Eisenberger M, Krasnow S, Ellenberg S, Silva H, Abrams J, Sinibaldi V, Van Echo D, Aisner J
Department of Medicine, University of Maryland Cancer Center, Baltimore 21201.
J Clin Oncol. 1989 Sep;7(9):1341-5. doi: 10.1200/JCO.1989.7.9.1341.
Patients with recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN) were stratified by performance status, extent of disease, and prior radiotherapy and subsequently randomized to receive carboplatin (CBDCA; Bristol-Myers, Wallingford, CT) administered intravenously (IV) monthly, initially at doses of 400 mg/m2 in combination with methotrexate (MTX) given IV weekly at doses of 40 mg/m2 or MTX alone at the same dose/schedule. Significant dose-limiting myelosuppression required CBDCA dose reductions to 300 mg/m2 and, subsequently, 200 mg/m2. Nonhematological toxicities were not significant. Our study objective was to determine whether CBDCA plus MTX produce a substantial improvement in response rate over single-agent MTX. A response rate of 50% (complete [CR] plus partial response [PR]) for CBDCA plus MTX compared with 25% for MTX was specified as the difference to be detected. We employed a two-stage study design for randomized trials that allowed for early termination of studies involving relatively ineffective treatment regimens. With this design, the study could be closed after the first stage (20 patients entered onto each treatment arm) if the number of responders to CBDCA plus MTX were not superior to MTX. Five of 20 patients responded to treatment in each arm, and we were able to conclude that the addition of CBDCA to MTX is unlikely to result in a twofold increase in response rate compared with MTX alone in this group of patients. This two-stage design represents a simple and efficient method of testing the relative efficacy of new combinations containing at least one active agent against a suitable control arm in this disease. It addresses scientific and ethical issues of continuing testing with relatively ineffective treatments, and at the same time provides a reliable method for identifying very active regimens likely to represent significant therapeutic advances.
复发性和转移性头颈部鳞状细胞癌（SCCHN）患者按体能状态、疾病范围和既往放疗情况进行分层，随后随机分为两组，一组接受静脉注射（IV）卡铂（CBDCA；百时美施贵宝公司，沃灵福德，康涅狄格州），每月一次，初始剂量为400mg/m²，联合静脉注射甲氨蝶呤（MTX），每周一次，剂量为40mg/m²；另一组单独使用相同剂量/方案的MTX。显著的剂量限制性骨髓抑制需要将CBDCA剂量降至300mg/m²，随后降至200mg/m²。非血液学毒性不显著。我们的研究目的是确定CBDCA加MTX与单药MTX相比是否能显著提高缓解率。将CBDCA加MTX的缓解率（完全缓解[CR]加部分缓解[PR]）设定为50%，与MTX的25%进行比较，作为待检测的差异。我们采用两阶段研究设计进行随机试验，允许早期终止涉及相对无效治疗方案的研究。采用这种设计，如果CBDCA加MTX的缓解者数量不优于MTX，则在第一阶段（每个治疗组纳入20名患者）后即可结束研究。每组20名患者中有5名对治疗有反应，我们能够得出结论，在这组患者中，与单独使用MTX相比，在MTX中添加CBDCA不太可能使缓解率提高两倍。这种两阶段设计是一种简单有效的方法，用于测试在该疾病中含有至少一种活性剂的新组合相对于合适对照组的相对疗效。它解决了继续使用相对无效治疗进行测试的科学和伦理问题，同时提供了一种可靠的方法来识别可能代表重大治疗进展的非常有效的治疗方案。
