A Phase I–II Study on the Toxicity and Therapeutic Efficacy of 5-Fluorouracil in Combination with Leucovorin and Cisplatinum in Patients with Advanced Colorectal Carcinoma

Abstract

5-Fluorouracil (5-FU) has been the treatment of choice for colorectal carcinoma with an overall response rate of about 20%. Recent studies have shown that folate (LV) can increase 5-FU therapeutic efficacy, achieving about a 40% response rate without a clear impact on survival. Cisplatinum (CDDP) is usually inactive in colorectal carcinoma, but the association with 5-FU results in a synergistic antineoplastic effect. A phase I-II study was done to assess the maximally tolerated dose (MTD) of CDDP in association with 5-FU + LV. The MTD for CDDP was 20 mg/m2/wk in association with 5-FU 400-500 mg/m2/wk and LV 500 mg/m2/wk. WHO criteria were used for evaluation of both toxicity and response. In the phase I part we found that the main side-effect in 27 evaluable patients (pts) was gastrointestinal toxicity, mainly in the form of nausea/vomiting (92%) and diarrhea (70%) which caused one therapy-related death. Renal (26%) and marrow (59%) toxicity were acceptable. In the phase II part of the study 1 out of 19 evaluable pts (5%) had a complete response of 309 days, 3 pts achieved a partial response (16%) with a median duration od 410 days, 2 pts had a minimal response (10%) with a median duration of 261 days, and 8 pts experienced no change (42%) with a mean duration of 196 + days. In our opinion the 21% response rate obtained in this series is not satisfactory. Nevertheless the very high number of minimal response + no change patients together with the interesting impact on survival in responders may suggest further phase II-III studies.