Motzer R J, Gulati S C, Tong W P, Menendez-Botet C, Lyn P, Mazumdar M, Vlamis V, Lin S, Bosl G J
Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York.
Cancer Res. 1993 Aug 15;53(16):3730-5.
Thirty patients with cisplatin-refractory germ cell tumor were treated with high-dose carboplatin, etoposide, and cyclophosphamide and autologous bone marrow transplantation. The total dose of carboplatin was 1500 mg/m2, etoposide 1200 mg/m2, and cyclophosphamide was increased by increments from 60 to 150 mg/kg. Twenty-five cycles of treatment, given to 17 patients, did not include granulocyte-colony stimulating factor (G-CSF). Nineteen cycles of high-dose chemotherapy, given to 13 patients at the 2 highest dose levels of cyclophosphamide, included G-CSF. The dose of cyclophosphamide was escalated to 150 mg/kg/cycle without prohibitive toxicity. The use of G-CSF resulted in a shorter duration of neutropenia (P = 0.07); the median number of days until the recovery of an absolute granulocyte count > 0.5 was 25 without G-CSF and 14 with G-CSF. The most frequent nonhematological toxicity was hepatic, and there were 2 (7%) treatment-related deaths. Thirteen (43%) patients achieved a complete response, and 8 are alive and free of disease (27%); 7 are in continuous complete response (23%), and 1 after resection of a solitary site of disease following a relapse after high-dose chemotherapy. Five patients had pharmacology studies performed to determine the area under the curve (AUC) of free and total platinum, carboplatin, etoposide, cyclophosphamide, and phosphoramide mustard. There was a decrease in the AUC of cyclophosphamide and an increase in the AUC of phosphoramide mustard, the "active" metabolite, with successive days of treatment. The interpatient variability of the AUC of cyclophosphamide/phosphoramide mustard that was demonstrated was most likely a result of each individual's metabolic capacity. The measured AUC of carboplatin and/or free platinum closely approximated the predicted AUC of carboplatin calculated by renal function in 3 of the 5 patients. In summary, cyclophosphamide administered at a dose of 50 mg/kg x 3 days was achieved with acceptable toxicity, and no further dose escalation is planned. High-dose carboplatin, etoposide, and cyclophosphamide achieved a 23% continuous complete response proportion (27% alive, free of disease) when used as third-line therapy in germ cell tumor patients refractory to cisplatin + ifosfamide-based chemotherapy. Ongoing studies are addressing the role of high-dose carboplatin-containing chemotherapy in previously untreated patients with poor prognostic features or as a part of first-line salvage.
30例顺铂难治性生殖细胞肿瘤患者接受了大剂量卡铂、依托泊苷和环磷酰胺治疗及自体骨髓移植。卡铂总剂量为1500mg/m²，依托泊苷1200mg/m²，环磷酰胺剂量从60mg/kg递增至150mg/kg。给予17例患者的25个疗程治疗未使用粒细胞集落刺激因子（G-CSF）。给予13例患者的19个大剂量化疗疗程处于环磷酰胺的2个最高剂量水平，使用了G-CSF。环磷酰胺剂量增至150mg/kg/疗程且无严重毒性。使用G-CSF使中性粒细胞减少持续时间缩短（P = 0.07）；绝对粒细胞计数>0.5恢复前的中位天数，未使用G-CSF时为25天，使用G-CSF时为14天。最常见的非血液学毒性为肝脏毒性，有2例（7%）与治疗相关的死亡。13例（43%）患者达到完全缓解，8例存活且无疾病（27%）；7例持续完全缓解（23%），1例在大剂量化疗后复发，经手术切除单个病灶部位后缓解。5例患者进行了药理学研究以测定游离铂和总铂、卡铂、依托泊苷、环磷酰胺及磷酰胺芥的曲线下面积（AUC）。随着治疗天数的增加，环磷酰胺的AUC降低，“活性”代谢产物磷酰胺芥的AUC升高。所显示的环磷酰胺/磷酰胺芥AUC的患者间变异性很可能是由于个体代谢能力不同所致。5例患者中有3例测得的卡铂和/或游离铂的AUC与根据肾功能计算的卡铂预测AUC非常接近。总之，环磷酰胺以50mg/kg×3天的剂量给药毒性可接受，未计划进一步提高剂量。大剂量卡铂、依托泊苷和环磷酰胺作为三线治疗用于对基于顺铂+异环磷酰胺的化疗难治的生殖细胞肿瘤患者时，持续完全缓解率达23%（27%存活且无疾病）。正在进行的研究正在探讨含大剂量卡铂化疗在预后不良的既往未治疗患者中的作用或作为一线挽救治疗的一部分的作用。
