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Originally published as JCO Early Release 10.1200/JCO.2006.09.4664 on April 23 2007 © 2007 American Society of Clinical Oncology.
Lessons Learned in the Management of Advanced Pancreatic Cancer
1 Gastrointestinal Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium
2 Helen Graham F. Cancer Center, Newark, DE The treatment of patients with advanced pancreatic cancer remains a major challenge. The outcome for this condition is extremely poor, with the median survival of patients treated with best supportive care within approximately 3 to 4 months. Patients treated with gemcitabine have a median survival of approximately 6 months and a 1-year survival rate of approximately 20%. Gemcitabine has been widely accepted as the standard treatment based on a relatively small study showing a modest, but statistically significant, improvement in overall survival as well as improved clinical benefit compared with bolus fluorouracil plus leucovorin.1 Although a pharmacokinetic rationale exists for administering gemcitabine over a prolonged infused over 150 minutes (fixed dose rate [FDR]), with a small clinical study suggesting high activity, a randomized phase III study comparing the FDR regimen and the standard 30-minute infusion failed to show superiority for FDR gemcitabine.2,3 Gemcitabine has been combined with a variety of cytotoxic agents and targeted agents (Tables 1, 2, and 3).3-17 Most phase III studies, however, have failed to show improved survival compared with gemcitabine alone.3-8 One phase III study comparing the combination of gemcitabine and capecitabine with gemcitabine monotherapy has shown a significantly improved median and 1-year survival in favor of the combination arm: 7.4 months versus 6.0 months and 26% versus 19%, respectively, with a favorable safety profile.9 This study of 533 patients used a different regimen of gemcitabine plus capecitabine than a smaller study, in 319 patients that showed a trend, but no significant difference, compared with gemcitabine monotherapy.9,10 This latter study was underpowered to show a survival difference. Other studies with gemcitabine, with or without intravenous fluorouracil all failed to show a difference between gemcitabine monotherapy and combination treatment.11-13
Individual studies combining gemcitabine with either cisplatin or oxaliplatin also failed to show a significant survival advantage for the combination of these drugs, although there was a trend for improved survival in several studies.3,7,8 The relatively small number of patients included in these trials potentially led to the negative, statistically insignificant survival outcomes. A combined analysis of gemcitabine plus a platinum analog compared with gemcitabine monotherapy demonstrated a survival benefit for the combination of gemcitabine and the platinum analog, particularly in a subgroup of patients with a good performance status.14 To our knowledge, the study of the National Cancer Institute of Canada (NCIC) reported in this issue of the Journal of Clinical Oncology is the first study to show a significant survival benefit of the combination of gemcitabine plus a biologic agent compared with gemcitabine alone.15-17 Five hundred sixty nine patients were randomly assigned to receive either gemcitabine with or without erlotinib. Patients treated with the combination of gemcitabine and erlotinib had an improved overall survival with a statistically significant hazard ratio (HR) of 0.82.15 The median and 1-year survival rates were better for the combination treatment: 6.24 months versus 5.91 months and 23% versus 17%, respectively. Progression-free survival was also longer with erlotinib and gemcitabine with an estimated HR of 0.77 (P = .004). The excess toxicity of the combination with erlotinib was relatively limited. The question arises whether the survival benefit of the combination of gemcitabine plus erlotinib is clinically relevant. In most cancers, this difference would be considered as not clinically relevant, but in pancreatic cancer, this difference becomes more meaningful because of the poor outcome of advanced pancreatic cancer, the absence of impact of most other treatment options, the relatively limited impact of the reference treatment of gemcitabine monotherapy, and the acceptable toxicity profile. The HR of 0.82 represents an 18% relative reduction in the risk of death or an overall 22% improvement in survival. These numbers, as well as the 1-year survival difference, probably reflect better the impact of the treatment with erlotinib for an individual patient than the difference in median survival. The data of the pancreatic cancer study of the NCIC are important. There is a sound rationale for combining an epidermal growth factor receptor (EGFR) inhibitor and gemcitabine in pancreatic cancer.18,19 Erlotinib is a small molecule EGFR tyrosine kinase inhibitor that is active in non–small-cell lung cancer.20 Overexpression of EGFR is a common phenomenon in pancreatic cancer and is associated with more aggressive disease and poorer outcome. Anti-EGFR drugs inhibit growth in pancreatic cancer cell lines and additive activity has been seen in preclinical studies with the combination of erlotinib and cytotoxics. Moreover, another nonrandomized phase II study has shown a promising activity of the combination of gemcitabine and the chimeric anti-EGFR monoclonal antibody cetuximab: the median survival was 7.1 months and the 1-year survival was 31.7%.21 Results of the randomized phase III study of gemcitabine with or without cetuximab in pancreatic adenocarcinoma are expected in 2007. In colon cancer, anti-EGFR monoclonal antibodies have proven activity in EGFR-expressing chemotherapy refractory metastatic colorectal cancer, while the small molecule EGFR tyrosine kinase inhibitors seem to be inactive in this setting.22 Whether there is also a difference in activity in pancreatic cancer is uncertain. In this study, the NCIC demonstrated the activity of the EGFR tyrosine kinase inhibitor, while data showing the activity of the anti-EGFR monoclonal antibodies are pending. A few considerations should certainly be made in relation to the data. Increasing costs in relation to antitumoral agents are of concern to most clinicians and health care providers. The addition of erlotinib to gemcitabine increases the cost and expenses for patient management and leads to a significantly higher cost per life year gained than is usually accepted.23 Major efforts should therefore be made to try to increase the likelihood of a benefit of a treatment with erlotinib either by selecting patients who might benefit from the treatment or by combining another drug to this combination that further increases the survival. Better selection of patients is becoming increasingly important in almost all cancers because increasing therapeutic options have led to an increased economic burden to our health care system and led also to more complex drug regimens with higher toxicity. We can, therefore, hope that one of the messages of this study is that every effort should be made to prospectively collect tumor blocks and that collection of tumor material should be mandatory in trials evaluating new and more expensive treatment regimens. This is especially the case when only a small difference in outcome is anticipated in the whole patient population. This relatively small difference in the whole patient population can become more relevant in patients whose tumors express certain molecular characteristics. Tumor samples have been collected in a limited number of patients in the NCIC study, but detailed results are not analyzed prospectively in combination with the clinical data and are not reported in detail in this article.15 The lack of correlation of the EGFR expression rate as determined by immunohistochemistry shows the necessity for looking prospectively at molecular markers that can predict the likelihood of benefit of a targeted agent. In pancreatic cancer this may even be more difficult in view of the difficulty to obtain adequate tumor material. Indeed in many patients with pancreatic adenocarcinoma, the diagnosis is often made on cytology obtained during an endoscopic ultrasound examination and larger tumor samples are often not available. But even in some cancers, in which EGFR inhibitors have shown to be active, such as in chemorefractory colorectal cancer, we do not have yet validated markers that predict for outcome. The intensity of EGFR immunostaining is not related to antitumor activity in metastatic colorectal cancer and a clinical benefit has also been found in patients whose tumors had no EGFR immunostaining.22 EGFR gene mutations have not been demonstrated to play a role in the response prediction in colorectal cancer. Although it has been reported in a small study that EGFR gene copy number, as assessed by fluorescence in situ hybridization, correlates with the propensity of colorectal cancer to respond to EGFR-directed antibodies, this finding is at the moment very controversial.24 In another small study in colorectal cancer, K-ras mutations were associated with low activity to cetuximab.25 In non–small-cell lung cancer, mutations predict the outcome to treatment with another EGFR-tyrosine kinase inhibitor, gefitinib.26 Mutations predicting for outcome have not been identified in colorectal cancer and have not been found in pancreatic cancer. The outcome of patients with locally advanced and metastatic pancreatic cancer is different. Many trials have combined both groups of patients and some trials have suggested a benefit for one of the subgroups for the investigational treatment arm. The optimal design is therefore to develop separate treatment strategies in patients with locally advanced pancreatic cancer and with metastatic pancreatic cancer. Although the role of chemoradiotherapy is very controversial in locally advanced pancreatic cancer, patients responding initially to chemotherapy may possibly benefit from a further chemoradiotherapy. Moreover, the tumors of patients with locally advanced pancreatic cancer and metastatic pancreatic cancer may have different molecular characteristics. Therefore, optimally designed trials may include only one of these two groups or should at least stratify patients according to the categories metastatic versus locally advanced pancreatic cancer, and study enriched populations with patients most likely to benefit, as in the use of trastuzumab in HER2-overexpressing breast cancers. An important question is how we can increase further the outcome of patients with pancreatic cancer. An interesting concept might be to investigate whether an increasing dose of erlotinib, if it does not lead to other systemic toxicities, may increase the activity. Indeed a relation has been suggested between rash and the activity of EGFR inhibitors, not only in pancreatic cancer,15,21 but also in other cancers treated with EGFR inhibitors.22,27,28 Moreover, an increased response rate has been reported in patients with metastatic colorectal cancer who do experience no rash or only a slight rash, when the dose of cetuximab is gradually increased until a dose twice as high as the standard dose.29 There are plans within the European Organisation for the Research and Treatment of Cancer to investigate this concept in pancreatic cancer. Other ways to improve the outcome of patients with pancreatic cancer are to combine drugs that might have a synergistic activity with erlotinib. Preclinical data suggest a synergestic activity of EGFR inhibitors and vascular endothelial growth factor inhibitors.30 Therefore, the study comparing gemcitabine plus erlotinib with or without bevacizumab may be an important trial, despite a report of the failure of the combination of gemcitabine plus bevacizumab to show improved survival.31 Other new drugs directed against new targets are clearly needed in pancreatic cancer in order to improve the dismal outcome of patients. Cost and cost effectiveness will be a challenge with these combination regimens. The importance of trials showing an improved outcome in metastatic cancer can have a potentially larger impact in the adjuvant treatment of pancreatic cancer. The majority of patients relapse after surgical resection for pancreatic adenocarcinoma. There is growing evidence that adjuvant treatment improves the outcome. However, the most optimal treatment remains controversial. In the United States, postoperative chemoradiotherapy is often used, while in Europe adjuvant treatment with gemcitabine is most often proposed to patients. Trials implementing more active chemotherapy regimens, as well as the search for predictive molecular markers, are clearly needed in the adjuvant treatment of pancreatic cancer. A question that has to be answered after the data of the NCIC trial concerns the standard treatment for patients with advanced pancreatic cancer and the choice of the reference treatment in clinical trials. The answer to this question remains controversial. From a clinical view point, several standard options can be proposed. Gemcitabine monotherapy can certainly be defended, but the combination treatments gemcitabine plus erlotinib, gemcitabine plus capecitabine and —in patients with a good performance status gemcitabine plus a platinum analog—may result in small benefits. The choice of a reference arm in clinical trials is even more difficult. In this setting, one is intended to use the most active combination that is also widely used and accepted. Cooperative groups and other investigators still have the legitimate option of gemcitabine monotherapy, although the choice of the combination of gemcitabine with erlotinib or capecitabine might be a preferable option as a control treatment to which new treatment options and regimens should be compared. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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: N/A Leadership: N/A Consultant: Eric Van Cutsem, Roche Stock: N/A Honoraria: N/A Research Funds: Eric Van Cutsem, Roche Testimony: N/A Other: N/A AUTHOR CONTRIBUTIONS Conception and design: Eric Van Cutsem, Chris Verslype, Patrick A. Grusenmeyer Data analysis and interpretation: Eric Van Cutsem Manuscript writing: Eric Van Cutsem, Chris Verslype Final approval of manuscript: Eric Van Cutsem, Chris Verslype, Patrick A. Grusenmeyer
NOTES published online ahead of print at www.jco.org on April 23, 2007. REFERENCES
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Clin Cancer Res 9: 1469-1473, 2003 19. Tobita K, Kijima H, Dowaki S, et al: Epidermal growth factor receptor expression in human pancreatic cancer: Significance for liver metastasis. Int J Mol Med 11: 305-309, 2003[Medline] 20. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353: 123-132, 2005 21. Xiong HQ, 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 22. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351: 337-345, 2004 23. Grubbs B, Grusenmeyer P, Petrelli N, et al: Is it cost effective to add erlotinib to gemcitabine in advanced pancreatic cancer? J Clin Oncol 24: 313, 2006 (suppl 18S; abstr 6048) 24. 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Segaert S, Van Cutsem E: Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 16: 1425-1433, 2005 29. Van Cutsem E, Humblet Y, Gelderblom H, et al: Cetuximab dose-escalation study in patients with metastatic colorectal cancer with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): Pharmacokinetic and efficacy data of a randomized study. Proc Gastrointestinal Cancers Symposium January 19-21, 2007, Orlando, FL, 203, 237A 30. Ciardiello F, Bianco R, Damiano V, et al: Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res 6: 3739-3747, 2000 31. 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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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