Catimel G, Spielmann M, Dieras V, Tubiana-Hulin M, Bonneterre J, Pouillart P, Kayitalire L, Guastalla J P, Graffand N, Garet F, Dumortier A, Pellae-Cosset B
Centre Léon Bérard, Lyon, France.
Semin Oncol. 1997 Feb;24(1 Suppl 3):S8-12.
In an attempt to develop new, active, and convenient outpatient combination-chemotherapy regimens for patients with metastatic breast cancer, we performed two phase I studies combining paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) plus anthracycline for the first-line treatment of metastatic disease, without the use of hematopoietic growth factors. Study I was designed to test the tolerability and antitumor activity of a 3-hour infusion of paclitaxel in combination with an epirubicin intravenous bolus. Study 2 explored a three-drug chemotherapy regimen: a 3-hour paclitaxel infusion with epirubicin and cyclophosphamide. Courses were repeated every 3 weeks. If any dose-limiting events occurred in two or more of six patients in the first course of a given dose level, that dose level was defined as the maximum tolerated dose. Dose-limiting criteria included the following: neutrophils less than 0.25 x 10(9)/L lasting for > or = 5 days, any febrile neutropenia, World Health Organization grade 4 thrombocytopenia, World Health Organization grade > or = 3 nonhematologic toxicity or grade > or = 3 mucositis for more than 5 days, and absence of hematologic recovery at day 35. In both studies, paclitaxel doses were escalated in subsequent groups of three to six patients. For study I, the initial dose level consisted of paclitaxel (110 mg/m2)/epirubicin (50 mg/m2). To date 40 patients have entered the study at eight dose levels. Of the 181 cycles evaluated, grade 3 or 4 neutropenic episodes were observed in 63% of courses, with only five episodes of febrile neutropenia. Grade 2 or 3 neurotoxicity was observed in 43% of patients. Two patients experienced clinical heart failure. The dose-limiting toxicity has not been reached so far. At dose level 7 (paclitaxel [250 mg/m2]/epirubicin [50 mg/m2]), only one patient of six experienced febrile neutropenia. We are currently testing paclitaxel (200 mg/m2)/epirubicin (75 mg/m2). Preliminary evaluation of response documents two complete and 16 partial responses in 37 evaluable patients (48% overall response rate). In study 2, the initial dose level consisted of paclitaxel (150 mg/m2)/epirubicin (50 mg/m2)/cyclophosphamide (500 mg/m2). To date, three dose levels have been investigated in 16 evaluable patients (82 cycles). Grade 3 or 4 neutropenic episodes were observed in 80% of courses, and five episodes were associated with neutropenic fever. Grade 2 neurotoxicity was observed in 28% of patients. The dose-limiting toxicity has not been reached, and we are currently investigating dose level 4 (paclitaxel 225 mg/m2). These trials confirm the tolerability of combined paclitaxel/epirubicin and paclitaxel/epirubicin/cyclophosphamide. The antitumor activity is encouraging.
为了开发新的、有效的且方便的转移性乳腺癌患者门诊联合化疗方案，我们进行了两项I期研究，将紫杉醇（泰素；百时美施贵宝公司，新泽西州普林斯顿）与蒽环类药物联合用于转移性疾病的一线治疗，且不使用造血生长因子。研究I旨在测试3小时输注紫杉醇联合表柔比星静脉推注的耐受性和抗肿瘤活性。研究2探索了一种三药化疗方案：3小时输注紫杉醇联合表柔比星和环磷酰胺。疗程每3周重复一次。如果在给定剂量水平的第一个疗程中，六名患者中有两名或更多出现任何剂量限制性事件，则该剂量水平被定义为最大耐受剂量。剂量限制性标准包括以下内容：中性粒细胞低于0.25×10⁹/L持续≥5天、任何发热性中性粒细胞减少、世界卫生组织4级血小板减少、世界卫生组织≥3级非血液学毒性或≥3级粘膜炎超过5天，以及在第35天血液学未恢复。在两项研究中，后续每组三至六名患者的紫杉醇剂量逐步增加。对于研究I，初始剂量水平为紫杉醇（110mg/m²）/表柔比星（50mg/m²）。迄今为止，40名患者已在八个剂量水平进入该研究。在评估的181个疗程中，63%的疗程观察到3级或4级中性粒细胞减少事件，仅有五例发热性中性粒细胞减少。43%的患者观察到2级或3级神经毒性。两名患者出现临床心力衰竭。目前尚未达到剂量限制性毒性。在剂量水平7（紫杉醇[250mg/m²]/表柔比星[50mg/m²]）时，六名患者中只有一名出现发热性中性粒细胞减少。我们目前正在测试紫杉醇（200mg/m²）/表柔比星（75mg/m²）。对疗效的初步评估记录了37例可评估患者中有2例完全缓解和16例部分缓解（总缓解率48%）。在研究2中，初始剂量水平为紫杉醇（150mg/m²）/表柔比星（50mg/m²）/环磷酰胺（500mg/m²）。迄今为止，已在16例可评估患者（82个疗程）中研究了三个剂量水平。80%的疗程观察到3级或4级中性粒细胞减少事件，五例与中性粒细胞减少性发热相关。28%的患者观察到2级神经毒性。尚未达到剂量限制性毒性，我们目前正在研究剂量水平4（紫杉醇225mg/m²）。这些试验证实了紫杉醇/表柔比星联合以及紫杉醇/表柔比星/环磷酰胺联合的耐受性。抗肿瘤活性令人鼓舞。
