The prognostic significance of androgen receptor expression in gliomas.

Androgen receptor (AR) overexpression has been identified in gliomas and its stem cells, suggesting that AR plays an important role in tumor carcinogenesis. The prognostic significance of AR overexpression in gliomas remains unknown. AR mRNA expression in gliomas and relevant clinical data were obtained from The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. AR expression levels were compared across gliomas of different histopathologic grades and molecular subtypes. Kaplan-Meier analyses in patients with different AR expression levels were investigated for the potential prognostic values of AR. Compared with normal brain tissue, gliomas show significantly higher AR mRNA expression (p < 0.01). AR mRNA expression was more prominent in higher grade disease and in worse prognostic molecular subtypes (p < 0.01). AR protein is more abundant in glioblastoma than in lower grade gliomas (LGG) (grade 2/3) (p < 0.0001). This is corroborated by a linear association between AR mRNA and protein expression (r = 0.65). In LGG, both higher AR mRNA and protein expression was associated with significantly worse overall survival (OS). Five-year OS for LGG patients with high versus low AR expression were 59.1% and 73.3%, respectively (p < 0.0001). AR expression is not prognostic for OS within glioblastoma patients. Gender was not associated with AR expression or prognosis. Higher AR expression levels are associated with higher grade disease and histopathologic features predicting poorer prognosis in lower grade gliomas. Higher gene expression in LGG patients is correlated with poor prognosis but not in the glioblastoma cohort suggesting saturated expression/functions of AR in glioblastoma.

Synthetic CT for gamma knife radiosurgery dose calculation: A feasibility study.

PURPOSE: To determine if MRI-based synthetic CTs (sCT), generated with no predefined pulse sequence, can be used for inhomogeneity correction in routine gamma knife radiosurgery (GKRS) treatment planning dose calculation. METHODS: Two sets of sCTs were generated from T1post and T2 images using cycleGAN. Twenty-eight patients (18 training, 10 validation) were retrospectively selected. The image quality of the generated sCTs was compared with the original CT (oCT) regarding the HU value preservation using histogram comparison, RMSE and MAE, and structural integrity. Dosimetric comparisons were also made among GKRS plans from 3 calculation approaches: TMR10 (oCT), and convolution (oCT and sCT), at four locations: original disease site, bone/tissue interface, air/tissue interface, and mid-brain. RESULTS: The study showed that sCTs and oCTs' HU were similar, with T2-sCT performing better. TMR10 significantly underdosed the target by a mean of 5.4% compared to the convolution algorithm. There was no significant difference in convolution algorithm shot time between the oCT and sCT generated with T2. The highest and lowest dosimetric differences between the two CTs were observed in the bone and air interface, respectively. Dosimetric differences of 3.3% were observed in sCT predicted from MRI with stereotactic frames, which was not included in the training sets. CONCLUSIONS: MRI-based sCT can be utilized for GKRS convolution dose calculation without the unnecessary radiation dose, and sCT without metal artifacts could be generated in framed cases. Larger datasets inclusive of all pulse sequences can improve the training set. Further investigation and validation studies are needed before clinical implementation.

Tyrosine Kinase Inhibitors With and Without Up-Front Stereotactic Radiosurgery for Brain Metastases From EGFR and ALK Oncogene-Driven Non-Small Cell Lung Cancer (TURBO-NSCLC).

PURPOSE: Newer-generation tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements have demonstrated high CNS activity. The optimal use of up-front stereotactic radiosurgery (SRS) for brain metastases (BM) in patients eligible for CNS-penetrant TKIs is controversial, and data to guide patient management are limited. MATERIALS AND METHODS: Data on TKI-naïve patients with EGFR- and ALK-driven NSCLC with BM treated with CNS-penetrant TKIs with and without up-front SRS were retrospectively collected from seven academic centers in the United States. Time-to-CNS progression and overall survival (OS) were analyzed, with multivariable adjustment in Fine & Gray and Cox proportional hazards models for clinically relevant factors. RESULTS: From 2013 to 2022, 317 patients were identified (200 TKI-only and 117 TKI + SRS). Two hundred fifty (79%) and 61 (19%) patients received osimertinib and alectinib, respectively. Patients receiving TKI + SRS were more likely to have BM ≥1 cm (P < .001) and neurologic symptoms (P < .001) at presentation. Median OS was similar between the TKI and TKI + SRS groups (median 41 v 40 months, respectively; P = .5). On multivariable analysis, TKI + SRS was associated with a significant improvement in time-to-CNS progression (hazard ratio [HR], 0.63 [95% CI, 0.42 to 0.96]; P = .033). Local CNS control was significantly improved with TKI + SRS (HR, 0.30 [95% CI, 0.16 to 0.55]; P < .001), whereas no significant differences were observed in distant CNS control. Subgroup analyses demonstrated a greater benefit from TKI + SRS in patients with BM ≥1 cm in diameter for time-to-CNS progression and CNS progression-free survival. CONCLUSION: The addition of up-front SRS to CNS-penetrant TKI improved time-to-CNS progression and local CNS control, but not OS, in patients with BM from EGFR- and ALK-driven NSCLC. Patients with larger BM (≥1 cm) may benefit the most from up-front SRS.

The IDH paradox: Meta-analysis of alkylating chemotherapy in IDH-wildtype and -mutant lower grade gliomas.

BACKGROUND: IDH-wildtype (-wt) status is a pre-requisite for the diagnosis of glioblastoma (GBM); however, IDH-wt gliomas with low grade or anaplastic morphology have historically been excluded from GBM trials and may represent a distinct prognostic entity. While alkylating agent chemotherapy improves overall survival (OS) and progression-free survival (PFS) for IDH-wt GBM and also IDH-mutant gliomas, irrespective of grade, the benefit for IDH-wt diffuse histologic lower grade gliomas is unclear. METHODS: We performed a meta-analysis of randomized clinical trials for World Health Organization (WHO) grade 2-3 gliomas (2009 to present) to determine the effect of alkylating chemotherapy on IDH-wt and -mutant gliomas using a random-effects model with inverse-variance pooling. RESULTS: We identified six trials with 1,204 patients (430 IDH-wt, 774 IDH-mutant) that evaluated alkylating chemoradiotherapy versus radiotherapy alone, allowing us to perform an analysis focused on the value of adding alkylating chemotherapy to radiotherapy. For patients with IDH-wt tumors, alkylating chemotherapy added to radiotherapy was associated with improved PFS (HR:0.77 [95%CI 0.62-0.97], P=.03) but not OS (HR:0.87 [95%CI 0.64-1.18], P=.17). For patients with IDH-mutant tumors, alkylating chemotherapy added to radiotherapy improved both OS (HR:0.52 [95%CI 0.42-0.64], P<.001) and PFS (HR=0.47 [95%CI 0.39-0.57], P<.001) compared to radiotherapy alone. The magnitude of benefit was similar for IDH-mutant gliomas with or without 1p19q-codeletion. CONCLUSIONS: Alkylating chemotherapy reduces mortality by 48% and progression by 53% for patients with IDH-mutant gliomas. Optimal management of IDH-wt diffuse histologic lower grade gliomas remains to be determined, as there is little evidence supporting an OS benefit from alkylating chemotherapy.

Salvage Stereotactic Radiosurgery for Recurrent WHO Grade 2 and 3 Meningiomas: A Multicenter Study (STORM).

PURPOSE: The role of stereotactic radiosurgery (SRS) in the management of grade 2 and 3 meningiomas is not well elucidated. Unfortunately, local recurrence rates are high, and guidelines for management of recurrent disease are lacking. To address this knowledge gap, we conducted STORM (Salvage Stereotactic Radiosurgery for Recurrent WHO Grade 2 and 3 Meningiomas), a multicenter retrospective cohort study of patients treated with primary SRS for recurrent grade 2 and 3 meningiomas. METHODS AND MATERIALS: Data on patients with recurrent grade 2 and 3 meningioma treated with SRS at first recurrence were retrospectively collected from 8 academic centers in the United States. Patients with multiple lesions at the time of initial diagnosis or more than 2 lesions at the time of first recurrence were excluded from this analysis. Patient demographics and treatment parameters were extracted at time of diagnosis, first recurrence, and second recurrence. Oncologic outcomes, including progression-free survival (PFS) and overall survival, as well as toxicity outcomes, were reported at the patient level. RESULTS: From 2000 to 2022, 108 patients were identified (94% grade 2, 6.0% grade 3). A total of 106 patients (98%) had upfront surgical resection (60% gross-total resection) with 18% receiving adjuvant radiation therapy (RT). Median time to first progression was 2.5 years (IQR, 1.34-4.30). At first recurrence, patients were treated with single or fractionated SRS to a median marginal dose of 16 Gy to a maximum of 2 lesions (87% received single-fraction SRS). The median follow-up time after SRS was 2.6 years. The 1-, 2-, and 3-year PFS was 90%, 75%, and 57%, respectively, after treatment with SRS. The 1-, 2-, and 3-year overall survival was 97%, 94%, and 92%, respectively. In the multivariable analysis, grade 3 disease (HR, 6.80; 95% CI, 1.61-28.6), male gender (HR, 3.48; 95% CI, 1.47-8.26), and receipt of prior RT (HR, 2.69; 95% CI, 1.23-5.86) were associated with worse PFS. SRS dose and tumor volume were not correlated with progression. Treatment was well tolerated, with a 3.0% incidence of grade 2+ radiation necrosis. CONCLUSIONS: This is the largest multicenter study to evaluate salvage SRS in recurrent grade 2 and 3 meningiomas. In this select cohort of patients with primarily grade 2 meningioma with a potentially more favorable natural history of delayed, localized first recurrence amenable to salvage SRS, local control rates and toxicity profiles were favorable, warranting further prospective validation.

Executive summary of the American Radium Society appropriate use criteria for brain metastases in epidermal growth factor receptor mutated-mutated and ALK-fusion non-small cell lung cancer.

The American Radium Society (ARS) Central Nervous System (CNS) committee reviewed literature on epidermal growth factor receptor mutated (EGFRm) and ALK-fusion (ALK+) tyrosine kinase inhibitors (TKIs) for the treatment of brain metastases (BrMs) from non-small cell lung cancers (NSCLC) to generate appropriate use guidelines addressing use of TKIs in conjunction with or in lieu of radiotherapy (RT). The panel developed three key questions to guide systematic review: can radiotherapy be deferred in patients receiving EGFR or ALK TKIs at (1) diagnosis or (2) recurrence? Should TKI be administered concurrently with RT (3)? Two literature searches were performed (May 2019 and December 2023). The panel developed 8 model cases and voted on treatment options using a 9-point scale, with 1-3, 4-6 and 7-9 corresponding to usually not appropriate, may be appropriate, and usually appropriate (respectively), per the UCLA/RAND Appropriateness Method. Consensus was achieved in only 4 treatment scenarios, all consistent with existing ARS-AUC guidelines for multiple BrM. The panel did not reach consensus that RT can be appropriately deferred in patients with BrM receiving CNS penetrant ALK or EGFR TKIs, though median scores indicated deferral may be appropriate under most circumstances. Whole brain RT with concurrent TKI generated broad disagreement except in cases with 2-4 BrM, where it was considered usually not appropriate. We identified no definitive studies dictating optimal sequencing of TKIs and RT for EGFRm and ALK+ BrM. Until such studies are completed, the committee hopes these cases guide decision- making in this complex clinical space.

The role of radiotherapy in immunotherapy strategies in the central nervous system.

The clinical efficacy and relative tolerability of adverse effects of immune checkpoint immunotherapy have led to its increasingly routine use in the management of multiple advanced solid malignancies. Radiation therapy (RT) is well-known to have both local and distant immunomodulatory effects, which has led to extensive investigation into the synergism of these 2 therapies. While the central nervous system (CNS) has historically been thought to be a sanctuary site, well-protected by the blood-brain barrier from the effects of immunotherapy, over the last several years studies have shown the benefits of these drugs, particularly in metastatic disease involving the CNS. This review explores current progress and the future of combination therapy with immune checkpoint inhibitors and RT.

Radiation-Induced Sensorineural Hearing Loss and Potential Management.

The cochlear apparatus is one of the major organs at risk when considering radiation therapy (RT) for brain, head, and neck tumors. Radiation oncologists currently consider mean dose constraints of <35 Gy for conventionally fractioned radiation therapy (RT), <4 Gy for single fraction stereotactic radiosurgery, and <17.1 or 25 Gy for 3- or 5-fraction stereotactic radiosurgery, respectively, as the standard of care. Indeed, dose adjustments are made in the setting of concurrent platinum-based chemotherapy or when prioritizing tumor coverage during treatment planning. Despite guidelines, in many patients, RT to the cochlea may still cause sensorineural hearing loss through progressive degeneration and ossification of the inner ear. There are several audiologic and otolaryngologic interventions for incident RT-induced hearing loss, including hearing aids, cochlear implants, or, in the context of vestibular schwannoma due to neurofibromatosis type 2, auditory brain stem implantation. Cochlear implants are the most effective at restoring hearing and improving quality of life for those with an intact cochlear nerve. An early multidisciplinary approach is essential to optimally manage RT-induced hearing loss, and this topic discussion serves as a guide for radiation oncologists on cochlear dosimetric considerations as well as how to address potential RT-induced adverse effects.

Prognosis and risk of suicide after cancer diagnosis.

INTRODUCTION: Suicide rates are elevated after cancer diagnosis. Existential distress caused by awareness of one's impending death is well-described in patients with cancer. The authors hypothesized that suicide risk is associated with cancer prognosis, and the impact of prognosis on suicide risk is greatest for populations with higher baseline suicide risk. METHODS: The authors identified patients (≥16 years old) with newly diagnosed cancers from 2000 to 2019 in the Surveillance, Epidemiology, and End Results database, representing 27% of US cancers. Multiple primary-standardized mortality ratios (SMR) were used to estimate the relative risk of suicide within 6 months of diagnosis compared to the general US population, adjusted for age, sex, race, and year of follow-up. Suicide rates by 20 most common cancer sites were compared with respective 2-year overall survival rates (i.e., prognosis) using a weighted linear regression model. RESULTS: Among 6,754,704 persons diagnosed with cancer, there were 1610 suicide deaths within 6 months of diagnosis, three times higher than the general population (SMR = 3.1; 95% confidence interval, 3.0-3.3). Suicide risk by cancer site was closely associated with overall prognosis (9.5%/percent survival deficit, R2  = 0.88, p < .0001). The association of prognosis with suicide risk became attenuated over time. For men, the risk of suicide increased by 2.8 suicide deaths per 100,000 person-years (p < .0001) versus 0.3 in women (p < .0001). The risk was also higher for persons ≥60 old and for the White (vs. Black) race. CONCLUSIONS: Poorer prognosis was closely associated with suicide risk early after cancer diagnosis and had a greater effect on populations with higher baseline risks of suicide. This model highlights the need for enhanced psychiatric surveillance and continued research in this patient population.

MGMT promoter methylation in 1p19q-intact gliomas.

OBJECTIVE: Standard-of-care for 1p19q-intact anaplastic gliomas is defined by the international randomized phase III CATNON trial, which found an overall survival (OS) benefit for adjuvant temozolomide (TMZ) when added to radiotherapy. Paradoxically, TMZ did not appear to benefit patients with IDH-wildtype gliomas, regardless of MGMT promoter status. The authors concluded that well-powered prospective study on the clinical efficacy of TMZ for patients with IDH-wildtype anaplastic gliomas (meeting criteria for glioblastoma) is warranted. Given that the prognostic and predictive role of MGMT status for grade 2-3 gliomas is unresolved, we determined the effect of MGMT status on OS in patients with 1p19q-intact gliomas in the National Cancer Database (NCDB). METHODS: We queried the NCDB from 2018 to 2019 for patients with diffuse (grade 2) and anaplastic (grade 3) IDH-wildtype or -mutant astrocytomas who received chemotherapy with follow-up through 2022. The Kaplan-Meier method and Cox proportional hazards regressions models were used to determine the association of MGMT with OS. RESULTS: We identified 1514 patients who were newly diagnosed with IDH-wildtype (n = 802, 33% methylated) or -mutant astrocytomas (n = 712, 48% methylated) and received chemotherapy during initial management. An unmethylated promoter was associated with poorer survival in patients with IDH-wildtype (3-year OS 34% [95%CI 29-39%] vs. 46% [95%CI 39-54%], p < .001, adjusted HR 1.53 [95%CI 1.24-1.89]) but not IDH-mutant astrocytomas (3-year OS 79% [95%CI 74-84%] vs. 80% [95%CI 75-86%], p =0 .81, HR 1.04 [95%CI 0.73-1.50]). CONCLUSIONS: This ancillary analysis supports conclusions from the CATNON trial for adjuvant TMZ as standard-of-care for anaplastic astrocytomas (IDH-mutant and 1p19q-intact), irrespective of MGMT status. Determining the optimal strategy for diffuse gliomas that are IDH-wildtype will be particularly important. MGMT promoter methylation should be considered as a stratification factor in future clinical trials for these patients.

Influenza activity and regional mortality for non-small cell lung cancer.

Lung cancer is the leading cause of cancer deaths in the United States and worldwide. While influenza illness is known to be particularly dangerous for frail and elderly patients, the relationship between influenza illness and outcomes in patients with cancer remains largely unknown. The Surveillance, Epidemiology, and End Results (SEER) database was queried to identify patients with non-small cell lung cancer (NSCLC) diagnosed between 2009 and 2015. Influenza-like illness (ILI) activity, provided by the Outpatient Influenza-like Illness Surveillance Network of the Center of Disease for Control and Prevention, was merged with the SEER dataset on the state-month level. Regional monthly mortality rates were compared during low versus high flu months in this ecological cohort study. 202,485 patients with NSCLC from 13 SEER-reporting states were included in the analysis. 53 of 1049 state-months (5.1%) had high flu activity. Monthly mortality rates during low and high flu months were 0.041 (95% CI 0.041-0.042) and 0.051 (95% CI 0.050-0.053), respectively (RR 1.24 [95% CI 1.21-1.27]). The association between ILI activity and mortality was observed at the individual state level and in all clinical and regional subgroups. Increased regional influenza activity is associated with higher mortality rates for patients with NSCLC. Vaccine-directed initiatives and increased awareness amongst providers will be necessary to address the growing but potentially preventable burden of influenza-related lung cancer deaths in the U.S.

MGMT promoter methylation in 1p19q-intact gliomas.

Objective: Standard-of-care for 1p19q-intact anaplastic gliomas is defined by the international randomized phase III CATNON trial, which found an overall survival (OS) benefit for adjuvant temozolomide (TMZ) when added to radiotherapy. Paradoxically, TMZ did not appear to benefit patients with IDH-wildtype gliomas, regardless of MGMT promoter status. The authors concluded that well-powered prospective study on the clinical efficacy of TMZ for patients with IDH-wildtype anaplastic gliomas (meeting criteria for glioblastoma) is warranted. Given that the prognostic and predictive role of MGMT status for grade 2-3 gliomas is unresolved, we determined the effect of MGMT status on OS in patients with 1p19q-intact gliomas in the National Cancer Database (NCDB). Methods: We queried the NCDB from 2018-2019 for patients with IDH-wildtype or -mutant astrocytomas who received chemotherapy with follow-up through 2022. The Kaplan-Meier method and Cox proportional hazards regressions models were used to determine the association of MGMT with OS. Results: We identified 1,514 patients who were newly diagnosed with IDH-wildtype (n = 802, 33% methylated) or - mutant astrocytomas (n = 712, 48% methylated) and received chemotherapy during initial management. An unmethylated promoter was associated with poorer survival in patients with IDH-wildtype (3-year OS 34% [95%CI 29-39%] vs. 46% [95%CI 39-54%], p < .001, adjusted HR 1.53 [95%CI 1.24-1.89]) but not IDH-mutant astrocytomas (3-year OS 79% [95%CI 74-84%] vs. 80% [95%CI 75-86%], p = .81, HR 1.04 [95%CI 0.73-1.50]). Conclusions: This ancillary analysis supports adjuvant TMZ as standard-of-care for anaplastic astrocytomas (IDH-mutant and 1p19q-intact), irrespective of MGMT status. Determining the optimal strategy for diffuse gliomas that are IDH-wildtype will be particularly important. MGMT promoter methylation should be considered as a stratification factor in future clinical trials for these patients.

MGMT Promoter Methylation Predicts Overall Survival after Chemotherapy for 1p/19q-Codeleted Gliomas.

PURPOSE: While MGMT promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy and guides treatment decisions in glioblastoma, its role in grade 2 and 3 glioma remains unclear. Recent data suggest that mMGMT is prognostic of progression-free survival in 1p/19q-codeleted oligodendrogliomas, but an effect on overall survival (OS) has not been demonstrated. EXPERIMENTAL DESIGN: We identified patients with newly diagnosed 1p/19q-codeleted gliomas and known MGMT promoter status in the National Cancer Database from 2010 to 2019. Multivariable Cox proportional hazards regression modeling was used to assess the effect of mMGMT on OS after adjusting for age, sex, race, comorbidity, grade, extent of resection, chemotherapy, and radiotherapy. RESULTS: We identified 1,297 eligible patients, 938 (72.3%) of whom received chemotherapy in their initial course of treatment. The MGMT promoter was methylated in 1,009 (77.8%) patients. Unmethylated MGMT (uMGMT) was associated with worse survival compared with mMGMT [70% {95% confidence interval (CI), 64%-77%} vs. 81% (95% CI, 78%-85%); P < 0.001; adjusted HR (aHR), 2.35 (95% CI, 1.77-3.14)]. uMGMT was associated with worse survival in patients who received chemotherapy [63% (95% CI, 55-73%) vs. 80% (95% CI, 76%-84%); P < 0.001; aHR, 2.61 (95% CI, 1.89-3.60)] but not in patients who did not receive chemotherapy [P = 0.38; HR, 1.31 (95% CI, 0.71-2.42)]. Similar results were observed regardless of World Health Organization grade and after single- or multiagent chemotherapy. CONCLUSIONS: Our study demonstrates an association between mMGMT and OS in 1p/19q-codeleted gliomas. MGMT promoter status should be considered as a stratification factor in future clinical trials of 1p/19q-codeleted gliomas that use OS as an endpoint.

The Use of Stereotactic Radiosurgery to Treat Functional Disorders: A Topic Discussion.

Stereotactic radiosurgery (SRS) is a well-known modality for the treatment of malignant brain tumors. SRS, however, can also be used to treat non-malignant functional disorders such as epilepsy, tremor, trigeminal neuralgia (TN), obsessive compulsive disorder (OCD), and intractable pain among others. Given the limited prospective data guiding treatment of these benign disorders, this article serves as a consolidated discussion of the application of SRS for functional ailments, hopefully serving as a reference for those considering application of this technique in clinical practice.

Association of MGMT Promoter Methylation With Survival in Low-grade and Anaplastic Gliomas After Alkylating Chemotherapy.

Importance: O6-methylguanine-DNA methyltransferase (MGMT [OMIM 156569]) promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy for glioblastomas and is routinely used to guide treatment decisions. However, the utility of MGMT promoter status for low-grade and anaplastic gliomas remains unclear due to molecular heterogeneity and the lack of sufficiently large data sets. Objective: To evaluate the association of mMGMT for low-grade and anaplastic gliomas with chemotherapy response. Design, Setting, and Participants: This cohort study aggregated grade II and III primary glioma data from 3 prospective cohort studies with patient data collected from August 13, 1995, to August 3, 2022, comprising 411 patients: MSK-IMPACT, EORTC (European Organization of Research and Treatment of Cancer) 26951, and Columbia University. Statistical analysis was performed from April 2022 to January 2023. Exposure: MGMT promoter methylation status. Main Outcomes and Measures: Multivariable Cox proportional hazards regression modeling was used to assess the association of mMGMT status with progression-free survival (PFS) and overall survival (OS) after adjusting for age, sex, molecular class, grade, chemotherapy, and radiotherapy. Subgroups were stratified by treatment status and World Health Organization 2016 molecular classification. Results: A total of 411 patients (mean [SD] age, 44.1 [14.5] years; 283 men [58%]) met the inclusion criteria, 288 of whom received alkylating chemotherapy. MGMT promoter methylation was observed in 42% of isocitrate dehydrogenase (IDH)-wild-type gliomas (56 of 135), 53% of IDH-mutant and non-codeleted gliomas (79 of 149), and 74% of IDH-mutant and 1p/19q-codeleted gliomas (94 of 127). Among patients who received chemotherapy, mMGMT was associated with improved PFS (median, 68 months [95% CI, 54-132 months] vs 30 months [95% CI, 15-54 months]; log-rank P < .001; adjusted hazard ratio [aHR] for unmethylated MGMT, 1.95 [95% CI, 1.39-2.75]; P < .001) and OS (median, 137 months [95% CI, 104 months to not reached] vs 61 months [95% CI, 47-97 months]; log-rank P < .001; aHR, 1.65 [95% CI, 1.11-2.46]; P = .01). After adjusting for clinical factors, MGMT promoter status was associated with chemotherapy response in IDH-wild-type gliomas (aHR for PFS, 2.15 [95% CI, 1.26-3.66]; P = .005; aHR for OS, 1.69 [95% CI, 0.98-2.91]; P = .06) and IDH-mutant and codeleted gliomas (aHR for PFS, 2.99 [95% CI, 1.44-6.21]; P = .003; aHR for OS, 4.21 [95% CI, 1.25-14.2]; P = .02), but not IDH-mutant and non-codeleted gliomas (aHR for PFS, 1.19 [95% CI, 0.67-2.12]; P = .56; aHR for OS, 1.07 [95% CI, 0.54-2.12]; P = .85). Among patients who did not receive chemotherapy, mMGMT status was not associated with PFS or OS. Conclusions and Relevance: This study suggests that mMGMT is associated with response to alkylating chemotherapy for low-grade and anaplastic gliomas and may be considered as a stratification factor in future clinical trials of patients with IDH-wild-type and IDH-mutant and codeleted tumors.