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Purpose: This study sought to determine the prognostic significance of the WHO-defined glioma molecular subgroups along with additional alterations, including MGMT promoter methylation and mutations in ATRX , CIC , FUBP1 , TERT , and TP53 , in NRG/RTOG 0424 using long-term follow-up data., Methods: Mutations were determined using an Ion Torrent sequencing panel. 1p/19q co-deletion and MGMT promoter methylation were determined by Affymetrix OncoScan and Illumina 450K arrays. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and tested using the log-rank test. Hazard ratios were calculated using the Cox proportional hazard model. Multivariable analyses (MVAs) included patient pretreatment characteristics., Results: We obtained complete molecular data to categorize 80/129 eligible patients within the WHO subgroups. Of these, 26 (32.5%) were IDH mutant/co-deleted, 28 (35%) were IDH mutant/non-co-deleted, and 26 (32.5%) were IDH wild-type. Upon single-marker MVA, both IDH mutant subgroups were associated with significantly better OS and PFS ( P values < .001), compared with the IDH wild-type subgroup. MGMT promoter methylation was obtained on 76 patients, where 58 (76%) were methylated and 18 (24%) were unmethylated. Single-marker MVAs demonstrated that MGMT promoter methylation was statistically significant for OS ( P value < .001) and PFS ( P value = .003). In a multimarker MVA, one WHO subgroup comparison ( IDH mutant/co-deleted v IDH wild-type) was significant for OS ( P value = .045), whereas MGMT methylation did not retain significance., Conclusion: This study reports the long-term prognostic effect of the WHO molecular subgroups, MGMT promoter methylation, and other mutations in NRG/RTOG 0424. These results demonstrate that the WHO molecular classification and MGMT both serve as strong prognostic indicators, but that MGMT does not appear to add statistically significant prognostic value to the WHO subgrouping, above and beyond IDH and 1p/19q status., Competing Interests: Stephanie L. Pugh Research Funding: Pfizer, Millennium Glenn J. Lesser Honoraria: SDP Oncology Consulting or Advisory Role: Cancer Expert Now, Agios, Incysus Research Funding: Novocure, Oblato, Denovo Biopharma, Global Coalition for Adaptive Research Other Relationship: NCI, ASCO David R. Macdonald Research Funding: Celgene, Servier Erica H. Bell Patents, Royalties, Other Intellectual Property: US20180002762A1 Joseph P. McElroy Employment: Pfizer Cynthia D. Timmers Employment: Incyte Stock and Other Ownership Interests: Array BioPharma, Seattle Genetics, Exact Sciences, Incyte, Arbutus Biopharma, PDS Biotechnology Consulting or Advisory Role: Ventana Medical Systems C. Leland Rogers Employment: Barrow Neurological Institute, GammaWest Cancer Services Stock and Other Ownership Interests: GT Technologies Maria Werner-Wasik Stock and Other Ownership Interests: Illumina Honoraria: AstraZeneca Patents, Royalties, Other Intellectual Property: Signal transduction inhibitor in lymphoma Hsiang-Hsuan Michael Yu Honoraria: UpToDate, Elsevier, Sermo, Guidepoint Global Consulting or Advisory Role: Novocure Speakers' Bureau: BrainLAB Research Funding: Bristol Myers Squibb/Sanofi, Merck Travel, Accommodations, Expenses: BrainLAB David P. D'Souza Consulting or Advisory Role: AbbVie Nadia N. Laack Research Funding: Bristol Myers Squibb Minesh P. Mehta Leadership: Oncoceutics Stock and Other Ownership Interests: Chimerix Consulting or Advisory Role: Tocagen, Karyopharm Therapeutics, Mevion Medical Systems, ZappRx, Sapience Therapeutics Patents, Royalties, Other Intellectual Property: WARF patent 14/934,27, Topical Vasoconstritor Preparations and Methods for Protecting Cells During Cancer Chemotherapy and Radiotherapy Uncompensated Relationships: Xcision Medical Systems, ViewRay Arnab Chakravarti Research Funding: Varian Medical Systems No other potential conflicts of interest were reported. Stephanie L. Pugh Research Funding: Pfizer, Millennium Glenn J. Lesser Honoraria: SDP Oncology Consulting or Advisory Role: Cancer Expert Now, Agios, Incysus Research Funding: Novocure, Oblato, Denovo Biopharma, Global Coalition for Adaptive Research Other Relationship: NCI, ASCO David R. Macdonald Research Funding: Celgene, Servier Erica H. Bell Patents, Royalties, Other Intellectual Property: US20180002762A1 Joseph P. McElroy Employment: Pfizer Cynthia D. Timmers Employment: Incyte Stock and Other Ownership Interests: Array BioPharma, Seattle Genetics, Exact Sciences, Incyte, Arbutus Biopharma, PDS Biotechnology Consulting or Advisory Role: Ventana Medical Systems C. Leland Rogers Employment: Barrow Neurological Institute, GammaWest Cancer Services Stock and Other Ownership Interests: GT Technologies Maria Werner-Wasik Stock and Other Ownership Interests: Illumina Honoraria: AstraZeneca Patents, Royalties, Other Intellectual Property: Signal transduction inhibitor in lymphoma Hsiang-Hsuan Michael Yu Honoraria: UpToDate, Elsevier, Sermo, Guidepoint Global Consulting or Advisory Role: Novocure Speakers' Bureau: BrainLAB Research Funding: Bristol Myers Squibb/Sanofi, Merck Travel, Accommodations, Expenses: BrainLAB David P. D'Souza Consulting or Advisory Role: AbbVie Nadia N. Laack Research Funding: Bristol Myers Squibb Minesh P. Mehta Leadership: Oncoceutics Stock and Other Ownership Interests: Chimerix Consulting or Advisory Role: Tocagen, Karyopharm Therapeutics, Mevion Medical Systems, ZappRx, Sapience Therapeutics Patents, Royalties, Other Intellectual Property: WARF patent 14/934,27, Topical Vasoconstritor Preparations and Methods for Protecting Cells During Cancer Chemotherapy and Radiotherapy Uncompensated Relationships: Xcision Medical Systems, ViewRay Arnab Chakravarti Research Funding: Varian Medical Systems No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Purpose: Our group has previously published the Graded Prognostic Assessment (GPA), a prognostic index for patients with brain metastases. Updates have been published with refinements to create diagnosis-specific Graded Prognostic Assessment indices. The purpose of this report is to present the updated diagnosis-specific GPA indices in a single, unified, user-friendly report to allow ease of access and use by treating physicians., Methods: A multi-institutional retrospective (1985 to 2007) database of 3,940 patients with newly diagnosed brain metastases underwent univariate and multivariate analyses of prognostic factors associated with outcomes by primary site and treatment. Significant prognostic factors were used to define the diagnosis-specific GPA prognostic indices. A GPA of 4.0 correlates with the best prognosis, whereas a GPA of 0.0 corresponds with the worst prognosis., Results: Significant prognostic factors varied by diagnosis. For lung cancer, prognostic factors were Karnofsky performance score, age, presence of extracranial metastases, and number of brain metastases, confirming the original Lung-GPA. For melanoma and renal cell cancer, prognostic factors were Karnofsky performance score and the number of brain metastases. For breast cancer, prognostic factors were tumor subtype, Karnofsky performance score, and age. For GI cancer, the only prognostic factor was the Karnofsky performance score. The median survival times by GPA score and diagnosis were determined., Conclusion: Prognostic factors for patients with brain metastases vary by diagnosis, and for each diagnosis, a robust separation into different GPA scores was discerned, implying considerable heterogeneity in outcome, even within a single tumor type. In summary, these indices and related worksheet provide an accurate and facile diagnosis-specific tool to estimate survival, potentially select appropriate treatment, and stratify clinical trials for patients with brain metastases.

High-grade gliomas represent a significant source of cancer-related death, and usually recur despite treatment. In this analysis of current brain tumor medicine, we review diagnosis, standard treatment, and emerging therapies for recurrent astrocytomas. Difficulties in interpreting radiographic evidence, especially with regard to differentiating between tumor and necrosis, present a formidable challenge. The most accurate diagnoses come from tissue confirmation of recurrent tumor, but a combination of imaging techniques, such as magnetic resonance spectroscopy imaging, may also be relevant for diagnosis. Repeat resection can prolong life, but repeat irradiation of the brain poses serious risks and results in necrosis of healthy brain tissue; therefore, reirradiation is usually not offered to patients with recurrent tumors. We describe the use of conventional radiotherapy, intensity-modulated radiotherapy, brachytherapy, radiosurgery, and photodynamic therapy for recurrent high-grade glioma. The use of chemotherapy is limited by drug distribution and toxicity, but the development of new drug-delivery techniques such as convection-enhanced delivery, which delivers therapeutic molecules at an effective concentration directly to the brain, may provide a way to reduce systemic exposure to cytotoxic agents. We also discuss targeted therapies designed to inhibit aberrant cell-signaling pathways, as well as new experimental therapies such as immunotherapy. The treatment of this devastating disease has so far been met with limited success, but emerging knowledge of neuroscience and the development of novel therapeutic agents will likely give patients new options and require the neuro-oncology community to redefine clinical trial design and strategy continually.