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Journal of Clinical Oncology, Vol 26, No 7 (March 1), 2008: pp. 1178-1179 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.3304
Second-Line Therapy in Gemcitabine-Pretreated Patients With Advanced Pancreatic CancerDepartment of Internal Medicine III, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany To the Editor: We read with great interest the article by Kulke et al1 on second-line therapy with capecitabine and erlotinib in advanced pancreatic cancer. While we congratulate the authors to the results of their well-designed trial, we think that it is about time to reappraise the clinical position and relevance of second-line therapy in advanced pancreatic cancer. During the last years, only few clinical trials (mainly phase II) have been conducted in patients with advanced pancreatic cancer after failure of first-line gemcitabine or a gemcitabine-based combination regimen. However, final results from a randomized study confirming a survival advantage for second-line treatment (compared to best supportive care [BSC] only) are still lacking. A small randomized trial (n = 46) comparing BSC alone versus fluorouracil, folinic acid, and oxaliplatin plus BSC had to be terminated prematurely due to low accrual. Preliminary results from this trial indicated that chemotherapy may prolong median survival by about 2.6 months (2.3 v 4.9 months).2 Based on phase II data, a median survival of about 4 to 6 months (after the initiation of second-line treatment) may be achieved with salvage chemotherapy in selected patients.1,3 Thus, the use of second-line therapy may also have a possible impact on the survival results of first-line phase III trials. In this context, it may be a general request that results on second-line therapy should be reported in phase III trials evaluating first-line treatment of advanced pancreatic cancer (Table 1). This request becomes specifically important in those trials which set out to define new treatment standards.4
To better understand the clinical relevance of second-line therapy, we need to ask how many patients actually received second-line therapy. Only about half of the currently published randomized phase III studies of first-line therapy have reported data on second-line treatment in their study populations (Table 1). The percentage of patients receiving salvage chemotherapy in these randomized studies ranged widely from 16% to 57%.5,6 To the greatest part, it remains unclear why second-line therapy was not applied. In many patients with progressive disease, second-line therapy is precluded due to a rapid deterioration of performance status. Other patients may not receive salvage therapy since there is no recommended standard of treatment to date. This is of interest since outside of clinical trials—second-line therapy implies off-label use of anticancer agents in most countries. Randomized clinical trials of second-line therapy are urgently needed in pancreatic cancer to provide evidence-based guidelines of treatment. The increased awareness of pancreatic cancer and improved imaging techniques are factors responsible for earlier diagnosis of advanced disease. As a consequence, an increasing proportion of patients are still in a good performance status when progression on gemcitabine-based therapy is diagnosed. Preliminary data from a clinical trial randomly comparing fluorouracil/folinic acid versus fluorouracil/folinic acid plus oxaliplatin provide first evidence for a possible survival benefit with the use of oxaliplatin in the second-line setting after gemcitabine failure.7 A further aspect is the investigation of new agents. In pancreatic cancer, new treatment strategies have predominantly been explored in the setting of first-line therapy. This is explained by the rather short survival of patients with metastatic pancreatic cancer. The trial by Kulke et al now indicates that capecitabine plus erlotinib is active in gemcitabine-pretreated patients.1 These results suggest that this all-oral regimen may also be effective in first-line treatment of chemotherapy-naive patients. Currently, an ongoing German multicenter phase III study (ClinicalTrials.gov Identifier: NCT00440167 [ClinicalTrials.gov] ) of the "Arbeitsgemeinschaft Internistische Onkologie" is randomly assigning patients with treatment-naive pancreatic cancer between a capecitabine + erlotinib arm (using the same regimen like Kulke et al) and a gemcitabine + erlotinib arm. 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: Volker Heinemann, Hoffman-La Roche, Germany (C), Lilly, Germany (C) Stock Ownership: None Honoraria: Stefan Boeck, Hoffman-La Roche, Germany, Lilly, Germany; Volker Heinemann, Hoffman-La Roche, Germany, Lilly, Germany Research Funding: Stefan Boeck, Hoffman-La Roche, Germany, Lilly, Germany; Volker Heinemann, Hoffman-La Roche, Germany, Lilly, Germany Expert Testimony: None Other Remuneration: None
REFERENCES
1. Kulke MH, Blaszkowsky LS, Ryan DR, et al: Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol 25:4787-4792, 2007 2. 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 23:315s, 2005 (suppl; abstr 4031) 3. Boeck S, Weigang-Köhler 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 18:745-751, 2007 4. 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 5. 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 24:3946-3952, 2006 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 Res and the Central European Cooperative Oncology Group. J Clin Oncol 25:2212-2217, 2007 7. Riess H, Pelzer U, Stieler J, et al: A randomized second line trial in patients with gemcitabine refractory advanced pancreatic cancer: CONKO 003. J Clin Oncol 25:201s, 2007 (suppl; abstr 4517)
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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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