Thank you for sharing the valuable comments from Katkuri and colleagues on our article.1 We highly appreciate these constructive insights and would like to address each raised concern in detail below to further clarify the reliability and clinical significance of our findings: Consistent eligibility criteria: The extension cohort (enrolled 2020–2022) strictly adhered to the same inclusion/exclusion criteria as the initial randomized cohort (2016–2019), including molecular characteristics (isocitrate dehydrogenase IDH wild type + telomerase reverse transcriptase TERT promoter mutation + 1p/19q non–co-deletion), age (18–70 years), and Karnofsky performance scale score (≥60). Moreover, no statistically significant differences were observed in baseline characteristics between the two cohorts (see Table S2). Multidimensional statistical adjustments: In addition to multivariable Cox regression and propensity score matching, we performed inverse probability of treatment weighting analysis. Both adjustment methods confirmed consistent survival benefits of chemoradiotherapy (CRT) compared with unadjusted results (progression-free survival: hazard ratio, 0.393–0.375; overall survival OS, hazard ratio, 0.368–0.436; all p < .05), indicating that time-period effects did not significantly alter the core conclusions. Although we reported the findings in two separate parts, the enrollment of patients was consecutive, and all participants were recruited during the period after the integration of molecular pathology into the 2016 World Health Organization classification. We supplement that the proportion of patients receiving salvage therapy after progression was higher in the CRT group (58.9%; 20 of 34 patients) than in the RT group (47.1%, 8/17). The median time to progression was significantly longer in the CRT group (14.2 months) than in the RT group (7.1 months, P = 0.002). The longer progression-free period provided CRT patients with more sufficient time to receive salvage therapy. However, this is inherently an extension of the initial treatment benefit rather than an independent confounding factor. Salvage therapy was initiated only after disease progression. However, PFS has shown a statistically significant difference, and OS is theoretically expected to benefit accordingly though discrepancies in salvage therapy may influence the trend of OS. Due to the limited sample size of this study, we did not conduct a dedicated stratified analysis by “whether salvage therapy was received,” and thus cannot provide survival comparison data under this stratification. The study used pyrosequencing to measure the average methylation level of seven CpG sites in the MGMT promoter (cutoff value, 10%), a method validated in multiple glioma studies for its reliability. As highlighted by the reviewers, although MGMT promoter methylation has clear prognostic value in histologically defined glioblastoma, its association in IDH–wild type, lower-grade gliomas remains unclear. Multiple previous studies, including Radiation Therapy Oncology Group trial RTOG 9802 and CATNON (ClinicalTrials.gov identifiers NCT00003375 and NCT00626990, respectively), have reported no definite correlation between prognosis and MGMT promoter methylation in IDH–wild type, lower grade gliomas, consistent with our findings. This suggests that temozolomide sensitivity in this molecular subtype may be regulated by other mechanisms.2, 3 Regarding the molecular features of interest to the commentators, such as epidermal growth factor receptor (EGFR) amplification and combined chromosome 7 gain/10 loss (+7/−10), we provide the following clarifications: When the initial study was designed (2016), indicators such as EGFR amplification and +7/−10 were not included in routine detection panels. Therefore, relevant data were only available for a subset of patients in the extension cohort (EGFR amplification rate, 7.5%; +7/−10 incidence, 17.5%), with a sample size insufficient for stratified analysis. We again thank the commentators for their insightful perspectives, which have helped us interpret the study results more comprehensively. Our supplementary analyses further confirm that, in IDH–wild type/TERT promoter–mutated, World Health Organization grade 2/3 gliomas (molecular glioblastomas), concurrent CRT combined with adjuvant temozolomide provides significant survival benefits independent of time-period effects and MGMT methylation status, with favorable safety (no grade ≥3 toxicities). The limitation of the small sample size in this study may require validation through clinical trials with larger samples. National Key Research and Development Program of China; 2023YFC2510005 Thank you for the editor's and reviewers' attention and support for this study! The authors declare no conflicts of interest.
Zhang et al. (Wed,) studied this question.