Sparano J A, Wadler S, Liebes L, Robert N J, Schwartz E L, Dutcher J P
Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10467.
Cancer Res. 1993 Aug 1;53(15):3509-12.
alpha-Interferon (IFN-alpha) enhances the activity of 5-fluorouracil in patients with advanced colorectal carcinoma. Preclinical evidence suggests a similar potential role for IFN-alpha combined with cyclophosphamide, doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH), and 5-fluorouracil (CAF) in advanced adenocarcinoma of the breast. To determine a maximum tolerated dose of IFN-alpha that could be combined with CAF and that did not compromise CAF dose intensity and to determine the effect of IFN-alpha on the pharmacokinetics of doxorubicin, a phase I study of IFN-alpha plus CAF was performed by the Eastern Cooperative Oncology Group. Nine patients with advanced breast cancer received CAF (cyclophosphamide at 100 mg/m2/day p.o. on days 1-14, doxorubicin at 30 mg/m2 and 5-fluorouracil at 500 mg/m2 i.v. bolus on days 1 and 8) plus IFN-alpha (1 milliunit/m2, n = 6, or 2 milliunits/m2, n = 3) given s.c. on days 1, 3, 5, and 8 (1 h prior to the doxorubicin and 5-FU injection on days 1 and 8) of each cycle every 28 or more days. Escalation of the IFN-alpha dose occurred in cohorts of 3-6 patients if a dose-limiting toxic event (neutropenic fever, platelet nadir of < 25,000/microliters, > 2-week treatment delay, or a > 50% dose reduction in day 8 CAF) occurred during the first two cycles in 0 of 3 or 1 of 6 patients. During cycle 1, IFN-alpha was omitted on day 1, and multiple plasma samples were drawn on day 1 (without IFN-alpha) and day 8 (with IFN-alpha) after each doxorubicin injection and were analyzed for plasma doxorubicin concentration. The maximum tolerated dose of IFN-alpha by our criteria was 1 milliunit/m2, and neutropenia was the predominant toxic effect that precluded IFN-alpha dose escalation. The dose intensity of CAF achieved with IFN-alpha was identical to that for CAF alone observed in prior studies. IFN-alpha had no significant effect on the pharmacokinetics of doxorubicin, although 3 of 7 patients studied had reduced doxorubicin clearance, ranging from 32% to 69%. Alternative CAF drug delivery schedules (all drugs given i.v. every 3-4 weeks) that are more amendable to hematopoietic growth factor support may be more suitable to combine with higher doses of IFN-alpha that may produce modulation.
α-干扰素（IFN-α）可增强晚期结直肠癌患者体内5-氟尿嘧啶的活性。临床前证据表明，IFN-α联合环磷酰胺、阿霉素（阿霉素，阿德里亚实验室，俄亥俄州哥伦布市）和5-氟尿嘧啶（CAF方案）在晚期乳腺癌中可能发挥类似作用。为确定可与CAF方案联合使用且不影响CAF方案剂量强度的IFN-α最大耐受剂量，并确定IFN-α对阿霉素药代动力学的影响，东部肿瘤协作组开展了一项IFN-α联合CAF方案的I期研究。9例晚期乳腺癌患者接受CAF方案（环磷酰胺100mg/m²，口服，第1 - 14天；阿霉素30mg/m²；5-氟尿嘧啶500mg/m²，静脉推注，第1天和第8天）加IFN-α（1百万单位/m²，n = 6；或2百万单位/m²，n = 3），皮下注射，每28天或更长时间为一个周期，在每个周期的第1、3、5和8天（第1天和第8天在阿霉素和5-氟尿嘧啶注射前1小时）给药。如果在前两个周期中3例患者中的0例或6例患者中的1例出现剂量限制性毒性事件（中性粒细胞减少性发热、血小板最低点<25,000/微升、治疗延迟>2周或第8天CAF方案剂量减少>50%），则在3 - 6例患者的队列中增加IFN-α剂量。在第1周期，第1天未使用IFN-α，在每次阿霉素注射后的第1天（未使用IFN-α）和第8天（使用IFN-α）采集多个血浆样本，分析血浆阿霉素浓度。按照我们的标准，IFN-α的最大耐受剂量为1百万单位/m²，中性粒细胞减少是阻止IFN-α剂量增加的主要毒性作用。与IFN-α联合使用时CAF方案的剂量强度与之前单独使用CAF方案时观察到的剂量强度相同。IFN-α对阿霉素的药代动力学没有显著影响，尽管7例研究患者中有3例阿霉素清除率降低，范围为32%至69%。更适合造血生长因子支持的替代CAF给药方案（所有药物每3 - 4周静脉给药一次）可能更适合与可能产生调节作用的更高剂量的IFN-α联合使用。
