Phase II study of extended-dose temozolomide in patients with melanoma
Phase II study of extended-dose temozolomide in patients with melanoma
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DOI：
10.1200/jco.2007.14.5292
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发表时间：
2008-05-10
影响因子：
45.3
通讯作者：
Chapman, Paul B.
中科院分区：
文献类型：
--
作者：
Rietschel, Petra;Wolchok, Jedd D.;Chapman, Paul B.
我们进行了一项延长剂量替莫唑胺（TMZ）治疗黑色素瘤患者的II期临床试验，以检验以下假设：在接受延长剂量TMZ联合抗血管生成药物治疗的患者中观察到的约30%的缓解率是由TMZ单独引起的。我们假设，甲基鸟嘌呤甲基转移酶（MGMT）在肿瘤中的表达将与耐药性TMZ.Patients和MethodsPatients与IV期或不可切除的III期黑色素瘤与TMZ 75 mg/m2/d治疗6周，然后休息2周。重复周期直至进展。按M1 c疾病或非M1 c疾病对患者进行分层。主要终点是客观反应比例。MGMT的表达进行了评估甲基化特异性焦磷酸测序的启动子和免疫组化。ResultsForty-nine例（25 M1 C疾病）进行评估。每个队列中有3例患者（12.5%）出现部分缓解;无完全缓解。10名患者（21%）病情稳定，持续时间超过24周。中位进展时间为3.3个月。中位生存期为10.1个月;两个队列的生存期相似。估计18个月生存率为27%。反应与MGMT或MGMT启动子甲基化的免疫组织化学染色之间没有相关性。75%的患者开发的CD 4（+）淋巴细胞减少症后，three cycles.ConclusionExtended-dose TMZ治疗没有导致30%的反应率，这已被观察到使用抗血管生成剂的延长剂量TMZ。反应与MGMT表达或启动子甲基化作为连续变量无关，表明其他耐药机制也很重要。
PurposeWe conducted a phase II trial of extended-dose temozolomide (TMZ) in patients with melanoma to test the hypothesis that the approximately 30% response rate observed in patients treated with extended-dose TMZ with antiangiogenic agents was caused by TMZ alone. We hypothesized that expression of methylguanine methyltransferase (MGMT) in the tumor would correlate with drug resistance to TMZ.Patients and MethodsPatients with stage IV or unresectable stage III melanoma were treated with TMZ 75 mg/m(2)/d for 6 weeks followed by a 2-week rest period. Cycles were repeated until progression. Patients were stratified by M1c disease or not. The primary end point was objective response proportion. MGMT expression was assessed by methylation-specific pyrosequencing of the promoter and by immunohistochemistry.ResultsForty-nine patients (25 with M1c disease) were assessable. Three patients (12.5%) in each cohort experienced partial responses; there were no complete responses. Ten patients (21%) had stable disease lasting more than 24 weeks. Median time to progression was 3.3 months. Median survival was 10.1 months; survival was similar in the two cohorts. The estimated 18-month survival was 27%. There was no correlation between response and either immunohistochemistry staining for MGMT or for MGMT promoter methylation. Seventy-five percent of patients developed CD4(+) lymphopenia after three cycles.ConclusionExtended-dose TMZ therapy did not result in a 30% responses rate, which has been observed using extended-dose TMZ with antiangiogenic agents. Response did not correlate with MGMT expression or promoter methylation as a continuous variable, suggesting that other resistance mechanisms are important.