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Journal of Clinical Oncology, Vol 25, No 16 (June 1), 2007: pp. 2159-2161 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.9788
Combination Chemotherapy in Advanced Pancreatic Cancer: Time to Raise the White Flag?Princess Margaret Hospital, Toronto, Ontario, Canada Gemcitabine has been the standard palliative chemotherapy in advanced pancreatic cancer since 1997; this standard was established by a phase III trial that randomly assigned 126 symptomatic patients with advanced pancreatic cancer to either gemcitabine or fluorouracil (FU).1 Treatment with gemcitabine versus FU was associated with improvements in 1-year survival (18% v 2%, respectively) and clinical benefit response (24% v 5%, respectively). Subsequently, thousands of patients have participated in large phase III trials comparing gemcitabine alone with gemcitabine plus a second cytotoxic agent.2-5 In the current issue, Herrmann et al6 present another such study, comparing gemcitabine plus capecitabine with gemcitabine alone in advanced disease. The trial by Herrmann et al6 is of high quality and was based on evidence from earlier phase studies that suggested the combination had sufficient activity to warrant further testing.7,8 Similar to all prior studies of combination chemotherapy, this trial failed to meet its primary end point of improving overall survival in advanced pancreatic cancer. Given our consistent failures in large randomized clinical trials of combination chemotherapy, the inevitable questions arise: Why were all these trials negative? Should we reassess our approach to clinical investigation of the most devastating of solid tumor malignancies? Gemcitabine and FU have been the most widely used chemotherapy agents in pancreatic cancer. Therefore, it was rational to combine them in the hopes of achieving benefit over either drug alone. This was first attempted by the Eastern Cooperative Oncology Group in a trial of 327 patients comparing weekly gemcitabine plus bolus FU with gemcitabine alone.3 The median survival time for gemcitabine alone was 5.4 months compared with 6.7 months for gemcitabine plus FU (P = .09), survival at 1 year was identical, and there was an improvement in progression-free survival time from 2.2 to 3.4 months (P = .02). In their discussion, the authors conclude that, although further modifications of scheduling of these two drugs may be possible, "it is unlikely that any of these changes alone would improve therapy of pancreas cancer significantly" and that "clinical trials resources should address other combinations and novel agents."3 Subsequent experience has generally supported their conclusions. Modulating the effect of FU, by the use of either 24-hour infusions or leucovorin, was not successful, and the present Swiss Group for Clinical Cancer Research/Central European Cooperative Oncology Group study by Herrmann et al6 showed no clear benefit from an oral fluoropyrimidine.9,10 A phase III trial of 533 patients conducted in the United Kingdom comparing gemcitabine plus capecitabine with gemcitabine alone has been reported in abstract form11 and does suggest a significant survival advantage (hazard ratio = 0.8; P = .026) for the combination therapy. Given this seemingly contradictory result to previous experience with gemcitabine plus a fluoropyrimidine, the full analysis and publication of the United Kingdom trial is awaited with interest; it was larger and thus powered to show a smaller benefit and also used a higher dose-intensity regimen. Similar to the fluoropyrimidines, other cytotoxic agents, such as irinotecan, pemetrexed, and oxaliplatin, have also failed to meaningfully impact survival in combination with gemcitabine. In some cases, the phase II data of the newer drug in combination with gemcitabine were not encouraging, and the decision to move forward to a phase III study could be questioned. Gemcitabine plus oxaliplatin did show encouraging phase II activity but subsequently failed to meet survival end points in two large randomized trials. The development of this combination does demonstrate other potential issues, such as the suitability of gemcitabine as a partner for a doublet or triplet regimen, the incremental toxicity of adding a second drug in the palliative setting, and the inclusion of locally advanced patients in phase II studies in advanced disease. The dose-intensity of gemcitabine that can be administered in combination with oxaliplatin is approximately 50% of what can be administered as a single agent, and this reduction may counter any modest improvement added by oxaliplatin. Gemcitabine-oxaliplatin combinations are also associated with higher rates of severe nausea and neuropathy, which may counter any clinical benefit derived from tumor control. Locally advanced pancreatic cancer is a more heterogeneous disease that has a better survival, slower rates of progression, and possibly a different response to therapy. The proportion of patients with locally advanced disease included in a phase II study will impact on the observed survival and progression rates. In the case of gemcitabine plus oxaliplatin, almost half of the patients in the original phase II study and 31% of patients in the first phase III study had locally advanced disease.2,12 It is possible that, with further refinements in scheduling and in a very large trial, we will be able to demonstrate a small survival benefit with combination chemotherapy. We suggest that this would not be a wise investment of patient, financial, and intellectual resources. Improvements in the therapy of advanced solid tumors are generally incremental, with hazard ratios in positive trials of 0.65 to 0.80, which corresponds to reductions in the risk of death of 20% to 35% (or analogously, to 25% to 50% improvements in survival). In pancreatic cancer, where the median survival time is consistently approximately 6 months, a 25% improvement in survival corresponds to an absolute 1- to 2-month improvement and still leaves this disease as the most lethal of malignancies. So how do we best move forward in pancreatic cancer? This is the age of molecular targeted therapy, and there are many such agents undergoing clinical trials and many more agents and targets in preclinical evaluation. Many of these new drugs target molecules or pathways that are overexpressed in pancreatic cancer and deserve evaluation. The recent successes in renal cell cancer point out that relative resistance to cytotoxic chemotherapy may not correlate with resistance to targeted agents. Admittedly, the results of targeted therapy in pancreatic cancer to date have been unsatisfactory. The matrix metalloproteinase inhibitors did not show value.13 The combination of gemcitabine with bevacizumab showed considerable promise in a phase II study, but it was recently announced that the phase III trial did not show benefit over gemcitabine alone.14 The combination of gemcitabine and erlotinib, an orally available antagonist of the epidermal growth factor receptor (EGFR), was the first combination regimen to demonstrate statistically significant superiority in terms of overall survival compared with gemcitabine alone.15 The hazard ratio was 0.81, which corresponded to an overall 23% improvement in survival, but this led to an absolute difference in median survival time of less than 1 month and an absolute difference in 1-year survival rate of 6%. A second randomized study evaluating EGFR as a target in pancreatic cancer, using the monoclonal antibody cetuximab, has been completed by the Southwest Oncology Group and will be reported next year.15 Studies evaluating other targeted agents and using combinations of targeted agents are underway. The number of potential therapies that presently warrant phase III testing is limited, and an investment in more developmental phase I and II studies is appropriate. The restriction of these studies to a more uniform population of patients with metastatic disease may assist in deciding what regimens merit further testing. Approaches not containing gemcitabine should also be tested but probably as second-line therapy because of the negative experience when patients have been randomly assigned upfront to a nongemcitabine arm.16 Future trials should also provide the platform for necessary translational research to identify predictive biomarkers for these new agents. We need to better understand why agents do or do not work in individual patients and seek to define enriched subsets of patients who might obtain a greater benefit from any of a number of available combination therapies. To date, such predictive biomarkers have been elusive for EGFR antagonists and antiangiogenic agents, as well as for traditional cytotoxic agents. The increase in tumor control rates and the association between rash and outcome seen in the gemcitabine plus erlotinib study suggest that benefit of EGFR inhibition is confined to a subset of patients that we need to be able to prospectively identify.14 The trend over the last 10 years has been a gradual increase in the size of randomized trials in advanced pancreatic cancer. The original study that led to gemcitabine approval had only 126 patients in total; the more recent studies have had 250 to 300 patients per arm. In a disease where the median survival is so poor, it can be argued that, if 600 randomly assigned patients are required to demonstrate a difference, then the clinical significance of that result is debatable.17 Such large trials also limit the number of strategies that can be efficiently and economically evaluated. It is time to return to smaller randomized trials in advanced pancreatic cancer where a positive result would be clinically important and to engage in a discussion of what represents a clinically meaningful difference. So, has the last decade of clinical investigation in pancreatic cancer been futile? The answer to this is clearly no. In the last 10 years, we have demonstrated that adjuvant therapy improves survival in resectable disease. We have improved 1-year survival in advanced disease from less than 2% to 25% and have developed a much better understanding of pancreatic cancer as a distinct disease. We have also created a clinical trials infrastructure that leaves us well positioned to proficiently answer future questions. However, it is time to lay down our sword and concede that this future will not likely be found in further evaluating combinations of cytotoxic agents. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Employment: N/A Leadership: N/A Consultant: Malcolm J. Moore, OSI, Roche Stock: N/A Honoraria: Malcolm J. Moore, OSI, Roche Research Funds: N/A Testimony: Malcolm J. Moore, OSI Other: N/A AUTHOR CONTRIBUTIONS Conception and design: Stephen A. Welch, Malcolm J. Moore Collection and assembly of data: Malcolm J. Moore Manuscript writing: Stephen A. Welch, Malcolm J. Moore Final approval of manuscript: Stephen A. Welch, Malcolm J. Moore REFERENCES
1. Burris HA III, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 15:2403-2413, 1997 2. 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 23:3509-3516, 2005 3. Berlin JD, Catalano P, Thomas JP, et al: Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol 20:3270-3275, 2002 4. Rocha Lima CM, Green MR, 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 22:3776-3783, 2004 5. Oettle H, Richards D, Ramanathan RK, et al: A phase III trial or pemetrexed plus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol 16:1639-1645, 2005 6. Herrmann R, Bodoky G, Ruhstaller T, et al: Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: A randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol 25:2212-2217, 2007 7. Cartwright TH, Cohn A, Varkey JA, et al: Phase II study of oral capecitabine in patient with advanced or metastatic pancreatic cancer. J Clin Oncol 20:160-164, 2002 8. Hess V, Salzberg M, Borner M, et al: Combining capecitabine and gemcitabine in patients with advanced pancreatic carcinoma: A phase I/II trial. J Clin Oncol 21:66-68, 2003 9. Correale P, Messinese S, Marsili S, et al: A novel biweekly pancreatic cancer treatment schedule with gemcitabine, 5-fluorouracil and folinic acid. Br J Cancer 89:239-242, 2003[CrossRef][Medline] 10. Riess H, Helm A, Niedergethmann M, et al: A randomized, prospective, multicenter, phase III trial of gemcitabine, 5-fluorouracil (5-FU), folinic acid vs. gemcitabine alone in patients with advanced pancreatic cancer. J Clin Oncol 23:310s, 2005 (abstr LBA4009) 11. Cunningham D, Chau I, Stocken C, et al: Phase III randomised comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer. Eur J Cancer 3:4, 2005 (suppl) 12. Louvet C, Andre T, Lledo G, et al: Gemcitabine combined with oxaliplatin in advanced pancreatic adenocarcinoma: Final results of a GERCOR multicenter phase II study. J Clin Oncol 20:1512-1518, 2002 13. Moore MJ, Hamm J, Dancey J, et al: A comparison of gemcitabine versus the matrix metalloproteinase inhibitor, BAY 12-9566, in patients with advanced or metastatic adenocarcinoma of the pancreas: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21:3296-3302, 2003 14. Kindler H, Friberg G, Singh DA, et al: Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 23:8033-8040, 2005 15. Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). J Clin Oncol 23:1s, 2005 (abstr 1) 16. 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 Clin Oncol 22:2610-2616, 2004 17. Stenning SP, Parmar MK: Designing randomized trials: Both large and small trials are needed. Ann Oncol 13:161-168, 2002 (suppl 4) Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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