Four-Drug Regimen Promising in Cancer of Pancreas, Gallbladder

NEW YORK—Dose escalation of irinotecan (Camptosar) is continuing in a phase I trial of a four-drug regimen that has shown encouraging activity in patients with pancreatic and gallbladder cancer, according to a report at the Mount Sinai School of Medicine Chemotherapy Foundation Symposium XX.

The regimen adds irinotecan to a previously tested three-drug protocol, reported Peter Kozuch, MD, assistant professor of clinical medicine, Columbia University College of Physicians and Surgeons, and Department of Hematology-Oncology, St. Luke’s Roosevelt Hospital Center. Known by the acronym G-FLIP, the regimen includes gemcitabine (Gemzar), fluorouracil (5-FU)/leucovorin, irinotecan, and cisplatin (Platinol).

Between March and September, 2002, 14 patients were enrolled in the phase I trial of G-FLIP, eight with pancreatic cancer, five with gallbladder cancer, and one with squamous cell carcinoma of the head and neck. Ages of the patients ranged from 45 to 78 years (median, 62.4). Four had received previous chemotherapy.

Of the 10 patients evaluable after four cycles of therapy, Dr. Kozuch reported, one with pancreatic cancer attained a complete response. Partial responses occurred in three patients, two with gallbladder cancer and one with pancreatic cancer. Disease stabilization of at least 8 weeks was seen in two pancreatic cancer patients. "The median duration of response," Dr. Kozuch said, "has not been defined, with a median follow-up of 10.6 weeks."

The outpatient administration of G-FLIP begins with infusion of 500 mg/m² of gemcitabine given at a rate of 10 mg/m² per minute, for a total of 50 minutes. This is followed by administration of irinotecan according to the dose-escalation schedule, Dr. Kozuch said. Doses start at 80 mg/m² and increase stepwise by 20 mg/m².

Next in the drug sequence is 300 mg of leucovorin. This is followed by a 400 mg/m2 bolus of 5-FU. Patients are then sent home with a portable pump to receive 1,500 mg/m2 of 5-FU over the next 24 hours. "They return to the infusion suite on day 2 for cisplatin and vigorous hydration with saline and mannitol," Dr. Kozuch said. The cisplatin dose is 35 mg/m². Treatment cycles are scheduled for every 2 weeks.

"The G-FLIP program was designed to exploit sequence-dependent synergistic activity between drugs while minimizing sequence-dependent toxicity," Dr. Kozuch said. In vitro, he noted, preceding cisplatin with 5-FU maximizes synergistic activity. If irinotecan is given before 5-FU, he added, less diarrhea and neutropenia occurs.

"Similarly," he said, "gemcitabine given 24 hours before cisplatin has been associated, with lower cisplatin plasma levels and less leukopenia but higher platinum DNA adducts."

No sequence-dependent effects have been reported between irinotecan and cisplatin nor between irinotecan and gemcitabine. No data have been published, Dr. Kozuch noted, on gemcitabine and 5-FU sequence relationships.

In the phase I G-FLIP trial, one patient had grade 3 nausea and vomiting at an irinotecan dose of 100 mg/m². Grade 3-4 hematologic toxicities recorded on a per patient basis included thrombocytopenia (8%), anemia (16%) and neutropenia (8%). There have been no cases of neutropenic fever, Dr. Kozuch reported, and no instances of nephrotoxicity or neurotoxicity.

Dose escalation of irinotecan at the time of evaluation of patients for the preliminary report had reached 120 mg/m². Encouraged by the results to date, Dr. Kozuch and his colleagues are moving forward to the 140 mg/m² dose.