Guo Chengcheng, Yang Qunying, Xu Pengfei, Deng Meiling, Jiang Taipeng, Cai Linbo, Li Jibin, Sai Ke, Xi Shaoyan, Ouyang Hui, Liu Mingfa, Li Xianming, Li Zihuang, Ni Xiangrong, Cao Xi, Li Cong, Wu Shaoxiong, Du Xiaojing, Su Jun, Xue Xiaoying, Wang Yiming, Li Gang, Qin Zhiyong, Yang Hui, Zhou Tao, Liu Jinquan, Hu Xuefeng, Wang Jian, Jiang Xiaobing, Lin Fuhua, Zhang Xiangheng, Ke Chao, Lv Xiaofei, Lv Yanchun, Hu Wanming, Zeng Jing, Chen Zhenghe, Zhong Sheng, Wang Hairong, Chen Yinsheng, Zhang Ji, Li Depei, Mou Yonggao, Chen Zhongping
Department of Neurosurgery and Neuro-oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
Department of Radiation, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
JAMA Netw Open. 2023 Jan 3;6(1):e2253285. doi: 10.1001/jamanetworkopen.2022.53285.
High-grade gliomas (HGGs) constitute the most common and aggressive primary brain tumor, with 5-year survival rates of 30.9% for grade 3 gliomas and 6.6% for grade 4 gliomas. The add-on efficacy of interferon alfa is unclear for the treatment of HGG.
To compare the therapeutic efficacy and toxic effects of the combination of temozolomide and interferon alfa and temozolomide alone in patients with newly diagnosed HGG.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter, randomized, phase 3 clinical trial enrolled 199 patients with newly diagnosed HGG from May 1, 2012, to March 30, 2016, at 15 Chinese medical centers. Follow-up was completed July 31, 2021, and data were analyzed from September 13 to November 24, 2021. Eligible patients were aged 18 to 75 years with newly diagnosed and histologically confirmed HGG and had received no prior chemotherapy, radiotherapy, or immunotherapy for their HGG.
All patients received standard radiotherapy concurrent with temozolomide. After a 4-week break, patients in the temozolomide with interferon alfa group received standard temozolomide combined with interferon alfa every 28 days. Patients in the temozolomide group received standard temozolomide.
The primary end point was 2-year overall survival (OS). Secondary end points were 2-year progression-free survival (PFS) and treatment tolerability.
A total of 199 patients with HGG were enrolled, with a median follow-up time of 66.0 (95% CI, 59.1-72.9) months. Seventy-nine patients (39.7%) were women and 120 (60.3%) were men, with ages ranging from 18 to 75 years and a median age of 46.9 (95% CI, 45.3-48.7) years. The median OS of patients in the temozolomide plus interferon alfa group (26.7 [95% CI, 21.6-31.7] months) was significantly longer than that in the standard group (18.8 [95% CI, 16.9-20.7] months; hazard ratio [HR], 0.64 [95% CI, 0.47-0.88]; P = .005). Temozolomide plus interferon alfa also significantly improved median OS in patients with O6-methylguanine-DNA methyltransferase (MGMT) unmethylation (24.7 [95% CI, 20.5-28.8] months) compared with temozolomide (17.4 [95% CI, 14.1-20.7] months; HR, 0.57 [95% CI, 0.37-0.87]; P = .008). Seizure and influenzalike symptoms were more common in the temozolomide plus interferon alfa group, with 2 of 100 (2.0%) and 5 of 100 (5.0%) patients with grades 1 and 2 toxic effects, respectively (P = .02). Finally, results suggested that methylation level at the IFNAR1/2 promoter was a marker of sensitivity to temozolomide plus interferon alfa.
Compared with the standard regimen, temozolomide plus interferon alfa treatment could prolong the survival time of patients with HGG, especially the MGMT promoter unmethylation variant, and the toxic effects remained tolerable.
ClinicalTrials.gov Identifier: NCT01765088.
高级别胶质瘤（HGG）是最常见且侵袭性最强的原发性脑肿瘤，3级胶质瘤的5年生存率为30.9%，4级胶质瘤的5年生存率为6.6%。干扰素α在HGG治疗中的附加疗效尚不清楚。
比较替莫唑胺与干扰素α联合治疗和单独使用替莫唑胺治疗新诊断HGG患者的疗效和毒性作用。
设计、地点和参与者：这项多中心、随机、3期临床试验于2012年5月1日至2016年3月30日在中国15个医学中心招募了199例新诊断的HGG患者。随访于2021年7月31日完成，数据于2021年9月13日至11月24日进行分析。符合条件的患者年龄在18至75岁之间，新诊断且经组织学证实为HGG，且此前未接受过针对其HGG的化疗、放疗或免疫治疗。
所有患者均接受与替莫唑胺同步的标准放疗。休息4周后，替莫唑胺联合干扰素α组的患者每28天接受标准替莫唑胺联合干扰素α治疗。替莫唑胺组的患者接受标准替莫唑胺治疗。
主要终点为2年总生存期（OS）。次要终点为2年无进展生存期（PFS）和治疗耐受性。
共纳入199例HGG患者，中位随访时间为66.0（95%CI:59.1 - 72.9）个月。79例（39.7%）为女性，120例（60.3%）为男性，年龄范围为18至75岁，中位年龄为46.9（95%CI:45.3 - 48.7）岁。替莫唑胺加干扰素α组患者的中位OS（26.7[95%CI:21.6 - 31.7]个月）显著长于标准组（18.8[95%CI:16.9 - 20.7]个月；风险比[HR]，0.64[95%CI:0.47 - 0.88]；P = 0.005）。与替莫唑胺（17.4[95%CI:14.1 - 20.7]个月；HR，0.57[95%CI:0.37 - 0.87]；P = 0.008）相比，替莫唑胺加干扰素α也显著改善了O6 - 甲基鸟嘌呤 - DNA甲基转移酶（MGMT）未甲基化患者的中位OS（24.7[95%CI:20.5 - 28.8]个月）。癫痫和流感样症状在替莫唑胺加干扰素α组中更常见，100例患者中有2例（2.0%）出现1级毒性作用，5例（5.0%）出现2级毒性作用（P = 0.02）。最后，结果表明IFNAR1/2启动子处的甲基化水平是对替莫唑胺加干扰素α敏感性的一个标志物。（P = 0.02）。最后，结果表明IFNAR1/2启动子处的甲基化水平是对替莫唑胺加干扰素α敏感性的一个标志物。
与标准方案相比，替莫唑胺加干扰素α治疗可延长HGG患者的生存时间，尤其是MGMT启动子未甲基化变异型患者，且毒性作用仍可耐受。
ClinicalTrials.gov标识符：NCT01765088。
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