Prados Michael D, Chang Susan M, Butowski Nicholas, DeBoer Rebecca, Parvataneni Rupa, Carliner Hannah, Kabuubi Paul, Ayers-Ringler Jennifer, Rabbitt Jane, Page Margaretta, Fedoroff Anne, Sneed Penny K, Berger Mitchel S, McDermott Michael W, Parsa Andrew T, Vandenberg Scott, James C David, Lamborn Kathleen R, Stokoe David, Haas-Kogan Daphne A
University of California, San Francisco, CA 94143, USA.
J Clin Oncol. 2009 Feb 1;27(4):579-84. doi: 10.1200/JCO.2008.18.9639. Epub 2008 Dec 15.
This open-label, prospective, single-arm, phase II study combined erlotinib with radiation therapy (XRT) and temozolomide to treat glioblastoma multiforme (GBM) and gliosarcoma. The objectives were to determine efficacy of this treatment as measured by survival and to explore the relationship between molecular markers and treatment response.
Sixty-five eligible adults with newly diagnosed GBM or gliosarcoma were enrolled. We intended to treat patients not currently treated with enzyme-inducing antiepileptic drugs (EIAEDs) with 100 mg/d of erlotinib during XRT and 150 mg/d after XRT. Patients receiving EIAEDs were to receive 200 mg/d of erlotinib during XRT and 300 mg/d after XRT. After XRT, the erlotinib dose was escalated until patients developed tolerable grade 2 rash or until the maximum allowed dose was reached. All patients received temozolomide during and after XRT. Molecular markers of epidermal growth factor receptor (EGFR), EGFRvIII, phosphatase and tensin homolog (PTEN), and methylation status of the promotor region of the MGMT gene were analyzed from tumor tissue. Survival was compared with outcomes from two historical phase II trials.
Median survival was 19.3 months in the current study and 14.1 months in the combined historical control studies, with a hazard ratio for survival (treated/control) of 0.64 (95% CI, 0.45 to 0.91). Treatment was well tolerated. There was a strong positive correlation between MGMT promotor methylation and survival, as well as an association between MGMT promotor-methylated tumors and PTEN positivity shown by immunohistochemistry with improved survival.
Patients treated with the combination of erlotinib and temozolomide during and following radiotherapy had better survival than historical controls. Additional studies are warranted.
本开放标签、前瞻性、单臂、II期研究将厄洛替尼与放射治疗（XRT）及替莫唑胺联合用于治疗多形性胶质母细胞瘤（GBM）和胶质肉瘤。目的是确定这种治疗方法以生存为指标的疗效，并探索分子标志物与治疗反应之间的关系。
招募了65例新诊断为GBM或胶质肉瘤的符合条件的成年人。我们打算对目前未接受酶诱导抗癫痫药物（EIAEDs）治疗的患者在放疗期间给予100mg/d的厄洛替尼，放疗后给予150mg/d。接受EIAEDs治疗的患者在放疗期间给予200mg/d的厄洛替尼，放疗后给予300mg/d。放疗后，厄洛替尼剂量逐步增加，直至患者出现可耐受的2级皮疹或达到最大允许剂量。所有患者在放疗期间及放疗后均接受替莫唑胺治疗。从肿瘤组织中分析表皮生长因子受体（EGFR）、EGFRvIII、磷酸酶和张力蛋白同源物（PTEN）的分子标志物以及MGMT基因启动子区域的甲基化状态。将生存情况与两项历史II期试验的结果进行比较。
在本研究中，中位生存期为19.3个月，在合并的历史对照研究中为14.1个月，生存风险比（治疗组/对照组）为0.64（95%CI，0.45至0.91）。治疗耐受性良好。MGMT启动子甲基化与生存之间存在强正相关，并且通过免疫组织化学显示MGMT启动子甲基化的肿瘤与PTEN阳性之间存在关联，生存情况有所改善。
在放疗期间及放疗后接受厄洛替尼和替莫唑胺联合治疗的患者比历史对照患者生存情况更好。有必要进行进一步研究。
