Adjuvant Temozolomide Chemotherapy With or Without Interferon Alfa Among Patients With Newly Diagnosed High-grade Gliomas: A Randomized Clinical Trial.

in JAMA network open by Chengcheng Guo, Qunying Yang, Pengfei Xu, Meiling Deng, Taipeng Jiang, Linbo Cai, Jibin Li, Ke Sai, Shaoyan Xi, Hui Ouyang, Mingfa Liu, Xianming Li, Zihuang Li, Xiangrong Ni, Xi Cao, Cong Li, Shaoxiong Wu, Xiaojing Du, Jun Su, Xiaoying Xue, Yiming Wang, Gang Li, Zhiyong Qin, Hui Yang, Tao Zhou, Jinquan Liu, Xuefeng Hu, Jian Wang, Xiaobing Jiang, Fuhua Lin, Xiangheng Zhang, Chao Ke, Xiaofei Lv, Yanchun Lv, Wanming Hu, Jing Zeng, Zhenghe Chen, Sheng Zhong, Hairong Wang, Yinsheng Chen, Ji Zhang, Depei Li, Yonggao Mou, Zhongping Chen

TLDR

  • This study found that combining temozolomide and interferon alfa significantly improved overall survival in patients with newly diagnosed high-grade gliomas, especially those with MGMT promoter unmethylation variant.
  • The study suggests that this combination therapy could be a promising treatment option for patients with high-grade gliomas.

Abstract

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. 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.

Overview

  • The study investigated the therapeutic efficacy and toxic effects of combining temozolomide and interferon alfa in patients with newly diagnosed high-grade gliomas (HGG).
  • The primary objective was to compare the 2-year overall survival (OS) between the two treatment groups, with temozolomide plus interferon alfa and temozolomide alone.
  • The study enrolled 199 patients with newly diagnosed HGG from 15 Chinese medical centers between May 2012 and March 2016.

Comparative Analysis & Findings

  • The results showed that the median OS was significantly longer in the temozolomide plus interferon alfa group (26.7 months) compared to the standard group (18.8 months), with a hazard ratio of 0.64 and P-value 0.005.
  • The study also found that temozolomide plus interferon alfa significantly improved median OS in patients with O6-methylguanine-DNA methyltransferase (MGMT) unmethylation compared to temozolomide, with a hazard ratio of 0.57 and P-value 0.008.
  • The most common toxic effects were seizures and influenzalike symptoms in the temozolomide plus interferon alfa group, with 2.0% and 5.0% of patients experiencing grades 1 and 2 toxic effects, respectively.

Implications and Future Directions

  • The study suggests that combining temozolomide and interferon alfa could prolong the survival time of patients with HGG, especially those with MGMT promoter unmethylation variant.
  • The study also suggests that methylation level at the IFNAR1/2 promoter could be a marker of sensitivity to temozolomide plus interferon alfa therapy.
  • Future studies could investigate the optimal dose and duration of interferon alfa treatment in combination with temozolomide to maximize its therapeutic benefit.
Read Full Article