RANDOMIZED PHASE-III STUDY OF 5-FLUOROURACIL PLUS HIGH-DOSE FOLINIC ACID VERSUS 5-FLUOROURACIL PLUS FOLINIC ACID PLUS METHYL-LOMUSTINE FOR PATIENTS WITH ADVANCED COLORECTAL-CANCER

Background. Metastatic colorectal cancer is generally incurable. The m ost active regimen available, 5-fluorouracil (5-FU) and folinic acid ( Leucovorin), produces response rates of approximately 25% to 30%. Meth yl-lomustine is a nitrosourea with modest activity against colorectal cancer. A randomized trial was undertaken to evaluate the impact the a ddition of methyl-lomustine would have on response, duration of surviv al, and survival rates in patients with advanced colorectal cancer. Me thods. The methyl-lomustine/5-FU/Leucovorin (MFL) regimen consisted of methyl-lomustine (110 mg/m(2)), administered on Day 1 of each 8-week cycle with six weekly boluses of 5-FU (600 mg/m(2)), and Leucovorin (5 00 mg/m(2)). The FL treatment arm consisted of the administration of 5 -FU and Leucovorin as described above. Patients were evaluated for res ponse and toxicity after each 8-week cycle. Results. Of 319 patients i ncluded in this trial, 297 (93.1%) had disease evaluable for response and toxicity: 145 received MFL, and 152 received FL. in this trial, 52 6 courses of MFL and 529 courses of FL were administered. Methyl-lomus tine/5-FU/Leucovorin treatment resulted in 4 complete and 30 partial r esponses (response rate, 21.9%), and FL treatment resulted in 9 comple te and 33 partial responses (response rate, 26.4%). There was no signi ficant difference in median survival duration between patients in the two arms (MFL = 48 weeks, FL = 51 weeks). However, MFL was significant ly more toxic with greater myelosuppression than was FL (Grade 3-4 neu tropenia: MFL = 56 patients, FL = 27 patients, P < 0.001; Grade 3-4 th rombocytopenia: MFL = 49 patients, FL = 2 patients, P < 0.001; Grade 3 -4 anemia: MFL = 15 patients, FL = 6 patients, P < 0.001; and more pro longed median duration of granulocytopenia: MFL = 9 days, FL = 7 days, P < 0.001; and thrombocytopenia: MFL = 14 days, FL = 7.5 days, P < 0. 001). Conclusion. Because the addition of methyl-lomustine in the MFL schedule markedly increased the toxicity of the regimen and because th e FL regimen was as effective as MFL, the authors recommend that Leuco vorin and 5-FU remain the treatment choice for treating patients with metastatic colorectal cancer.