The paper by Almhanna and Kim addresses a clinical dilemma in the treatment of pancreatic cancer, for which no standard currently exists. The review article concisely summarizes studies in the second-line setting that have been conducted to date, many of which have been published only in abstract form. The authors organize the studies into tables according to the number of agents in the trials and highlight the response rates and toxicities. The inclusion of study endpoints (both primary and secondary) would have made the tables more informative. In the article, the studies are organized according to the specific agent studied. Several of the studies continue to use gemcitabine(Drug information on gemcitabine) (Gemzar) in combination with other agents in the second-line setting, but we have insufficient data to determine that continuing gemcitabine in this setting is worthwhile.
Unfortunately, the nature of the studies reviewed limits the usefulness of the article. Specifically, the small number of patients and the single-arm design of these studies make a meta-analysis infeasible. The authors logically conclude that the published studies are inadequate in scope to establish a standard of care for second-line therapy in pancreatic cancer. The issue of a best supportive care arm as a comparative arm is raised, but the authors acknowledge that this would be difficult to support in the United States. Even the German cooperative group found a best supportive care arm to be impracticable in this setting.
For future studies, the authors suggest that a composite endpoint of “clinical benefit” might be more appropriate than just response rate and overall survival, given that gemcitabine was initially approved based on a study using a similar composite clinical endpoint. Although quality of life is an important endpoint in this setting, time to disease progression can also provide important information on the activity of any new agent or combination in the second-line setting. Given that any new therapies are likely to be costly, the authors suggest that the inclusion of cost-effectiveness analysis would also be important.
At the time the article was written, the final results of the CONKO-3 trial were not yet available. At the 2008 meeting of the American Society of Clinical Oncology (ASCO), Pelzer et al presented updated results from the study, which randomized patients progressing on gemcitabine to OFF (oxaliplatin [Eloxatin], fluorouracil(Drug information on fluorouracil) [5-FU], and leucovorin) or to 5-FU (24-hour infusion) and leucovorin alone. The primary endpoint was overall survival. The minimum Karnofsky performance status was 70%, but no data on prior response to gemcitabine was given.
Based on the 168 patients enrolled, the median overall survival was 26 weeks in the OFF group as compared to 13 weeks in the FU/FA arm. Although this was a small trial, the doubling of survival is an impressive result and potentially clinically meaningful. Unfortunately, Pelzer and colleagues did not present any quality-of-life data, although the toxicity profile appeared to be acceptable. Nevertheless, a randomized study in this setting represents a modest but significant result.
First- vs Second-Line Strategies
For diseases such as pancreatic cancer and malignant melanoma, first-line therapies are modestly effective at best, and second- and third-line treatments are generally unproven and wanting. Efforts at improving the efficacy of first-line treatments for advanced pancreatic cancer in the past several years have been generally disappointing, as highlighted by Almhanna and Kim. At the 2007 ASCO meeting, trials conducted by both the Southwest Oncology Group (which studied gemcitabine/cetuximab [Erbitux]) and Cancer and Leukemia Group B (gemcitabine/bevacizumab [Avastin]) were presented as negative trials despite encouraging phase II data.[2,3] This reinforces the need to separate locally advanced pancreatic cancer and metastatic disease into distinct cohorts for future trials, given the distinct survival expectations.
The only positive trial in this setting is the gemcitabine/erlotinib (Tarceva) study by the National Cancer Institute of Canada, which showed a minimal increase in median survival, albeit at a cost of some toxicity. The median survival remains in the 5- to 6-month range for advanced pancreatic cancer. Until there is significant progress in the initial treatment of the disease to slow the often aggressive course, few patients will have the time (and maintain an adequate performance status) to move onto second-line therapies.
The authors also address the lack of consensus on who should be classified as having gemcitabine-refractory disease. Given that many patients are now treated with adjuvant gemcitabine with or without chemoradiation, should those who develop recurrent disease within 12 months be considered to have gemcitabine-refractory disease?
Generally less than 25% of patients who receive gemcitabine or gemcitabine-based chemotherapy for advanced disease derive clinical benefit from those treatments but subsequently develop progressive, refractory disease. Perhaps those who initially respond to gemcitabine should represent the cohort of patients who should be eligible for second-line studies. At a minimum, randomized second-line studies should stratify patients according to prior benefit from gemcitabine in addition to performance status. More research to identify other predictive markers is needed to select those who will benefit from both first- and second-line therapies.
—Yoo-Joung Ko, MD
The main article can be found here.