This multi-institutional, randomized, phase II study showed that four gemcitabine-based regimens (gemcitabine/cisplatin, fixed dose rate gemcitabine, gemcitabine/docetaxel, and gemcitabine/irinotecan) result in similar response and survival times in patients with advanced pancreatic cancer. Objective tumor response rates associated with the four regimens were within the narrow range of 12% to 14%. Median OS times were also similar and ranged from 6.4 to 7.1 months. Toxicities, although not prohibitive, were apparent in all four arms and were consistent with the anticipated effects of the four regimens. Consequently, we concluded that none of these regimens merited further assessment in a phase III study.
After the completion of this study, three of the four regimens we evaluated were directly compared with standard gemcitabine in randomized phase III trials performed by other groups. The combination of gemcitabine and cisplatin was evaluated in a German multicenter randomized trial comprising 195 patients, of whom 20% had locally advanced disease and 80% had metastatic disease.14
The treatment regimen used in that study (cisplatin 50 mg/m2
on days 1 and 15 and gemcitabine 1,000 mg/m2
on days 1, 8, and 15 of a 28-day cycle) was identical to that used in our study. As in our study, nausea and vomiting, presumably secondary to the incorporation of cisplatin, were common. Tumor response rates were similar in the cisplatin/gemcitabine and gemcitabine alone arms (10.2% v
8.2%, respectively). Although both the reported progression-free and median survival times associated with the combination arm were longer than those associated with standard gemcitabine, the median survival difference did not reach statistical significance.
Fixed dose rate gemcitabine, which comprised the second arm of our study, was first compared with gemcitabine administered as a standard infusion in a randomized phase II study and, subsequently, with standard gemcitabine or fixed dose rate gemcitabine/oxaliplatin in an 833-patient, three-arm, randomized phase III study performed by the ECOG (ECOG 6201).12,15
The randomized phase II study compared gemcitabine 1,500 mg/m2
administered at a fixed dose rate of 10 mg/m2
/min (the regimen used in our study) with a standard 30-minute infusion of high-dose gemcitabine (2,200 mg/m2
The median survival time was 8 months in the fixed dose rate arm compared with only 5 months in the standard infusion arm (P
= .013). In the subsequent phase III study (ECOG 6201), a small improvement in survival was observed with fixed dose rate gemcitabine, although this did not meet the threshold set for statistical significance.15
Two randomized trials have compared gemcitabine and irinotecan with standard gemcitabine. In the first study, which used the same gemcitabine/irinotecan regimen that was part of our study, the combination arm, compared with standard gemcitabine, was associated with a higher tumor response rate (16.1% v
4.4%, respectively) but no difference in OS (6.3 v
6.6 months, respectively).16
The incidence of grade 3 or 4 diarrhea in patients receiving irinotecan in this study was 18.5%, which is identical to the 18% incidence observed in arm D of our study. A second randomized study comprising 145 patients used a different combination regimen, in which standard gemcitabine was compared with gemcitabine administered at a dose of 900 mg/m2
weekly for 3 out of 4 weeks combined with irinotecan 300 mg/m2
on day 8.17
Combination therapy was again associated with a higher response rate compared with standard gemcitabine (15% v
10%, respectively), but there were no significant differences in TTP or median survival.
Survival durations associated with other combinations have also been either equivalent or only marginally superior to those associated with single-agent gemcitabine in randomized studies. The median survival time associated with gemcitabine/pemetrexed was 6.2 months, compared with 6.3 months with single-agent gemcitabine, in a randomized study comprising 565 patients.18
A study performed by the Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR) and Italian Group for the Study of Gastrointestinal Tract Cancer (GISCAD) compared standard gemcitabine with a regimen of fixed dose rate gemcitabine administered in combination with oxaliplatin.19
This study reported an improvement in progression-free survival associated with the combination regimen but failed to demonstrate a significant OS difference.
One potential difficulty in comparing results across studies of novel regimens in pancreatic cancer has been the variable inclusion of patients with locally advanced and metastatic disease. To minimize patient heterogeneity in our study, we included only patients with metastatic disease. The median survival times associated with combination chemotherapy in our study, which ranged from 6.4 to 7.1 months, match closely with the median survival time reported for patients with metastatic disease receiving single-agent gemcitabine (6.7 months) in the GERCOR/GISCAD trial. This finding is consistent with our interpretation that none of the four regimens evaluated in our study is likely to offer a significant improvement over treatment with gemcitabine alone.
To date, only two gemcitabine-based regimens—gemcitabine/erlotinib and, in a preliminary report, gemcitabine/capecitabine—have been associated with statistically significant improvements in OS when compared directly with gemcitabine alone in the randomized setting.3,4
In both of these two studies, the survival benefit was relatively small and was achieved at a cost of increased toxicity. Both the gemcitabine/capecitabine and gemcitabine/erlotinib randomized studies included more than 500 patients and were thus powered to detect small survival differences. Several meta-analyses have, in fact, suggested a benefit associated with combination chemotherapy.20,21
The largest of these studies evaluated 9,970 patients from 51 randomized trials and reported a statistically significant survival advantage associated with gemcitabine combination therapy compared with gemcitabine alone (hazard ratio = 0.91; 95% CI, 0.85 to 0.97).22
Whether this difference is clinically meaningful remains unclear, particularly in light of the enhanced toxicity associated with many combination regimens.
In conclusion, we observed similar efficacy associated with four gemcitabine-based regimens in patients with metastatic pancreatic adenocarcinoma. These findings do not support the further study of any of these regimens in this setting. Our study demonstrates the feasibility of evaluating four potentially promising regimens in a randomized fashion in this disease. The observed results are consistent with subsequent phase III studies in advanced pancreatic cancer and suggest that adopting a similar approach to evaluate future agents in pancreatic cancer may be an efficient way to rapidly assess which regimens to bring forward in phase III randomized studies.