In 2002, an estimated 30,300 new cases of pancreatic cancer will be diagnosed, and 29,700 people will die from the disease. The overall 5-year survival rate for patients with pancreatic cancer ranges from less than 1% to less than 5% with little improvement in survival observed in the past 20 years. Approximately two-thirds of all pancreatic cancer patients have metastatic disease at the time of diagnosis,[2,3] while the majority of the remaining patients have locally advanced unresectable disease.[4,5]
Several chemotherapeutic agents have been evaluated either alone or in combination in patients with metastatic pancreatic cancer, but the results continue to be disappointing: reproducible objective response rates range from 0% to 20% and median survival times are less than 6 months.[6-9] Results for patients presenting with locally advanced (nonmetastatic) unresectable disease have also been disappointing. The combination of concurrent fluorouracil(Drug information on fluorouracil) (5-FU) and ionizing radiation therapy for patients with unresectable disease has resulted in a twofold increase in median survival: approximately 10 months vs 5 months.[10-12] Despite these limited benefits, many consider external beam radiation and concurrent 5-FU as the standard therapy for locally advanced pancreatic cancer.
In an attempt to improve systemic disease control, which could possibly impact overall survival, investigators at several centers are testing neoadjuvant chemotherapy strategies. Such strategies have potential advantages for patients with pancreatic cancer. The morbidity of definitive chemoradiation is not insignificant, and can thwart the possibility of using systemic chemotherapy. In addition, preoperative chemotherapy allows the oncologist to identify those patients with aggressive disease who are destined to progress quicklyspecifically, patients with micrometastatic disease who are less likely to benefit from a course of locoregional chemoradiotherapy. While induction chemotherapy has several potential advantages, a challenge for investigators is to discover a regimen with consistent activity in pancreatic cancer.
Results of phase I and II clinical trials have demonstrated that single-agent irinotecan(Drug information on irinotecan) (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin [CPT-11, Camptosar]), a camptothecin analog, has activity in pancreatic cancer. In previously untreated patients with advanced pancreatic cancer, Sakata et al reported an 11% partial response rate (4 out of 35 patients) using irinotecan at 100 mg/m²/wk or 150 mg/m² every other week. Wagener et al observed three partial responses among 32 patients (9%) with pancreatic cancer who received irinotecan at 350 mg/m² by 30-minute intravenous infusion every 3 weeks. Response durations were 7.2, 7.5, and 7.8 months.
In contrast, O’Reilly et al evaluated topotecan(Drug information on topotecan) (Hycamtin), another topoisomerase I inhibitor, in 27 previously untreated advanced pancreatic cancer patients, and noted no responses. Scher et al, however, reported three (10%) partial responders in a similar patient cohort receiving a comparable topotecan dosing schedule. Additional information on this combination has been discussed by Rocha Lima et al elsewhere in this supplement.
Use of a gemcitabine(Drug information on gemcitabine)/irinotecan combination regimen seems attractive, based on the complementary toxicity profiles, different mechanisms of cytotoxicity, and overlapping antitumor activity spectra of the two compounds.
Early results of limited phase I/II trials that combined radiation and gemcitabine have been reported.[17-20] Data from a phase I study from Wake Forest University/University of North Carolina Chapel Hill determined that the maximum tolerated dose of concurrent twice-weekly gemcitabine with upper abdominal radiation was 40 mg/m² given each Monday and Thursday of the radiation. The preliminary Cancer and Leukemia Group B report of this regimen in the phase II setting indicated that it was safe and feasible. While only four local (in-field) failures were observed, systemic disease progression limited median survival to 13.7 months and 7.8 months in patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 and 1 to 2, respectively.