卡莫司汀、顺铂、依托泊苷预照射化疗联合加速放射治疗在高级别胶质瘤患者中的Ⅰ期及药代动力学研究

Phase I and pharmacokinetic study of preirradiation chemotherapy with BCNU, cisplatin, etoposide, and accelerated radiation therapy in patients with high-grade glioma.

作者信息

Rajkumar S V, Buckner J C, Schomberg P J, Reid J M, Bagniewski P J, Ames M M, Cascino T L, Marks R S

机构信息

Division of Medical Oncology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.

出版信息

Int J Radiat Oncol Biol Phys. 1998 Dec 1;42(5):969-75. doi: 10.1016/s0360-3016(98)00352-6.

DOI:10.1016/s0360-3016(98)00352-6

PMID:9869217

Abstract

PURPOSE

We conducted a Phase I study of bischloroethylnitrosourea (BCNU), cisplatin, and oral etoposide administered prior to and during accelerated hyperfractionated radiation therapy in newly diagnosed high-grade glioma. Pharmacokinetic studies of oral etoposide were also done.

METHODS AND MATERIALS

Patients started chemotherapy after surgery but prior to definitive radiation therapy (160 cGy twice daily x 15 days; 4800 cGy total). Initial chemotherapy consisted of BCNU 40 mg/m2 days 1-3, cisplatin 30 mg/m2 days 1-3 and 29-31, and etoposide 50 mg orally days 1-14 and 29-42, repeated in 8 weeks concurrent with radiation therapy. BCNU 200 mg/m2 every 8 weeks x 4 cycles was given after radiation therapy.

RESULTS

Sixteen patients, 5 with grade 3 anaplastic astrocytoma and 11 with glioblastoma were studied. Grade 3-4 leukopenia (38%) and thrombocytopenia (31%) were dose-limiting. Other toxicities were anorexia (81%), nausea (94%), emesis (56%), alopecia (88%), and ototoxicity (38%). The maximum tolerated dose was BCNU 40 mg/m2 days 1-3, cisplatin 20 mg/m2 days 1-3 and 29-31, and oral etoposide 50 mg days 1-21 and 29-49 prior to radiation therapy and repeated in 8 weeks with the start of radiation therapy followed by BCNU 200 mg/m2 every 8 weeks for 4 cycles. Median time to progression and survival were 13 and 14 months respectively. Responses occurred in 2 of 9 (22%) patients with evaluable disease. In pharmacokinetic studies, all patients achieved plasma concentrations of >0.1 microg/ml etoposide (the in vitro radiosensitizing threshold), following a 50 mg oral dose. The mean +/- SD 2 hr and 6 hr plasma concentrations were 0.92 +/- 0.43 microg/ml and 0.36 +/- 0.12 microg/ml, respectively. Estimated duration of exposure to >0.1 microg/ml etoposide was 10-17 hr.

CONCLUSIONS

Preirradiation chemotherapy with BCNU, cisplatin, and oral etoposide with accelerated hyperfractionated radiation therapy in high-grade gliomas is feasible and merits further investigation. Sustained radiosensitizing concentrations can be achieved with low oral doses of etoposide.

摘要

目的

我们开展了一项针对新诊断的高级别胶质瘤患者的Ⅰ期研究，在加速超分割放射治疗之前及期间给予双氯乙基亚硝脲（BCNU）、顺铂和口服依托泊苷，并对口服依托泊苷进行了药代动力学研究。

方法与材料

患者在手术后但在确定性放射治疗之前开始化疗（每天两次，每次160 cGy，共15天；总剂量4800 cGy）。初始化疗包括第1 - 3天给予BCNU 40 mg/m²，第1 - 3天和第29 - 31天给予顺铂30 mg/m²，第1 - 14天和第29 - 42天口服依托泊苷50 mg，在8周内与放射治疗同时重复进行。放射治疗后每8周给予BCNU 200 mg/m²，共4个周期。

结果

研究了16例患者，其中5例为3级间变性星形细胞瘤，11例为胶质母细胞瘤。3 - 4级白细胞减少（38%）和血小板减少（31%）为剂量限制性毒性。其他毒性包括厌食（81%）、恶心（94%）、呕吐（56%）、脱发（88%）和耳毒性（38%）。最大耐受剂量为放射治疗前第1 - 3天给予BCNU 40 mg/m²，第1 - 3天和第29 - 31天给予顺铂20 mg/m²，第1 - 21天和第29 - 49天口服依托泊苷50 mg，并在放射治疗开始时8周后重复，随后每8周给予BCNU 200 mg/m²，共进行4个周期。进展和生存的中位时间分别为13个月和14个月。9例可评估疾病的患者中有2例（22%）出现缓解。在药代动力学研究中，所有患者口服50 mg剂量后，血浆依托泊苷浓度均达到>0.1 μg/ml（体外放射增敏阈值）。2小时和6小时的平均±标准差血浆浓度分别为0.92±0.43 μg/ml和0.36±0.12 μg/ml。估计血浆依托泊苷浓度>0.1 μg/ml的暴露持续时间为10 - 17小时。