8.4

4.6 8.3 9.2

Median Survival (months)

*p value for each arm compared to RT alone. No significant difference between two chemo/RT arms ⫹ NR ⫽ Not reported

Kryzanowska 200313

1696

114

Cohen 200512

GITSG

106

Number

Trials of Radiation versus Chemoradiotherapy (5-FU)

197911

Trial

Table 5.1

NR⫹

0.16

⬍ .02* ⬍ .01

p-value

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52 Chapter 5 did not reach statistical significance (8.4 vs. 7.1 months, p ⫽ 0.16).

■ Chemoradiation Versus Chemotherapy Alone ■

■

■

Several trials have evaluated chemotherapy alone compared to chemoradiation; most of these were small trials involving less than 100 patients. Three trials published in the 1980s compared 5-FU–based chemoradiation to varying chemotherapy alone arms including methyl CCNU, streptozocin, and methotrexate in combination with 5-FU.14-15 No advantage in terms of overall survival was seen with the addition of radiation to chemotherapy in any of these studies. (See Table 5.2.) In 2008, two randomized phase III trials were published and preliminarily presented comparing chemotherapy alone to chemoradiation with contrasting results.16-17 The French FFCD-SFRO trial randomized 119 patients to gemcitabine alone or cisplatin and gemcitabine in combination with high-dose radiation.16 In both arms chemotherapy was continued until disease progression. The trial was closed early by the Data and Safety Monitoring Board in view of an inferior outcome in the combined modality therapy arm. The chemoradiation therapy had a greater incidence of grade 3 and 4 toxicity compared to chemotherapy alone. There was a statistically significant improvement in survival in the gemcitabine alone arm, with median overall survival 13 months compared to 8.6 months in the chemoradiation arm (p ⫽ 0.03). The ECOG 4201 trial randomized 74 patients to gemcitabine versus chemoradiation with gemcitabine as radiosensitizer followed by gemcitabine alone.17 Again, there was a significantly higher incidence of grade 4 toxicity seen in the combined modality arm (41.2% versus 5.7%, p ⬍ 0.0001). A significant benefit in overall survival was seen with the addition of combined chemoradiotherapy (11.0 versus 9.2 months, p ⫽ 0.044). However, it is worth noting that this trial was halted early due to poor

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74

Loehrer 200817

Phase III

Phase III

Phase III

Phase III

Phase III

Type of Trial

Gem vs. RT/Gem _Gem

Gem vs. Cisplatin/ Gem/RT _Gem

SMF# vs. RT +5-FU _SMF

5-FU + Methyl CCNU vs. RT + 5-FU/Methyl CCNU

5-FU 600 mg/m weekly vs. RT & 5-FU 600 mg/m weekly

Regimen

*NS ⫽ not significant; NR ⫽ not reported #SMF ⫽ 5-Fluorouracil, streptozocin, and mitomycin

119

Chauffert 200816

43

GITSG 198826

91

30

198514

Number

Trials of Chemotherapy Versus Chemoradiotherapy

Hazel 198115

Klassen

Trial

Table 5.2

9.2 11.0

13 8.6

9.7 7.4

7.8 7.3

8.2 8.3

Median OS (months)

0.044

0.03

NR*

NS

NS*

P-value

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54 Chapter 5

■

accrual and was significantly underpowered to evaluate overall survival. A recently published meta-analysis and systematic review has evaluated the use of chemoradiation for locally advanced disease.18-19 In 2007 Sultana et al. looked at 11 trials including a total of 794 patients.18 The findings confirmed an overall survival benefit for chemoradiation over radiation alone (HR 0.69; CI 0.51–0.94). A comparison of chemoradiation followed by chemotherapy to chemotherapy alone, however, failed to demonstrate a survival benefit to the addition of chemoradiation (HR 0.79; 95% CI 0.32–1.95). Subsequently, in 2009, Huguet et al. published a systematic review of 21 studies.19 They again concluded that chemoradiation is superior in outcomes to radiation alone but also found no survival benefit for chemoradiation over chemotherapy alone.

■ Outcomes for LAPC in Systemic Chemotherapy Trials

■

■

Several large randomized phase III trials of gemcitabine alone versus a combination cytotoxic arm have included significant numbers of patients with locally advanced disease, up to 30–40% in some trials. Although the primary outcome of these studies in terms of a benefit to the combination arm for patients with advanced disease was not met, examination of the outcomes of patients with locally advanced disease gives an indication as to survival outcomes for this subgroup when treated with gemcitabine alone (Table 5.3). A phase III trial by Louvet et al. randomized 98 patients with locally advanced disease to gemcitabine or gemcitabine and oxaliplatin.20 Median survival in both arms was 10.3 months. A phase III trial of gemcitabine in combination with tipifarnib randomized 164 patients with locally advanced disease to gemcitabine alone or the combination.21 Median survival in the gemcitabine alone arm was 10.5 months, and 8.7 months in the combination arm. A smaller phase III trial of gemcitabine alone

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Locally Advanced Disease 55 Table 5.3

Trial

Outcomes for LAPC in Chemotherapy Alone Trials Number of LA Patients

Louvet 200520

Trial Type Regimen

98

Phase II

Van Cutsem 200421

164

Rocha Lima 200422

27

Median Survival (months)

Gem vs. Gem/oxali*

10.3 10.3

Phase III

Gem vs. Gem/tipifarnib

10.5 8.7

Phase III

Gem vs. Gem/ Irinotecan

11.7 9.9

*26 patients received chemo/RT post 3 months of chemo.

■

versus gemcitabine and irinotecan included 27 patients with LAPC , for which the median survival in the gemcitabine alone arm was 11.7 months.22 The survival of patients with locally advanced disease in the gemcitabine alone arms of these trials suggests that the outcomes of patients with locally advanced disease treated with chemotherapy alone are at least comparable if not superior to outcomes with chemoradiation therapy.

■ Induction Chemotherapy Followed by Chemoradiation Therapy

■

Given the multitude of small trials with conflicting results, no standard approach to the use of chemoradiation in the LAPC setting has been reached. A reasonable approach is to initiate systemic chemotherapy as first-line treatment, then to introduce chemoradiation after several months in the absence of progression of disease. This allows for the selection of patients with truly locally advanced disease and more favorable tumor biology who are at less risk of rapid systemic progression and therefore more likely to benefit from local chemoradiotherapy (Table 5.4).

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323

48

Krishnan 200724

Goldstein 200927

Phase II

Retrospective

Retrospective

Trial Type

Gem/oxaliplatin_5FU/RT Consolidation Gem/oxaliplatin

Gem-based chemo_ chemo/RT vs. Chemo/RT (Gem/5-FU or Cap)

Chemo vs Chemo_Chemo/RT*

Regimen

9.9

11.9 8.4

15 11.7

Median Overall Survival (months)

—

⬍0.01

.009

P-value

*Patients without progression assigned to chemo alone or chemo/RT post completion of initial chemotherapy at investigator discretion.

Huguet

181

Number

Trials of Chemotherapy Followed by Chemoradiotherapy

200723

Trial

Table 5.4

56 Chapter 5

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Locally Advanced Disease 57 ■

■

■

■

Two retrospective analyses have offered support for this approach. A retrospective evaluation of 181 patients with locally advanced disease treated on two GERCOR clinical trials was performed.23 In these trials, patients without progression of disease following completion of chemotherapy were assigned to continuation of chemotherapy or chemoradiation at the investigator’s discretion. Huguet et al. looked at outcomes only of patients who did not progress on 3 months of initial chemotherapy. There was a survival advantage seen in patients who proceeded to chemoradiation compared to those who continued systemic therapy alone (15 months versus 11.7 months, p ⫽ 0.009). A larger series from Krishnan et al. reported an institutional series of 323 patients who received gemcitabinebased chemotherapy followed by chemoradiation in the absence of progressive disease, or upfront chemoradiation with 5-FU or capecitabine.24 Again a survival benefit for an initial period of chemotherapy followed by chemoradiation was seen when compared to chemoradiation as first line (11.9 months versus 8.4 months, p ⬍ 0.01). A prospective phase II trial reported on 59 patients treated initially with gemcitabine and oxaliplatin for 2 months. This was followed in the absence of progression 1 month postcompletion of chemotherapy by 5-FU and low-dose oxaliplatin-based chemoradiation.25 The median overall survival of 12.2 months was encouraging; reported grade 3 and 4 toxicities were neutropenia (10.4%), thrombocytopenia (8.4%), nausea and vomiting (16.7%), and diarrhea (12.5%). The GERCOR randomized phase III trial of gemcitabine with or without erlotinib and with a second randomization to include or not to include chemoradiation is currently recruiting in Europe and will provide prospective information regarding this approach.

■ Summary and Recommendations ■

There is no single standard therapy for locally advanced pancreatic adenocarcinoma. Chemoradiation has been established as superior in outcome compared to radiation

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alone; however, outcomes achieved with systemic chemotherapy alone are comparable to those achieved with chemoradiation but often with a more acceptable toxicity profile. Management options include: • Gemcitabine or gemcitabine-based combination alone • Gemcitabine or 5-FU based chemoradiation followed by sytemic chemotherapy • Induction gemcitabine-based therapy followed by chemoradiation in patients without progression of disease on chemotherapy A clear survival benefit to the addition of chemoradiation to chemotherapy alone has not been established by the available evidence to date. Knowing that up to 20% of patients with radiologically staged LAPC will in fact have radiographically occult metastases at laparoscopy, a reasonable approach is to use induction systemic therapy to select the patients with true locally advanced disease and most likely to benefit from local chemoradiotherapy. This approach is supported by retrospective, phase II, and single-institutional data; prospective assessment from the currently recruiting GERCOR phase III trial is awaited.

■ References 1.

2. 3.

Reproduced with permission from The NCCN 1.2010 Pancreatic Adenocarcinoma Clinical Practice Guidelines in Oncology. © National Comprehensive Cancer Network, 2010. Available at: http://www.nccn.org. Accessed 06/09/2010. To view the most recent and complete version of the guidelines, go online to www.nccn.org. NCCN Pancreatic Adenocarcinoma Panel recognize the work of the experts and adapt their criteria to define resectability status. Callery M, Chang K, Fishman EK, et al. Pretreatment Assessment of Resectable and Borderline Resectable Pancreatic Cancer: Expert Consensus Statement. Ann Surg Oncol. 2009;16:1727–1733. AJCC Cancer Staging Manual, 7th edition, 2010. Horner M, Ries L, Krapcho M, et al. SEER cancer statistics review, 1975–2006. Bethesda, MD: National Cancer Institute.

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Locally Advanced Disease 59 4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

Shoup M, Winston C, Brennan M, et al. Is there a role for staging laparoscopy in patients with locally advanced, unresectable pancreatic adenocarcinoma? J Gastrointest Surg. 2004;8:1068–1071. Iacobuzio-Donahue C, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27:1806–1813. Saif MW, Eloubeidi M, Russo S, et al. Phase I study of capecitabine with concomitant radiotherapy for patients with locally advanced pancreatic cancer: expression analysis of genes related to outcome. J Clin Oncol. 2005;23: 8679–8687. Wolff RA, Evans DB, Gravel DM, et al. Phase I trial of gemcitabine combined with radiation for the treatment of locally advanced pancreatic adenocarcinoma. Clin Cancer Res. 2001;7:2246–2253. Mattiucci GC, Morganti AG, Valentini V, et al. External beam radiotherapy plus 24-hour continuous infusion of gemcitabine in unresectable pancreatic carcinoma: longterm results of a phase II study. Int J Radiat Oncol Biol Phys. In press, corrected proof. Rich T, Harris J, Abrams R, et al. Phase II study of external irradiation and weekly paclitaxel for nonmetastatic, unresectable pancreatic cancer: RTOG-98-12. Am J Clin Oncol: cancer clinical trials. 2004;27:51–56. Shinchi H, Takao S, Noma H, et al. Length and quality of survival after external-beam radiotherapy with concurrent continuous 5-fluorouracil infusion for locally unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. 2002;53:146–150. The Gastrointestinal Tumor Study Group. A multiinstitutional comparative trial of radiation therapy alone and in combination with 5-fluorouracil for locally unresectable pancreatic carcinoma. Ann Surg. 1979;189:205–208. Cohen S, Dobelbower R, Lipsitz S, et al. A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282. Internat J Radiat Oncol Biol Phys. 2005;62:1345–1350. Krzyzanowska M, Weeks J, Earle C. Treatment of locally advanced pancreatic cancer in the real world: populationbased practices and effectiveness. J Clin Oncol. 2003; 21:3409–3414. Klaassen DJ, MacIntyre JM, Catton GE, et al. Treatment of locally unresectable cancer of the stomach and pancreas: a

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15.

16.

17.

18.

19.

20.

21.

22.

23.

randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil—an Eastern Cooperative Oncology Group study. J Clin Oncol. 1985;3:373–378. Hazel JJ, Thirlwell MP, Huggins M, et al. Multi-drug chemotherapy with and without radiation for carcinoma of the stomach and pancreas: a prospective randomized trial. J Can Assoc Radiol. 1981;32:164–165. Chauffert B, Mornex F, Bonnetain F, et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000–01 FFCD/SFRO study. Ann Oncol. 2008;19: 1592–1599. Loehrer PJ, Sr, Powell ME, Cardenes HR, et al. A randomized phase III study of gemcitabine in combination with radiation therapy versus gemcitabine alone in patients with localized, unresectable pancreatic cancer: E4201. J Clin Oncol (Meeting Abstracts). 2008;26:4506–. Sultana A, Smith CT, Cunningham D, et al. Systematic review, including meta-analyses, on the management of locally advanced pancreatic cancer using radiation/combined modality therapy. Br J Cancer. 2007;96:1183–1190. Huguet F, Girard N, Guerche C, et al. Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: a qualitative systematic review. J Clin Oncol. 2009; 27:2269–2277. Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005;23:3509–3516. Van Cutsem E, van de Velde H, Karasek P, et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol. 2004;22:1430–1438. Rocha Lima CM, Green M, Rotche R, et al. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol. 2004;22:3776–3783. Huguet F, Andr T, Hammel P, et al. Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clinical Oncol. 2007;25:326–331.

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Locally Advanced Disease 61 24.

25.

26.

27.

Krishnan S, Rana V, Janjan N, et al. Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy. Cancer. 110:47–55. Moureau-Zabotto L, Phélip J-M, Afchain P, et al. Concomitant administration of weekly oxaliplatin, fluorouracil continuous infusion, and radiotherapy after 2 months of gemcitabine and oxaliplatin induction in patients with locally advanced pancreatic cancer: a Groupe Coordinateur Multidisciplinaire en Oncologie phase II study. J Clin Oncol. 2008;26:1080–1085. Gastrointestinal Tumor Study Group. Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J Natl Cancer Inst. 1988;80:751–755. Goldstein D, van Hazel G, Selva-Nayagam S, et al. GOFURTGO trial (GFG): An AGITG multicenter phase II study of fixed dose rate gemcitabine-oxaliplatin (Gem-Ox) integrated with concomitant 5FU and 3-D conformal radiotherapy (5FU-3DRT) for the treatment of locally advanced pancreatic cancer (LAPC). J Clin Oncol (Meeting Abstracts). 2009;27:4616–.

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C H A P T E R

6

Metastatic Disease ■ Metastatic Disease ■

■

■

Approximately 50% of patients with pancreatic ductal adenocarcinoma (PDAC) present with distant metastases; median survival in these patients ranges from 4 to 8 months. Randomized trials comparing systemic therapy to no treatment has provided an overall survival benefit and an improvement in quality of life. However, overall these benefits for patients are modest. Several possible mechanisms accounting for the relative resistance of pancreatic adenocarcinoma to therapy have been suggested, including increased DNA repair, alterations in apoptotic pathways, enhanced inactivation of active drug metabolites, and abnormal membrane receptor transport, along with low penetration of drugs in the tumor, possibly related to hypovascularity and a dense stromal reaction. The past decade has seen significant advances in our understanding of the molecular pathogenesis of PDAC; new generations of therapeutic agents targeting key oncogenic cellular signaling pathways are currently under evaluation both alone and in combination with cytotoxic therapy. Coupled with anticipated developments in biomarker analysis and pharmacogenomics, these novel agents offer the possibility of achieving a meaningful improvement in clinical outcomes in patients with advanced disease. Given the short median survival of patients with advanced PDAC, consideration of quality of life benefit is clinically relevant when evaluating the use of systemic therapy in this disease and is frequently included as an endpoint in randomized trials of therapy.

63

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■ Chemotherapy Versus Best Supportive Care ■

A small but consistent overall survival benefit to chemotherapy over best supportive care has been demonstrated in several meta-analyses. The most recently published report by Sultana et al. evaluated seven trials including 432 patients, treated mainly with 5-fluorouracil (5-FU)– based combination regimens.1 The calculated hazard ratio for death was 0.64 for patients who received chemotherapy compared to those who received best supportive care, confirming that patients with advanced PDAC consistently achieve a benefit from systemic therapy. This finding is consistent with two previously published metaanalyses, which also found a survival benefit from 5-FU– based chemotherapy for advanced disease.2-3

■ Single-Agent Chemotherapy ■

■

■

5-FU as single-agent treatment for advanced PDAC has demonstrated a response rate of up to 9% and median overall survival of 10–24 weeks. 4 Single-agent capecitabine has demonstrated similar activity as firstline treatment with a reported response rate of 7%; however, the authors also reported an improvement in clinical benefit based on assessment of pain scores and functional status.5 A landmark trial comparing 5-FU to gemcitabine monotherapy for first-line treatment of advanced disease demonstrated a modest but statistically significant improvement in disease-free and median survival benefit from gemcitabine, leading to FDA approval of gemcitabine for advanced PDAC in 1997.6 The median survival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU–treated patients, respectively (P ⫽ .0025). This phase III trial included clinical benefit as a primary endpoint, based on a composite assessment of pain scores, analgesic consumption measured in morphine equivalents, performance status, and weight changes. Clinical benefit was defined as an improvement in one of these scores, sustained for at least four weeks, without

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■

deterioration in any other of these parameters. A clinical benefit response was seen in 23.8% of gemcitabinetreated patients compared with 4.8% of 5-FU–treated patients (P ⫽ .0022). The other notable finding in this trial was the 1-year survival, which was 18% for gemcitabine and 2% for 5-FU–treated patients, and arguably it was the latter observation that was most compelling regarding FDA approval. Additionally, given the modest median survival improvement seen in this trial, the conclusion that quality of life was better in patients treated on the gemcitabine arm was another key factor in establishing gemcitabine as a standard of care for advanced pancreatic cancer. It remains the backbone for combination regimens of conventional cytotoxic chemotherapy and newer targeted therapies. Gemcitabine is metabolized intracellularly to an activated triphosphate form by a process that includes the saturable enzyme deoxycytidine kinase. Investigators have tried to exploit this pharmacologic property by administering the drug at a slower rate, which prevents saturation of the enzyme and maximizes intracellular triphosphate accumulation. This approach, called fixed rate infusion (FDR) gemcitabine, was evaluated initially in a phase II trial of 67 patients with metastatic pancreas cancer and suggested a promising improvement in median and one-year survival. Subsequent evaluation of 832 patients in a phase III randomized trial compared to regular gemcitabine infusion showed no improvement in response rates; a trend toward improvement in median survival was seen (6.2 vs. 4.9 months, p ⫽ 0.04); however, there was an increase in grade 3–4 thrombocytopenia and neutropenia in the FDR arm.7 Given increased risk of toxicity and no significant survival benefit, this mode of administration is hard to advocate over standard 30-minute infusion. Other single-agent cytotoxics have demonstrated limited activity in the first-line setting, including campothecins and taxanes. Published data are limited to small singlearm trials with reported response rates in single figures.

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■ Combination Chemotherapy Regimens ■

■

Multiple trials have evaluated the addition of a second chemotherapeutic agent to the gemcitabine backbone; while an increase in response rate has been consistently seen with the use of gemcitabine doublet chemotherapy regimens, a significant improvement in overall survival has been more difficult to demonstrate. (See Table 6.1.) Recently presented data indicate that three drug combinations offer a significant benefit in overall survival compared to single agent gemcitabine for a select group of patients with good performance status. Cunningham et al. recently published results of a randomized phase III trial of 530 patients treated with

Table 6.1 Selected Trials of Combination Chemotherapy for Advanced PDAC

Drug

N

RR

Median Survival (months)

Gem + Cisplatin11 Gemcitabine

53 54

26% 9%

6.9 4.6

—

Gem + Cisplatin38 Gemcitabine

96 99

—

8.3 6.0

—

Gem + Irinotecan39 Gemcitabine

180 180

16% 4%

6.3 6.4

20% 20%

Gem + Exatecan17 Gemcitabine

175 174

8% 7%

6.7 6.2

23% 21%

Gem + Pemetrexed40 Gemcitabine

283 282

15% 7%

6.2 6.3

21.4% 20%

Gem + Oxaliplatin41 Gemcitabine

157 156

26% 16%

9.0 7.1

34.7% 27.8%

Gem + Xeloda42 Gemcitabine

267 266

14% 7%

7.4 6.0

26% 19%

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1-Year Survival (%)

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■

■

gemcitabine alone or in combination with capecitabine.8 A statistically significant improvement in progressionfree survival and response rate was seen in the combination arm: RR 19.1% vs. 12.4% (p ⫽ 0.034), PFS 5.3 vs. 3.8 months (p ⫽ 0.004). The addition of capecitabine was also associated with a trend toward improvement in overall survival (HR 0.86, p ⫽ 0.08). Median survival was 6.2 vs. 7.1 months in the gemcitabine alone and combination arms, respectively. Results of this trial were pooled with data from two further randomized phase III trials of gemcitabine alone or in combination with capecitabine in a meta-analysis.9-10 A significant improvement in overall survival was seen in this analysis, HR 0.86, p ⫽ 0.02. A 4% incidence of hand-foot syndrome was seen, along with an increase in grade 3–4 neutropenia, without an increase in febrile neutropenia. There was no other clinically significant increase in toxicity. Based on this data, a combination of gemcitabine with capecitabine is a reasonable choice of first-line chemotherapy for patients with good performance status presenting with advanced disease. One question that has been raised, however, is the feasibility of administering a 21-day capecitabine dosing schedule in the U.S. population with a folate-supplemented diet. Several trials have evaluated the addition of platinumcontaining regimens to gemcitabine. A phase III trial of gemcitabine alone or in combination with cisplatin demonstrated a significant improvement in response rate (9.2% vs. 26.4%, p ⫽ .02) and in time to progression (8 weeks vs. 20 weeks, p ⫽ .048); however, no significant improvement in overall survival was seen (20 weeks vs. 30 weeks, p ⫽ .43)8,11. A further phase III trial of gemcitabine alone or in combination with oxaliplatin for advanced disease similarly reported an improvement in response rate (17.3% vs. 26.8%, p ⫽ .04) and in progression-free survival (3.7 months vs. 5.8 months, p ⫽ .04), but again this failed to translate into a statistically significant overall survival benefit (7.1 months vs. 9.0 months, p ⫽ .13).12 A subsequent meta-analysis did show

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a survival benefit to the addition of platinum compounds in selected patients;13 however, a recently reported phase III trial of 400 patients with advanced pancreatic cancer treated with gemcitabine monotherapy vs. gemcitabine and cisplatin showed no overall or progression-free survival benefit to the combination arm.14 Although it has been difficult to discern a definite survival benefit from the addition of a platinum agent to gemcitabine, the combination has consistently shown activity in advanced disease and remains a reasonable choice of therapy in young patients with good performance status. Combinations of gemcitabine with multiple other cytotoxic agents including pemetrexed,15 docetaxel,16 exatecan,17 and irinotecan18 have failed to show a significant survival benefit in advanced disease. Multidrug combinations have also been tested in advanced PDAC. The first randomized phase III trial to demonstrate an overall survival benefit to a combination chemotherapy regimen over single agent gemcitabine for treatment of metastatic pancreatic cancer was presented at the 2010 American Society of Clinical Oncology Annual Meeting.21 The PRODIGE4/ACCORD II trial randomized 342 patients with metastatic pancreatic adenocarcinoma to six months of chemotherapy with FOLFIRINOX (5FU/LV/oxaliplatin/irinotecan) or gemcitabine alone. Enrollment was limited to patients with ECOG performance status 0/1 and age less than 75 years. No prior therapy was allowed, and patients with significant elevation of bilirubin were excluded. A significant overall survival benefit was seen in the FOLFIRINOX arm, with median survival of 11.1 months vs 6.8 months in the gemcitabine arm (p⬍0.0001, HR 0.57). The 18-month survival rate in the combination arm was 18.6% compared to 6% in the gemcitabine arm. The response rate to FOLFIRINOX was 31.6%, compared to 9.4% with single agent therapy. There was also a significant prolongation in progression free survival. However, this benefit came at the cost of an increase in febrile neutropenia rates, with grade 3 or 4 febrile neutropenia rate of

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69

5.4% vs 0.6% (P⫽0.009); there was also more diarrhea, fatigue, and peripheral neuropathy with the combination regimen. The rates of toxic death, however, were equal in both arms (one patient in each). Based on this data, FOLFIRINOX is a reasonable choice of first line chemotherapy in highly selected patients who retain an excellent performance status. The high response rate makes this a promising regimen for prospective evaluation in trials of neo-adjuvant therapy. This combination will also undergo prospective evaluation in the adjuvant setting. The PGEF regimen is a combination of gemcitabine, cisplatin, 5-FU, and epirubicin, evaluated in a randomized phase III trial compared to gemcitabine monotherapy.19 Ninety-nine patients were randomized, a significant improvement in response rate in the combination arm was seen (39% vs. 9%), and the trial met its primary endpoint of an improvement in 4 months PFS. This came at the expense of increased grade 3 and 4 hematologic toxicity. The three-drug combination of gemcitabine, capecitabine, and docetaxel (GTX) has also shown encouraging response rates in both first- and second-line treatment of metastatic pancreatic cancer. The experience is currently limited to retrospective or prospective single-institution data. Prospective randomized data are awaited.20 Novel formations of taxanes have recently shown encouraging data in treatment of advanced pancreatic cancer. A phase I–II trial of nab-paclitaxel, an albumin-bound nanoparticle form of paclitaxel, was evaluated in combination with gemcitabine as first-line treatment for advanced disease. Secreted protein and rich in cysteine (SPARC), expressed on the surface of pancreatic cancer cells and on surrounding stroma, appeared to predict response to nab-paclitaxel. Median progression-free survival was 4.8 months for SPARC-negative patients vs. 6.2 months for SPARC-positive patients; median overall survival was 9 months. These findings will be further evaluated in a phase III clinical trial, which is currently ongoing.22 Other taxane derivates that have shown potential promise include Endo-Tag-1, a novel paclitaxel

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70 Chapter 6 formulation that proffers antivascular and cytotoxic impacts; it has been tested in a European randomized phase II trial by Loehr et al.23 Preliminary results indicate potential for gemcitabine combined with EndoTag-1; the combination is poised to commence phase III testing in advanced pancreas cancer.

■ Targeted Therapies ■

■

Novel agents have attempted to target key oncogenic signaling pathways involved in tumor growth with as yet limited success; however, this approach holds promise for future developments building on an increasingly sophisticated understanding of tumor biology. The epidermal growth factor receptor (EGFR) is a member of the HER2 family of receptor tyrosine kinases. Mutations within or overexpression of EGFR may result in oncogenic deregulation of protein synthesis, cell apoptosis, angiogenesis, and metabolism.24 Erlotinib, a smallmolecule tyrosine kinase inhibitor directed against the intracellular portion of the EGFR receptor, was approved by the FDA in November 2005 for treatment of locally advanced, unresectable, or metastatic pancreatic carcinoma following publication of the NCIC CTG PA.3 trial. This was a double-blind, placebo-controlled, phase III trial of erlotinib plus gemcitabine in 569 patients with locally advanced or metastatic pancreatic adenocarcinoma. Overall survival was significantly longer in the erlotinib and gemcitabine arm versus the placebo and gemcitabine arm with median survival 6.24 months versus 5.91 months and 1-year survival rates of 23% and 17%, respectively (P ⫽ .023). Progression-free survival was also significantly longer in the erlotinib and gemcitabine arm than the placebo and gemcitabine arm with an estimated HR of 0.77. Despite the improvement in survival, there was no significant difference in response rate between the two arms. The combination arm was well tolerated, although there was an increased incidence of interstitial lung disease–like syndrome in the gemcitabine erlotinib

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■

■

■

arm of 2.4%, somewhat higher than has been reported in previous trials of gem/erlotinib. This trial also reported a positive association between severity of rash and overall survival.25 A phase II trial of erlotinib in combination with gemcitabine and capecitabine in patients with recurrent or metastatic pancreatic cancer was presented at the American Society of Clinical Oncology (ASCO) 2009 annual meeting. The combination was well tolerated and showed promising efficacy, with PFS of 6.5 months, overall survival 12.0 months, and response rate 32.6%. While EGFR expression was associated with reduced PFS and OS, presence of K-RAS mutation had no impact on either outcome.26 Other EGFR and HER-2 targeted therapies including the antibodies cetuximab, trastuzumab, and the smallmolecule tyrosine kinase inhibitor lapatinib have failed to demonstrate a benefit in phase II or III randomized trials. Despite preclinical data demonstrating expression of vascular endothelial growth factor (VEGF) in PDAC, trials of antivascular agents have produced disappointing results to date. A randomized phase III trial by the CALGB group of gemcitabine alone or in combination with the anti-VEGF antibody bevacizumab failed to show a benefit from the addition of bevacizumab;27 similarly disappointing results were reported from several phase II trials evaluating bevacizumab in combination with gemcitabine and oxaliplatin.28-29 Similarly, despite encouraging phase II data, a phase III trial of the antiangiogenic agent axitinib, a dual inhibitor of PDGF and VEGF, was recently discontinued due to lack of efficacy.30 Several novel compounds including inhibitors of Poly ADP-Ribose polymerase 1 (PARP) and insulin-like growth factor receptor 1 (IGFR-1) and the hedgehog pathway, along with novel therapeutic vaccines, have shown promising results in preclinical and phase I trials in advanced PDAC and are currently undergoing prospective evaluation in advanced PDAC. (See Table 6.2 and Chapter 9.)

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72 Chapter 6 Table 6.2

Key Therapeutic Targets and Related Drugs in Development in PDAC

Target

Class of Drug

Drug

EGFR

Antibody to EGFR Tyrosine kinase inhibitor

Cetuximab43-45 Trastuzumab46-47 Erlotinib25,48 Lapatinib49-50

IGFR-1

Antibody to IGFR-1 Tyrosine kinase inhibitor

AMG-47951 PQIP52

RAS

Farnesyl transferase inhibitor Oncolytic viral therapy

Tipifarnib53 Reovirus54

mTOR

mTOR inhibitor

Everolimus55 Temsirolimus56

Hedgehog proteins

Small-molecule inhibitor of hedgehog signaling

GDC-044957

Matrix Metalloproteinases

MMP inhibitor

Marimastat58-59 Talabostat60

Src

Src/bcr-abl inhibitor

Dasatinib61 AZD 053062

STAT

STAT 3 inhibitor

RTA-40263

TRAIL

Antibody to Dr4, DR5

Mapatumumab64 AMG 65565

VEGF

Anti-VEGF antibody

Bevacizumab27,66

Integrin

IgG antibody to _5_1 integrin

Volociximab67

PDGFR

Tyrosine kinase inhibitor

Imatinib68-69 Masitinib70-71 Sorafenib72

COX-2

COX-2 inhibitor

Celecoxib73-74

PARP

PARP inhibitor

AZD228175 ABT-08876 BSI-20177

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■ Second-Line Chemotherapy ■

■

■

■

There is currently no standard of care for second-line therapy for patients with progression of disease following gemcitabine-based chemotherapy. Although a significant number of patients with progressive disease are not candidates for further therapy due to an associated decline in performance status and disease-related complications, there remains a substantial group of patients who remain candidates for second and subsequent lines of therapy. Several factors have been shown to predict survival postprogression of disease on gemcitabine chemotherapy, most significantly performance status and time to progression on first-line therapy.31 One small study evaluated second-line chemotherapy versus best supportive care; however, only 46 of a planned 165 patients were enrolled and the study closed early due to poor accrual.32 Patients were randomized following progression on first-line gemcitabine to best supportive care or oxaliplatin/5-FU chemotherapy (OFF regimen). Median survival was doubled in the chemotherapy arm (21 vs. 10 weeks, p ⫽ 0.0077). Limited conclusions can be drawn from this small incomplete trial; however, it is clear that there are a number of patients who retain a good performance status despite initial progression of disease and who derive a significant benefit from secondline therapy. Few agents have been prospectively evaluated in randomized phase III trials of second-line therapy for PDAC. Rubitecan is an oral topoisomerase I inhibitor, which was evaluated in a randomized phase III trial of 409 patients, all of whom had progressed on first-line chemotherapy. Patients were randomized to the rubitecan single-agent or physician’s choice of best available therapy or supportive care.33 Median PFS was greater for the rubitecan arm; however, there was no difference in median survival (108 vs. 94 days, p ⫽ 0.626). Further experience with second-line therapy for pancreatic cancer is limited to small single-arm phase II trials or retrospective studies conducted in populations of highly

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74 Chapter 6

■

■

■

■

selected patients, making cross comparison between trials difficult. Several agents have been evaluated as monotherapy in the second-line setting, including paclitaxel, the oral fluoropyrimidine, S1, and capecitabine, thymidate synthase inhibitors (e.g., raltitrexed, pemetrexed, and irinotecan). Overall survival ranged from 3.6 to 7.1 months, with response rates reported between 5–15%; however, none of these trials enrolled more than 60 patients.31 Combination chemotherapy has demonstrated more encouraging results in the second-line setting. Oxaliplatin and 5-FU combination chemotherapy administered as a FOLFOX or OFF regimen has been shown to be superior to best supportive care and also to 5-FU/LV alone.34 Median overall survival has ranged from 4 to 10 months, with response rates of up to 23% reported.35 This combination has also been shown to be well tolerated in patients with good performance status. Irinotecan in combination with 5-FU (FOLFIRI regimen) has demonstrated similar activity to FOLFOX in the second-line setting, with a randomized trial of 60 patients reporting median overall survival of four months in both arms.36 Gemcitabine in combination with oxaliplatin was evaluated in a phase II trial of 33 patients with advanced PDAC who had progressed on first-line gemcitabine; response rate was 22% with median overall survival of 6 months.37 Although there is a lack of level I evidence currently supporting the use of second-line therapy for pancreatic cancer, the experience to date strongly suggests that combination chemotherapy in patients with good performance status is well tolerated and results in significant clinical benefit for a selected subgroup of patients. Reasonable choices include 5-FU or gemcitabine in combination with oxaliplatin or irinotecan; prognostic factors including performance status, baseline ca 19.9 levels, and time to progression on first-line chemotherapy may help guide management decisions in the second-line setting. (See Table 6.3.)

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Metastatic Disease Table 6.3

75

Selected Trials of Second-Line Chemotherapy for Advanced PDAC Median Survival (months)

Phase

Number Enrolled

Response Rate

Rubitecan vs. Investigator choice33

III

409

—

3.5 3.1

Gem/Oxali37

II

33

22%

6.0

5-FU/LV/oxali35

II

30

23%

6.0

FOLFOX vs FOLFIRI36

II

60

—

4.0 4.0

CPT11/oxali78

II

30

10%

5.9

CAPOX79

II

41

2%

5.3

Pemetrexed80

II

52

4%

4.6

Ralitrexed vs. raltitrexed/ CPT1181

II

38

0 16%

4.3 6.5

Drug

■ References 1. 2. 3.

4.

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previously untreated metastatic/recurrent pancreatic cancer: Combined analysis with translational research. Presented at the ASCO Annual Meeting, 2009. Kindler HL, Niedzwiecki D, Hollis D, et al. A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): a preliminary analysis of Cancer and Leukemia Group B (CALGB). J Clin Oncol (Meeting Abstracts). 2007;25:4508–. Kim GP, Oberg AL, Foster NR, et al. Phase II trial of bevacizumab, gemcitabine, oxaliplatin in patients with metastatic pancreatic adenocarcinoma. J Clin Oncol (Meeting Abstracts). 2007;25:4553–. Crane CH, Winter K, Regine WF, et al. Phase II study of bevacizumab with concurrent capecitabine and radiation followed by Maintenance Gemcitabine and Bevacizumab for Locally Advanced Pancreatic Cancer: Radiation Therapy Oncology Group RTOG 0411. J Clin Oncol. JCO.2009.21.8529, 2009. Study of gemcitabine plus AG-013736 versus gemcitabine for advanced pancreatic cancer, NCT00471146. Custodio A, Puente J, Sastre J, et al. Second-line therapy for advanced pancreatic cancer: a review of the literature and future directions. Cancer Treat Rev. 2009;35:676–684. Oettle H, Pelzer U, Stieler J, et al. Oxaliplatin/folinic acid/5-fluorouracil [24h] (OFF) plus best supportive care versus best supportive care alone (BSC) in second-line therapy of gemcitabine-refractory advanced pancreatic cancer (CONKO 003). J Clin Oncol. (Meeting Abstracts) 2005;23:4031–. Jacobs AD, Burris HA, Rivkin S, et al. A randomized phase III study of rubitecan (ORA) vs. best choice (BC) in 409 patients with refractory pancreatic cancer report from a North American multi-center study. J Clin Oncol (Meeting Abstracts). 2004;22:4013–. Pelzer U, Kubica K, Stieler J, et al. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. J Clin Oncol (Meeting Abstracts). 2008;26:4508–. Tsavaris N, Kosmas C, Skopelitis H, et al. Second-line treatment with oxaliplatin, leucovorin and 5-fluorouracil in gemcitabine-pretreated advanced pancreatic cancer: a phase II study. Invest New Drugs. 2005;23:369–375. Hwang JY, Yoo C, Kim T, et al. A randomized phase II study of FOLFOX or FOLFIRI.3 as second-line therapy in patients with advanced pancreatic cancer previously

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treated with gemcitabine-based chemotherapy. J Clin Oncol (Meeting Abstracts). 2009;27:4618–. Demols A, Peeters M, Polus M, et al. Gemcitabine and oxaliplatin (GEMOX) in gemcitabine refractory advanced pancreatic adenocarcinoma: a phase II study. Br J Cancer. 2006;94:481–485. Heinemann V, Quietzsch D, Gieseler F, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006;24:3946–3952. Rocha Lima C, Green M, Rotche R, et al. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol. 2004;22:3776–3883. Oettle H, Richards D, Ramanathan R, et al. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol. 2005;16:1639–1645. Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005;23:3509–3516. Cunningham D, Chau I, Stocken D, et al. Phase III randomised comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer. Eur J Cancer. 2005;3. Kullmann F, Hollerbach S, Dollinger MM, et al. Cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line metastatic pancreatic cancer: a multicentre phase II study. Br J Cancer. 2009;100:1032–1036. Xiong H, Rosenberg A, LoBuglio A, et al. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II trial. J Clinical Oncol. 2004;22:2610–2616. Philip PA, Benedetti J, Fenoglio-Preiser C, et al. Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study. J Clin Oncol (Meeting Abstracts). 2007;25:LBA4509–. Mihaljevic A, Buchler P, Harder J, et al. A prospective, nonrandomized phase II trial of trastuzumab and capecitabine in patients with HER2 expressing metastasized pancreatic cancer. BMC Surg. 2009;9:1.

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Safran H, Iannitti D, Ramanathan R, et al. Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Invest. 2004;22:706–712. Oh D, Lee K, Sohn C, et al. A phase II trial of erlotinib in combination with gemcitabine and capecitabine in previously untreated metastatic/recurrent pancreatic cancer: Combined analysis with translational research. J Clin Oncol (Meeting Abstracts). 2009;27:4607–. Safran H, Miner T, Resnick M, et al. Lapatinib/gemcitabine and lapatinib/gemcitabine/oxaliplatin: a phase I study for advanced pancreaticobiliary cancer. Am J Clin Oncol: cancer clinical trials. 2008;31:140–144. Safran H, Miner T, Bahary N, et al. Lapatinib and gemcitabine for metastatic pancreatic cancer: a phase II study. J Clin Oncol (Meeting Abstracts). 2009;27:e15653–. Beltran PJ, Mitchell P, Moody G, et al. Effect of AMG 479 on anti-tumor effects of gemcitabine and erlotinib against pancreatic carcinoma xenograft models. J Clin Oncol (Meeting Abstracts). 2008;26:4617–. Yendluri V. WJR, Coppola D. et al. A small molecule inhibitor of insulin-like growth factor 1 receptor (PQIP) inhibits human pancreatic cancer cell proliferation in vitro and synergizes with erlotinib. ASCO Gastrointestinal Cancers Symposium, 2008. Van Cutsem E, van de Velde H, Karasek P, et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol. 2004;22:1430–1438. Kelly K, Nawrocki S, Mita A, et al. Reovirus-based therapy for cancer. Expert Opin Biol Ther. 2009;9:817–830. Wolpin B, Hezel A, Abrams T, et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol. 2009;27:193–198. Javle MM, Xiong H, Reddy S, et al. Inhibition of mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: The results of two prospective phase II studies. J Clin Oncol (Meeting Abstracts). 2009;27:4621–. Von Hoff D, LoRusso P, Rudin C, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009;361:1164–1172. Bramhall SR, Rosemurgy A, Brown PD, et al. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol. 2001;19:3447–3455. Bramhall SR, Schulz J, Nemunaitis J, et al. A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as

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Hammel P, Mornex F, Deplanque G, et al. Oral tyrosine kinase inhibitor masitinib in combination with gemcitabine in patients with advanced pancreatic cancer: A multicenter phase II study. J Clin Oncol (Meeting Abstracts). 2009;27:4617–. Wallace JA, Locker G, Nattam S, et al. Sorafenib (S) plus gemcitabine (G) for advanced pancreatic cancer (PC): a phase II trial of the University of Chicago Phase II Consortium. J Clin Oncol (Meeting Abstracts). 2007;25: 4608–. Ferrari V, Valcamonico F, Amoroso V, et al. Gemcitabine plus celecoxib (GECO) in advanced pancreatic cancer: a phase II trial. Cancer Chemother Pharmacol. 2006;57:185–190. Pino M, Milella M, Gelibter A, et al. Capecitabine and celecoxib as second-line treatment of advanced pancreatic and biliary tract cancers. Oncology; Basel. 2009;76:254–261. Study to assess the safety & tolerability of a PARP inhibitor in combination with gemcitabine in pancreatic cancer, NCT00515866. A phase I study of ABT-888 in combination with carboplatin and paclitaxel in advanced solid malignancies (NCI 7967). NCI study number 7967. A phase 1B, open-label, dose escalation study evaluating the safety of BSI-201 in combination with chemotherapeutic regimens in subjects with advanced solid tumors (20060102). ClinicalTrials.gov Identifier: NCT00422682. Cantore M, Rabbi C, Fiorentini G, et al. Combined irinotecan and oxaliplatin in patients with advanced pre-treated pancreatic cancer. Oncology; Basel. 2004;67:93–97. Xiong H, Varadhachary G, Blais J, et al. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008;113:2046–2052. Boeck S, Weigang-Khler K, Fuchs M, et al. Second-line chemotherapy with pemetrexed after gemcitabine failure in patients with advanced pancreatic cancer: a multicenter phase II trial. Ann Oncol. 2007;18:745–751. Ulrich-Pur H, Raderer M, Kornek GV, et al. Irinotecan plus raltitrexed vs. raltitrexed alone in patients with gemcitabinepretreated advanced pancreatic adenocarcinoma. Br J Cancer. 2003;88:1180–1184.

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C H A P T E R

7

Uncommon Pancreatic Malignancies ■ Uncommon Exocrine Pancreatic Malignancies Uncommon Ductal Carcinomas ■ Ductal carcinoma is the most common malignant histology found in pancreatic neoplasms, accounting for 85% of all pancreatic cancers. Several subtypes of pancreatic ductal carcinoma exist, including signet ring carcinoma, undifferentiated or anaplastic carcinoma, adenosquamous carcinoma, and colloid carcinoma. Colloid carcinoma is thought to frequently arise from intraductal papillary mucinous neoplasms (IPMN) and carries a more favorable prognosis than regular ductal adenocarcinoma. The other subtypes, however, are associated with aggressive tumor biology and poor survival. A recently published institutional review of 38 cases of resected localized pancreatic adenosquamous carcinomas reported a median overall survival of 10.9 months; in this small series the degree of squamous differentiation did not correlate with clinical outcomes.1 See Table 7.1 for histopathology of tumors arising in the panceas. Acinar Cell Carcinoma Acinar cell carcinoma accounts for less than 1% of all pancreatic malignancies. It carries a prognosis intermediate between that of pancreatic ductal and neuroendocrine cancers; a recently published large population-based study of 672 patients reported a median survival for unresected patients of 25 months compared to 3 months for patients with adenocarcinoma.2 ■ Acinar cell carcinomas rarely present with jaundice due to infrequent involvement of the bile duct. Typical histological findings include highly cellular lobules separated ■

83

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84 Chapter 7 Table 7.1

Histopathological Description of Tumors Arising in the Pancreas

Pancreatic intraepithelial neoplasia (PANIN) Ductal adenocarcinoma Mucinous noncystic carcinoma Signet ring carcinoma Adenosquamous carcinoma Undifferentiated carcinoma (small cell/spindle cell types) Osteoclast-like giant cell tumor Serous cystadenocarcinoma Mucinous cystadenocarcinoma Intraductal papillary mucinous neoplasm (IPMN) Acinar cell carcinoma Acinar cell cystadenocarcinoma Mixed acinar-endocrine carcinoma Pancreaticoblastoma Solid pseudopapillary carcinoma Adenocarcinoid tumor Mixed islet cell and exocrine carcinoma Islet cell carcinoma Insulinoma Glucagonoma Gastrinoma Vipoma Somatostatinoma Enteroglucagonoma

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by bands of collagenized stroma, with cells containing a granular, eosinophilic cytoplasm. Cells typically stain positively for trypsin and chymotrypsin.3 An interesting clinical manifestation occurs in about 10% of acinar cell carcinoma cases; the lipase hypersecretion syndrome, characterized by the development of subcutaneous fat necrosis, polyarthralgias, and peripheral blood eosinophilia. This occurs usually in the presence of liver metastases; levels of serum lipase in patients with this condition may reflect clinical response to therapy.4 Several characteristic radiological features may be used to distinguish preoperatively between ductal and acinar carcinoma of the pancreas.5 Acinar cell carcinoma typically presents as an exophytic, hypodense mass, with enhancement at a level intermediate between adenocarcinoma and endocrine carcinoma, and is less frequently located in the pancreatic head than endocrine or ductal cancers. Other classical features include a well-defined tumor margin with enhancing capsule and internal calcifications, with central necrosis common in larger tumors (see Figure 7.1).

Figure 7.1 Acinar cell carcinoma.

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The molecular signature of acinar tumors is distinct from that of ductal pancreatic carcinomas—p53, K-RAS, and DPC4 gene alterations common to ductal adenocarcinoma (PDAC) are not found in acinar cell carcinoma, while mutations in the APC/-catenin pathway are common in acinar carcinoma but not in PDAC.6 Limited data are available regarding the optimum systemic therapy for acinar carcinoma, with experience limited to small case series and case reports. Anecdotal responses have been reported to fluoropyrimidines, cisplatin, streptozocin, doxorubicin, paclitaxel, and gemcitabine. The use of agents active in colon cancer such as irinotecan and oxaliplatin also has a reasonable biologic rationale, as mutations in the Wnt/APC pathway observed in acinar cell cancer are also frequently found in colon cancer with microsatellite instability, but not in PDAC.

Solid-Pseudopapillary Carcinoma ■ Solid-pseudopapillary carcinoma is typically a low-grade epithelial neoplasm, which differs from other malignant pancreatic neoplasms due to its occurrence mainly in young females, with the average age of diagnosis in the third decade of life.7 It accounts for 1–2% of all pancreatic neoplasms and occurs with equal frequency in all parts of the pancreas. Most tumors of this histology pursue an indolent clinical course; however, approximately 10–15% exhibit malignant and occasionally a relatively aggressive clinical behavior (see Figure 7.2). ■ The characteristic histological appearance of solidpseudopapillary carcinoma consists of sheets of uniform polygonal cells with an abundant network of capillary-sized vessels. Cells typically do not show immunohistochemical staining for ductal markers or for synaptophysin, chromogranin, trypsin, or chymotrypsin. These tumors also lack the characteristic genetic alterations found in PDAC and frequently carry a mutation in exon 3 of the B-catenin gene.7 ■ For localized disease, surgical resection is generally curative, with 95% of patients cured by surgical excision

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Figure 7.2 Hypervascular liver metastases from pancreatic neuroendocrine tumor.

alone.8 Even in the setting of locally advanced or metastatic disease, long-term survival has been reported post– extended pancreatic resection, including vessels or resection of synchronous hepatic metastases. For the small number of patients with unresectable disease, however, no standard of care exists for systemic therapy. Anecdotal responses to several cytotoxic regimens including irinotecan, cisplatin, etoposide, and gemcitabine-based combinations have been reported. Given the vascular structure of this histological subtype, a plausible biologic rationale for the use of targeted antiangiogenic agents such as sunitinib or bevacizumab exists; this hypothesis has not yet been tested in the clinical setting.

■ Giant Cell Tumors ■

Giant cell tumors (GCT) of the pancreas are rare, accounting for less than 1% of pancreatic tumors.9 They are subdivided into three groups: osteoclastic, pleomorphic, and mixed. Histologically osteoclastic GCT contains

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88 Chapter 7 osteoclast-like multinucleated cells and mononuclear cells, while pleomorphic GCT has an anaplastic appearance with multinucleated giant cells. The tumors tend to be large, with a heterogenous appearance at EUS. While the pleomorphic variant generally follows an aggressive clinical course similar to PDAC, osteoclastic GCTs are thought to carry a more favorable outcome, although given the rarity of the tumor, this has been difficult to establish with certainty.

■ Resection of Metastatic Nonpancreatic Cancers ■

As the mortality and morbidity from pancreatic resection has improved over recent decades, surgical resection of a synchronous or metachronous solitary pancreatic metastasis has become increasingly common. The most common primary tumor causing isolated pancreatic metastases is renal cell carcinoma (RCC). One retrospective review of 21 patients who underwent pancreatic resection of an isolated RCC metastasis reported a median survival of 4.8 years.10 Long-term survival has also been reported, however, for patients undergoing pancreatic resection for a variety of histologies, although the literature is limited to single-center retrospective case series.11 As expected, the underlying tumor biology plays a significant role in determining long-term outcomes postmetastasectomy; this is reflected in the poor survival reported in patients undergoing pancreatic resection for metastatic melanoma.

■ Primary Pancreatic Lymphoma ■

Primary pancreatic lymphoma is rare, accounting for less than 0.5% of all pancreatic neoplasms. It occurs more commonly in men than women, usually in the fifth or sixth decades, and most are located in the pancreatic head.12 Although clinically they frequently present with symptoms mimicking those of pancreatic adenocarcinoma, the prognosis is significantly better.13 Primary pancreatic lymphomas are classified as extranodal non-Hodgkins lymphomas

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(NHL); the majority are intermediate- to high-grade diffuse large B-cell lymphomas. Management is nonsurgical unless diagnostic histology is required, with the optimal regimen of combination chemotherapy dependent on the final histopathological subtype.

■ Primary Pancreatic Sarcomas ■

Primary sarcoma of the pancreas is extremely rare, with most sarcomatoid histology found in the pancreas arising in the setting of a poorly differentiated carcinoma with sarcomatoid differentiation. Primary pancreatic malignant mesenchymal tumors described in the literature include leiomyosarcomas, malignant peripheral nerve sheath tumors, malignant fibrous histiocytomas, liposarcomas, rhabdomyosarcomas, and hemangiopericytomas.14 The management is predominantly surgical, with margin negative resection offering the best chance of long-term survival.

■ Pancreatic Endocrine Neoplasms ■

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Pancreatic neuroendocrine tumors (PNETs) account for 1–2% of all pancreatic neoplasms, with an annual incidence in the United States of 1 per 100,000 people. Autopsy studies, however, have demonstrated the presence of a PNET in up to 1% of specimens, suggesting that the majority of PNETs go undiagnosed and are not of clinical significance. Over the last few years, an increase in incidence of PNETs has been seen, with a significant number being diagnosed as incidental findings on imaging studies performed for an unrelated indication.15 Several genetic conditions are associated with increased risk of PNET, including neurofibromatosis type 1, tuberous sclerosis, multiple endocrine neoplasia type 1, and Von Hippel Lindau disease. A wide spectrum of malignant potential is seen in PNETs, with histology ranging from well-differentiated neuroendocrine carcinomas with an indolent clinical course to poorly differentiated PNETs, which typically

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pursue an aggressive clinical course.16 Fifty to 60% of well-differentiated PNETs are associated with hormonal secretion syndromes due to systemic hypersecretion of a variety of active hormones including insulin, glucagon, vasoactive intestinal peptide, and gastrin. With the exception of insulinomas, PNETs are usually malignant. Criteria predictive of malignancy, apart from local invasion or distant metastases, include tumor size of more than 2 cm, vascular invasion, and Ki67 proliferative index of more than 2%.17 The WHO classification system for PNETs was updated in 200018 (see Table 7.2). The standard of care for localized PNETs is surgical resection, regardless of the histological grade. There are currently no data to support the use of postoperative adjuvant systemic therapy, hormonal therapy, or radiation therapy. Disease-free survival approaches 100% at 5 years for insulinomas and 40–50% for gastrinomas in experienced centers.18 Other PNETs have a higher likelihood of recurrence postoperatively. Management of metastatic disease requires consideration of several patient- and tumor-related factors including the histologic tumor grade, volume of metastases, patient performance status, and the presence or absence of disease-related symptoms. Patients who are asymptomatic may be followed expectantly, with treatment initiated only in the setting of clinical evidence of progressive disease. Systemic treatment is indicated for patients with symptoms or rapidly progressive disease. The role of hepatic resection for PNET metastases remains controversial, with a high recurrence rate within the liver postresection. Although excellent overall survival rates are reported in large surgical series, the disease-free survival remains low, likely due to the presence of multiple radiographically occult hepatic metastases at time of surgery.19 Surgical resection of the primary tumor in the presence of distant metastases is not recommended, except in rare cases where it may be required for relief of local symptoms such as gastric outlet obstruction or bleeding. Occasionally, in the case of pancreatic tail tumors, surgical

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Benign/low-grade malignant:* • Confined to pancreas •  2 cm in size •  2 mitoses/HPF •  2% Ki-67–positive cells • Vascular invasion

Benign:* • Confined to pancreas •  2 cm in size • No vascular invasion •  2 mitoses/HPF •  2% Ki-67–positive cells

*May be functional or nonfunctional.

Well-Differentiated Neuroendocrine Tumor Low-grade malignant:* • Invasion of adjacent organs and/or metastases

Well-Differentiated Neuroendocrine Carcinoma

WHO Classification of Neuroendocrine Tumors of the Pancreas

Well-Differentiated Neuroendocrine Tumor

Table 7.2

Poorly differentiated carcinoma: • High-grade malignant

Poorly Differentiated Neuroendocrine Carcinoma

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resection is indicated for relief of portal hypertension with formation of gastric varices. Liver transplantation for metastatic PNET remains experimental. Hepatic artery embolization, either bland or with chemotherapy, is based on the observation that tumors derive their blood supply predominantly from the hepatic artery, while normal hepatocytes are mainly supplied with oxygenated blood via the portal vein. The vascular nature of PNETs makes this technique an attractive approach for palliative management of large-volume hepatic metastases. The duration of response following embolization is variable; patients who achieve a satisfactory response may be candidates for a repeat procedure at the development of progressive disease. The majority of well-differentiated PNETs express the somatostatin receptor on the cell surface, which can be detected by a radiolabeled octreotide scan (Octreoscan). Tumors that are octreotide scan–positive may be treated with a long-acting depot injection of synthetic somatostatin analogue. This is particularly effective for relief of the carcinoid sydrome of flushing and diarrhea related to tumor serotonin secretion. The benefit of long-acting somatostatin analogues in asymptomatic patients remains unclear. The PROMID trial randomized 85 treatment-naïve patients with histologically confirmed locally inoperable or metastasized well-differentiated PNET to receive either long-acting octreotide 30 mg/month or placebo.20 Median time to tumor progression in the octreotide and placebo groups were 14.3 months and 6 months, respectively (HR: 0.34, P  0.000072). The indolent natural history of the disease makes assessment of an overall survival benefit difficult. Somatostatin receptor expression may also be exploited for treatment using radiolabeled somatostatin analogues, with several different compounds available using a variety of radionuclides. Most recently, tumor response rates of up to 30% have been reported with the use of octreotide labeled with 177Lu, a  and -particle emitter.21 Kwekkeboom et al. reported on 504 patients with

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gastropancreatic neuroendocrine tumors treated with this compound, 54% of whom had received prior somatostatin analogue therapy and 17% of whom had received prior chemotherapy. Median time to progression was 40 months, with overall survival from time of treatment of 46 months; this survival compares favorably with historical controls. Serious adverse events including liver failure and myelodysplasia occurred in 1% of patients. Radiolabeled octreotide is available for treatment at several centers in Europe but is not yet licensed for use in the United States. Chemotherapy has demonstrated more efficacy in the treatment of PNET than in carcinoid tumors. Combination regimens using 5-FU, streptozocin, and doxorubicin demonstrated response rates of up to 39% in a recent retrospective analysis, with an early randomized trial of streptozocin in combination with either 5-FU or doxorubin reporting response rates of 45% and 69%, respectively.22 These trials were felt to overestimate the true activity of combination regimens, however, due to use of nonstandard tumor response criteria. More recently, the oral combination of temozolomide and capecitabine has shown promising results in two retrospective series, with response rates of 59% to 71%.23 High-grade, poorly differentiated tumors behave similarly to small-cell carcinoma of the lung and frequently respond to a platinum doublet with etoposide or irinotecan. Newer targeted therapies have shown promising results in early clinical trials. The oral multitargeted tyrosine kinase inhibitor sunitinib was evaluated in a phase III randomized trial of 170 patients with progressive disease on somatostatin analogue, randomly assigned to sunitinib 37.5 mg daily or placebo. The trial was stopped early when an interim analysis found that progression-free survival in the sunitinib arm was 11.1 months, compared to 5.5 months in the placebo arm (p  0.001).24 A prospective phase III trial is currently evaluating sunitinib compared to placebo to validate these findings. Mammalian target of rapamycin (mTOR) inhibitors temsirolimus and

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94 Chapter 7 everolimus have also shown encouraging results in early clinical trials. Yao et al. reported on 30 patients with PNET treated with a combination of somatostatin analogue and everolimus, demonstrating a response rate of 27%.25 This combination is currently being investigated in RADIANT 3, a randomized phase III trial of everolimus and long-acting octreotide compared to octreotide alone.

■ References 1.

2.

3. 4. 5.

6.

7. 8. 9.

10.

Voong KR, Davison J, Pawlik T, et al. Resected pancreatic adenosquamous carcinoma: clinicopathologic review and evaluation of adjuvant chemotherapy and radiation in 38 patients. Hum Pathol. 2010;41:113–122. Wisnoski N, Townsend C, Nealon W, et al. 672 patients with acinar cell carcinoma of the pancreas: a populationbased comparison to pancreatic adenocarcinoma. Surgery. 2008;144:141–148. Klimstra DS: Nonductal neoplasms of the pancreas. Mod Pathol. 2000;20:S94–S112. Klimstra DS, Adsay NV. Acinar cell carcinoma of the pancreas: a case associated with the lipase hypersecretion syndrome. Pathology Case Reviews. 2001;6:121–126. Seth A, Argani P, Campbell K, et al. Acinar cell carcinoma of the pancreas: an institutional series of resected patients and review of the current literature. J Gastrointest Surg. 2008;12:1061–1067. Abraham S, Wu T-T, Hruban R, et al. Genetic and immunohistochemical analysis of pancreatic acinar cell carcinoma: frequent allelic loss on chromosome 11p and alterations in the APC/beta-catenin pathway. Am J Pathol. 2002;160:953–962. Reddy S, Wolfgang CL: Solid pseudopapillary neoplasms of the pancreas. Adv Surg. 2009;43:269–282. Papavramidis T, Papavramidis S: Solid pseudopapillary tumors of the pancreas: review of 718 patients reported in English literature. J Am Coll Surg. 2005;200:965–972. Moore J, Hilden K, Bentz J, et al. Osteoclastic and pleomorphic giant cell tumors of the pancreas diagnosed via EUS-guided FNA: unique clinical, endoscopic, and pathologic findings in a series of 5 patients. Gastrointest Endosc. 2009;69:162–166. Reddy S, Edil B, Cameron J, et al. Pancreatic resection of isolated metastases from nonpancreatic primary cancers. Ann Surg Oncol. 2008;15:3199–3206.

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16. 17.

18. 19. 20.

21.

22.

23.

24.

Hiotis S, Klimstra D, Conlon K, et al. Results after pancreatic resection for metastatic lesions. Ann SurgOncol. 2002;9:675–679. Mortenson M, Katz MHG, Tamm E, et al. Current diagnosis and management of unusual pancreatic tumors. Am J Surg. 2008;196:100–113. Nayer H, Weir EG, Sheth S, et al. Primary pancreatic lymphomas. Cancer Cytopathol. 2004;102:315–321. Nesi G, Pantalone D, Ragionieri I, et al. Primary leiomyosarcoma of the pancreas: a case report and review of literature. Arch Pathol Lab Med. 2001;125:152–155. Yao J, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clinical Oncol. 2008;26:3063–3072. Chan J, Kulke M. Progress in the treatment of neuroendocrine tumors. Curr Oncol Rep. 2009;11:193–199. Klöppel G, Anlauf M. Epidemiology, tumour biology and histopathological classification of neuroendocrine tumours of the gastrointestinal tract. Best Pract Res Clin Gastroenterol. 2005;19:507–517. Kloppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci. 2004;1014:13–27. Sarmiento J, Que F. Hepatic surgery for metastases from neuroendocrine tumors. Surg Oncol Clin N Am. 2003;12:231–242. Rinke A, Muller H-H, Schade-Brittinger C, et al. Placebocontrolled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID study group. J Clin Oncol. 2009;27:4656–4663. Kwekkeboom D, de Herder W, Kam B, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26:2124–2130. Moertel CG, Lefkopoulo M, Lipsitz S, et al. Streptozocindoxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992;326:519–523. Strosberg JR, Choi J, Gardner N, et al. First-line treatment of metastatic pancreatic endocrine carcinomas with capecitabine and temozolomide. J Clin Oncol (Meeting Abstracts). 2008;26:4612–. Raymond E, Niccoli-Sire P, Bang Y, et al. Updated results of the phase III trial of sunitinib (SU) versus placebo (PBO)

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for treatment of advanced pancreatic neuroendocrine tumors (NET). Abstract No.127, American Society of Clinical Oncology, Gastrointestinal Cancer Symposium 2010. Yao J, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010;28:69–76.

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C H A P T E R

8

Supportive Care ■ Supportive Care ■

The majority of patients with pancreatic adenocarcinoma (PDAC) have advanced disease at diagnosis. Appropriate management of local symptoms related to the primary tumor, systemic symptoms due to distant metastases, and psychosocial issues associated with the diagnosis are crucial to enable patients to maintain quality of life and functional status (see Figure 8.1).

Biliary Obstruction ■ Jaundice is a common presenting symptom of pancreatic head tumors, frequently causing pruritus, fat malabsorption, and poor appetite and contributing to GI upset and weight loss. In patients who undergo exploratory laparotomy and are deemed to have unresectable disease, a surgical biliary bypass is a reasonable option for palliation of current or future risk of biliary obstruction; this involves the creation of an anastomosis between the common bile duct and the duodenum or jejunum to bypass the obstruction. The majority of patients, however, are managed with endoscopic biliary stent insertion by endoscopic retrograde cholangiopancreatography (ERCP). In a small number of patients, endoscopic biliary stent insertion is not feasible and percutaneous transhepatic cholangiopancreatography (PTC) and internal/external biliary drain placement or primary wallstenting is required. ERCP is preferable to PTC if feasible due to lower risk of procedure-related complications and higher success rate.1 ■ Either plastic or self-expanding metal wallstents may be used; plastic stents usually remain patent for 3–4 months 97

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98 Chapter 8 Analgesia Nutritional support Endocrine and exocrine pancreatic insufficiency Biliary and gastric outlet obstruction Psychological distress Venous thromboembolism Figure 8.1 Key elements to consider in supportive care of the patient with pancreatic cancer.

compared to 10–12 months for metal wallstents. Metal stents are therefore preferable for longer term palliation of jaundice, or in patients with operable disease undergoing neoadjuvant therapy, but may not be easily removed. Although traditionally metal stents have been considered to make surgical resection more challenging, most experienced surgeons are now comfortable proceeding to surgical intervention with a metal biliary stent in place. Gastric Outlet Obstruction ■ Gastric outlet obstruction, more correctly named duodenal obstruction, occurs in up to 20% of patients with pancreatic cancer due to local tumor extension to involve the duodenum. Traditionally this was managed by surgical bypass with a gastrojejunostomy, but more recently advances in endoscopic and interventional radiologic techniques have made duodenal wallstent placement a safe and effective management option. Duodenal stent insertion results in relief from obstructive symptoms in 79–91% of patients, with patients able to resume oral intake almost immediately postprocedure.2 ■ Complications of duodenal stenting include stent obstruction, malposition, perforation, aspiration, and bleeding, with later risks of stent migration and fistula formation. Overall, however, the procedure is generally well tolerated and leads to relief of symptoms in the majority of patients. The placement of a duodenal stent limits access to the biliary tree endoscopically; given that patients

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with duodenal obstruction also frequently develop biliary obstruction, consideration should be given to biliary stent insertion prior to duodenal stent insertion so as to avoid the need for PTC. Endoscopic intervention for relief of obstructive symptoms related to pancreatic head tumors has been shown to result in durable control of duodenal and biliary obstruction. A series of 100 patients with unresectable pancreatic head tumors found that biliary or duodenal stent insertion was required in 81% and 25% of patients, with procedural success rates of 91% and 96%, respectively.3 The majority of patients did not require a repeat procedure if a metallic stent was used.

Surgical Palliation for Advanced Disease ■ In patients found to have unresectable disease at exploratory laparotomy, the surgeon may elect to perform a palliative biliary and gastric bypass to prevent the development of future obstructive complications. Increasingly sophisticated endoscopic techniques have brought into question the value of palliative surgery in patients with advanced disease; endoscopic intervention has not been prospectively compared to surgical palliation in this setting. A retrospective series evaluated 83 patients found at laparotomy to have unresectable adenocarcinoma of the pancreatic head, all of whom underwent concomitant biliary and gastric bypass.4 Only 1 patient required subsequent transhepatic stenting for recurrent biliary obstruction, while 4.8% went on to develop gastric outlet obstruction, suggesting that surgical palliation does provide durable and effective palliation of local obstructive symptoms. ■ More recently, laparoscopic staging is increasingly used preoperatively to avoid laparotomy in unresectable patients with PDAC. Analysis of 155 patients found to have unresectable disease at laparoscopy found that only 2% of patients subsequently required a palliative operative intervention. This suggests that the majority of patients are successfully managed endoscopically, leaving little

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100 Chapter 8 justification for performing surgical palliation in this patient population.5 Venous Thromboembolism ■ The association between gastrointestinal cancers and venous thromboembolism (VTE) was first described by Trousseau in 1865; it has since become apparent that PDAC is particularly associated with a high risk of thrombotic complications. The development of thrombotic complications in patients with PDAC has been associated with reduced survival.6-7 This finding is not solely explained by death from thromboembolic causes, suggesting that the development of VTE reflects more aggressive tumor biology with a rapidly progressive clinical course. ■ Several underlying biologic mechanisms are thought to contribute to the development of VTE, including increased production of prothrombotic factors, direct and indirect activation of coagulation, and increased platelet aggregation.8 ■ Several trials have evaluated the use of low molecular weight heparin (LMWH) in patients with advanced PDAC. The CONKO-004 trial randomized 540 patients with locally advanced or metastatic PDAC, none of whom had a prior history of VTE, to receive palliative chemotherapy with gemcitabine or gemcitabine and cisplatin depending on performance status, with or without the addition of LMWH at therapeutic dose.9 The use of enoxaparin was found to significantly reduce the incidence of thrombotic events without increased frequency of major bleeding complications; there was no significant difference in overall survival or time to progression. Interim results from the FRAGEM trial were presented in 2007. This trial randomized patients with advanced pancreatic cancer to gemcitabine alone or in combination with therapeutic dalteparin.10 Early results following interim analysis on the first 51 patients recruited showed no increase in bleeding complications with the use of LMWH; no occurrence of VTE

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was seen in the LMWH group compared to a 33% incidence in the chemotherapy-alone group. Final results are awaited. A nonrandomized trial of patients with advanced PDAC compared outcomes in 69 patients treated with gemcitabine, cisplatin, and prophylactic LMWH to patients treated with the same chemotherapy regimen alone. An improvement in median survival was reported, although limited conclusions can be drawn from this small nonrandomized trial.11 The role of routine anticoagulation in patients with advanced PDAC remains controversial; pending results from the FRAGEM trial may help to further define the role of LMWH in this high-risk group of patients. Given the high incidence of VTE in patients with PDAC, a high index of suspicion for thrombotic complications should be maintained when assessing patients clinically. In patients with advanced disease and established VTE, anticoagulation should be continued indefinitely in the absence of treatment-related complications, and consideration should be given to inferior vena cava (IVC) filter insertion with involvement of a coagulation specialist for patients who experience recurrent thromboembolic episodes despite therapeutic anticoagulation.

Pain Control ■ Patients with advanced PDAC typically develop epigastric and back pain related to infiltration of the celiac nerve plexus and the anterior capsule of the pancreas; back pain as a presenting symptom frequently heralds unresectable disease with tumor infiltration of the celiac nerve plexus. Some patients experience a postprandial pain syndrome in association with dilatation of the pancreatic duct, which may respond to endoscopic stent placement. Moderate to severe pain is reported in approximately one-third of patients at time of diagnosis of pancreatic cancer; the presence of uncontrolled pain has been shown to correlate with increased incidence of depression and with reduced quality of life and functional

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status.12 Both systemic and local approaches may be used for optimization of pain control. The WHO analgesic ladder provides guidance on the use of analgesia in a stepwise fashion from nonsteroidal antiinflammatory drugs (NSAIDS) to opioids (see Figure 8.2). Opioid use should include a long-acting regular formulation with an as-needed short-acting opioid at a dose of approximately 15% of the total daily opioid dose. Regular use of laxatives and stool softeners during opioid use is important to avoid discomfort and obstructive symptoms related to constipation. While oral analgesia remains a mainstay of pain management, transdermal preparations of stronger opioids such as fentanyl can provide an effective method of pain management. This mode of administration allows for continuous controlled delivery of drug, avoids the need for absorption of drug from the gastrointestinal tract, and reduces tablet burden. By avoiding the peaks and troughs of systemic concentration associated with oral opioids it also results in less frequent complications including constipation and drowsiness. Some patients may require rotation of opioids; ideally patients with significant cancer-related pain should be managed in conjunction with a pain management specialist.

Strong opioid ⫹Ⲑ⫺ non-opioid ⫹Ⲑ⫺ Adjuvant Persistent pain Weak opioid ⫹Ⲑ⫺non-opioid ⫹Ⲑ⫺ Adjuvant

Persistent pain Non-opiod ⫹Ⲑ⫺ Adjuvant Figure 8.2 WHO analgesic ladder.

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A proportion of patients have persistent back pain related to tumor infiltration of the celiac nerve plexus, which contains both afferent and efferent sympathetic and parasympathetic fibers that supply the upper abdominal viscera including the pancreas gland. Given its location directly below the diaphragm and around the origin of the celiac artery, the celiac plexus is frequently involved by malignant pancreatic tumors. Several local techniques have been developed for relief of celiac plexus–mediated pain; regardless of the approach, all techniques involve the injection of local anesthetic to the celiac trunk, followed by injection of a neurolytic agent such as alcohol.13 The nerve plexus may be accessed at surgery, under CT or ultrasound guidance, and more recently under endoscopic ultrasound (EUS) guidance. In patients found to be unresectable at laparotomy or laparoscopy, celiac plexus block (CPB) may be performed by the surgeon, sometimes in combination with a gastric and biliary bypass procedure. The majority of patients, however, undergo CPB under fluoroscopic, radiologic, or endoscopic guidance. No one approach has been shown to be superior as yet and further randomized trials are planned. EUS is used with increasing frequency in the staging and histological diagnosis of pancreatic cancer. Celiac axis blockade may be added to the procedure without significant increase in morbidity or mortality to the patient.13 A metaanalysis of CPB performed in 1145 patients for relief of cancer pain reported a significant improvement in symptoms in 89% of patients, with 90% of these achieving a response lasting longer than 3 months.14 Complications associated with the procedure were mild and usually transient, including local pain (96%), diarrhea (44%), and hypotension (38%).

Nutritional Support ■ Approximately three-quarters of patients with pancreatic cancer have weight loss at presentation.15 Apart from cachexia associated with the underlying malignancy, several issues faced by pancreatic cancer patients can

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further compound weight loss, including uncontrolled diabetes mellitus due to endocrine pancreatic insufficiency, fat malabsorption related to exocrine pancreatic insufficiency, and duodenal obstruction. The use of appetite stimulants including megestrol acetate or oral corticosteroids can be helpful in maintaining oral intake, although the increased risk of VTE associated with progestational agents is especially relevant in the pancreatic cancer population. More recently, the synthetic tetrahydrocannabinol, dronabinol, has been licensed for use as an appetite stimulant; it has the added benefit of also relieving nausea. A significant number of patients with pancreatic cancer will develop exocrine insufficiency, commonly occurring due to a lesion at the head of the pancreas causing distal gland atrophy, or postpartial or total pancreatic resection. Patients generally complain of steatorrhea, with oily stools, abdominal cramping, and excess gas production. Several formulations of synthetic pancreatic enzyme supplementation are commercially available; the dose should be titrated liberally upward until adequate relief of symptoms is obtained. Patients may also benefit from the use of standard nutritional supplements to increase calorie intake and prevent further weight loss.

Psychological Factors ■ Patients with advanced pancreatic cancer have been shown to have a greater incidence of depressive symptoms and psychological distress when compared to patients with other advanced cancers. A study of 304 patients with advanced pancreatic cancer found that 28.8% reported depression as measured by the Brief Symptom Inventory (BSI) score, compared to 18.5% of patients with other cancer diagnoses.16 Scores for anxiety, somatization, and general distress were also significantly higher among pancreatic cancer patients. The relationship between pancreatic cancer and depression has not yet been fully elucidated, with one hypothesis suggesting that proinflammatory cytokine release may be a physiological cause of

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depression. Contributing factors also include persistent fatigue or poorly controlled pain, along with the obvious psychological impact of receiving a diagnosis of incurable malignancy. Given the significant effect of psychosocial stressors on patient quality of life and well-being, early identification and intervention to support affected patients is of paramount importance. A low threshold for initiation of pharmacologic antidepressant therapy, along with early referral for supportive counseling and practical social support services can help to avoid the development of psychological distress.

■ References 1. 2. 3.

4. 5.

6. 7. 8. 9.

Stern N, Sturgess R. Endoscopic therapy in the management of malignant biliary obstruction. Eur J Surg Oncol. 2008;34:313–317. Gaidos JKJ, Draganov P. Treatment of malignant gastric outlet obstruction with endoscopically placed self-expandable metal stents. World J Gastroenterol. 2009;15:4365–4371. Maire F, Hammel P, Ponsot P, et al. Long-term outcome of biliary and duodenal stents in palliative treatment of patients with unresectable adenocarcinoma of the head of pancreas. Am J Gastroenterol. 2006;101:735–742. Lesurtel M, Dehni N, Tiret E, et al. Palliative surgery for unresectable pancreatic and periampullary cancer: a reappraisal. J Gastrointest Surg. 2006;10:286–291. Espat NJ, Brennan MF, Conlon KC: Patients with laparoscopically staged unresectable pancreatic adenocarcinoma do not require subsequent surgical biliary or gastric bypass. J Am Coll Surg. 1999;188:649–655. Chew HK, Wun T, Harvey D, et al. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med. 2006;166:458–464. Mandalà M, Reni M, Cascinu S, et al. Venous thromboembolism predicts poor prognosis in irresectable pancreatic cancer patients. Ann Oncol. 2007;18:1660–1665. Sohail M, Saif M. Role of anticoagulation in the management of pancreatic cancer. JOP. 2009;10:82–87. Riess H, Pelzer U et al. A prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy: Final results of the CONKO-004 trial. J Clin Oncol 28:7s, 2010 (suppl; abstr 4033).

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106 Chapter 8 10.

11.

12. 13. 14. 15. 16.

Maraveyas A, Holmes M, Lofts F, et al. Chemoanticoagulation versus chemotherapy in advanced pancreatic cancer (APC): Results of the interim analysis of the FRAGEM trial. J Clin Oncol (Meeting Abstracts). 2007;25:4583–. Icli F, Akbulut H, Utkan G, et al. Low molecular weight heparin (LMWH) increases the efficacy of cisplatinum plus gemcitabine combination in advanced pancreatic cancer. J Surgical Oncol. 2007;95:507–512. Kelsen DP, Portenoy RK, Thaler HT, et al. Pain and depression in patients with newly diagnosed pancreas cancer. J Clin Oncol. 1995;13:748–755. Moore J, Adler D. Celiac plexus neurolysis for pain relief in pancreatic cancer. J Support Oncol. 2009;7:83–87, 90. Eisenberg E, Carr DB, Chalmers TC. Neurolytic celiac plexus block for treatment of cancer pain: a meta-analysis. Anesth Analg. 1995;80:290–295. Cancer of the Pancreas Task Force. Staging of cancer of the pancreas. Cancer. 1981;47:1631–1639. Clark KL, Loscalzo M, Trask PC, et al. Psychological distress in patients with pancreatic cancer—an understudied group. Psycho-Oncology. 2010; DOI: 10.1002/pon.1697.

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C H A P T E R

9

Future Directions ■ Future Directions ■

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Pancreatic adenocarcinoma remains a challenging malignancy, but several recent advances offer hope for further incremental improvement in clinical outcomes over the coming decade. In parallel with an increasingly sophisticated understanding of the molecular pathogenesis underlying the disease, several pathways have emerged as potential targets for therapeutic intervention. Comprehensive sequencing of the genome of 24 human pancreatic cancers has yielded important information regarding the molecular signature of pancreatic adenocarcinoma. It is now clear that there is considerable heterogeneity in the genetic mutations identified between individual pancreatic tumors. However, these molecular alterations have been shown to exert their oncogenic effect via 12 common key signaling pathways involved in diffuse cellular processes, including cell cycle regulation, metabolism, genomic repair, and cell surface expression proteins.1 Directing targeted therapy at these altered pathways resulting from a wide variety of genetic mutations may be the key to successfully achieving significant clinical benefit from the multiple novel agents currently under development. It is anticipated that as genomic sequencing techniques advance and become more widely available over the coming decade, personalized cancer therapy may become a realistic prospect, offering hope for a significant improvement in the prognosis of patients with advanced pancreatic cancer. The insulin-like growth factor receptor-1 (IGFR-1) is a receptor tyrosine kinase composed of an extracellular ligand binding domain, a transmembrane portion, and an 107

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intracellular tyrosine kinase domain. Activation of the receptor initiates signaling via intracellular pathways including the Ras-Raf-MAPK and PI3K–protein kinase B (PKB) pathways, causing cell proliferation, transformation, and inhibition of apoptosis.2 In xenograft models of pancreatic cancer, blockade of IGFR-1 with the monoclonal antibody AMG-479 was shown to enhance the antitumor effect of gemcitabine and erlotinib, suggesting that blockade of IGFR-1 signaling may reverse resistance to anti-EGFR therapy.3 Similarly, a small-molecule tyrosine kinase inhibitor of the IGFR-1, PQIP, demonstrated enhanced in vitro antitumor effect when combined with erlotinib.4 Several phase I/II clinical trials are currently evaluating the use of anti-IGFR-1 therapy in combination with gemcitabine alone and erlotinib.5 A 3-arm trial of AMG-479 in combination with gemcitabine compared to gemcitabine alone or in combination with the death receptor 5 agonist conatumumab was recently presented. A modest trend toward increased PFS and 6-month overall survival was seen in both combination arms compared to gemcitabine alone.6 Poly ADP-Ribose polymerase 1 is a DNA-binding enzyme that detects single- and double-stranded breaks in DNA and initiates repair, avoiding subsequent cell death or mutation. Inhibition of this pathway has been shown to be particularly effective in cells that are deficient in the tumor suppressor proteins BRCA 1 and 2, as these cells are already unable to repair SSB and DSBs via the preferred cellular pathway.7 A recently presented phase II clinical trial reported significant activity of the oral PARP inhibitor olaparib in BRCA 1 and 2–deficient metastatic breast cancers. Phase III trials are ongoing.8 Germline mutations in the BRCA 1 and 2 genes are known to carry an increased risk of development of pancreatic cancer;9 it is possible that PARP inhibition may have a similar dramatic effect on BRCA 1, 2–associated pancreatic cancers, and possibly in pancreatic adenocarcinomas with acquired defects in BRCA 1 or 2 or with homologous repair pathway deficiencies. A phase I study

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is currently evaluating the oral PARP inhibitor AZD2281 in combination with gemcitabine as first-line therapy for metastatic pancreatic adenocarcinoma. This trial is not limited to patients with a known BRCA-related mutation and will provide some early hints as to whether this class of drugs may have activity in an unselected group of patients with advanced pancreas adenocarcinoma. Two other compounds, ABT-888 and BSI-201, are also undergoing preliminary assessment of activity in pancreas cancer for patients with pancreas cancer and known BRCArelated mutations.10-11 Encouraging preclinical data have also been reported regarding the effect of hedgehog pathway inhibition on both pancreatic ductal tumor cells and on the surrounding tumor-associated stromal tissue and vasculature; orally administered hedgehog antagonists are currently in phase I testing. This pathway has been found to be upregulated in the recently described population of cancer stem cells within pancreatic tumors. This population of cells, which retain the ability for self-renewal and differentiation, are thought to be responsible for the initiation and propagation of tumors; it is anticipated that further advances in our understanding of the biologic properties of these cells will result in the development of novel therapeutic approaches.12 Other emerging targeted therapies in development include agents directed against the TNF related apoptosis inducing ligand (TRAIL), histone deacetylase (HDAC) inhibitors. The development of more accurate genetically engineered models of pancreatic neoplasia by mouse models now more accurately reflect human PDAC than earlier xenograft models, which allows for more accurate in vivo testing of novel therapies. The development of primary patient–derived xenografts also offers potential advantages over cell line–derived models. The development and validation of accurate predictive and prognostic biomarkers for PDAC is an important area of ongoing research. Ideally, in the future, predictive biomarkers may be used to select subgroups of patients

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for treatment with a given targeted agent, heralding the era of tailored therapy. Immunotherapy is also an evolving field in treatment of PDAC. A recently completed phase II trial treated patients postresection of PDAC with escalating doses of an allogeneic vaccine transduced with a GM-CSF gene in combination with chemoradiation. Encouraging results from this led to phase II development of this strategy. As of now a decision regarding larger-scale development is awaited. The identification of patients at high risk for development of pancreatic adenocarcinoma and the role of screening for the disease is still an evolving area of research. Ongoing family registry studies at several institutions are assessing the role of screening based on family history or known genetic predisposition. The genetic alterations underlying familial pancreatic cancer have not been fully defined; hopefully the identification of specific genetic mutations responsible will result in the discovery of further potential therapeutic targets.

■ References 1. 2. 3.

4.

5.

Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801–1806. Hofmann F, Garca-Echeverra C. Blocking the insulin-like growth factor-I receptor as a strategy for targeting cancer. Drug Discov Today. 2005;10:1041–1047. Beltran PJ, Mitchell P, Moody G, et al. Effect of AMG 479 on anti-tumor effects of gemcitabine and erlotinib against pancreatic carcinoma xenograft models. J Clin Oncol (Meeting Abstracts). 2008;26:4617–. Yendluri V WJR, Coppola D, et al. A small molecule inhibitor of insulin-like growth factor 1 receptor (PQIP) inhibits human pancreatic cancer cell proliferation in vitro and synergizes with erlotinib. ASCO Gastrointestinal Cancers Symposium. 2008. Phase I/II randomized study of gemcitabine hydrochloride and erlotinib hydrochloride with versus without anti-IGF1R recombinant monoclonal antibody IMC-A12 as first-line therapy in patients with unresectable metastatic pancreatic cancer NCT00617708.

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Future Directions 111 6.

7. 8.

9. 10.

11. 12.

Kindler HL, Richards DA, et al. A placebo controlled, randomized phase II study of conatumumab or AMG 479 or placebo plus gemcitabine in patients with metastatic pancreatic cancer. J Clin Oncol. 28:7s, 2010 (suppl; abstr 4035). Rodon J, Iniesta M, Papadopoulos K. Development of PARP inhibitors in oncology. Expert Opin Investig Drugs. 2009;18:31–43. Tutt A, Robson M, Garber JE, et al. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. J Clin Oncol (Meeting Abstracts). 2009; 27:CRA501–. Greer J, Whitcomb D. Role of BRCA1 and BRCA2 mutations in pancreatic cancer. Gut. 2007;56:601–605. A phase 1B, open-label, dose escalation study evaluating the safety of BSI-201 in combination with chemotherapeutic regimens in subjects with advanced solid tumors (20060102). ClinicalTrials.gov Identifier: NCT00422682. A phase I study of ABT-888 in combination with carboplatin and paclitaxel in advanced solid malignancies ClinicalTrials. gov Identifier: NCT00535119. Simeone DM. Pancreatic cancer stem cells: implications for the treatment of pancreatic cancer. Clin Cancer Res. 2008;14:5646–5648.

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Index Note: Page numbers followed by f indicate figures; numbers followed by t indicate tables.

A ABT-888, 109 acinar cell carcinoma, 83, 85–86 ACOSOG Z05041, 43t adenocarcinoma. See pancreatic ductal adenocarcinoma adenosquamous carcinoma, 83 adjuvant chemoradiation, 39–40, 41t adjuvant chemotherapy, 37–39 adjuvant gemcitabine chemotherapy, 37–39, 41, 42–43. See also gemcitabine adjuvant therapy, 37–44 adjuvant chemoradiation: randomized trials, 39–40, 41t adjuvant chemotherapy: randomized trials, 37–39 neoadjuvant therapy for resectable disease, 40–42 summary and recommendations, 42–44 advanced disease, surgical palliation for, 99–100 age, PDAC and, 1 American Joint Committee on Cancer (AJCC), 16, 17t, 31 American Society of Clinical Oncology (ASCO), 71 American Society of Clinical Oncology Annual Meeting (2010), 68 AMG-479, 108 analgesics, 102 anaplastic carcinoma, 83

antidepressants, 105 anxiety, 104 APC/beta-catenin pathway, 86 arterial resection, 34–35 autopsies, PANIN and, 22

B back pain, 103 biliary obstruction, 97–98 body mass index (BMI), 4 borderline resectable disease, 35–36 branch-duct IPMN, 25, 26 BRCA 1, 5, 6t, 108 BRCA 2, 5, 6t, 23, 108 Brief Symptom Inventory (BSI), 104 brushings, 14 BSI-201, 109

C CALGB, 71 cancer. See locally advanced pancreatic cancer; pancreatic cancer; pancreatic ductal adenocarcinoma capecitabine, 67, 69 CAPOX, 75t CAPS 5 trial, 8 CEA levels, 27 celiac axis (CA), 31, 34 celiac plexus block (CPB), 103 cellular damage, 21

113

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114 Index Chauffert 2008 trial, 53t chemoradiation adjuvant, 39–40, 41t chemotherapy versus, 52–54 induction chemotherapy and, 55–57 radiation versus, 50–52 radiosensitizers for, 49–50 supportive care versus, 50 chemotherapy adjuvant, 37–39 chemoradiation versus, 52–54 combination, 66–70 second-line, 73–74, 75t single-agent, 64–65 supportive care versus, 64 chemotherapy trials, LAPC in, 54–55 chronic pancreatitis, 3–4 cigarette smoking, 3, 8 cisplatin, 66t, 67, 68, 69 Cohen 2005 trial, 51t colloid carcinoma, 83 combination chemotherapy regimens, 66–70 combined-duct IPMN, 25 conatumumab, 108 CONKO-001, 38, 39t CONKO-004, 100 CONKO-005, 39, 43 counseling, 105 COX-2, 72t CPT11/oxali, 75t CT imaging, 11–12, 13, 14, 18 cyst fluid analysis, 27

D Data and Safety Monitoring Board, 52 depression, 104–5 diabetes mellitus, type I and II, 2–3 diagnosis/diagnostic tests, 11–15, 18 diet, PDAC and, 4 distal pancreatectomy, 31

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distant metastases, 17t distress, 104 docetaxel, 68, 69 DPC4 (Deleted in Pancreas Cancer-4), 49 ductal carcinomas, uncommon, 83, 84t duodenal obstruction, 98–99

E EBRT 30Gy, 41 ECOG 4201, 52 endocrine neoplasms. See pancreatic endocrine neoplasms endoscopic intervention, 99 endoscopic retrograde cholangiopancreatography (ERCP), 13–14, 97 endoscopic ultrasound (EUS), 8, 12–13, 18 borderline resectable disease, 35 IPMN and, 26 Endo-Tag-1, 69–70 EORTC, 40, 41t epidemiology, 1 PDAC, genetic conditions associated with, 5–8 risk factors, 1–5 epidermal growth factor receptor (EGFR), 70, 71, 72t epirubicin, 69 erlotinib, 70–71, 108 ESPAC-1, 37, 40, 41t ESPAC-3, 38, 39t, 43 ESPAC-4, 39, 43 exatecan, 66t, 68 exocrine pancreatic malignancies, 83–87 extended lymph node dissection (ELND), 32–33 extended pancreatectomy, 32 external beam radiation (EBRT), 49–50 extranodal non-Hodgkins lymphomas (NHL), 88–89

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Index 115

F

H

familial adenomatous polyposis (FAP), 6t, 7 familial atypical multiple mole and melanoma syndrome (FAMMM), 6t, 7 familial pancreatic adenocarcinoma, 4–5 FDG-PET imaging, 14 FFCD-SFRO, 52 fine needle aspiration (FNA), 13 fixed rate infusion (FDR) gemcitabine, 65 5-fluorouracil (5-FU) adjuvant therapy, 37–38, 39, 41, 43 LAPC, 49, 50, 51t, 52, 58 metastatic disease, 64, 65, 69, 73, 74, 75t FOLFIRI, 75t FOLFIRINOX, 68–69 FOLFOX, 74, 75t FRAGEM, 100, 101

Hazel 1981 trial, 53t hedgehog pathway, 71, 72t, 109 hepatic artery (HA), 31, 34 hepatic artery embolization, 92 hepatic resection, 90 HER2, 70, 71 hereditary conditions. See genetic conditions hereditary non-polyposis colorectal cancer (HNPCC), 6t, 7 hereditary pancreatitis, 3–4, 6 heterogeneity, 23 high-risk patients, screening in, 7–8 histological confirmation, of diagnosis, 18 Huguet 2007 trial, 56t

G gastric outlet obstruction, 98–99 gastric resection, 32 gastric type IPMN, 24–25 gemcitabine adjuvant therapy, 37–39, 41, 42–43 future directions, 108 LAPC, 54–55, 57, 58 metastatic disease, 64, 65, 66t, 67, 68, 69, 70–71, 73, 74, 75t gender, PDAC and, 1 general distress, 104 genetic alterations/mutations, PANIN and, 22, 23 genetic conditions, PDAC and, 5–8 GERCOR, 57, 58 giant cell tumors (GCT), 87–88 GITSG, 39–40, 41t, 50, 51t, 53t GM-CSF gene, 110 Goldstein 2009 trial, 56t

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I immunotherapy, 110 induction chemotherapy, chemoradiation therapy and, 55–57 insulin-like growth factor receptor 1 (IGFR-1), 71, 72t, 107–8 intestinal type IPMN, 24, 25t intraductal papillary mucinous neoplasm (IPMN), 6 localized disease, 34 molecular pathogenesis, 21, 24–27, 28f pancreatic malignancies, uncommon, 83 irinotecan, 66t, 68, 74

J jaundice, 32, 97 Johns Hopkins, 8 JSPAC, 43t

K Klassen 1985 trial, 53t K-RAS, 22–23, 24

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116 Index Krishnan 2007 trial, 56t, 57 Kryzanowska 2003 trial, 50, 51t

L laparoscopy staging, 14–15, 18, 99–100 lesions, IPMN and, 26 localized disease, 31 adjuvant chemoradiation: randomized trials, 39–40, 41t adjuvant chemotherapy: randomized trials, 37–39 adjuvant therapy for, 37–44 arterial resection, 34–35 borderline resectable disease, 35–36 extended lymph node dissection, 32–33 extended pancreatectomy, 32 neoadjuvant therapy for resectable disease, 40–42 portal/mesenteric vascular resection, 34 pylorous preservation, 32 resectability, definition of, 31–32 summary and recommendations, 42–44 total pancreatectomy, 33–34 locally advanced pancreatic cancer (LAPC) background, 47–49 chemotherapy versus chemoradiation, 52–54 induction chemotherapy and chemoradiation therapy, 55–57 LAPC in systemic chemotherapy trials, 54–55 radiation versus chemoradiation, 50–52 radiosensitizers and chemoradiation, 49–50 summary and recommendations, 57–58

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supportive care versus chemoradiation, 50 systemic chemotherapy trials, 54–55 Loehrer 2008 trial, 53t Louvet 2005 trial, 55t low molecular weight heparin (LMWH), 100–101 lymph node dissection. See extended lymph node dissection lymph nodes, regional, 17t lymphoma, primary pancreatic, 88–89

M main-duct IPMN, 25 malignancies. See pancreatic malignancies margin positivity, 36 matrix metalloproteinases, 72t MD Anderson, 35, 36 mesenteric vascular resection. See portal/mesenteric vascular resection metastases, 17t metastatic disease, 63 chemotherapy versus supportive care, 64 combination chemotherapy regimens, 66–70 management of, 90 second-line chemotherapy, 73–74, 75t single-agent chemotherapy, 64–65 targeted therapies, 70–71, 72t metastatic nonpancreatic cancers, resection of, 88 molecular pathogenesis, 21 IPMN, 24–27, 28f MCN, 27, 29 PANIN, 21–23 MRCP, 14, 18 MRI, 12, 14, 18 mTOR (mammalian target of rapamycin), 72t, 93–94

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Index mucinous cystic neoplasm (MCN), 21, 27, 29 multidetector CT (MDCT), 11, 12, 35

N nab-paclitaxel, 69 National Cancer Database, 31 National Comprehensive Cancer Network (NCCN), 35, 47 National Familial Pancreas Tumor Registry, 4 NCIC CTG PA.3 trial, 70 neoadjuvant therapy, for resectable disease, 40–42 nodal tumor staging, 17t non-Hodgkins lymphomas (NHL), extranodal, 88–89 nonpancreatic cancers, resection of, 88 nonsteroidal anti-inflammatory drugs (NSAIDs), 102 nutritional support, 103–4

O obesity, pancreatic cancer and, 4 Octreoscan, 92 oncocytic type IPMN, 24, 25t opioids, 102 osteoclastic GCTs, 88 oxaliplatin, 57, 66t, 67, 73, 74, 75t

P p16/INK4A, 23 paclitaxel, 50, 69–70 pain, 64, 105 pain control, 101–3 palliation biliary obstruction, 97 surgical, 99–100 pancreatectomy distal, 31

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117

extended, 32 total, 33–34 pancreatic cancer future directions, 107–10 risk factors, 1–5 See also diagnosis/diagnostic tests; epidemiology; localized disease; locally advanced pancreatic cancer; metastatic disease; pancreatic malignancies; staging; supportive care Pancreatic Cancer Cohort Consortium, 3 pancreatic ductal adenocarcinoma (PDAC), 1 future directions, 107–10 genetic conditions associated with, 5–8 risk factors, 1–5 See also diagnosis/diagnostic tests; epidemiology; localized disease; locally advanced pancreatic cancer; metastatic disease; pancreatic malignancies; staging; supportive care pancreatic endocrine neoplasms, 89–94 pancreatic intraepithelial neoplasia (PANIN), 21–23 pancreatic lymphoma, primary, 88–89 pancreatic malignancies exocrine, 83–87 giant cell tumors, 87–88 metastatic nonpancreatic cancers, resection of, 88 pancreatic endocrine neoplasms, 89–94 primary pancreatic lymphoma, 88–89 primary pancreatic sarcomas, 89 pancreatic neuroendocrine tumors (PNETs), 89–94 pancreaticobiliary type IPMN, 24, 25t

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118 Index pancreaticoduodenectomy. See Whipple pancreaticoduodenectomy pancreatic sarcomas, primary, 89 pancreatitis, 3–4 pathogenesis. See molecular pathogenesis pathophysiology, of PDAC, 21 PDGFR, 72t pemetrexed, 66t, 68, 75t percutaneous transhepatic cholangiopancreatography (PTC), 97 Peutz-Jeghers syndrome, 5–6, 8 PGEF, 69 PI3K-protein kinase B (PKB) pathways, 108 PIK3CA, 24 plastic stents, 97–98 platinum compounds, 67–68 pleomorphic GCT, 88 Poly ADP-Ribose polymerase 1 (PARP), 5, 71, 72t, 108–9 portal/mesenteric vascular resection, 34 portal vein (PV), 31, 34, 35 positron emission tomography (PET), 14, 18 PQIP, 108 primary pancreatic lymphoma, 88–89 primary pancreatic sarcomas, 89 primary tumor staging, 16t PRODIGE4/ACCORD II, 68 PROMID, 92 psychological factors, 104–5 psychosocial stressors, 105 pylorous preservation, 32

radiation, chemoradiation versus, 50–52 radiological characteristics, of IPMN, 25–26 radiological follow-up, for IPMN, 27 radiosensitizers, for chemoradiation, 49–50 ralitrexed, 75t ralitrexed/CPT 11, 75t randomized trials adjuvant chemoradiation, 39–40, 41t adjuvant chemotherapy, 37–39 LAPC in, 54–55 See also specific trials Rapid Autopsy Series, 49 RAS, 72t Ras-Raf-MAPK, 108 regional lymph nodes, 17t renal cell carcinoma (RCC), 88 resectability, definition of, 31–32 resectable disease, neoadjuvant therapy for, 40–42 resection arterial, 34–35 hepatic, 90 metastatic nonpancreatic cancers, 88 portal/mesenteric vascular resection, 34 reverse transcriptase PCR (RT-PCR), 15 risk factors, for pancreatic cancer, 1–5 Rocha Lima trial, 55t RTOG 8048, 39, 43, 44 RTOG 9704, 37–38, 39t rubitecan, 73, 75t

Q

S

quality of life, 63, 64–65

sarcomas, primary pancreatic, 89 screening future directions in, 110 high-risk patients, 7–8 second-line chemotherapy, 73–74, 75t

R R0 resection, 40 RADIANT 3, 94

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Index 119 signaling pathways, 23 signet ring carcinoma, 83 single-agent chemotherapy, 64–65 SMAD4/DPC4 tumor suppressor gene, 23 smoking. See cigarette smoking social support services, 105 solid-pseudopapillary carcinoma, 86–87 somatization, 104 somatostatin receptor, 92–94 SPARC (secreted protein and rich in cysteine), 69 Src, 72t staging, 14–15, 16–18, 99–100 STAT, 72t stem cells, 21 stents, 97–99 STK11/LKB1, 24 sunitinib, 93 superior mesenteric artery (SMA), 31, 33, 34, 36 superior mesenteric vein (SMV), 31, 35 supportive care, 97 biliary obstruction, 97–98 gastric outlet obstruction, 98–99 LAPC, 50 metastatic disease, 64 nutritional support, 103–4 pain control, 101–3 psychological factors, 104–5 surgical palliation for advanced disease, 99–100 venous thromboembolism, 100–101 surgical palliation, for advanced disease, 99–100 Surveillance Epidemiology and End Results (SEER), 4 systemic chemotherapy trials, LAPC in, 54–55

thromboembolism. See venous thromboembolism tipifarnib, 54 TNF related apoptosis inducing ligand (TRAIL), 109 TNM staging, 16t, 17t tobacco smoking. See cigarette smoking total pancreatectomy, 33–34 TRAIL, 72t transabdominal ultrasound, 11 type I diabetes mellitus, 2–3 type II diabetes mellitus, 2–3

U ultrasound, 11 undifferentiated carcinoma, 83 unresectable disease, 48f U.S. Intergroup/RTOG 0848, 39, 43, 44

V Van Cutsem trial, 55t vascular endothelial growth factor (VEGF), 71, 72t vascular resection. See portal/ mesenteric vascular resection venous thromboembolism (VTE), 100–101

W Whipple pancreaticoduodenectomy, 31–32 Wnt/APC pathway, 86 World Health Organization (WHO), 24, 90, 91t, 102

T targeted therapies, 70–71, 72t TGF-B mediated cell growth, 23

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X xeloda, 66t

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