Second-line therapy in gemcitabine-pretreated patients with advanced pancreatic cancer.

TO THE EDITOR: We read with great interest the article by Kulke et al 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). 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. 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. 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%. To the greatest part, it remains unclear why second-line therapy was not applied. In many patients with progressive disease, secondline 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.