The story begins in the 1970s, when the RTOG Brain Tumor Committee emerged in the wake of the seminal Brain Tumor Study Group trials to prospectively evaluate new strategies for CNS malignancies. Early protocols tackled the most basic questions: how much radiation should be delivered, to what volume, and in how many fractions. These studies established foundational paradigms, including the biphasic 60 Gy approach for glioblastoma, in which 46 Gy is delivered to a larger target volume followed by a 14 Gy boost, and demonstrated the feasibility of combining radiation with nitrosourea chemotherapy. Just as importantly, they revealed a sobering truth that would steer the field for decades: pushing radiation doses higher and intensifying schedules was technically achievable but did not translate into longer survival, and it frequently increased toxicity. Randomized phase I and II studies of hyperfractionated and accelerated regimens, fast neutrons, and hypoxic-cell and S-phase sensitizers collectively established the limits of radiotherapy intensification in malignant gliomas.

That negative finding proved generative rather than deflating. It spawned three hypotheses that still animate research today: that gliomas harbor innate radioresistance, later attributed in part to stem-like cells; that legacy imaging inadequately targets microscopic disease, catalyzing advanced imaging-based targeting; and that combinatorial approaches are needed to eradicate disease lurking outside the radiation field. It also redirected the group toward methodological refinement. Large accumulated datasets enabled the creation of prognostic tools such as the recursive partitioning analysis, or RPA, classification, which stratified patients by expected outcome and became a standard stratification variable. A series of highly efficient single-arm phase II trials harnessed historical data for comparison, minimizing the number of control patients required and predating the modern concept of synthetic control arms. Agents such as the hypoxic-cell toxin tirapazamine and anti-angiogenic thalidomide were screened in this disciplined framework; most failed to justify phase III testing, but the triage system itself became a durable cooperative-group asset.

The molecular era arrived through some of the group’s most consequential work. Long-term follow-up of RTOG 94-02, a trial first launched in the 1990s that added procarbazine, lomustine, and vincristine, known as PCV chemotherapy, to radiotherapy for anaplastic oligodendroglial tumors, demonstrated that patients whose tumors carried both the 1p/19q co-deletion and an IDH mutation, now classified as grade 3 oligodendroglioma, saw their survival roughly doubled by PCV. Patients with IDH-mutant but non-co-deleted tumors, now called grade 3 astrocytoma, benefited less dramatically, while those with IDH-wildtype disease, now termed molecular glioblastoma, gained nothing. This was among the earliest prospective validations of molecularly informed treatment benefit in neuro-oncology, and it directly influenced subsequent tumor classification systems and trial eligibility paradigms. The companion trial RTOG 9402, together with its European counterpart, cemented PCV plus radiotherapy as a categorical standard for these tumors, even as temozolomide was being adopted broadly across all glioma grades on thinner evidence, prompting definitive head-to-head testing through the CODEL trial.

Glioblastoma itself proved a harder nut to crack, and the trial record is a study in disciplined negative results. After the EORTC and NCI-Canada trial established temozolomide-based chemoradiation as the standard for glioblastoma, RTOG 9813 extended temozolomide to anaplastic astrocytoma, finding no overall survival advantage over nitrosourea but a more favorable toxicity profile, effectively making temozolomide the standard, with post-hoc analysis identifying IDH mutation as both a prognostic and predictive biomarker. RTOG 0525 then showed that dose-dense temozolomide improved neither survival nor progression-free survival and carried higher toxicity, measured with a battery of neurocognitive, symptom, and quality-of-life tests. RTOG 0825 tested the addition of the anti-angiogenic antibody bevacizumab to standard chemoradiation and found no survival benefit despite longer progression-free survival, along with worse patient-reported outcomes and cognitive decline over time. NRG-BN011 could not reproduce the survival benefit of combined temozolomide and lomustine seen in a smaller German trial. Each disappointment sharpened the field’s appreciation that functional endpoints, not just survival curves, must anchor brain tumor research.

Not every modern effort has come up short. RTOG/NRG 1205, reported in 2023, provided the first high-level evidence supporting re-irradiation in recurrent glioblastoma, showing that adding radiation to bevacizumab significantly improved progression-free survival compared with bevacizumab alone in a disease where median survival after recurrence hovers at six to nine months. On the technology frontier, NRG-BN001, a signal-seeking randomized phase II study, met its overall survival endpoint for dose-escalated proton therapy to 75 Gy, and a definitive phase III trial is now in development. NRG-BN005 has completed accrual comparing proton with photon therapy in IDH-mutant lower-grade gliomas with cognitive preservation as its primary focus, and a newly launched study, NRG-CC017, is testing temporally modulated pulsed reduced dose-rate radiotherapy for neurofunctional preservation in glioblastoma. Biomarker-selected trials, including RTOG 0627 of dasatinib in target-selected recurrent glioblastoma, RTOG Foundation Study 3508 of the EGFR-targeted antibody-drug conjugate depatuxizumab mafodotin, and NRG-BN007 of dual checkpoint inhibition in MGMT-unmethylated tumors, illustrate the steady shift toward biology-guided designs.

In brain metastases, the group’s trials arguably transformed practice most visibly. Early studies fixed whole brain radiotherapy schedules of 30 Gy in 10 fractions and 37.5 Gy in 15 fractions as standards, but subsequent attempts at dose escalation, altered fractionation, and radiosensitization yielded no survival gains. RTOG 9508 then inaugurated the stereotactic radiosurgery era, and subsequent randomized work established radiosurgery alone as a standard that preserves neurocognitive function without compromising survival for many patients with limited metastases. Ongoing studies now push the paradigm further, including a trial of radiosurgery for up to 15 brain metastases, a comparison of radiosurgery against hippocampal-avoidance whole brain radiotherapy in small cell lung cancer, and NRG-BN013’s formal test of single versus fractionated radiosurgery for larger lesions. On the spine, RTOG 0631 found no clinical benefit for single-fraction stereotactic body radiotherapy over conventional radiotherapy for localized metastases, a reminder that precision techniques must earn their place.

Perhaps the most patient-centered triumph is the neuroprotection portfolio. RTOG 0614 demonstrated that the NMDA receptor antagonist memantine could delay cognitive decline after whole brain radiotherapy, the first prospective evidence of pharmacologic neuroprotection in this setting. Building on the insight that the hippocampal neural stem-cell niche repopulates the cells subserving memory, the group developed hippocampal-avoidance techniques and validated them in NRG-CC001, a randomized phase III trial showing a significant reduction in cognitive failure when hippocampal-avoidance whole brain radiotherapy was combined with memantine. Crucially, the achievement was as much infrastructural as scientific: standardized contouring atlases, credentialing processes, real-time centralized plan review, and widespread educational programs trained large numbers of radiation oncologists in consistent hippocampal-sparing, enabling rapid adoption into routine practice. The strategy is now extending to prophylactic cranial irradiation in small cell lung cancer through NRG-CC003, and to leptomeningeal disease, where a recent randomized phase II trial showed that proton craniospinal irradiation significantly improved progression-free and overall survival, with the definitive NRG-BN014 trial underway.

The review also documents quieter but meaningful advances in meningioma and primary CNS lymphoma. RTOG 0539 pioneered risk-stratified, prospective radiotherapy for meningioma, demonstrating excellent progression-free survival in intermediate-risk patients treated after surgery, and its infrastructure of centralized imaging review and protocol-driven delivery has spun off a portfolio of trials incorporating molecular imaging with DOTATATE-PET and even a radioligand therapeutic, lutetium-177 DOTATATE, for recurrent high-risk disease. In primary CNS lymphoma, RTOG 1114 showed that reduced-dose whole brain radiotherapy added to R-MPV-A chemoimmunotherapy significantly improved progression-free survival, exemplifying response-adapted radiotherapy that balances disease control against neurotoxicity. The authors distill the lessons into a roadmap: enrich patient selection with molecular profiling, choose realistic endpoints, plan accrual conservatively, recognize barriers in de-escalation trials, insist on central pathology and real-time radiotherapy quality review, and keep trials patient-centric. Taken together, fifty years of cooperative group science trace a clear arc, from empiric dose-finding to precision, biology-informed, and cognitively protective care, and they suggest that the collaborative trial network remains the indispensable engine for the next generation of brain tumor breakthroughs.

Subject of Research: Evolution of cooperative group clinical trials for central nervous system tumors by RTOG and NRG Oncology

Article Title: The evolution of RTOG and NRG Oncology CNS tumors clinical trials

Article References: Sehrawat, K., Polley, M.-Y. C., Vogelbaum, M. A., Gilbert, M., Chakravarti, A., Cahill, D. P., Lassman, A. B., Raleigh, D. R., Sulman, E. P., Machtay, M., Le, Q. T., Curran, W., Gondi, V., & Mehta, M. P. (2026). The evolution of RTOG and NRG Oncology CNS tumors clinical trials. Journal of Neuro-Oncology, 179(2), Article 83. https://doi.org/10.1007/s11060-026-05788-w

Image Credits: AI Generated

DOI: 10.1007/s11060-026-05788-w

Keywords: RTOG, NRG Oncology, CNS tumors, glioblastoma, brain metastases, stereotactic radiosurgery, hippocampal-avoidance radiotherapy, temozolomide, PCV chemotherapy, primary CNS lymphoma, meningioma, clinical trials