O'Brien M E, Nicolson M, Montes A, Tidy A, Ashley S, Powles T J
Section of Medicine, Royal Marsden Hospital, Sutton, Surrey, UK.
Br J Cancer. 1994 Nov;70(5):980-3. doi: 10.1038/bjc.1994.433.
The combination of mitozantrone, methotrexate and mitomycin (3M) gives a response rate of around 50% in patients with advanced breast cancer. The predominant toxicity is haematological. In this study, previously untreated patients were given 3M with increasing doses of mitozantrone (7-14 mg m-2) with recombinant human granulocyte colony-stimulating factor (metHuG-CSF) (filgrastim) to prevent marrow toxicity. Doses administered were 7 mg m-2 mitomycin i.v. 6 weekly, methotrexate i.v. 35 mg m-2 (maximum 50 mg) 3 weekly and mitozantrone i.v. 3 weekly as follows: 7 mg m-2, six patients (group 1); 10 mg m-2, six patients (group 2); 12 mg m-2, six patients (group 3); 14 mg m-2, six patients (group 4); all on day 1 for six cycles at the assigned dose. All patients received filgrastim (Amgen 0.3 mg ml-1) at a dose of 5 micrograms kg-1 subcutaneously daily on days 4-17 of each cycle. All treatment was given on an out-patient basis. A total of 24 patients were entered into the study. The median age was 63 years (range 48-75). ECOG performance status was 0 in ten, 1 in 11 patients and 2 in three patients. Locoregional disease alone was present in seven patients. The remainder had one or more sites of metastases. The actual dose administered to the 24 patients was as follows. The six patients in group 1 all completed six courses of treatment as per protocol. In group 2, three patients completed six courses, two stopped because of toxicity after one and four courses and one had progressive disease after one course. In group 3, three patients completed and three stopped early because of progressive disease. In group 4, two patients completed, one progressed after four courses and three responding patients stopped treatment because of toxicity. The maximum tolerated dose of mitozantrone in the 3M combination was 12 mg m-2. The use of filgrastim with increasing doses of chemotherapy prevents neutropenia, but other toxicities, namely thrombocytopenia and lethargy, then become dose limiting.
米托蒽醌、甲氨蝶呤和丝裂霉素联合方案（3M方案）治疗晚期乳腺癌患者的缓解率约为50%。主要毒性为血液学毒性。在本研究中，对既往未接受过治疗的患者给予3M方案，并增加米托蒽醌的剂量（7 - 14mg/m²），同时使用重组人粒细胞集落刺激因子（metHuG - CSF）（非格司亭）以预防骨髓毒性。给药剂量为：丝裂霉素静脉注射7mg/m²，每6周1次；甲氨蝶呤静脉注射35mg/m²（最大剂量50mg），每3周1次；米托蒽醌静脉注射，每3周1次，具体如下：7mg/m²，6例患者（第1组）；10mg/m²，6例患者（第2组）；12mg/m²，6例患者（第3组）；14mg/m²，6例患者（第4组）；均在第1天给予规定剂量，共6个周期。所有患者在每个周期的第4 - 17天每天皮下注射非格司亭（安进公司生产，0.3mg/ml），剂量为5μg/kg。所有治疗均在门诊进行。共有24例患者进入本研究。中位年龄为63岁（范围48 - 75岁）。东部肿瘤协作组（ECOG）体能状态评分为0分的有10例患者，1分的有11例患者，2分的有3例患者。仅存在局部区域病变的患者有7例。其余患者有一处或多处转移灶。给予24例患者的实际剂量如下。第1组的6例患者均按方案完成了6个疗程的治疗。第2组中，3例患者完成了6个疗程，2例患者分别在第1个疗程和第4个疗程后因毒性反应而停药，1例患者在第1个疗程后病情进展。第3组中，3例患者完成了治疗，3例患者因病情进展提前停药。第4组中，2例患者完成了治疗，1例患者在第4个疗程后病情进展，3例有反应的患者因毒性反应停止治疗。3M联合方案中米托蒽醌的最大耐受剂量为12mg/m²。使用非格司亭并增加化疗剂量可预防中性粒细胞减少症，但其他毒性反应，即血小板减少症和嗜睡，随后成为剂量限制因素。
