Lessons Learned in the Management of Advanced Pancreatic Cancer

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 clinicalbenefitcomparedwithbolusfluorouracilplusleucovorin. 1 Although a pharmacokinetic rationale exists for administering gemcitabineoveraprolongedinfusedover150minutes(fixeddose 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 comparedwithgemcitabinealone. 3-8 OnephaseIIIstudycomparingthecombinationofgemcitabineandcapecitabinewithgemcitabine 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