Basser R L, To L B, Begley C G, Juttner C A, Maher D W, Szer J, Cebon J, Collins J P, Russell I, Olver I
Centre for Developmental Therapeutics-affiliates: Melbourne Tumor Biology Branch, Ludwig Institute for Cancer Research, Department of Medical Oncology,Heidelberg, Victoria, Australia.
Clin Cancer Res. 1995 Jul;1(7):715-21.
Women with primary breast cancer associated with extensive axillary node involvement or large primary tumors have a very poor prognosis despite treatment with standard-dose adjuvant chemotherapy. In an attempt to improve the outlook of these patients, we investigated the safety and feasibility of delivering three cycles of high-dose epirubicin and cyclophosphamide supported with filgrastim-mobilized peripheral blood progenitor cells (PBPC). Fifteen previously untreated women, median age 50 (range, 30-58) years, with poor prognosis early stage breast cancer received filgrastim (12 microgram/kg daily for 6 days) prior to chemotherapy to mobilize progenitor cells. Patients were then given three cycles of epirubicin (200 mg/m2) and cyclophosphamide (4 g/m2) at planned 28-day intervals, each followed by infusion of one third of the PBPC collected and daily administration of filgrastim (5 microgram/kg s.c.). Three leukaphereses collected a median of 114.9 (range, 22.7-273.5) x 10(4) granulocyte-macrophage-colony-forming cells/kg body weight. Hemopoietic recovery was rapid after each cycle, and there was no correlation between the rate of recovery and the number of granulocyte-macrophage-colony-forming cells infused. There was a small but significant progressive delay in recovery from hematological and nonhematological toxicities across the three cycles. Left ventricular ejection fraction fell to below 50% in eight (53%) patients, but none developed congestive cardiac failure. Two patients did not complete three cycles because of insufficient PBPC for a third cycle (n = 1) and 2-mercaptoethane sodium sulfonate- related drug reaction during the second cycle (n = 1). There were no deaths during the study or during the follow-up period (median, 70 weeks; range, 50-85 weeks), and no late toxicities occurred. Therefore, we concluded that the delivery of multiple cycles of nonmyeloablative, dose-intensive chemotherapy supported by PBPC and filgrastim is safe, and may be widely applicable to a variety of common chemosensitive cancers with a poor prognosis. The efficacy of three cycles of high-dose epirubicin and cyclophosphamide is to be compared with standard-dose chemotherapy in a randomized trial in patients with high-risk, operable stage II and III breast cancer.
尽管接受了标准剂量的辅助化疗，但伴有广泛腋窝淋巴结受累或原发性肿瘤较大的原发性乳腺癌女性预后很差。为了改善这些患者的预后，我们研究了给予三个周期的高剂量表柔比星和环磷酰胺，并辅以非格司亭动员的外周血祖细胞（PBPC）的安全性和可行性。15名先前未接受过治疗、年龄中位数为50岁（范围30 - 58岁）、预后不良的早期乳腺癌女性在化疗前接受非格司亭（每日12微克/千克，共6天）以动员祖细胞。然后患者每28天接受三个周期的表柔比星（200毫克/平方米）和环磷酰胺（4克/平方米）治疗，每个周期后输注所采集PBPC的三分之一，并每日皮下注射非格司亭（5微克/千克）。三次白细胞分离术采集的粒细胞 - 巨噬细胞集落形成细胞中位数为114.9（范围22.7 - 273.5）×10⁴/千克体重。每个周期后造血恢复迅速，恢复速率与输注的粒细胞 - 巨噬细胞集落形成细胞数量之间无相关性。在三个周期中，血液学和非血液学毒性的恢复出现了轻微但显著的逐渐延迟。八名（53%）患者的左心室射血分数降至50%以下，但无一例发生充血性心力衰竭。两名患者未完成三个周期，原因分别是第三个周期的PBPC不足（n = 1）以及第二个周期出现与2 - 巯基乙烷磺酸钠相关的药物反应（n = 1）。研究期间及随访期（中位数70周；范围50 - 85周）均无死亡病例，也未出现晚期毒性反应。因此，我们得出结论，由PBPC和非格司亭支持的多个周期非清髓性、剂量密集化疗是安全的，可能广泛适用于各种预后不良的常见化疗敏感性癌症。在一项针对高危、可手术的II期和III期乳腺癌患者的随机试验中，将比较三个周期高剂量表柔比星和环磷酰胺与标准剂量化疗的疗效。
