Mattson K, Maasilta P, Tammilehto L, Holsti L R, Grove W
Department of Pulmonary Medicine, Helsinki University Central Hospital, Finland.
Semin Oncol. 1988 Apr;15(2 Suppl 2):32-7.
To determine the maximum tolerated dose (MTD) of trimetrexate glucuronate in combination with cyclophosphamide in patients with metastatic or inoperable nonsmall cell lung cancer (NSCLC), trimetrexate in dosages ranging from 3 to 13.5 mg/m2/day was administered intravenously (IV) to 27 patients for 5 days in combination with cyclophosphamide, 600 mg/m2, on day 1. Patients received between one and six courses of treatment at 3 week intervals, 69 treatment courses in all. Hematological toxicity was mainly mild anemia (81%), leukopenia (67%), and thrombocytopenia (52%). Nonhematological toxicity included nausea and vomiting (67%), mucositis (30%), and urticaria or rash (22%). The incidences of leukopenia and mucositis were dose related. The MTD of trimetrexate in combination with cyclophosphamide was 7.5 mg/m2/day. The dosage chosen for the Phase 2 study, based only on the hematological dose limiting toxicity, was 10.5 mg/m2/day. Of 31 patients with previously untreated metastatic or inoperable NSCLC who have entered in the Phase 2 study, 22 are evaluable for clinical efficacy (World Health Organization criteria, 1979). Treatment was discontinued in four patients because of toxicity. One patient refused further therapy. Four patients are too early to evaluate. Five patients had confirmed partial responses (23%), 12 patients achieved stable disease (54%), and five patients had progressive disease. Results suggest that trimetrexate 10.5 mg/m2/day in combination with cyclophosphamide is active against previously untreated NSCLC. Dose limiting toxicity was mucositis and myelosuppression. An 11 item linear analogue scale assessing quality of life during treatment indicated this combination was well accepted by patients and did not compromise quality of life. The Phase 2 study is continuing.
为确定葡糖醛酸三甲曲沙联合环磷酰胺用于转移性或不可切除非小细胞肺癌（NSCLC）患者时的最大耐受剂量（MTD），对27例患者静脉注射（IV）剂量范围为3至13.5 mg/m²/天的三甲曲沙，持续5天，并在第1天联合使用600 mg/m²的环磷酰胺。患者每3周接受1至6个疗程的治疗，共69个疗程。血液学毒性主要为轻度贫血（81%）、白细胞减少（67%）和血小板减少（52%）。非血液学毒性包括恶心和呕吐（67%）、粘膜炎（30%）以及荨麻疹或皮疹（22%）。白细胞减少和粘膜炎的发生率与剂量相关。三甲曲沙联合环磷酰胺的MTD为7.5 mg/m²/天。仅基于血液学剂量限制毒性选择的2期研究剂量为10.5 mg/m²/天。在进入2期研究的31例既往未治疗的转移性或不可切除NSCLC患者中，22例可评估临床疗效（按照1979年世界卫生组织标准）。4例患者因毒性而停止治疗。1例患者拒绝进一步治疗。4例患者因时间过早无法评估。5例患者确认部分缓解（23%），12例患者病情稳定（54%），5例患者病情进展。结果表明，10.5 mg/m²/天的三甲曲沙联合环磷酰胺对既往未治疗的NSCLC有活性。剂量限制毒性为粘膜炎和骨髓抑制。一项评估治疗期间生活质量的11项线性模拟量表表明，该联合治疗方案为患者所接受，且未影响生活质量。2期研究仍在继续。
