A PHASE-II STUDY OF CONTINUOUS-INFUSION 5-FLUOROURACIL AND LEUCOVORINWITH WEEKLY CISPLATIN IN METASTATIC COLORECTAL-CARCINOMA

Background. Prolonged infusional 5-fluorouracil (5-FU) and bolus 5-FU modulated by leucovorin are associated with higher response rates than bolus 5-FU alone. Cisplatin enhances 5-FU cytotoxicity in some precli nical models. Methods. The authors tested the feasibility of combining concurrent infusional leucovorin (500 mg/m2/d) with protracted infusi onal 5-FU (200 mg/m2/d) and weekly bolus cisplatin (20 mg/m2) in 22 pa tients with metastatic colorectal cancer. Results. Four partial respon ses (PR) were noticed among 21 evaluable patients (19%). The median ti me to treatment failure and median survival were 6 months and 11 month s, respectively. All but two patients required 5-FU dose reduction aft er a median of 2 weeks because of mucositis. However, severe mucositis and diarrhea occurred in only 18% and 5% of the patients, respectivel y. Palmar-plantar erythrodysesthesia of mild to moderate severity occu rred in 55% of patients. Megaloblastic changes were evident in the per ipheral blood during therapy, and may reflect prolonged DNA-directed t oxicity of 5-FU. The median tolerated dose level of 5-FU was 113 mg/m2 /d (range, 64-150 mg/m2/d). Mean steady-state plasma concentrations (C p(ss)) of 5-FU appeared to increase linearly from 0.19 muM to 0.39 muM over the dose range 64 to 200 mg/m2/d. Patients with grade 2 gastroin testinal toxicity had significantly higher 5-FU Cp(ss) than patients w ith grade 0 or 1 toxicity. Conclusions. The early onset of toxicity wi th this regimen of protracted infusional 5-FU/high-dose leucovorin and weekly cisplatin required marked attenuation of the 5-FU dose intensi ty, and the results were no better than that expected with infusional 5-FU alone.