Changing the Paradigm in Conducting Randomized Clinical Studies in Advanced Pancreatic Cancer: An Opportunity for Better Clinical Development

Pancreatic cancer constitutes the fourth leading cause of cancerrelated deaths in the United States. Because symptoms typically occur late, most patients are diagnosed with advanced disease, and thus the prognosis for this population of patients remains very poor, with an estimated median overall survival (mOS) of only 2 to 5 months with supportive care only. Gemcitabine has been considered the standard treatment for patients with advanced pancreatic cancer since Burris et al demonstrated in the pivotal study that patients treated with gemcitabine had a modest, yet statistically significant, improvement in mOS (5.65 v 4.41 months, P .0025) and a significant clinical benefit (23.8% v 4.8%; P .0022) compared with those patients treated with fluorouracil. However, single-agent gemcitabine in multiple trials consistently achieves mOS figures of approximately 6 months, a finding that clearly indicates the need for the development of new treatment strategies. Various cytotoxic agents have been clinically investigated in combination with gemcitabine in phase I and phase II trials with promising activity. Nevertheless, when these gemcitabinebased combinations have been evaluated in randomized phase III trials compared with single-agent gemcitabine, the results have been globally disappointing. Some of these combinations have resulted in improvement in the objective response rate (RR) or progression-free survival (PFS), but they have not translated into a statistically or clinically meaningful impact on OS. This has been the case for the combinations of gemcitabine with platinum analogs. In contrast, some other phase III studies have been completely negative without any suggestion of increased efficacy, such as the combinations of gemcitabine with the cytotoxic agents exatecan or pemetrexed or with the targeted agents tipifarnib or marimastat. Capecitabine, an oral fluoropyrimidine, has been evaluated in combination with gemcitabine in one randomized phase II and two phase III studies. In this issue of Journal of Clinical Oncology (JCO), Cunningham et al have published the results of one of the largest studies of metastatic pancreatic cancer conducted in the United Kingdom by the Medical Research Council, comparing the combination of gemcitabine and capecitabine with gemcitabine as a single agent, the latter being considered the standard of care in this setting. Although the initial results of this study, presented at the 2005 biannual European Cancer Organisation meeting, were positive for the primary end point of the study OS, the more mature data of the study being published now show that the combination of gemcitabine with capecitabine has an increased RR (19.1% v 12.4%; P .034), a statistically significant increase in PFS (hazard ratio [HR], 0.78; 95% CI, 0.66 to 0.93; P .004) with a trend towards improvement in OS (HR, 0.85; 95% CI, 0.72 to 1.02; P .08) over single-agent gemcitabine treatment. Some potential caveats of this study are related to the wide range of the inclusion criteria, with patients with either locally advanced or metastatic disease being entered—having these two populations of patients with a different prognosis—as well as patients with either performance status 0 to 1 or 2. It has been shown that patients with poor prognosis status do not benefit from the treatment of advanced disease. These two factors, among others, may have contributed to dilute the potential benefit of the combination over gemcitabine as a single agent. Herrmann et al had published the results of a phase III study evaluating a similar gemcitabine and capecitabine combination over single-agent gemcitabine. This study also failed to demonstrate an advantage in OS, its primary objective. Similarly, Scheithauer et al had also previously published the results of a randomized phase II study comparing the combination of gemcitabine plus capecitabine with gemcitabine as a single agent, this study showing no efficacy differences between the two arms. Of note, in these two additional studies, capecitabine was administered with a lower dose intensity and the sample size of the studies was quite smaller than that of the Cunningham et al study. In the study by Cunningham et al in this issue of JCO, the authors have in addition performed a meta-analysis, also including the patients from the two previously published studies evaluating the combination of gemcitabine and capecitabine. The results of this meta-analysis with a total of 935 patients demonstrate a significant benefit in OS favoring the combination arm (HR, 0.86; 95% CI, 0.75 to 0.98; P .002) over gemcitabine as a single agent. On the basis of these results the authors have concluded that the combination of gemcitabine and capecitabine can be considered a new treatment option for patients with advanced pancreatic cancer. Nevertheless, some caution has to be raised about this conclusion as the schedules and dose intensities of gemcitabine and capecitabine in the three studies that composed this meta-analysis were completely different and the three trials when considered individually do not show a significant advantage in OS for the combination arm.