Brem H, Mahaley M S, Vick N A, Black K L, Schold S C, Burger P C, Friedman A H, Ciric I S, Eller T W, Cozzens J W
Department of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland.
J Neurosurg. 1991 Mar;74(3):441-6. doi: 10.3171/jns.1991.74.3.0441.
Malignant gliomas have been difficult to treat with chemotherapy. The most effective agent, BCNU (carmustine), has considerable systemic toxicity and a short half-life in serum. To obviate these problems, a method has been developed for the local sustained release of chemotherapeutic agents by their incorporation into biodegradable polymers. Implantation of the drug-impregnated polymer at the tumor site allows prolonged local exposure with minimal systemic exposure. In this Phase I-II study, 21 patients with recurrent malignant glioma were treated with BCNU released interstitially by means of a polyanhydride biodegradable polymer implant. Up to eight polymer wafers were placed in the resection cavity intraoperatively, upon completion of tumor debulking. The polymer releases the therapeutic drug for approximately 3 weeks. Three increasing concentrations of BCNU were studied; the treatment was well tolerated at all three levels. There were no adverse reactions to the BCNU wafer treatment itself. The average survival period after reoperation was 65 weeks for the first dose group, 64 weeks for the second dose group, and 32 weeks for the highest dose group. The overall mean survival time was 48 weeks from reoperation and 94 weeks from the original operation. The overall median survival times were 46 weeks postimplant and 87 weeks from initial surgery. Eighteen (86%) of 21 patients lived more than 1 year from the time of their initial diagnosis and eight (38%) of 21 patients lived more than 1 year after intracranial implantation of the polymer. Frequent hematology, blood chemistry, and urinalysis tests did not reveal any systemic effect from this interstitial chemotherapy. Since the therapy is well tolerated and safe, a placebo-controlled clinical trial has been started. The trial will measure the effect of the second treatment dose on survival of patients with recurrent malignant glioma.
恶性胶质瘤一直难以通过化疗进行治疗。最有效的药物卡莫司汀（BCNU）具有相当大的全身毒性，且在血清中的半衰期较短。为了避免这些问题，人们开发了一种方法，即将化疗药物掺入可生物降解的聚合物中进行局部持续释放。将含药聚合物植入肿瘤部位可使局部暴露时间延长，全身暴露降至最低。在这项I-II期研究中，21例复发性恶性胶质瘤患者接受了通过聚酐可生物降解聚合物植入物进行间质内释放的BCNU治疗。在肿瘤切除完成后，术中在切除腔内放置多达8个聚合物薄片。聚合物可释放治疗药物约3周。研究了三种递增浓度的BCNU；在所有三个剂量水平下，治疗的耐受性都良好。对BCNU薄片治疗本身没有不良反应。第一剂量组再次手术后的平均生存期为65周，第二剂量组为64周，最高剂量组为32周。总体平均生存时间从再次手术起为48周，从初次手术起为94周。总体中位生存时间为植入后46周，从初次手术起为87周。21例患者中有18例（86%）自初次诊断起存活超过1年，21例患者中有8例（38%）在颅内植入聚合物后存活超过1年。频繁的血液学、血液化学和尿液分析检查未发现这种间质化疗有任何全身影响。由于该疗法耐受性良好且安全，已启动一项安慰剂对照的临床试验。该试验将测量第二次治疗剂量对复发性恶性胶质瘤患者生存的影响。
