Shinkai T, Arioka H, Kunikane H, Eguchi K, Sasaki Y, Tamura T, Ohe Y, Oshita F, Nishio M, Karato A
Department of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan.
Cancer Res. 1994 May 15;54(10):2636-42.
Irinotecan hydrochloride (CPT-11), a semisynthetic derivative of camptothecin, has been demonstrated to be active against solid tumors such as non-small cell lung cancer and colorectal cancer. Two combination phase I trials were undertaken to determine the maximum tolerated dose of CPT-11 in combination with cisplatin and vindesine in patients with advanced non-small cell lung cancer. All 46 patients (age 32-73 years) entered into these trials had a good performance status (Eastern Cooperative Oncology Group score, 0-1) and had received no prior chemotherapy or radiotherapy. In the first trial, 14 stage IV and 2 stage IIIb patients were studied; in the second trial 30 patients with stage IV disease were accrued. In the first trial, CPT-11 was given as a 90-min i.v. infusion on days 1 and 8 in combination with a fixed dose of cisplatin (100 mg/m2, i.v., on day 1) and vindesine (3 mg/m2, i.v., on days 1 and 8), every 4 weeks. The starting dose of CPT-11 was 25 mg/m2, and the dose was increased in increments of 25 mg/m2. In the second trial, the doses of either CPT-11 (days 1 and 8) or cisplatin (day 1) were escalated with a fixed dose of vindesine (same dose as the first study) given in a 4-week cycle. The starting doses of CPT-11 and cisplatin were 20 and 60 mg/m2, respectively, and the dose of either CPT-11 or cisplatin was increased in increments of 20 mg/m2. At least 3 patients were entered at each dose level in both trials. Use of granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor was not permitted in this trial. In the first trial, grade 4 granulocytopenia and grade > or = 3 diarrhea were dose limiting at 50 mg/m2 CPT-11, which represented the maximum tolerated dose. At the subsequent dose of CPT-11, 7 new patients were requited at the 50% reduced dose level of 37.5 mg/m2 on days 1 and 8. Nine patients were evaluated for response, and 4 of them achieved a partial response. In spite of a low dose of CPT-11 (25-37.5 mg/m2), the maximum concentration in plasma of CPT-11 (> 0.4 micrograms/ml) reached > 10-fold the in vitro concentration of CPT-11 required for 50% inhibition of growth. In the second trial, the dose-limiting toxicities were grade 4 granulocytopenia lasting for > or = 7 days and grade > or = 3 diarrhea.(ABSTRACT TRUNCATED AT 400 WORDS)
盐酸伊立替康（CPT-11）是喜树碱的半合成衍生物，已被证明对实体瘤如非小细胞肺癌和结直肠癌具有活性。进行了两项联合I期试验，以确定CPT-11与顺铂和长春地辛联合用于晚期非小细胞肺癌患者时的最大耐受剂量。所有46例（年龄32 - 73岁）进入这些试验的患者均具有良好的身体状况（东部肿瘤协作组评分，0 - 1），且未接受过先前的化疗或放疗。在第一项试验中，研究了14例IV期和2例IIIb期患者；在第二项试验中，纳入了30例IV期疾病患者。在第一项试验中，CPT-11在第1天和第8天静脉输注90分钟，与固定剂量的顺铂（100 mg/m²，静脉注射，第1天）和长春地辛（3 mg/m²，静脉注射，第1天和第8天）联合使用，每4周一次。CPT-11的起始剂量为25 mg/m²，剂量以25 mg/m²的增量增加。在第二项试验中，CPT-11（第1天和第8天）或顺铂（第1天）的剂量逐步增加，在4周周期内给予固定剂量的长春地辛（与第一项研究相同剂量）。CPT-11和顺铂的起始剂量分别为20和60 mg/m²，CPT-11或顺铂的剂量以20 mg/m²的增量增加。两项试验中每个剂量水平至少纳入3例患者。本试验不允许使用粒细胞集落刺激因子或粒细胞巨噬细胞集落刺激因子。在第一项试验中，CPT-11剂量为50 mg/m²时，4级粒细胞减少和≥3级腹泻是剂量限制毒性，这代表了最大耐受剂量。在随后的CPT-11剂量下，7例新患者在第1天和第8天以37.5 mg/m²的50%降低剂量水平入组。9例患者接受了疗效评估，其中4例获得部分缓解。尽管CPT-11剂量较低（25 - 37.5 mg/m²），但CPT-11在血浆中的最大浓度（>0.4微克/毫升）达到了体外抑制生长50%所需CPT-11浓度的10倍以上。在第二项试验中，剂量限制毒性为持续≥7天的4级粒细胞减少和≥3级腹泻。（摘要截断于400字）
