Kouroussis C, Xydakis E, Potamianou A, Giannakakis T, Kakolyris S, Agelaki S, Sara E, Malamos N, Alexopoulos A, Mavroudis D, Samonis G, Papadouris S, Georgoulias V, Panagos G
Department of Medical Oncology, University General Hospital of Heraklion, Greece.
Ann Oncol. 1999 May;10(5):547-52. doi: 10.1023/a:1026441804889.
To determine the maximum tolerable dose (MTD) and the dose-limiting toxicity (DLT) of docetaxel (D) in combination with epirubicin (Epi) in patients with advanced breast cancer.
Forty-seven chemotherapy-naïve metastatic breast cancer patients aged < 75 years with PS (WHO) 0-2 and adequate bone marrow, renal, liver and cardiac function, were enrolled in the study. Epi was given as a five-min bolus i.v. infusion on day 1 (d1) in escalated doses with increments of 10 mg/m2; D was given in a one-hour infusion after appropriate premedication on either day 1 or on day 2 in escalated doses with increments of 10 mg/m2. The patients' median age was 60 years, 42 (89%) had a PS (WHO) 0-1, 16 (34%) were premenopausal and 25 (53%) had visceral disease.
When the two drugs were given on the same day, the MTD1 was reached at the doses of Epi 60 mg/m2 and D 80 mg/m2; administration of G-CSF could not result in a dose intensification. When the drugs were given on two consecutive days, the MTD2 was reached at the doses of Epi 80 mg/m2 (d1) and D 90 mg/m2 (d2). The dose-limiting events were febrile neutropenia and grade 4 neutropenia, which developed in 30 (64%) patients during the study; among 227 delivered cycles grade 3-4 neutropenia occurred in 64 (28%) cycles but only 22 (10%) of them were complicated by fever. There were no septic deaths. Grade 1-2 neurosensory toxicity occurred in nine (19%) patients, mild edema in eight (17%) and allergic reactions in five (11%). Four (9%) patients presented a greater than 10% decrease of LVEF and treatment discontinuation was required in two of them; none of the patients developed congestive heart failure. Nevertheless, one patient suddenly died 10 days after treatment initiation of myocardial ischemia, and this death is considered treatment-related. Five (14.7%) complete and thirteen (38.2%) partial responses (ORR: 53.9%; 95% confidence interval: 36.1%-69.7%) were observed in 34 evaluable patients. Ten (29.4%) and six (17.6%) patients had stable and progressive disease, respectively. The median duration of response and time to tumor progression were five and seven months, respectively. The median survival has not yet been reached.
The combination of epirubicin and docetaxel is a feasible and well tolerated regimen, but the MTD depends on the administration schedule of the drugs.
确定多西他赛（D）联合表柔比星（Epi）治疗晚期乳腺癌患者的最大耐受剂量（MTD）和剂量限制毒性（DLT）。
47例年龄<75岁、PS（WHO）0 - 2且骨髓、肾脏、肝脏和心脏功能良好的初治转移性乳腺癌患者纳入本研究。Epi于第1天（d1）静脉推注5分钟，剂量递增，每次增加10 mg/m²；D在第1天或第2天适当预处理后静脉输注1小时，剂量递增，每次增加10 mg/m²。患者的中位年龄为60岁，42例（89%）PS（WHO）为0 - 1，16例（34%）为绝经前，25例（53%）有内脏疾病。
当两种药物在同一天给药时，Epi 60 mg/m²和D 80 mg/m²的剂量达到MTD1；给予粒细胞集落刺激因子（G-CSF）不能导致剂量强化。当药物连续两天给药时，Epi 80 mg/m²（d1）和D 90 mg/m²（d2）的剂量达到MTD2。剂量限制事件为发热性中性粒细胞减少和4级中性粒细胞减少，在研究期间30例（64%）患者中出现；在227个给药周期中，3 - 4级中性粒细胞减少发生在64个（28%）周期，但其中只有22个（10%）伴有发热。没有败血症死亡病例。9例（19%）患者出现1 - 2级神经感觉毒性，8例（17%）出现轻度水肿，5例（11%）出现过敏反应。4例（9%）患者左心室射血分数（LVEF）下降超过10%，其中2例需要停药；没有患者发生充血性心力衰竭。然而，1例患者在治疗开始10天后因心肌缺血突然死亡，该死亡被认为与治疗相关。在34例可评估患者中观察到5例（14.7%）完全缓解和13例（38.2%）部分缓解（客观缓解率：53.9%；95%置信区间：36.1% - 69.7%）。10例（29.4%）和6例（17.6%）患者分别疾病稳定和进展。缓解持续时间和肿瘤进展时间的中位数分别为5个月和7个月。中位生存期尚未达到。
表柔比星和多西他赛联合是一种可行且耐受性良好的方案，但MTD取决于药物的给药方案。
