Prince H M, Rischin D, Quinn M, Allen D, Planner R, Neesham D, Gates P, Davison J
Blood and Marrow Transplant Service, Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Melbourne, Victoria 3000, Australia.
Gynecol Oncol. 2001 May;81(2):216-24. doi: 10.1006/gyno.2001.6121.
In view of the significant activity of topotecan in ovarian cancer with dose-limiting toxicity (DLT) of myelosuppression, we evaluated the addition of topotecan to carboplatin and paclitaxel with peripheral blood progenitor cell (PBPC) support.
Patients with previously untreated stage IIIC or IV ovarian cancer with macroscopic residual disease following primary debulking surgery were eligible. Patients received two cycles of carboplatin AUC = 5 and 175 mg/m(2) of paclitaxel with collection of PBPCs after the second cycle. Patients subsequently received three cycles of high-dose therapy (HDT) with topotecan on a daily x5 schedule, paclitaxel (250 mg/m(2) over 24 h), and carboplatin (AUC = 12-16).
Nineteen patients with a median age of 49 years (range 21-63) were enrolled and topotecan was escalated in 6 patient cohorts up to a dose of 4.5 mg/m(2)/day. Fifty-two of the planned 57 treatment cycles were delivered with no treatment-related deaths. Neutrophil and platelet recovery was rapid and the interval between HDT was 28 days. Febrile neutropenia occurred following 57% of all HDT cycles. DLTs of mucositis and diarrhea were observed at topotecan (4.5 mg/m(2)/day), paclitaxel (250 mg/m(2)) and carboplatin (AUC = 12). The protocol was subsequently modified to administer topotecan (2.5 mg/m(2)/day) with carboplatin (AUC = 16); however, 2 patients developed grade 4 diarrhea (1 with grade 3 mucositis and 1 with grade 4 mucositis). The clinical CR rate was 73% (14/19) with an overall clinical response rate of 95% (18/19). Of the 14 patients with a CCR, 13 of these underwent a second-look laparotomy with 8 (61%) achieving a pathological CR. With a median follow-up of 28 months (range 11-40 months), the median PFS is 36 months and OS has not been reached.
When combined with carboplatin (AUC = 12) and paclitaxel (250 mg/m(2)), the recommended topotecan dose is 3.5 mg/m(2)/day for 5 days. This outpatient HDT regimen combines three of the most active drugs in ovarian cancer with acceptable toxicity and promising activity.
鉴于拓扑替康对卵巢癌具有显著活性，但存在骨髓抑制这一剂量限制性毒性（DLT），我们评估了在给予外周血祖细胞（PBPC）支持的情况下，将拓扑替康添加到卡铂和紫杉醇治疗方案中的效果。
符合条件的患者为初次肿瘤细胞减灭术后有肉眼可见残留病灶的IIIC期或IV期未经治疗的卵巢癌患者。患者接受两个周期的卡铂（AUC = 5）和175 mg/m²的紫杉醇治疗，在第二个周期后采集PBPC。随后，患者接受三个周期的高剂量治疗（HDT），拓扑替康采用每日×5的给药方案，紫杉醇（24小时内给予250 mg/m²），卡铂（AUC = 12 - 16）。
纳入了19例患者，中位年龄49岁（范围21 - 63岁），拓扑替康在6个患者队列中进行剂量递增，最高剂量达到4.5 mg/m²/天。计划的57个治疗周期中有52个完成，无治疗相关死亡。中性粒细胞和血小板恢复迅速，HDT之间的间隔为28天。所有HDT周期中有57%发生发热性中性粒细胞减少。在拓扑替康剂量为4.5 mg/m²/天、紫杉醇剂量为250 mg/m²和卡铂剂量为AUC = 12时，观察到黏膜炎和腹泻的DLT。随后对方案进行修改，给予拓扑替康（2.5 mg/m²/天）和卡铂（AUC = 16）；然而，有2例患者出现4级腹泻（1例伴有3级黏膜炎，1例伴有4级黏膜炎）。临床完全缓解（CR）率为73%（14/19），总体临床缓解率为95%（18/19）。在14例达到临床CR的患者中，13例接受了二次剖腹探查，其中8例（61%）实现了病理CR。中位随访28个月（范围11 - 40个月），中位无进展生存期（PFS）为36个月，总生存期（OS）尚未达到。
当与卡铂（AUC = 12）和紫杉醇（250 mg/m²）联合使用时，拓扑替康的推荐剂量为3.5 mg/m²/天，持续5天。这种门诊HDT方案将卵巢癌中三种最具活性的药物联合使用，毒性可接受且活性良好。
