Tolcher A W, Cowan K H, Noone M H, Denicoff A M, Kohler D R, Goldspiel B R, Barnes C S, McCabe M, Gossard M R, Zujewski J, O'Shaughnessy J A
Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
J Clin Oncol. 1996 Jan;14(1):95-102. doi: 10.1200/JCO.1996.14.1.95.
In vitro data suggest that prolonged exposure to paclitaxel enhances breast cancer cytotoxicity. Our objective in this phase I study was to determine the tolerability of paclitaxel administered by 72-hour continuous intravenous (i.v.) infusion (CIVI) in combination with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) in the ambulatory setting to metastatic breast cancer patients.
Paclitaxel was administered over 72 hours by CIVI and cyclophosphamide was given daily by i.v. bolus on days 1, 2, and 3, followed by G-CSF every 21 days. The availability of ambulatory infusion pumps and paclitaxel-compatible tubing permitted outpatient administration.
Fifty-five patients with metastatic breast cancer who had been previously treated with a median of two prior chemotherapy regimens were entered onto the study. Dose-limiting toxicity of grade 4 neutropenia for longer than 5 days and grade 4 thrombocytopenia occurred in three of five patients treated with paclitaxel 160 mg/m2 CIVI and cyclophosphamide 3,300 mg/m2 followed by G-CSF. The maximum-tolerated dose (MTD) was paclitaxel 160 mg/m2 CIVI and cyclophosphamide 2,700 mg/m2 in divided doses with G-CSF. Nonhematologic toxicities were moderate and included diarrhea, mucositis, and arthalgias. Although hemorrhagic cystitis developed in six patients, recurrence was prevented with i.v. and oral mesna, which permitted continued outpatient delivery. One hundred seventy-four cycles were safely administered in the ambulatory setting using infusional pumps and tubing. Objective responses occurred in 23 (one complete and 22 partial) of 42 patients with bidimensionally measurable disease (55%; 95% confidence interval, 38% to 70%), with a response rate of 73% (11 of 15) seen at the highest dose levels.
Paclitaxel by 72-hour CIVI with daily cyclophosphamide followed by G-CSF can be administered safely in the ambulatory setting, has acceptable toxicity, and is an active regimen in the treatment of metastatic breast cancer.
体外数据表明，长时间暴露于紫杉醇可增强对乳腺癌的细胞毒性。我们在这项I期研究中的目标是确定在门诊环境中，对转移性乳腺癌患者采用72小时持续静脉输注（CIVI）紫杉醇联合大剂量环磷酰胺和粒细胞集落刺激因子（G-CSF）的耐受性。
紫杉醇通过CIVI持续输注72小时，环磷酰胺在第1、2和3天每日静脉推注，随后每21天给予G-CSF。门诊输注泵和与紫杉醇兼容的输液管的可用性使得可以在门诊给药。
55例转移性乳腺癌患者进入本研究，这些患者此前接受的化疗方案中位数为两种。在接受紫杉醇160mg/m² CIVI和环磷酰胺3300mg/m² 随后给予G-CSF治疗的5例患者中，有3例出现了持续超过5天的4级中性粒细胞减少和4级血小板减少的剂量限制性毒性。最大耐受剂量（MTD）为紫杉醇160mg/m² CIVI和环磷酰胺2700mg/m² 分剂量给药并联合G-CSF。非血液学毒性为中度，包括腹泻、粘膜炎和关节痛。尽管有6例患者发生了出血性膀胱炎，但通过静脉和口服美司钠预防了复发，从而使得可以继续在门诊给药。使用输注泵和输液管在门诊环境中安全地进行了174个周期的治疗。在42例具有二维可测量病灶的患者中，有23例（1例完全缓解和22例部分缓解）出现了客观缓解（55%；95%置信区间，38%至70%），在最高剂量水平时缓解率为73%（15例中的11例）。
72小时CIVI输注紫杉醇联合每日环磷酰胺随后给予G-CSF可以在门诊环境中安全给药，具有可接受的毒性，并且是治疗转移性乳腺癌的一种有效方案。
