Glioma Outcomes Shaped by Subtype More Than Tx Sequence

Molecular subtype is more important than treatment sequence in shaping survival outcomes among patients with high-risk low-grade glioma (LGG), suggest long-term results of a randomized phase 3 trial.Among patients with astrocytoma, median overall survival (OS) remained the same regardless of whether the chemotherapy temozolomide (TMZ) or radiotherapy (RT) was used for frontline treatment. Similarly, among patients with oligodendroglioma, OS was comparable whether they started with RT or TMZ. Patients with oligodendroglioma, on average, had longer median OS than patients with astrocytoma, regardless of the order in which they received chemotherapy and radiation.When using “single-modality cytotoxic treatments with TMZ or RT for patients with an isocitrate dehydrogenase (IDH)-mutated glioma, the sequence of chemotherapy or RT has no overall effect on outcome, neither progression-free survival (PFS) nor OS,” lead author Brigitta Baumert, MD, of Haaglanden Medisch Centrum, the Hague, Netherlands, told Medscape Medical News.The findings were published in July in the Journal of Clinical Oncology.Testing Whether Chemotherapy Can Defer RadiationLGGs often affect younger adults who may survive for decades, increasing concerns about the delayed cognitive effects of brain radiation, according to the investigators. The trial set out to test whether upfront dose-dense TMZ could match the efficacy of RT while sparing patients radiation-related adverse effects.The population included 478 patients with clinical high-risk World Health Organization (WHO) grade 2 LGG, defined by features such as progressive disease or older age. Participants were randomly assigned to standard RT (50.4 Gy in 28 fractions) or dose-dense TMZ (75 mg/m2 daily for 21 of every 28 days, for up to 12 cycles).Baumert noted that the trial was designed more than 25 years ago, and patients enrolled from 2005 to 2012, so they were originally only stratified by deletion of chromosome 1p. Since then, however, WHO criteria added the IDH mutation and 1p/19q codeletion status, so the original samples were reanalyzed to determine these molecular profiles before being compared with long-term outcomes.Tissue from 73% of patients (351 of 478) could be reanalyzed after a median follow-up of 13 years, creating the largest molecularly defined cohort of WHO grade 2 LGG to date.Molecular Subtype, Not Sequence, Drives SurvivalAcross the intent-to-treat population, initial treatment choice did not significantly affect PFS or OS. Among patients with astrocytoma, median OS was approximately 6.6-6.7 years for frontline TMZ or RT (P = .9300). Similarly, among patients with oligodendroglioma, OS was not statistically different for first-line RT or TMZ (12.9 vs 14.9 years; P = .6300).In astrocytoma, PFS was shorter when patients started with TMZ, although OS was comparable. In contrast, among patients with IDH-wildtype disease, TMZ was associated with longer median OS than RT (4.7 vs 2.5 years; P = .0068).Of note, patients aged 40 years or older fared better than younger patients, challenging the long-standing use of age to define risk, according to Baumert.Clinical ImplicationsThe shorter PFS with upfront TMZ in astrocytoma suggests that “primary use of RT may be an advantage for better PFS for this subgroup,” Baumert said.However, because combined-modality treatment with RT and alkylating chemotherapy has since become standard of care for high-risk LGG, and it was not tested in the trial, the results do not change current practice, she added.Baumert predicted that the age finding may actually have a greater impact on future research and practice. She said the threshold of 40 years “may no longer be a single risk factor to choose a treatment for patients with an IDH-mutant LGG.” More data are needed to confirm this possibility, she added.Looking ahead, Baumert said molecular analyses “may provide essential insights into patient-specific responses to treatment, thus providing new potential therapies without the question of therapeutic sequencing.”For example, vorasidenib, an IDH inhibitor, is now being investigated as a molecularly guided frontline option in several trials, she said.Combined Therapy Remains Standard of CareIn an accompanying editorial, Ariel E. Marciscano, MD, and Helen A. Shih, MD, of Mass General Brigham and Harvard Medical School, Boston, agreed that the data support molecular subtype as the primary driver of prognosis in glioma, not treatment sequence.They also pointed out two study limitations.First, the editorialists underscored the high rate of crossover at progression (about two out of three patients crossed over), which clouds interpretation of OS. Although it is reassuring that each modality showed efficacy as a salvage option, the survival edge for TMZ in the IDH-wildtype group should be interpreted cautiously given the small sample size and biological heterogeneity.Second, Marciscano and Shih questioned the trial’s founding premise.“Although preservation of neurocognition was a primary justification for up-front TMZ vs RT, the reporting of comprehensive long-term neurocognition remains an undercharacterized aspect of this mature dataset,” the editorialists wrote, noting that earlier readouts from the trial showed stronger associations between disease progression and health-related quality of life rather than volume of irradiated brain tissue.Concerning the age-related findings, the editorialists suggested that the threshold of 40 years may be less a biological risk factor than a “crude surrogate” for IDH-wildtype tumors, further emphasizing the importance of molecular subtyping to predict outcomes and shape trial design.“As the field further refines molecular risk stratification and advances toward biology-guided treatment paradigms, the insights offered in this mature…data set will continue to shape how we select, sequence, and individualize treatment for patients with IDH-mutant LGG,” Marciscano and Shih concluded.The trial was supported in part by an unrestricted educational grant and study drug from MSD, the maker of TMZ, with additional support from the Swiss Cancer Research Foundation, the SwissBridge Award, and US National Cancer Institute grants. Baumert disclosed having relationships with MSD and Servier. Shih disclosed having relationships with Advanced Accelerator Applications/Novartis, AbbVie, Servier, and others.