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 in colorectal cancer used in
combination with 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.