Paclitaxel/Irinotecan/Cisplatin Combination Seen as Alternative to Cisplatin/5-FU in Upper GI Cancers

NEW YORK—Regimens based on cisplatin (Platinol), irinotecan (Camptosar), and paclitaxel (Taxol) may provide a better alternative than cisplatin and 5-fluorouracil (5-FU) in treating difficult cases of gastric and esophageal cancers. Developing more effective therapies has considerable public health importance because of the high incidence and mortality rates of these cancers, commented Eileen M. O’Reilly, MD, of Memorial Sloan-Kettering Cancer Center in New York.

Gastric and esophageal cancers affect 33,800 per year. Mortality is 60% for gastric cancer and 90% for esophageal cancer. Dr. O’Reilly spoke at a clinical investigators’ workshop sponsored by the University of Texas M. D. Anderson Cancer Center and Pharmacia Oncology.

As described by Dr. O’Reilly, the rationale for combining irinotecan and cisplatin is based on the following: each is active as a single agent; cisplatin induces DNA-cisplatin adducts; and irinotecan blocks DNA repair mechanisms by inhibiting topoisomerase-I.

Phase I studies using cisplatin at 30 mg/m² plus irinotecan at 65 mg/m² found manageable toxicity and produced seven partial responses among 30 evaluable patients with varied cancers. This was followed by a phase II study in 38 patients with metastatic or unresectable esophageal cancer. Cisplatin 30 mg/m² and irinotecan 65 mg/m² were cycled weekly, with a 4 weeks on, 2 weeks off schedule.

Complete and Partial Responses

“The primary endpoint was response rate, and secondary end-points were dysphagia relief, quality of life, toxicity, and survival,” Dr. O’Reilly said.

Cisplatin/irinotecan produced partial responses in 52% of patients (18/34) and complete responses in 5% of patients (2/34), for an overall response rate of 57% (20/34). The median response duration was 4.2 months, and median survival was 14.6 months. Responses occurred in 52% of adenocarcinomas and in 66% of squamous cancers.

Dysphagia relief was a major secondary endpoint. Dr. O’Reilly reported that dysphagia resolved in 70% of patients (14/20), improved in 20%, and worsened or was unchanged in 10%.

The most serious toxicities were grade 3 or 4 neutropenia in 46% of patients, grade 3 anemia in 31%, and grade 3 diarrhea in 11%. “A number of patients required delay or shortening of the treatment cycles, mostly due to failure to meet white blood cell and neutrophil recovery requirements in weeks 3-4,” Dr. O’Reilly said.

This regimen is now being studied in a confirmatory multicenter community-based phase II trial in metastatic or unresectable esophageal cancer. Patients will be cycled 2 weeks on and 1 week off in an effort to limit toxicity.

Gastric Cancer Results

Results with cisplatin/irinotecan in gastric cancer have been “less encouraging” than those in esophageal cancer, Dr. O’Reilly acknowledged. There were 33% partial responses and no complete responses. In addition, 38% of doses had to be delayed, and 23% of doses could not be given, even though G-CSF was used in 59% of patients. “One third of patients had outright disease progression despite treatment, and one third had to be hospitalized, mainly for neutropenia or diarrhea,” Dr. O’Reilly said.

Phase I trials now underway are testing weekly irinotecan plus radiation therapy, biweekly irinotecan/cisplatin, and weekly paclitaxel plus irinotecan/cisplatin in locally advanced upper gastrointestinal cancers. Dr. O’Reilly said that preliminary data from a phase I study of radiation therapy plus irinotecan/cisplatin in locally advanced esophageal cancer found pathological complete remission in two of three evaluable patients at the 40 mg/m² irinotecan dose level and that five of six patients showed improvement on barium swallow after induction. The phase I trial of weekly paclitaxel plus irinotecan/cisplatin has enrolled 16 patients with upper GI tumors and has so far shown partial remission in five of eight patients with esophageal cancer (all previously treatment-naive) and in two of three patients with gastric cancer.

“Paclitaxel plus irinotecan/cis-platin is an active treatment in esophageal cancer and offers an alternative to cisplatin/5-FU,” Dr. O’Reilly concluded. “It is potentially an active regimen to develop for esophageal and for gastric cancers.”