Siegert W, Beyer J, Strohscheer I, Baurmann H, Oettle H, Zingsem J, Zimmermann R, Bokemeyer C, Schmoll H J, Huhn D
Universitätsklinikum Rudolf Virchow, Abteilung für Innere, Medizin mit Schwerpunkt Hämatologie und Onkologie, Freie Universität Berlin, Germany.
J Clin Oncol. 1994 Jun;12(6):1223-31. doi: 10.1200/JCO.1994.12.6.1223.
This trial evaluated the toxicity and efficacy of high-dose carboplatin, etoposide, and ifosfamide followed by autologous stem-cell transplantation in patients with refractory or relapsed germ cell cancer.
Between August 1989 and September 1992, 74 patients with refractory or recurrent germ-cell tumors received one cycle of escalating doses of carboplatin (1,500 to 2,000 mg/m2), etoposide (1,200 to 2,400 mg/m2), and ifosfamide (0 to 10 g/m2). Before high-dose therapy, two cycles of conventional-dose cisplatin, etoposide, and ifosfamide were administered to assess tumor responsiveness. Seventy-four patients were assessable for toxicity and 68 for response.
The doses of carboplatin 1,500 mg/m2, etoposide 2,400 mg/m2, and ifosfamide 10 g/m2 appeared to be safe. At this dosage, we treated 20 patients and observed World Health Organization (WHO) grade 3 and 4 hematotoxicity (100%), nausea (100%), diarrhea (30%), and hepatotoxicity (10%). All patients developed granulocytopenic fever. At carboplatin doses of 1,500 mg/m2, kidney toxicity was mild, with a median maximum creatinine level of 1.4 mg/dL (range, 1.1 to 3.0 mg/dL). However, at carboplatin doses of 1,750 and 2,000 mg/m2, we observed nonacceptable nephrotoxicity and neurotoxicity. Two (3%) patients died of treatment-related complications. Six patients required hemodialysis, which was temporary in five patients and permanent in one. Objective responses were obtained in 43 of 68 (63%) patients, including 21 (31%) complete remissions (CRs) and 14 (20%) inoperable partial remissions (PRs) with marker normalization. The median observation time of surviving patients was 12 months (range, 2 to 32). The probabilities of overall survival, event-free survival, and the relapse-free survival at 2 years were 44% (SD 8%), 35% (SD 6%), and 67% (SD 9%), respectively. Patients with disease refractory to conventional-dose pretreatment had a poor prognosis, with only one of 23 patients surviving event-free at 7 months after high-dose chemotherapy (HDT). In contrast, 24 of 45 (53.3%) patients with sensitive disease survive event-free with a probability of event-free survival at 2 years of 50% (SD 8%).
High-dose carboplatin, etoposide, and ifosfamide plus autologous stem-cell transplantation can be used in refractory and relapsed germ cell cancer with acceptable toxicity, and represents an effective, potentially curative salvage treatment.
本试验评估了大剂量卡铂、依托泊苷和异环磷酰胺联合自体干细胞移植治疗难治性或复发性生殖细胞癌患者的毒性和疗效。
1989年8月至1992年9月期间，74例难治性或复发性生殖细胞肿瘤患者接受了一个周期递增剂量的卡铂（1500至2000mg/m²）、依托泊苷（1200至2400mg/m²）和异环磷酰胺（0至10g/m²）治疗。在大剂量治疗前，给予两个周期的常规剂量顺铂、依托泊苷和异环磷酰胺以评估肿瘤反应性。74例患者可评估毒性，68例可评估反应。
卡铂1500mg/m²、依托泊苷2400mg/m²和异环磷酰胺10g/m²的剂量似乎是安全的。在此剂量下，我们治疗了20例患者，观察到世界卫生组织（WHO）3级和4级血液毒性（100%）、恶心（100%）、腹泻（30%）和肝毒性（10%）。所有患者均发生粒细胞减少性发热。卡铂剂量为1500mg/m²时，肾脏毒性较轻，肌酐最高水平中位数为1.4mg/dL（范围为1.1至3.0mg/dL）。然而，卡铂剂量为1750和2000mg/m²时，我们观察到不可接受的肾毒性和神经毒性。2例（3%）患者死于治疗相关并发症。6例患者需要血液透析，其中5例为暂时性，1例为永久性。68例患者中有43例（63%）获得客观反应，包括21例（31%）完全缓解（CR）和14例（20%）无法手术的部分缓解（PR）且标志物正常化。存活患者的中位观察时间为12个月（范围为2至32个月）。2年时的总生存率、无事件生存率和无复发生存率分别为44%（标准差8%）、35%（标准差6%）和67%（标准差9%）。对常规剂量预处理难治的疾病患者预后较差，大剂量化疗（HDT）后23例患者中只有1例在7个月时无事件存活。相比之下，45例（53.3%）敏感疾病患者中有24例无事件存活，2年时无事件生存率为50%（标准差8%）。
大剂量卡铂、依托泊苷和异环磷酰胺联合自体干细胞移植可用于难治性和复发性生殖细胞癌，毒性可接受，是一种有效的、潜在可治愈的挽救治疗方法。
