Adding capecitabine to gemcitabine improved survival, response in pancreatic cancer

The addition of capecitabine to gemcitabine improved response and survival as first-line treatment compared with gemcitabine alone for patients with locally advanced or metastatic pancreatic carcinoma, according to the results of a randomized trial and a meta-analysis.

Based on an observed trend toward improved OS with the addition of capecitabine (Xeloda, Roche), researchers suggested the combination be considered as a standard first-line option in locally advanced and metastatic pancreatic cancer. They randomly assigned 533 patients to gemcitabine (n=266) or gemcitabine and capecitabine (n=267) between May 2002 and January 2005.

Patients in the combination arm achieved an objective response rate of 19.1% vs. 12.4% in the gemcitabine alone arm (P=.034). Patients who received gemcitabine and capecitabine also had longer PFS (HR=0.78; 95% CI, 0.66-0.93): 5.3 months vs. 3.8 months. At 12 months, PFS rates were 13.9% for patients who received the combined treatment and 8.4% for those who received gemcitabine alone.

Researchers also reported a trend toward improved OS for patients who received the combined treatment (HR=0.86; 95% CI, 0.72-1.02). Median survival was 7.1 months for those who received gemcitabine and capecitabine compared with 6.2 months for those who received gemcitabine alone. This trend was consistent across disease stage and performance status, and after adjusting for these factors, the trend remained (P=.077).

The researchers also conducted a meta-analysis of two studies with an overall enrollment of 935 patients. The meta-analysis also revealed a survival benefit for patients receiving the combination of gemcitabine and capecitabine (HR=0.86; 95% CI, 0.75-0.98). – by Tina DiMarcantonio

Cunningham D. J Clin Oncol. 2009;doi:10.1200/JCO.2009.24.2446.

Mature data from this trial have been long awaited since its interim analysis presented four years ago at the European Cancer Conference suggested a statistically significant survival benefit to the combination of gemcitabine and capecitabine. Aside from gemcitabine plus erlotinib (Tarceva, OSI Pharmaceuticals), it had been the only other phase-3 study in pancreatic cancer that appeared to show a significant survival advantage to a combination regimen compared with gemcitabine monotherapy. So, it’s perhaps slightly disappointing that with longer-term follow-up and maturation of data, this survival benefit did not hold up, although there still remained a trend toward improved OS with the combination arm, as well as benefits in other clinically meaningful outcome parameters.

The authors then do go on to pool their data with a couple of other phase-3 gemcitabine/capecitabine studies and show that the combination does result in a significantly improved survival benefit on meta-analysis. Does this publication change clinical practice? The fact is, many of us have been using gemcitabine/capecitabine as a front-line regimen for advanced pancreatic cancer; the fact that this study did not quite meet statistical significance will not change our practice of continuing to look at it as an appropriate first-line choice, especially for patients with good performance status. However, we're faced with the sobering reality that, aside from one trial (gemcitabine/erlotinib, which produced only a very marginal incremental benefit), no other single large-scale phase-3 trial has clearly demonstrated a significant survival advantage to combination therapy in advanced pancreatic cancer. We are still left to look for novel combinations of cytotoxic and targeted agents that may offer improved outcomes for this patient population.

– Andrew H. Ko, MD

HemOnc Today Editorial Board member