Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study.

PURPOSE: The objective of this multicenter study was to compare the efficacy and toxicity profiles of a combination of 5-fluorouracil (5-FU) given by bolus injection together with intravenous leucovorin (LV) versus high-dose 5-FU in continuous infusion (CI) in the treatment of advanced colorectal cancer. PATIENTS AND METHODS: A total of 306 patients were randomized to receive either 5-FU 425 mg/m2 given by bolus injection on days 1-5 plus intravenous (i.v.) LV 20 mg/m2 every four to five weeks or 5-FU 3.5 g/m2/week in a 48-hour CI. Therapy was continued until disease progression. Second-line chemotherapy was allowed in both arms. RESULTS: The response rates in 306 patients with measurable lesions were 19.2% (modulated arm) and 30.3% (CI arm, P < 0.05). The median progression-free survival times were 23.5 weeks (modulated arm) and 25 weeks (CI arm, P = NS). Median survival times were 42.5 weeks (modulated arm) and 48 weeks (CI arm, P = NS). There were no significant differences in grade 3-4 toxicity profiles but if we consider all grades we observed more mucositis in the modulated arm and more hand-foot syndrome in the CI arm. CONCLUSIONS: In terms of response rate, the continuous infusion regimen was more effective than the modulated regimen. There was no significant difference in survival and time to progression, and none in grade 3-4 toxicity.

Outpatient weekly high-dose continuous-infusion 5-fluorouracil plus oral leucovorin in advanced colorectal cancer. A phase II trial. Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD).

BACKGROUND: In a previous phase I-II trial we showed that the maximum tolerable dose (MTD) of 5-fluorouracil (5-FU) in a weekly 48-hour continuous infusion (CI) was 3.5 g/m2. In a subsequent confirmative phase II trial with 85 evaluable patients, a 38.5% response rate was obtained, and a median survival of 12 months. These data were comparable to those achieved by biochemical modulation of 5-FU with leucovorin. On this basis we attempted to modulate high-dose 5-FU (3 g/m2) with oral leucovorin (LV) but the regimen was too toxic and the dose had to be reduced. A new phase II trial with 2 g/m2/week plus oral leucovorin was planned. PATIENTS AND METHODS: From July 1992 to June 1994, 110 previously untreated patients with advanced, measurable colorectal cancer were included in a multicenter study. The patients received, on an outpatient basis, 5-FU 2 g/m2 by continuous infusion for 48 hours once a week until progression or the appearance of toxic effects. Oral leucovorin (60 mg every six hours) was also given during the 5-FU infusion. RESULTS: Patients received a median dose intensity of 5-FU of 1.6 g/m2/week (range 0.9-2). Three complete responses and 36 partial responses were observed. The overall response rate was 37.5% (95% CI, 28% to 46.8%), the median time to progression 7.4 months and median survival 14.5 months. W.H.O. grade 3 diarrhea occurred in 27 patients (24.5%); grade 3 mucositis was observed in 9 (8.1%) patients and grade 4 in one. Grade 3 nausea and vomiting was reported in 13 (11.7%) patients, while grade 3 hand-foot syndrome was detected in only 5 (4.5%). Grade 4 leukopenia occurred in one patient and grade 3-4 thrombocytopenia in two. CONCLUSIONS: Oral leucovorin modulation of weekly 48-hour continuous infusion of 5-FU at 2 g/m2 is an active regimen, with diarrhea and mucositis as the main limiting toxic effects. Its antitumor activity does not seem superior to that obtained with a weekly 48-hour continuous infusion of 5-FU alone at a dose of 3.5 g/m2.

Weekly high-dose infusion of 5-fluorouracil in advanced colorectal cancer.

18 patients with advanced colorectal cancer entered a phase I-II study of high-dose 48 h continuous infusion 5-fluorouracil (5-FU) for 6 weeks. 7 patients were included at the first dose level (3 g/m2) and only 1 had serious toxicity (grade 3 diarrhoea and mucositis). 7 patients were included at the second dose level (3.5 g/m2). 6 had a good tolerance to treatment, while the remaining patient had grade 4 leukopenia. 4 patients received 4 g/m2: 3 had severe toxicity (grade 4 diarrhoea, myelosuppression, mucositis, central nervous system), such that the entry of new patients was stopped. Anti-tumour activity was seen in 33% (95% confidence interval 13-59%) of the overall population. Only patients who had not had previous chemotherapy responded to treatment (response rate in this subgroup [43%, 18-71%]). The optimal dose of 5-FU was 3.5 g/m2 weekly for six cycles.