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Purpose: To define the maximum tolerated dose (MTD) of irinotecan (CPT-11) given on days 1 and 8 with mitomycin C (MMC) given on day 1 in a monthly cycle, and to assess the toxicity and activity of this regimen in patients with previously treated colorectal carcinoma., Methods: Fifty-two patients, all pretreated with adjuvant 5-fluorouracil (20 patients) and/or one (35 patients) or two (8 patients) lines of chemotherapy, were entered in this study. Escalating doses of CPT-11 (starting from 150 mg/m2) were administered on days 1 and 8, with escalating doses of MMC (starting from 8 mg/m2) given on day 1, recycling every 28 days. At least 3 patients were treated at each dose level. Escalation proceeded unless 2 out of 3 or 4 out of 6 patients experienced a dose-limiting toxicity (DLT) after the first cycle., Results: Twelve patients were entered in the phase I study, and 4 consecutive dose levels were tested. At the last dose level (CPT-11 200 mg/m2 plus MMC 10 mg/m2) 4 of 6 patients experienced a DLT (i.e., grade 4 neutropenia in 2 patients and grade 3 diarrhea in 2 patients). Therefore, this dose level was considered as the MTD. Forty patients were treated at the previous dose level (CPT-11, 175 mg/m2 plus MMC 10 mg/m2). One complete, 4 partial, 3 minor responses and 11 cases of stable disease were registered, giving a response rate of 12% [95% confidence interval (CI), 4-27%] and an overall control of tumor growth in 47% (95% CI, 31-64%) of patients. The median time to treatment failure was 6 months (range 1-19+). The median survival time was 14.5 months, and the 1-year and 2-year probability of survival were 56 and 43%. Neutropenia and diarrhea affected 62 and 58% of patients, grade 3 or 4 being registered in 26 and 23% of them, respectively. One episode of neutropenic fever was reported. Other acute toxicities were usually mild and manageable., Conclusions: CPT-11 175 mg/m2 on days 1 and 8 associated with MMC 10 mg/m2 on day 1, every 4 weeks, is a safe and moderately active regimen in heavily pretreated patients with advanced colorectal carcinoma. The role of MMC in this combination is doubtful, and further attempts with other new agents should be made to improve the outcome in these patients.

In our previous randomized trial of advanced gastric cancer patients, the addition of epirubicin (EPI) to 5-fluorouracil (FU) with folinic acid (FA) resulted in an improved response rate and survival in the responder patients. Preclinical studies also showed an enhancement of FU and anthracyclines with interferon. To evaluate the possibility of human lymphoblastoid interferon (IFN) to enhance the therapeutic activity of the FA-FU + EPI combination regimen, 39 advanced gastric cancer patients received: FU at 375 mg/m2 i.v. immediately after FA (l-isomer form) at 100 mg/m2 i.v. for 5 consecutive days; EPI at 60 mg/m2 i.v. on day 1, and IFN 3 MU s.c. for 7 consecutive days, starting 2 days before the FA-FU administration. Thirty-seven patients were evaluable for response and toxicity. Twelve partial responses were observed with an overall response rate of 32% (95% CI, 17-48%). The median response duration was 6 months, and the median survival time was 8 months. Toxicity was mild and no grade 4 side effects or treatment-related deaths were observed. However, the addition of IFN to the FA-FU + EPI regimen did not improve response, duration of response or survival.

In order to assess the maximum tolerated dose of 5'-deoxy-5-fluorouridine (5dFUR) combined with a cisplatin (20 mg/m2 i.v.) and L-folinic acid (100 mg/m2 i.v.), 5-day schedule 19 consecutive chemotherapy-naive patients affected by advanced or recurrent carcinoma of the head and neck were entered in this phase I trial. Doses of 5dFUR were escalated from a starting level of 2,000 mg/m2/day up to 3,000 and 5,000 mg/m2/day. At the latter step the dose-limiting acute toxicities were stomatitis and diarrhea, which were of WHO grade 3-4 and occurred in 3 and 1 out of 4 evaluated patients, respectively. Other grade 3 acute toxicities were leukopenia, anemia, renal impairment, and neurologic symptoms, observed in 1 patient each. Furthermore, one possibly treatment-related death was registered among patients entered in the highest dose level. Eleven out of 19 patients (58%; 95% CI:34-80%) showed a complete (2 cases) or partial (9 cases) response to this treatment, regardless of the 5dFUR dosage employed. From our results we may define the maximum tolerated dose of 5dFUR to be associated with cisplatin and L-folin acid used in this trial as 3,000 mg/m2/day x 5 days. Assessment of the real activity of this combination chemotherapy deserves further studies.