Eder J P, Elias A, Shea T C, Schryber S M, Teicher B A, Hunt M, Burke J, Siegel R, Schnipper L E, Frei E
Department of Medicine, Dana-Farber Cancer Institute, Boston, MA 02115.
J Clin Oncol. 1990 Jul;8(7):1239-45. doi: 10.1200/JCO.1990.8.7.1239.
The principles of dose-response and combination chemotherapy were basic to the design of the initial curative standard-dose treatment regimens for leukemias, lymphomas, and testis cancer. Agents were selected with different dose-limiting toxicities, resulting in subadditive toxicity in combination. A fourth principle in the design of curative regimens was to combine agents with different mechanisms of action to avoid cross-resistance. Based on these principles, combinations of the highest tolerated doses of active noncross-resistant agents are required to decrease the emergence of drug resistance and achieve optimum cytotoxicity. Hematopoietic stem-cell support provides a mechanism for significantly increasing the doses of active agents, a strategy that has resulted in the cure of 10% to 50% of selected patients with lymphoma who could not be cured with standard-dose therapy. The lack of sufficiently effective cytoreductive conditioning regimens remains the major impediment to improving the high-dose therapy of patients with solid tumors. In this study, 27 patients with solid tumors were treated with a combination of cyclophosphamide, thiotepa, and carboplatin (CTCb) in a phase I-II study. Severe mucositis and neurotoxicity were dose-limiting. The maximum-tolerated dose (MTD) of the combination was 6.0 g/m2 of cyclophosphamide, 500 mg/m2 of thiotepa, and 800 mg/m2 of carboplatin. There were two deaths (7%) of sepsis, and an overall response rate of 72% in refractory tumors (81% in breast cancer). CTCb is a combination with low morbidity and high cytoreductive efficacy designed to exploit the principles of curative cancer chemotherapy.
剂量反应和联合化疗原则是白血病、淋巴瘤和睾丸癌初始根治性标准剂量治疗方案设计的基础。选择具有不同剂量限制性毒性的药物，联合使用时毒性呈亚相加性。根治性方案设计的第四个原则是联合使用作用机制不同的药物以避免交叉耐药。基于这些原则，需要联合使用活性非交叉耐药药物的最高耐受剂量，以减少耐药的出现并实现最佳细胞毒性。造血干细胞支持为显著增加活性药物剂量提供了一种机制，这一策略已使10%至50%的经标准剂量治疗无法治愈的特定淋巴瘤患者得到治愈。缺乏足够有效的细胞减灭预处理方案仍然是改善实体瘤患者高剂量治疗的主要障碍。在本研究中，27例实体瘤患者在一项I-II期研究中接受了环磷酰胺、噻替派和卡铂（CTCb）联合治疗。严重的黏膜炎和神经毒性是剂量限制性毒性。该联合方案的最大耐受剂量（MTD）为环磷酰胺6.0 g/m²、噻替派500 mg/m²和卡铂800 mg/m²。有2例（7%）死于败血症，难治性肿瘤的总缓解率为72%（乳腺癌为81%）。CTCb是一种发病率低且细胞减灭效果高的联合方案，旨在应用根治性癌症化疗原则。
