Klaassen U, Wilke H, Seeber S
Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen, Germany.
Semin Oncol. 1996 Oct;23(5 Suppl 11):32-7.
Our phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose 5-fluorouracil (5-FU)/folinic acid (FA) in intensively pretreated metastatic breast cancer patients prompted the addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this regimen in a phase I/ II outpatient study. Patients were treated with high-dose 5-FU (by 24-hour infusion) and FA (by 2-hour infusion prior to 5-FU) weekly for 6 weeks (day 1, 8, 15, 22, 29, and 36) repeated every 50 days; in addition, paclitaxel was administered by 3-hour infusion on days 1 and 22. The following dose levels were used in phase 1 of the study. In dose levels 1 through 4, FA was given at a fixed dose of 500 mg/m2, followed by escalating doses of high-dose 5-FU (24-hour infusions of 1.5 [dose level 1], 1.8 [dose level 2], and 2.0 g/m2 [dose levels 3 and 4]). The paclitaxel dose, given over 3 hours on days 1 and 22, was 135 mg/m2 for dose levels 1 through 3 and 175 mg/m2 at dose level 4. Dose level 4 was chosen for further evaluation in the phase II portion of the trial. Among the 46 patients who entered this part of the trial, the median age was 46 years (age range, 26 to 70 years), the World Health Organization performance status was 0 to 1, and the median number of metastatic sites was 2.5 (range, one to four). All patients had bidimensionally measurable disease. Nine patients previously had received adjuvant chemotherapy, 16 had received prior chemotherapy for metastasis, and 21 had been treated with both types of chemotherapy. Of 29 anthracycline-pretreated patients, 25 had anthracycline-resistant disease. Interim results in 35 evaluable patients show complete remission in one patient (3%), partial remissions in 18 (51%), stable disease in 14 (40%), and progressive disease in two (6%). The overall response rate was 54% (95% confidence interval, 36% to 76%). The median number of treatment cycles administered per patient was three (range, one to five), the median time to maximum response was 2 months (range, 1 to 5 months), and the median remission duration was 8+ months (range, 2 to 17 months). Median survival time has not yet been reached. The combination of paclitaxel with weekly high-dose 5-FU/FA was well tolerated in second-line treatment of metastatic breast cancer and results also indicate high efficacy against anthracycline-resistant disease. In an ongoing phase II study we are evaluating the addition of cisplatin to the regimen as first-line treatment of metastatic breast cancer.
我们的II期研究结果表明，对于经过强化预处理的转移性乳腺癌患者，每周一次的大剂量5-氟尿嘧啶（5-FU）/亚叶酸（FA）方案具有高效和低毒的特点，这促使我们在一项I/II期门诊研究中将紫杉醇（泰素；百时美施贵宝公司，新泽西州普林斯顿）添加到该方案中。患者每周接受大剂量5-FU（通过24小时输注）和FA（在5-FU之前通过2小时输注）治疗6周（第1、8、15、22、29和36天），每50天重复一次；此外，在第1天和第22天通过3小时输注给予紫杉醇。在研究的I期使用了以下剂量水平。在剂量水平1至4中，FA以500 mg/m2的固定剂量给药，随后逐步增加大剂量5-FU的剂量（1.5 [剂量水平1]、1.8 [剂量水平2]和2.0 g/m2 [剂量水平3和4]的24小时输注）。在第1天和第22天给药3小时的紫杉醇剂量，在剂量水平1至3为135 mg/m2，在剂量水平4为175 mg/m2。选择剂量水平4在试验的II期部分进行进一步评估。在进入该试验这一部分的46例患者中，中位年龄为46岁（年龄范围为26至70岁），世界卫生组织的体能状态为0至1，转移部位的中位数量为2.5（范围为1至4个）。所有患者均有二维可测量疾病。9例患者先前接受过辅助化疗，16例接受过先前的转移化疗，21例接受过两种类型的化疗。在29例接受过蒽环类药物预处理的患者中，25例患有蒽环类药物耐药疾病。35例可评估患者的中期结果显示，1例患者完全缓解（3%），18例部分缓解（51%），14例病情稳定（40%），2例病情进展（6%）。总缓解率为54%（95%置信区间为36%至76%）。每位患者接受治疗周期的中位数量为3个（范围为1至5个），达到最大缓解的中位时间为2个月（范围为1至5个月），中位缓解持续时间为8 +个月（范围为2至17个月）。中位生存时间尚未达到。紫杉醇与每周大剂量5-FU/FA联合应用在转移性乳腺癌的二线治疗中耐受性良好，结果还表明对蒽环类药物耐药疾病具有高效。在一项正在进行的II期研究中，我们正在评估将顺铂添加到该方案中作为转移性乳腺癌的一线治疗。
