Currently available therapies for advanced pancreatic cancer continue to yield poor results. Most chemotherapeutic regimens achieve objective response rates of 5% or less. Median survival ranges between 5 and 6 months, and 1-year survival averages less than 20%, regardless of the therapy employed. The poor outcomes with available therapies have led investigators to explore new therapies that offer potential to improve response rate and survival in patients who have advanced pancreatic cancer.

Investigators evaluated the clinical impact of the addition of antifolate agent pemetrexed to gemcitabine. Pemetrexed has shown efficacy against pancreatic cancer specimens in human tumor cloning assays. The agent also has produced evidence of efficacy against pancreatic and colorectal cancer in limited clinical evaluations. Pemetrexed and gemcitabine have demonstrated synergy in vitro, and the combination of pemetrexed and gemcitabine achieved an objective response rate of 21% in a phase I clinical investigation of the combination.

Investigators at 9 centers enrolled 42 patients who had untreated advanced pancreatic cancer. The treatment regimen consisted of gemcitabine 1250 mg/m² days 1 and 8 and pemetrexed 500 mg/m² day 8, repeated every 21 days. The patients received a total of 213 cycles of therapy and a median of 4 cycles. Most patients also received folic acid and vitamin B₁₂ supplementation after investigators learned of data that showed supplementation substantially reduces pemetrexed toxicity.

The regimen achieved 5 partial responses (12%) in 41patients who could be evaluated for response. Additionally, 18 (44%) patients had stable disease, including 3 patients who had unconfirmed partial responses. The cohort had a median survival of 6.6 months, and median time to progression was 3.1 months. Patients had weekly evaluations for clinical benefit response, which included performance status, pain score, analgesic use, and weight. Analysis of clinical benefit in 30 patients revealed a 13.3% clinical benefit response.

　

Clinical Activity of Pemetrexed-Gemcitabine Combination Therapy Parameter -- Partial Response 5 (12%) Stable Disease 18(44%) Median Survival 6.6 mo Median TTP 3.1 mo 1-year Survival 32% Clinical Benefit Response 4 (13.3%) 　Time to Response 2 wk 　Duration of Response 6.5 wk

The combination of pemetrexed and gemcitabine caused hematologic toxicity in most patients. Grade 3-4 neutropenia occurred in 84% of patients, grade 3-4 leukopenia in 74%, and grade 3-4 thrombocytopenia in 33%. Relatively few patients experienced severe non-hematologic toxicity. Grade 3 or greater non-hematologic toxicity included diarrhea in 2%, nausea in 5%, fatigue in 4%, elevated bilirubin in 2%, elevated liver enzymes (ALT or AST) in 24%, and elevated alkaline phosphatase in 7%.

Results of the study show that the combination of pemetrexed and gemcitabine has clinical activity in advanced pancreatic cancer. The data also indicate that the regimen has an acceptable toxicity profile.

(abstract #499)