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Journal of Clinical Oncology, Vol 26, No 21 (July 20), 2008: pp. 3478-3480 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.0811
Past and Future of Pancreas Cancer: Are We Ready to Move Forward Together?Department of Surgery, Vanderbilt University Medical Center, Nashville, TN
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN In this issue of Journal of Clinical Oncology, four articles are published on perioperative therapy of resectable pancreatic cancer.1-4 In two articles, we review the past efforts to improve the outcomes for postoperative patients and in the other two we get a glimpse at a future that may provide new hope for improving outcomes. Many questions are raised by these for articles, but few are answered. The history of randomized trials to understand the benefit of adjuvant therapy for pancreas cancer began with a trial from the Gastrointestinal Study Group (GITSG).5 The study was small and fraught with many flaws that opened the study to criticism. However, with a statistically significant benefit for the adjuvant therapy arm, the GITSG trial established combined modality adjuvant therapy as a commonly employed standard within the United States, but less so elsewhere. Since the GITSG trial, other trials have not been able to convincingly prove or disprove the role of radiation therapy and have suggested that adjuvant chemotherapy alone may be of benefit.6,7 This issue of the Journal contains both a retrospective analysis from the Mayo Clinic1 and an evaluation of a prospective database from Johns Hopkins,2 among the highest volume pancreas cancer research programs supporting the use of combined modality chemoradiotherapy as a standard of care. We laud the efforts of these investigators for their excellent analyses. There are two possible ways to interpret these articles. First, they add information to the literature on the outcomes of patients treated at two excellent institutions and also provide perspective through multivariate analyses on prognostic factors.1,2 Second, they come as a condemnation to pancreas cancer researchers throughout the country. While we have learned a lot about the disease, these articles demonstrate that we have made little to no progress in the treatment of pancreas cancer during the past 30 years. Similarly, several randomized trials suggest that we improve the survival of resected patients from approximately 10% for surgery alone to slightly more than 20% for patients receiving some form of adjuvant therapy.5-7 However, this means the vast majority of patients with seemingly localized disease still die of pancreas cancer. New radiographic techniques have been developed since GITSG for better staging. Operative morbidity and mortality have lessened.8,9 Techniques for delivery of radiation and chemotherapy have improved. Yet the outcomes for our patients remain unchanged. The article from Corsini et al evaluates only patients with R0 resection, self-selecting the optimally surgically treated patients while the Herman et al study includes all resected patients.1,2 In both studies, there remains a significant element of selection bias toward healthier patients and patients with more adverse prognostic factors receiving adjuvant therapy. The Corsini et al analysis reviews patients from 1975 onward.1 This means the included patients were treated through 30 years of refinement of imaging technology, as well as improvements in surgical, radiation, and medical management. With adjuvant chemoradiotherapy, 28% of these selected patients were alive at 5 years compared with 17% without chemoradiotherapy, although the comparison was not derived from a randomized population. The Herman et al study evaluates patients from a more modern era (1993 to 2005), and shows that patients receiving chemoradiotherapy followed by chemotherapy experienced an improved median survival compared with a cohort of patients undergoing surgery alone (21.2 months v 14.4 months, P < .001).2 Intriguingly, these results are nearly identical to those reported for patients from an earlier time also by Johns Hopkins (median survival, 20 months with CRT v 14 months with surgery alone).8 The outcomes in the Yeo article, as well as the two retrospective analyses in this issue of the Journal are similar: patients who were selected for and elected to receive chemoradiotherapy therapy after surgical resection of pancreas cancer lived longer than those patients who did not receive adjuvant chemoradiotherapy. How do we react to the reality the Corsini et al and Herman et al have made us face? We could regret the past, during which we conducted trials that failed to establish a true standard. In recent years, three important randomized trials have been published. The first, The European Study Group for Pancreatic Cancer-1, has been very heavily criticized.10 In a 2 x 2 randomization, the ESPAC-1 investigators attempted to resolve the merits of the chemoradiotherapy therapy portion of adjuvant treatment and of the chemotherapy portion.7 In fact, ESPAC-1 established that chemotherapy with fluorouracil (FU) can increase the median and long-term survival for patients with resected pancreas cancer. However, several legitimate criticisms have been leveled against the study design and the chemoradiotherapy results.10,11 The Charité Onkologie CONKO-001 trial compared postoperative gemcitabine with observation, demonstrating an improvement in disease-free survival, and a greater number of 5-year survivors with adjuvant therapy.12 The analyses by Herman et al and Corsini et al appear to be consistent with these data.1,2 It seems reasonable, therefore, that when treating patients with resected pancreas cancer, adjuvant therapy of some form should be given to improve outcomes. To analyze the data further, the components of adjuvant therapy should be reassessed. First, in both the Corsini et al and Herman et al articles, surgery cured only a minority of the patients.1,2 More than a decade ago, Yeo et al proved that surgeons at Johns Hopkins performed these surgeries with tolerable morbidity and minimal mortality.8,9 That is not the case everywhere. High volume surgeons at high volume hospitals (this does not mean teaching hospitals only) have better outcomes than low volume surgeons at low volume hospitals.13 While these data is retrospective, it is compelling and consistent and cannot be ignored. Access to such surgeons is not available to every patient, but if we are to move forward, should we not be making this access a priority whenever possible? Over the decades included in the articles from Johns Hopkins and Mayo Clinic, little has changed in the systemic adjuvant therapy of pancreas cancer. The chemotherapy standard during radiation remains fluoropyrimidines. While the switch from bolus to infusional FU is rational, it is difficult to prove in pancreas cancer that this change provides additional benefit. Since the first patients in the Corsini et al and Herman et al articles had their resections, gemcitabine was proven to be a better therapy for advanced disease than FU in a single randomized trial.14 However, in the adjuvant setting, when gemcitabine was given before and after FU-based chemoradiotherapy in a well-conducted, large intergroup study (R9704), there was no statistically significant benefit in outcomes for the gemcitabine arm over one that contained FU before and after the same chemoradiotherapy.14 There was a trend toward improved outcomes in the subgroup of patients with cancer of the pancreatic head, but only a trend. Currently, ESPAC-3 is asking the question of gemcitabine compared with FU without chemoradiotherapy and results from this study should resolve this issue. The true hopes for improvements in the future have to come from new systemic therapies; currently these options are limited. Finally, the component of radiation needs to be evaluated. Here, we get little help from the two reviews in the current issue of the Journal. Corsini et al1 gave only chemoradiotherapy for the most part, whereas Herman et al2 administered chemotherapy beyond that given with radiation. Overall, as discussed, both groups had similar results with their slightly different approaches. Significantly, the outcomes for patients on CONKO-01 and ESPAC-1 who received chemotherapy alone appeared to do as well as the selected patients treated at Hopkins and Mayo.1,2,7,12 There is no good evidence to prove or disprove the value of radiation as a component of therapy in this disease. It is not clear that continued exposure of patients off clinical trial to postoperative radiation provides enough benefit to warrant its use in all patients. Neither is there evidence that radiation should be dismissed altogether. Currently, the European Organisation for the Research and Treatment of Cancer is attempting to study the role of chemoradiotherapy in a randomized trial comparing gemcitabine alone to gemcitabine and gemcitabine plus radiation. If radiation does not prove beneficial in this study it may still require reanalysis when better systemic therapy is available for this disease. The local control that radiation may provide is likely to be of far less benefit when there is almost no control of the systemic disease. Because our therapies have such limitations, it would be more ideal if we target those who would benefit most from each modality. Another major finding from the Johns Hopkins study highlights the difficulty, even in the modern era, of identifying these patients. With the caveat that a tertiary center such as Johns Hopkins will take more complex patients to the operating room, in their analysis 45% of patients identified as resectable had an R1 (margin microscopically positive) resection.2 The two articles reported from M.D. Anderson Cancer Center provide one glimpse into a future option for adjuvant therapy.3,4 They report the results of two neoadjuvant trials in pancreas cancer. The rationale for this approach is clearly to identify those patients who are unlikely to benefit from surgery (those who rapidly progress to metastatic disease) and enriches the population of patients that will benefit from a large operation. The criticism to this approach is that some patients who may have been resectable at the time of initial presentation may progress to unresectability. However, the data presented in the two articles suggest that patients who struggle through induction therapy reflect the underlying biology of the host-tumor relationship and these patients succumb early to a poor outcome. Utilizing the neoadjuvant approach, between one third to one quarter of patients starting neoadjuvant chemoradiotherapy do not come to surgical resection due to intolerance of the therapy or the finding of metastatic disease.3,4 However, what cannot be overlooked is that of those who do undergo surgical resection, the median survival is 31 and 34 months in the two studies, comparing favorably with the postoperative analyses presented by the four articles in this issue.1-4 More importantly, in the study by Evans et al3 33% of resected patients remain alive without evidence of disease recurrence at a minimum follow-up of 5 years. The limitations of comparing neoadjuvant to adjuvant approaches without a randomized trial mean that it is still not yet time to declare neoadjuvant therapy as the new standard of care, but it should be increasingly studied in clinical trials. How do we use these four articles to move into the future? First, some form of adjuvant therapy is of benefit and currently designed trials will hopefully clarify the options we have available. The neoadjuvant approach provides opportunities in clinical trials not as easily afforded by postoperative therapy. After neoadjuvant therapy, post-treatment tissue is available for correlative studies. As newer systemic therapies come into clinical trials, being able to assess their effects at the level of the tumor is crucial and this approach will allow tissue to be obtained. The articles by M.D. Anderson also demonstrated that their approach allows for standardization of pathologic analysis for margin evaluation and for measurement of treatment effect. The intergroup randomized trial, R9704, demonstrated that large numbers of patients still have inadequate evaluation of margin status.15 In that study, 23% to 26% of patients had undefined margin status, which is far too high. To move forward, trials need to have common language and approaches. Institutional variability will always exist, but more efforts are needed to standardize the surgical and pathology approaches. A first attempt was made by the American Hepato-Pancreatico-biliary Association, who will soon be publishing the results of the first consensus conference on the approach to localized pancreas cancer (J-N Vauthey, personal communication, March 2008). In their conference, standards for diagnosis, radiologic evaluation, and pathologic analysis were all discussed with the goal of developing a common language that can be incorporated into future trials. It has been a tough millennium for clinical research in pancreas cancer. Only one positive phase III trial of chemotherapy for metastatic disease has been reported since the approval of gemcitabine more than 10 years ago.16 New agents and new regimens need to be explored. While gemcitabine remains the basis for standard of care off clinical trials, does it need to be part of every systemic therapy clinical trial since it benefits only a minority of patients? Analysis of new drugs should combine them with potentially a more effective partner rather than the current standard trial comparing gemcitabine with gemcitabine plus whichever new drug comes along. The articles presented in this issue of the Journal establish that apparently localized pancreas cancer is truly a systemic disease with less visible burden of disease.1-4 They inform us that it is time to move on. While the millennium has been tough for clinical trials the preclinical arena has moved forward. New models for pancreas cancer better mimic the human disease. Better understanding exists of the genetic changes and the drivers of this disease process. Collaborations have been made to share tissue and data and with the strength of modern computers, analysis and data sharing happen quickly. All this will soon translate into the clinic. In the meantime, it is time to prepare for the future. New paradigms need to be established in clinical trial design. The phase II process has failed to identify promising regimens and instead has suggested promise from ineffective regimens far too often. In the study of adjuvant therapy of pancreas cancer, new end points need to be established to allow the earlier assessment of experimental agents. It is time to standardize our language and approaches to the clinical trials to improve the ability to analyze the data from small trials in our attempts to select those approaches that most warrant large trials. We can stop rehashing the disappointments of the past. Instead, it is time to roll up our sleeves and start working toward a brighter future. Every year, 10 times as many people will die in the United States of pancreas cancer than died in terrorist attacks on September 11, 2001. While our government loses track of that fact, we should not. A lot of people are depending on us. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Jordan Berlin, Genentech, Amgen, Pfizer, Sanofi-aventis, Bristol-Myers Squibb Co, ImClone (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Nipun Merchant, Jordan D. Berlin Manuscript writing: Nipun Merchant, Jordan D. Berlin Final approval of manuscript: Nipun Merchant, Jordan D. Berlin REFERENCES
1. Corsini MM, Miller RC, Haddock MG, et al: Adjuvant radiotherapy and chemotherapy for pancreatic carcinoma: The Mayo Clinic experience (1975-2005). J Clin Oncol 26:3511-3516, 2008 2. Herman JM, Swartz MJ, Hsu Cc, et al: Analysis of 5-FU based adjuvant chemotherapy and radiation after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas: Results of a large prospectively collected database at the Johns Hopkins Hospital. J Clin Oncol 26:3503-3510, 2008 3. Evans DB, Varadhachary GR, Crane CH, et al: Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol 26:3496-3502, 2008 4. Varadhachary GR, Wolff RA, Crane CH, et al: Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol 26:3487-3495, 2008 5. Kalser M, Ellenberg S: Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 120:899-904, 1985[Abstract] 6. Klinkenbijl JH, Jeekel J, Sahmoud T, et al: Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region. Ann Surg 230:776-784, 1999[CrossRef][Medline] 7. Neoptolemos JP, Stocken DD, Friess H, et al: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350:1200-1210, 2004 8. Yeo C, Cameron J, Sohn T, et al: Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: Pathology, complications, and outcomes. Ann Surg 226:248-257, 1997[CrossRef][Medline] 9. Yeo CJ, Cameron JL, Lillemoe KD, et al: Pancreaticoduodenectomy for cancer of the head of the pancreas: 201 patients. Ann Surg 221:721-733, 1995[Medline] 10. Abrams RA, Lillemoe KD, Plantadosi S: Continuing controversy over adjuvant therapy of pancreatic cancer. Lancet 358:1565-1566, 2001[CrossRef][Medline] 11. Choti MA: Adjuvant therapy for pancreatic cancer-the debate continues. N Engl J Med 350:1249-1251, 2004 12. 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 297:267-277, 2007 13. Birkmeyer JD, Siewers AE, Finlayson EV, et al: Hospital volume and surgical mortality in the United States. N Engl J Med 346:1128-1137, 2002 14. 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 15. Regine WF, Winter KA, Abrams RA, et al: Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: A randomized controlled trial. JAMA 299:1019-1026, 2008 16. Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960-1966, 2007 Related Articles
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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