Green M D, Speyer J L, Hochster H S, Liebes L F, Dunleavy S, Widman T, Wernz J C, Blum R H, Spiegel R J, Muggia F M
Department of Medicine, Rita and Stanley Kaplan Cancer Center, New York University School of Medicine, New York 10016.
Cancer Res. 1988 May 1;48(9):2574-8.
The clinical use of alpha 2-interferon and doxorubicin is based on in vitro and preclinical in vivo observations of synergistic antitumor efficacy. To test this combination a Phase I clinical and pharmacokinetic study of the concurrent use of alpha 2-interferon and doxorubicin was initiated in patients with malignant solid tumors. Each 5-wk treatment cycle consisted of 3 wk of drug administration and 2 wk of rest. The alpha 2-interferon was administered s.c. at a constant dose of 10 million IU/m2 on Mondays, Wednesdays, and Fridays in all patients while the doxorubicin was administered weekly beginning with a dose of 5 mg/m2 and escalated to the maximum tolerated dose of 25 mg/m2. At least three evaluable patients were entered at each dose level, and no dose escalations were allowed within patients. The dose-limiting toxicities were granulocytopenia and thrombocytopenia. Hepatic enzyme elevations and systemic symptoms due to interferon occurred at all dose levels. None was severe or dose limiting, and all were reversible. These toxicity data suggest that the hepatotoxic effects of interferon do not enhance doxorubicin toxicity when given by this dose and schedule. Doxorubicin plasma levels were measured at each dose level. The recommended dose of doxorubicin is 25 mg/m2 per wk when administered with 10 million IU/m2 of interferon in this schedule. This schedule allows for the administration of a greater total dose of doxorubicin than has been achieved when given every 3 wk with the same dose and schedule of alpha 2-interferon in a parallel study.
α2干扰素和阿霉素的临床应用是基于体外及临床前体内观察到的协同抗肿瘤疗效。为了检验这种联合用药方案，针对恶性实体瘤患者启动了一项α2干扰素与阿霉素联合使用的I期临床和药代动力学研究。每个为期5周的治疗周期包括3周的药物给药期和2周的休息期。所有患者均于周一、周三和周五皮下注射α2干扰素，固定剂量为1000万IU/m²，而阿霉素则从5mg/m²的剂量开始每周给药一次，逐步递增至最大耐受剂量25mg/m²。每个剂量水平至少纳入三名可评估的患者，且不允许在患者内进行剂量递增。剂量限制性毒性为粒细胞减少和血小板减少。在所有剂量水平均出现了因干扰素导致的肝酶升高和全身症状。均不严重或构成剂量限制，且均为可逆性。这些毒性数据表明，按照此剂量和给药方案给予干扰素时，其肝毒性作用不会增强阿霉素的毒性。在每个剂量水平均测定了阿霉素的血浆水平。在此给药方案中，当与1000万IU/m²的干扰素联合使用时，阿霉素的推荐剂量为每周25mg/m²。与一项平行研究中以相同剂量和给药方案每3周给予α2干扰素时相比，此给药方案能够给予更大的阿霉素总剂量。
