Comments on chemoradiotherapy in IDH wild‐type/TERT‐mutant grade 2/3 gliomas

We read with great interest the article by Zhang et al. evaluating chemoradiotherapy (CRT) with concurrent and adjuvant temozolomide versus radiotherapy (RT) alone in patients with isocitrate dehydrogenase (IDH) wild-type, telomerase reverse transcriptase (TERT) promoter–mutant, histologic grade 2/3 gliomas, now recognized as molecular glioblastoma under the 2021 World Health Organization (WHO) classification.1 The authors should be congratulated for assembling a molecularly homogeneous cohort and for addressing an important therapeutic uncertainty in this aggressive subgroup. Several points warrant clarification and may help contextualize the reported survival benefit. Although the initial cohort was randomized, the extension phase enrolled additional patients nonrandomly and exclusively into the CRT arm after an interim overall survival (OS) signal. Even with multivariable modeling and propensity score analyses, residual confounding related to time-period effects cannot be excluded. Changes in imaging surveillance, supportive care, and access to salvage therapies over time may disproportionately influence OS, particularly given the relatively small RT cohort. Reporting postprogression survival or incorporating salvage therapy as a time-dependent covariate could strengthen causal inference because postprotocol treatments are known to affect OS in glioblastoma trials.2 The influence of salvage therapy deserves further discussion. A substantial proportion of patients received treatment after progression, with numerical differences between groups. Prior work demonstrates that postprogression strategies can meaningfully alter survival in glioblastoma, complicating the interpretation of OS as an end point independent of subsequent therapies.2, 3 Clarification regarding the timing, intensity, and selection criteria for salvage treatments would help readers determine whether the observed OS advantage reflects delayed progression alone or a sustained benefit beyond first progression. The lack of prognostic impact of O6-methylguanine-DNA methyl-transferase (MGMT) promoter methylation within the CRT cohort is notable. In histologically defined glioblastoma, MGMT methylation is both prognostic and predictive of benefit from alkylating chemotherapy.4 However, emerging data suggest that binary methylation thresholds may be insufficient; rather, the extent and pattern of CpG methylation may better stratify outcomes, including in IDH wild-type/TERT-mutated astrocytomas.5 Therefore, quantitative MGMT analyses could identify subsets with differential sensitivity to temozolomide within molecular glioblastoma. Although all tumors harbored TERT promoter mutations, information on other defining molecular features of WHO 2021 molecular glioblastoma—such as epidermal growth factor receptor amplification or combined chromosome 7 gain/10 loss—was incomplete. Prior studies indicate that IDH wild-type gliomas with isolated TERT promoter mutation may have more favorable outcomes than other molecular glioblastoma subsets.6 Stratified analyses incorporating these co-alterations could clarify whether the benefit of CRT is uniform across molecular subgroups or is driven by specific genomic contexts. The authors appropriately contrast their findings with prior randomized trials and recent meta-analyses demonstrating limited benefit of alkylating chemotherapy in broadly defined IDH wild-type, lower grade gliomas.7 Diagnostic heterogeneity predating routine IDH and TERT testing likely contributed to discrepant results. In this context, the current study supports the hypothesis that treatment paradigms aligned with conventional glioblastoma—namely, RT with concurrent and adjuvant temozolomide—may be appropriate for carefully defined WHO 2021 molecular glioblastoma. Prospective multicenter validation, however, remains essential. In summary, Zhang and colleagues provide important data suggesting that CRT may improve outcomes in IDH wild-type/TERT promoter–mutant, grade 2/3 gliomas. Addressing the potential impact of nonrandomized extension, salvage therapy, and refined molecular stratification would further strengthen confidence in the robustness and generalizability of these findings. We invite the authors to comment on these issues. The authors disclosed no conflicts of interest.