NEW YORKGemcitabine (Gem-zar), approved for the treatment of advanced pancreatic cancer, may have value as a modulator of standard chemotherapy in advanced colorectal cancer, Stefan Madajewicz, MD, said at the Chemotherapy Foundation Symposium XVII. Dr. Madajewicz, professor of medicine and chief of neoplastic diseases, Division of Medical Oncology, SUNY Health Center, Stony Brook, NY, reported on phase I/II trials of gemcitabine(Drug information on gemcitabine) in colorectal cancer used in combination with fluorouracil(Drug information on fluorouracil) (5-FU) and folinic acid.
Although 5-FU demonstrates an objective response in patients with colorectal cancer, it extends survival only slightlyby 6 to 8 weeks at most. There is a need, Dr. Madajewicz said, to improve survival in these patients.
Inhibition of DNA Synthesis
Folinic acid is added to 5-FU to augment clinical activity. Gemcitabine, a nucleoside analog, inhibits deoxycytidine kinase, a key enzyme in the salvage pathway of pyrimidine biosynthesis, as well as ribonucleic reductase. As such, it is theorized that gemcitabine can enhance the inhibition of DNA synthesis by 5-FU and further augment its clinical activity.
The phase I study enrolled 28 patients with advanced solid tumors; 21 of whom had colorectal cancer. Patients received an infusion of folinic acid (100 mg/m²) over 1 hour, with a 450 mg/m² bolus of 5-FU halfway through the infusion. Gemcitabine was infused at a rate of 10 mg/m²/min at the end. A maximum tolerated dose of 900 mg/m² gemcitabine over 90 minutes was established for the subsequent phase II trial, which enrolled 12 chemotherapy-naïve patients with advanced colorectal cancer.
Of 33 patients with advanced colorectal cancer (combined total from the phase I and II trials), 15 responded, with 1 complete response and 14 partial responses. Median survival was 18+ months. Adverse effects were minimal.
Dr. Madajewicz said that despite its lack of effectiveness when used alone in patients with colorectal cancer, gemcitabine may be an important addition to the standard regimen, giving new life to 5-FU/folinic acid chemotherapy.