Phase II Study of Protracted Daily Temozolomide for Low-Grade Gliomas in Adults
Phase II Study of Protracted Daily Temozolomide for Low-Grade Gliomas in Adults
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DOI：
10.1158/1078-0432.ccr-08-0888
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发表时间：
2009-01-01
影响因子：
11.5
通讯作者：
Wen, Patrick Y.
中科院分区：
文献类型：
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作者：
Kesari, Santosh;Schiff, David;Wen, Patrick Y.
目的：替莫唑胺耐药部分由O-6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）介导。替莫唑胺的普罗帕酮治疗可能克服MGMT耐药性并改善结局。我们进行了一项长期每日替莫唑胺治疗成人低级别胶质瘤的11期研究。实验设计：新诊断的少突胶质细胞瘤或少突星形细胞瘤患者，MIB-1指数> 5%，或复发的低级别胶质瘤患者接受替莫唑胺治疗（75 mg/m2/d，11周为1个周期，7周给药/4周停药）。治疗持续总共六个周期或直到肿瘤进展或不可接受的毒性。主要终点为最佳总缓解率;次要终点为无进展生存期、总生存期和毒性。我们将反应与MGMT启动子甲基化和染色体1 p/19 q缺失status.Results相关：44例患者接受治疗（14例女性，30例男性），中位随访时间为39.4个月。中位年龄为43岁（范围：20-68岁），中位Karnofsky体能状态为90（范围：70-100）。该方案耐受性良好。无患者完全缓解（0%），9例部分缓解（20%），33例疾病稳定（75%），2例疾病进展（5%）。共有21例患者最终进展，总体中位无进展生存期为38个月。MGMT启动子甲基化患者的总生存期较长（P = 0.008）。删除1 p或19 q染色体也预测较长的总生存期（风险比，0.17; 95%置信区间，0.03-0.93;对数秩P = 0.02）。结论：延长疗程的每日替莫唑胺是一种耐受性良好的方案，似乎产生有效的肿瘤控制。这与标准5天替莫唑胺方案的历史数据相比是有利的。
Purpose: Resistance to temozolomide chemotherapy is partly mediated by O-6-methylguanine-DNA methlytransferase (MGMT). Protracted treatment with temozolomide potentially overcomes MGMT resistance and improves outcome. We conducted a phase 11 study of protracted daily temozolomide in adults with low-grade gliomas.Experimental Design: Patients with newly diagnosed oligodendroglioma or oligoastrocytoma with a MIB-1 index of > 5% or recurrent low-grade gliomas received temozolomide (75 mg/m(2)/day in 11-week cycles of 7 weeks on/4 weeks off). Treatment continued for a total of six cycles or until tumor progression or unacceptable toxicity. Primary end point was best overall response rate; secondary end points were progression-free survival, overall survival, and toxicity. We correlated response with MGMT promoter methylation and chromosome 1p/19q deletion status.Results: Forty-four patients were treated (14 female, 30 male) with a median follow-up of 39.4 months. Median age was 43 years (range, 20-68 years) and median Karnofsky performance status was 90 (range, 70-100). The regimen was well tolerated. No patients had a complete response (0%), 9 had partial response (20%), 33 had stable disease (75%), and 2 had progressive disease (5%). A total of 21 patients eventually progressed with an overall median progression-free survival of 38 months. Patients with methylated MGMT promoter had a longer overall survival (P = 0.008). Deletion of either 1p or 19q chromosomes also predicted longer overall survival (hazard ratio, 0.17; 95% confidence interval, 0.03-0.93; log-rank P = 0.02).Conclusions: A protracted course of daily temozolomide is a well-tolerated regimen and seems to produce effective tumor control. This compares favorably with historical data on the standard 5-day temozolomide regimen.