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

Chengcheng Guo, MD, PhD¹; Qunying Yang, MD, PhD¹; Pengfei Xu, MD, PhD¹Meiling Deng, MD, PhD²; Taipeng Jiang, MD, PhD³; Linbo Cai, MD, PhD⁴; Jibin Li, MD, PhD⁵; Ke Sai, MD, PhD¹; Shaoyan Xi, MD, PhD⁶; Hui Ouyang, MD, PhD⁷; Mingfa Liu, MD, PhD⁸; Xianming Li, MD, PhD^9,10; Zihuang Li, MD, PhD^9,10; Xiangrong Ni, MD, PhD¹; Xi Cao, BSN¹; Cong Li, MD, PhD^11,12; Shaoxiong Wu, MD, PhD²; Xiaojing Du, MD, PhD²; Jun Su, MD, PhD¹³; Xiaoying Xue, MD, PhD¹⁴; Yiming Wang, MD, PhD¹⁵; Gang Li, MD, PhD¹⁶; Zhiyong Qin, MD, PhD^17,18,19; Hui Yang, MD, PhD²⁰; Tao Zhou, MD, PhD²¹; Jinquan Liu, MD, PhD²²; Xuefeng Hu, MD, PhD²³; Jian Wang, MD, PhD¹; Xiaobing Jiang, MD, PhD¹; Fuhua Lin, MD, PhD¹; Xiangheng Zhang, MD, PhD¹; Chao Ke, MD, PhD¹; Xiaofei Lv, MD, PhD²⁴; Yanchun Lv, MD, PhD²⁴; Wanming Hu, MD, PhD⁶; Jing Zeng, MD, PhD⁶; Zhenghe Chen, MD, PhD¹; Sheng Zhong, MD, PhD¹; Hairong Wang, MD¹; Yinsheng Chen, MD, PhD¹; Ji Zhang, MD, PhD¹; Depei Li, MD, PhD¹; Yonggao Mou, MD, PhD¹; Zhongping Chen, MD, PhD¹

doi:10.1001/jamanetworkopen.2022.53285

Abstract

 RCT: Adjuvant Temozolomide Chemotherapy With or Without Interferon alfa in Newly Diagnosed High-Grade Gliomas

Visual Abstract.

Importance  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.

Objectives  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.

Interventions  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.

Main Outcomes and Measures  The primary end point was 2-year overall survival (OS). Secondary end points were 2-year progression-free survival (PFS) and treatment tolerability.

Results  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.

Conclusions and Relevance  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.

Trial Registration  ClinicalTrials.gov Identifier: NCT01765088

초록(Abstract) 무작위 대조 연구(RCT): 새로 진단된 고등급 교종에서 테모졸로마이드 보조항암요법에 인터페론 알파 병용 여부

의의(Importance)·  고등급 교종(HGG)은 가장 흔하고 공격적인 원발성 뇌종양·  5년 생존율: 3등급 30.9%, 4등급 6.6%·  HGG 치료에서 인터페론 알파의 추가 효과는 불명확함

목적(Objectives)새로 진단된 HGG 환자에서 테모졸로마이드와 인터페론 알파 병용요법과 테모졸로마이드 단독요법의 치료 효과 및 독성(부작용)을 비교하는 것.

연구 설계, 장소, 참여자(Design, Setting, and Participants)·  다기관(중국 내 15개 의료기관), 무작위배정, 3상 임상시험·  기간: 2012.5.1 ~ 2016.3.30 등록, 추적 2021.7.31 완료·  자료 분석 : 2021.0913 ~ 2021.11.24·  환자 수: 199명 (여 79명 39.7%, 남 120명 60.3%)·  나이: 18~75세, 중앙값 46.9세·  조건: 새로 진단, 조직학적으로 HGG 확진, 해당 종양에 대해 화학요법 · 방사선치료 · 면역치료를 받은 적이 없는 경우.

중재(Interventions)·  모든 환자: 표준 방사선치료 + 동시 테모졸로마이드·  4주 휴식 후   병용군: 표준 테모졸로마이드 + 인터페론 알파 (28일 주기)   단독군: 표준 테모졸로마이드

주요 평가변수(Main Outcomes and Measures)주요 평가변수 : 2년 전체 생존율(2-year OS)이차 평가변수는 : 2년 무진행 생존율(2-year PFS), 치료 내약성(tolerability)

결과(Results)·  중앙 추적 기간: 66.0개월·  전체 생존기간(OS)   병용군: 26.7개월 (95% CI, 21.6~31.7)   단독군: 18.8개월 (95% CI, 16.9~20.7)   HR 0.64 (95% CI, 0.47~0.88), P=0.005·  MGMT 프로모터 비메틸화 환자   병용군: 24.7개월 (95% CI, 20.5~28.8)   단독군: 17.4개월 (95% CI, 14.1~20.7)   HR 0.57 (95% CI, 0.37~0.87), P=0.008·  부작용   병용군에서 발작(2.0%)과 독감 유사 증상(5.0%) 더 흔함   모두 1~2등급, P=0.02 전반적으로 내약 가능 수준.·  바이오마커   IFNAR1/2 프로모터 메틸화 수준이 병용치료 민감성 예측 가능성 시사

결론 및 의의(Conclusions and Relevance)·  표준 요법 대비 테모졸로마이드+인터페론 알파는 HGG 환자 생존기간을 연장·  특히 MGMT 비메틸화 환자에서 효과 뚜렷했음.·  독성은 수용 가능한 수준이었음.

임상시험 등록번호(Trial Registration): ClinicalTrials.gov Identifier: NCT01765088