Comella P, Biglietto M, Casaretti R, De Lucia L, Avallone A, Maiorino L, Di Lullo L, De Cataldis G, Rivellini F, Comella G
Division of Medical Oncology A, National Tumour Institute, Naples, Italy.
Oncology. 2001;60(2):127-33. doi: 10.1159/000055309.
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.
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.
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.
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.
确定伊立替康（CPT-11）在第1天和第8天给药、丝裂霉素C（MMC）在第1天给药，每月1个周期的最大耐受剂量（MTD），并评估该方案对既往接受过治疗的结直肠癌患者的毒性和活性。
52例患者均接受过辅助性5-氟尿嘧啶治疗（20例）和/或一线（35例）或二线（8例）化疗，进入本研究。CPT-11剂量递增（从150mg/m²开始）于第1天和第8天给药，MMC剂量递增（从8mg/m²开始）于第1天给药，每28天为1个周期。每个剂量水平至少治疗3例患者。除非在第1个周期后3例患者中有2例或6例患者中有4例出现剂量限制性毒性（DLT），否则继续剂量递增。
12例患者进入I期研究，测试了4个连续剂量水平。在最后一个剂量水平（CPT-11 200mg/m²加MMC 10mg/m²），6例患者中有4例出现DLT（即2例4级中性粒细胞减少和2例3级腹泻）。因此，该剂量水平被视为MTD。前一个剂量水平（CPT-11 175mg/m²加MMC 10mg/m²）治疗了40例患者。记录到1例完全缓解、4例部分缓解、3例轻微缓解和11例疾病稳定，缓解率为12%[95%置信区间（CI），4-27%]，47%（95%CI，31-64%）的患者肿瘤生长得到总体控制。治疗失败的中位时间为6个月（范围1-19+）。中位生存时间为14.5个月，1年和2年生存率分别为56%和43%。中性粒细胞减少和腹泻分别影响62%和58%的患者，其中3级或4级分别占26%和23%。报告了1例中性粒细胞减少性发热。其他急性毒性通常较轻且易于处理。
CPT-11 175mg/m²在第1天和第8天给药，联合MMC 10mg/m²在第1天给药，每4周1次，对于晚期结直肠癌的重度预处理患者是一种安全且具有中等活性的方案。MMC在该联合方案中的作用值得怀疑，应尝试使用其他新药以改善这些患者的治疗结果。
