Objectives: To determine the maximum tolerable doses (MTDs) of irinotecan (CPT-11) and 5-fluorouracil (5-FU) plus levofolinic acid (LFA) administered together every two weeks, to define the toxicity profile of this regimen, and to have a preliminary evidence of its activity in the first-line management of advanced colorectal cancer patients.
Patients and methods: Patients with histologically proven colorectal carcinoma, no prior chemotherapy for their advanced disease, and with at least one measurable or evaluable indicator lesion, were admitted to this study. The starting dose of CPT-11 was 150 mg/m2 given i.v. (90 min infusion) on day 1, followed on day 2 by a fixed dose of LFA (250 mg/m2) as a two-hour i.v. infusion plus a starting dose of 5-FU 600 mg/m2 as i.v. bolus. No intra-patient dose escalation was allowed. If no dose limiting toxicity (DLT) was observed among three patients of each cohort, CPT-11 and 5-FU were alternately escalated in the subsequent cohort. Otherwise, three more patients were enrolled at the same dose level. DLT was defined as: WHO grade 3 non-haematological toxicity (except for vomiting or alopecia), grade 3 febrile neutropenia, grade 4 neutro- or thombocytopenia, or a > 2-week delay in recycling. The MTDs were defined as the doses at which two of three, or four of six, patients showed the same DLT.
Results: Thirty-one patients (five pretreated in adjuvant setting) were enrolled in this study, and a total number of 293 cycles (median 6/patient) were administered. Dose escalation safely proceeded to 210/950/250 mg/m2 of CPT-11/5-FU/LFA. These dosages were considered as MTDs, since four of six patients showed grade 4 neutropenia, in one case associated with grade 3 stomatitis. A mild decrease of both the CPT-11 and 5-FU doses to 200 and 850 mg/m2, respectively, caused different DLTs (neutropenia and diarrhoea) in two out of seven patients. At these dosages, transient grades 3 or 4 neutropenia affected two patients each during their treatment, while only one patient suffered from a severe delayed diarrhoea. Other non-haematological toxicities were mild and manageable. Therefore, we recommend this latter dose level for further study. Major responses (3 complete and 11 partial) were reported in 14 patients, for an overall response rate of 45% (95% CI: 27%-64%) according to an intent-to-treat analysis. Responses were observed from first dose level, and in four of five previously treated patients. Median failure-free and overall survivals, after a median follow-up of 39 weeks, were 42 and 55 weeks, respectively.
Conclusions: The concurrent administration of CPT-11 and modulated 5-FU every two weeks is feasible at the recommended dosages. This regimen demonstrated interesting activity in the management of advanced colorectal cancer patients, and it probably better exploits the synergism between CPT-11 and 5-FU than recently tested alternating schedules. A phase II study is ongoing to more precisely define its activity and toxicity.