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

Abstract

ImportanceHigh-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.ObjectivesTo 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 ParticipantsThis 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.InterventionsAll 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 MeasuresThe primary end point was 2-year overall survival (OS). Secondary end points were 2-year progression-free survival (PFS) and treatment tolerability.ResultsA 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 RelevanceCompared 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 RegistrationClinicalTrials.gov Identifier: NCT01765088

Deciphering Glioblastoma: Fundamental and Novel Insights into the Biology and Therapeutic Strategies of Gliomas

“…Despite these interventions, tumor recurrence is common, typically within 6.9 months, leading to a median survival time of only 12 to 15 months post-diagnosis [ 315 ]. Moreover, associating temozolomide with alfa interferon increases the overall survival in patients [ 316 ].…”

Radiotherapy and radio‐sensitization in H3K27M‐mutated diffuse midline gliomas

“…The newest clinical trials showed that GD2 and B7‐H3 CAR‐T cells therapies following standard radiotherapy are beneficial and safe for H3 K27M DMGs or DIPGs 230,231 . Additionally, a latest randomized clinical trial demonstrated the patients undergoing concurrent radio‐chemotherapy with interferon α had a longer survival time than those without interferon α in high‐grade gliomas 232 . The oncolytic virus Delta‐24‐RGD is recently reported to elicit an elevated sensitivity of H3 K27M DMGs to radiotherapy by increasing the trafficking of CD4 + and CD8 + cells to the tumor niche, and the downregulation of kinase activities in DDR system 233,234 .…”

“…230,231 Additionally, a latest randomized clinical trial demonstrated the patients undergoing concurrent radio-chemotherapy with interferon α had a longer survival time than those without interferon α in high-grade gliomas. 232 The oncolytic virus Delta-24-RGD is recently reported to elicit an elevated sensitivity of H3 K27M…”

“… 230 , 231 Additionally, a latest randomized clinical trial demonstrated the patients undergoing concurrent radio‐chemotherapy with interferon α had a longer survival time than those without interferon α in high‐grade gliomas. 232 The oncolytic virus Delta‐24‐RGD is recently reported to elicit an elevated sensitivity of H3 K27M DMGs to radiotherapy by increasing the trafficking of CD4 + and CD8 + cells to the tumor niche, and the downregulation of kinase activities in DDR system. 233 , 234 Another oncolytic virus DNX‐2401 followed by radiotherapy can reduce and stabilize tumor size in pediatric DIPGs clinical trial.…”

Harnessing type I interferon-mediated immunity to target malignant brain tumors

“…The efficacy of recombinant IFN therapy has been demonstrated in a randomized clinical trial involving high-grade glioma patients. The overall survival was improved upon treatment with temozolomide and IFNα, demonstrating the benefits of combination treatment over the conventional use of temozolomide alone ( 108 ). In addition, the combination of IFNα with BCNU and radiation therapy showed increased overall survival among high-grade glioma patients, thus demonstrating the safe and feasible use of IFNs with other cancer therapies ( 109 ).…”