Study of nitrosourea glycosyl analogs—V. An oriented phase II trial of RFCNU

Abstract

Fifty-seven patients with digestive tract tumors or metastatic tumors of unknown origin were treated in a phase II trial with RFCNU [chloro-2-ethyl-1-ribofuranosyl-(isopropylidine-2′-3′-paranitrobenzoate-5′)3-nitrosourea] administered on a two-day schedule. Doses were based on the results of a phase I trial, and ranged from 300 to 350 mg/ m 2. When hematological tolerance was excellent, the dose was escalated to 570 mg/ m 2. In cases of documented bone-marrow intolerance, we decreased the total dose to below 300 mg and even gave only 150 mg/ m 2 to one patient. Courses were repeated every month. Three complete remissions (CR) and five partial regressions (PR) were achieved among 57 patients available for assessment of response. The overall rate of major responses (CR + PR) (PR being regressions superior to 50%) was 14%, with a median duration of 9 months. These major responses included 4 cases of liver metastases (including 2 CR) and 3 lung metastases of colorectal carcinoma (one CR). The responses were obtained at doses in excess of 275 mg/ m 2. We also obtained 30% CR + PR in the case of a metastasis of unknown origin. This above evaluation is severe because it only reports major responses according to the WHO-EORTC-NCI recommendation. We also mention in complement 12% responses inferior to 50% in colorectal cancers, one in a stomach carcinoma, one in a hepatoma and 15% more in metastasis of unknown site primary tumors. The hematological toxicity was mild. It consisted of thrombocytopenia 18%, which was only dose-limiting in 3 patients (6%) previously treated with other nitrosoureas. Leukopenia with white cell counts of 1500/ mm 3 was rarely observed. In 32 previously untreated patients, no correlation was found between hematologic toxicity and the number of cycles administered. Nausea and vomiting were noticed in 14% of patients. These results indicate that the efficacy of RFCNU for digestive tract tumors is at least comparable and probably slightly superior to that of other nitrosoureas. Adverse reactions, and mainly with hematological toxicity, were less marked that those observed with BCNU, CCNU or MeCCNU and do not appear to be cumulative.