The evolution of RTOG and NRG Oncology CNS tumors clinical trials

Abstract

Purpose

Radiation Therapy Oncology Group (RTOG) and NRG Oncology have played a key role in shaping evidence-based management of central nervous system (CNS) tumors. These have defined standards for radiotherapy delivery, integrated systemic therapies for multimodal approaches, and advanced trial methodology across a range of CNS malignancies through large, multi-institutional studies. This is a comprehensive narrative review of trials involving adult CNS tumors, focused on gliomas, metastases, meningioma, and primary CNS lymphoma (PCNSL).

Methods

Trials were identified through protocol archives, published literature, and curated trial inventories, and were analyzed with respect to treatment strategies, trial evolution, and impact on practice.

Results

Early trials established foundational radiotherapy paradigms, including dose, volume, and fractionation standards. Subsequent studies demonstrated limitations of dose escalation and led to development of prognostic tools such as recursive partitioning analysis (RPA). In gliomas, these trials defined the role of chemoradiation, setting new standards of care (SOC), and clarified the limited benefit of treatment intensification, while recent studies explored molecularly selected therapies. In BM, randomized trials transformed management through stereotactic radiosurgery (SRS)-based approaches and hippocampal-avoidance whole brain radiotherapy (HA-WBRT), with incorporation of neurocognitive function (NCF) and quality-of-life (QOL) endpoints. Trials in meningioma provided some of the first prospective data supporting role of radiotherapy, and PCNSL trials established the superiority of chemoradiotherapy, and response-adapted deployment of WBRT.

Conclusion

RTOG and NRG Oncology trials have driven iterative, evidence-based advances in transitioning to precision. These efforts continue to inform contemporary guidelines and provide a framework for future trials integrating molecular stratification, advanced imaging, and novel therapeutic strategies.

Introduction

RTOG/NRG trials, which at their very core are multimodal, and aim to change practice standards, have fundamentally shaped evidence-based care for CNS tumors which present unique challenges, including biological heterogeneity, infiltrative growth, proximity to critical structures, relative rarity, limited drug efficacy, and the need to balance disease control with NCF preservation. These complexities have limited the generalizability of single-institution studies emphasizing the importance of multi-institutional trials, to establish reproducible standards of care.

Following the seminal studies conducted by the Brain Tumor Study Group (BTSG), the RTOG Brain Tumor Committee emerged in the 1970s for prospective evaluation of novel strategies for CNS tumors. Early trials focused on radiotherapy dose escalation, altered fractionation, and integration of chemotherapy or radiosensitizers for malignant gliomas and brain metastases (BM). As the trials matured and larger datasets became available, statistical and technological advances were generated, and the significance of trial quality control was prospectively established.

These trials played a pivotal role in establishing the clinical relevance of molecular stratification. Illustratively, long-term follow-up of RTOG 94 − 02, first reported in 1990s, demonstrated that adding procarbazine, lomustine, and vincristine (PCV) to radiotherapy doubled survival for 1p19q co-deleted and isocitrate dehydrogenase (IDH) mutant high grade gliomas [now called Grade 3 (G3) Oligodendrogliomas] and less dramatically improved survival for IDH mutant, 1p19q non co-deleted tumors (Grade 3 Astrocytoma, and yielded no benefit for IDH wild-type, now called molecular Glioblastoma) [1, 2]. This represented one of the earliest prospective validations of molecularly informed treatment benefit in neuro-oncology, directly influencing subsequent tumor classification and trial eligibility paradigms.

With the adoption of Temozolomide (TMZ) based chemoradiation as a SOC for glioblastoma (GBM), subsequent trials explored its incorporation in other gliomas, as well as treatment intensification and combinatorial approaches with biologic therapies, while comprehensively incorporating patient-reported outcomes (PROs) and NCF assessment, and also conducting real-time central pathologic confirmation, and molecular profiling, such as for O⁶-methylguanine DNA methyltransferase (MGMT) gene promoter hypermethylation. Two illustrative examples include RTOG 0525 (2013), demonstrating lack of survival improvement from TMZ dose-intensification [3], and RTOG 0825 (2014), which evaluated the addition of bevacizumab for GBM, yielding data that tempered the lofty survival expectations from this agent [4–6].

As CNS trials grew increasingly complex, incorporating advanced imaging, rapid-response quality assurance (QA), correlative science, and longitudinal assessment of NCF, the infrastructure evolved to support these. Contemporary trials within the NRG Oncology framework built upon decades of methodological lessons derived from earlier investigations. Modern NRG studies allow robust testing of advanced radiotherapy techniques [such as SRS, fractionated stereotactic radiotherapy (FSRT), temporally-modulated pulsed reduced dose-rate radiotherapy, proton therapy, radioligand therapeutics, etc.], risk-adapted strategies [for example RTOG 1114 which demonstrated a significant progression free survival (PFS) benefit from adding reduced dose WBRT to rituximab, methotrexate, procarbazine, vincristine, and cytarabine (R-MPV-A) for PCNSL;2026] [7], preservation of cognitive function (an entire body of work on HA-WBRT and chemical modifiers such as Memantine), incorporating advanced imaging [such as ⁶⁸Ga-DOTATATE-positron emission tomography (DOTATATE-PET) for meningioma], reflecting iterative progression of cooperative group science.

A core collaborative function of NRG Oncology is to engage with other National Clinical Trials Network (NCTN) groups such as Alliance, CCTG, COG, ECOG, SWOG, etc., to partner intellectually in trial development, to provide robust central resources for trial conduct, and also to actively enroll patients to support timely trial accrual which significantly accelerates the rate at which trials are completed and evidence is generated.

Section 1: Evolution of RTOG/NRG glioma trials

Foundational era: establishing radiotherapy dose, fractionation, and feasibility for gliomas

As a comprehensive summary, all trials are listed in Table 1 and a select few are discussed further. Initial studies evaluated radiotherapy dose escalation, altered fractionation, and chemotherapeutic or radiosensitizing agents, demonstrating technical feasibility, and setting SOCs such as the biphasic 60 Gy approach (46 Gy to the larger volume and 14 Gy boost) for GBM and the incorporation of nitrosoureas [8–11]. Although higher doses and intensified schedules were technically feasible, they did not translate into improvements in overall survival (OS) and were frequently associated with increased toxicity, findings critical for future trials [9, 10, 12]. Multiple randomized phase I–II studies assessed hyperfractionated and accelerated radiotherapy regimens, fast neutrons, hypoxic cell, and S-phase sensitizers. As an early example of innovative technologies, RTOG 90 − 05 carried out in 1990s established lesion size–based maximum tolerated doses for SRS, providing a standardized framework for subsequent SRS trials [13]. In keeping with the strategy of sequential progress, this led to RTOG 9305 (2004), which demonstrated no survival benefit from SRS boost for GBM, thereby halting the proliferation of an approach which had entered clinical practice [14].

Table 1.

RTOG and NRG oncology clinical trials for CNS tumors

GLIOBLASTOMA / MALIGNANT GLIOMA
Name	Dx	Tumors	Ph	Dates	Pts (n)	Conclusions	PMID / NCT
RTOG 7401	MG	GBM + HGG	III	1974-79	626	↑ OS BCNU in subgroups No OS ↑ c̄ 70 Gy boost or MeCCNU/DTIC	3281031
RTOG 7611	MG	GBM + HGG	II	1977-80	166	No OS ↑ c̄ Neutron boost	6314799
RTOG 7801	MG	GBM + HGG	II	1978-79	54	Misonidazole + RT safety	7263341
RTOG 7918	MG	GBM + HGG	III	1979-83	293	No OS ↑ c̄ Misonidazole	3531110
RTOG 8007	MG	GBM + AA	II	1980-85	190	No OS ↑ from Neutrons	2838442
RTOG 8302	MG	GBM + AA	I/II	1983-87	466	No OS ↑ c̄ RT > 60 Gy	8380567
RTOG 8409	MG	GBM + AA	II	1984-88	NR	No OS ↑ c̄ AZQ	ASCO Proc. 1988; 7:86
RTOG 8612	MG	GBM + HGG	I	1987-91	22	Established IUDR dose	8407393
RTOG 9006	MG	GBM + HGG	III	1990-94	712	No OS ↑ c̄ HFRT	29404979
RTOG 9113	rMG		II	1990-93	30	No OS ↑ c̄ ATRA	9210068
RTOG 9305	GBM	GBM	III	1993-99	203	No OS ↑ c̄ SRS boost	15465203
RTOG 9411	GBM	GBM	II	1994–98	108	No OS ↑ c̄ AF	11121633
RTOG 9417	GBM	GBM	II	1995–97	124	No OS ↑ c̄ Tirapazamine	10715295
RTOG 9513	GBM	GBM	II	~ 1995-99	87	No OS ↑ c̄ Topotecan	12095566
RTOG 9602	GBM	GBM	II	1996-00	62	No OS ↑ c̄ Paclitaxel	11516860
RTOG 9710	GBM	GBM	II	1997-02	109	No OS ↑ c̄ RhIFN-β	16887285
RTOG 9806	GBM	GBM	II	1998-02	89	No OS ↑ c̄ Thalidomide	23086432
RTOG 9803	GBM	GBM	I/II	~ 1998-03	209	No OS ↑ c̄ DE-3DCRT	19533025
RTOG 0021	GBM	GBM	II	2000-01	77	No OS ↑ c̄ Tamoxifen	16443947
RTOG 0023	GBM	GBM	I/II	2001-05	76	No OS ↑ c̄ conformal AB	16750317
RTOG 0211	GBM	GBM	I/II	2002-05	178	No OS ↑ c̄ Gefitinib	23182702
RTOG 0525	GBM	GBM	III	2006-10	833	No OS ↑ c̄ Dose-dense TMZ	24101040
RTOG 0825	GBM	GBM	III	2009-11	978	No OS ↑ c̄ BEV	24552317
RTOG 0913	GBM	GBM	II	2010-13	171	No OS ↑ c̄ Everolimus	29126203
RTOG 1205	rGBM	Recurrent	II	2012-16	182	PFS ↑ c̄ BEV + re-RT	36260832
BN001 (Photon)	GBM	GBM	II	2014-18	229	No OS ↑ c̄ 75 Gy	https://doi.org/10.1016/j.ijrobp.2020.07.2109
BN001 (Proton)	GBM	GBM	II	2014-22	193	OS ↑ c̄ 75 Gy proton Signal-seeking	https://doi.org/10.1016/j.ijrobp.2025.08.068
BN002	GBM	GBM	I	2015-19	32	Ipi + nivo safe c̄ TMZ	38874333
RTOGF 3508	GBM	EGFR Amplified	IIb/III	2015-18	639	No OS ↑ c̄ Depatux-M	35849035
BN007	GBM	MGMT Unmethylated	II/III	2020-25	159	No PFS ↑ c̄ Ipi + nivo	40779733
BN010	rGBM	Recurrent	I/II	2021-25	53	No OS ↑ c̄ Toci/Atezo + RT	04729959
BN011	GBM	MGMT Methylated	III	2022-25	265	No OS ↑ c̄ Lomustine-TMZ	05095376
CC017	GBM	MGMT Unmethylated	III	2026-O	0/398*	Temporally modulated RT	07452458
LOW-GRADE AND ANAPLASTIC GLIOMA
RTOG 9802	LGG	G2 LGG	III	1998-02	251	OS ↑ c̄ RT + PCV	22851558
RTOG 9402	AO	AO	III	1994-02	289	PFS ↑ c̄ PCV + RT OS ↑ for 1p/19q codel	16782910
RTOG 0131	AG	AO + MOA	II	2001-04	42	TMZ comparable to PCV	18779504
RTOG 9813	AA	AA	III	1999-07	196	↑ OS for IDHmut; No OS ↑ c̄ TMZ v BCNU	27994066
RTOG 0424	LGG	High-Risk G2	II	2005-09	129	OS ↑ in TMZ + RT v historical controls.	25680596
BN005	LGG	G 2/3 IDH mut	III	2018-24	120	Proton v Photon Results pending.	03180502
BRAIN/LEPTOMENINGEAL METASTASES
RTOG 6901	BM	Various	III	~ 1969-76	910	Short course RT = longer	6853263
RTOG 7361	BM	Various	III	1973-76	902	20 Gy/1wk = prolonged RT	6154024
RTOG 7503	SCLC	PCI	III	1975-79	104	Rate of BM decreased	2996327
RTOG 7606	BM	Various	III	~ 1976-80	255	30 Gy/10 # = 50 Gy/20 #	6171553
RTOG 7916	BM	Various	III	1979-83	859	30 Gy/10 SOC No OS ↑ c̄ Misonidazole or AF	1993631
RTOG 8403	NSCLC	PCI	III	1984-86	187	No OS ↑ Rate of BM not reduced	1651304
RTOG 8528	BM	Various	I/II	1985-91	153	↑ OS c̄ AF	8435812
RTOG 8905	BM	Various	III	1989-93	72	No OS ↑ c̄ BUdR	7673021
RTOG 9005	BM/MG	Recurrent	I	1990-94	156	Established SRS dosing	10802351
RTOG 9104	BM	Various	III	1991-95	445	No OS ↑ c̄ AF	9336134
RTOG 9508	BM 1–3	Various	III	1996-01	333	WBRT + SRS ↑ OS in subset	15158627
RTOG 0118	BM	1–3	II	2001-05	332	No OS ↑ c̄ Thalidomide	18164847
RTOG 0212	PCI	LS SCLC	III	2002-07	720	No OS ↑ c̄ higher-dose PCI	19386548
RTOG 0214	PCI	Stage III NSCLC	III	2002-07	356	Reduced BM c̄ PCI No OS ↑ c̄ PCI	21135270
RTOG 0320	BM	NSCLC, 1–3	III	2004-09	126	No OS ↑ c̄ TMZ or Erlotinib	23391814
RTOG 0614	BM	Various	III	2008-13	554	↑ NCF c̄ Memantine	23956241
RTOG 0933	BM	Various	II	2011-12	113	↑ NCF c̄ HA-WBRT	25349290
RTOG 1119	BM	HER2 + Breast	III	2012-19	143	No ↑ RR c̄ Lapatinib	37506981
CC001	BM	Various	III	2015-18	518	↑ NCF c̄ Memantine + HA-WBRT	32058845
CC003	PCI	SCLC	III	2015-22	393	↑ NCF c̄ HA-PCI	40789106
CCTG CE.7	BM	Various, 1–15 BM	III	2018-O	175/206* (42 NRG)	HA-WBRT vs. SRS	03550391
CC009	BM	SCLC	III	2020-O	144/200*	SRS vs. HA-WBRT + Memantine	04804644
BN012	BM	Resectable	III	2022-25	237	Pre- v post-op SRS	05438212
BN013	BM	Various	III	2024-26	274/269	1 v 3-fx SRS	06500455
BN014	LMD	Lung/Breast	III	2024-O	62/115*	Proton CSI v IF-RT	06500481
SPINE METASTASES
RTOG 0631	Spine Mets	Various 1–3 Mets	II/III	2009-19	339	No ↑ in pain response	37079324
PRIMARY CNS LYMPHOMA
RTOG 8315	PCNSL	PCNSL	II	1983-87	41	↑ CR c̄ WBRT	1572835
RTOG 8806	PCNSL	PCNSL	II	1988-93	54	No OS ↑ c̄ CHOD	8636771
RTOG 9310	PCNSL	PCNSL	II	1993-99	102	↑ OS c̄ MTX-chemoRT Significant neurotoxicity	12,488,408
RTOG 0227	PCNSL	PCNSL	I/II	2004-12	53	↑ OS and PFS c̄ MTX, Rituximab, TMZ +WBRT	27022122
MENINGIOMA
RTOG 0539	Mening	G1	II	2009-16	60	↑ 3y PFS c̄ GTR	35657335
RTOG 0539	Mening	G2 New Dx, GTR G1 rec	II	2009-16	56	↑ 3y PFS c̄ RT	28984517
RTOG 0539	Mening	G3, G2 STR G2 rec	II	2009-16	57	↑ 3y PFS c̄ IMRT	31786276
BN003	Mening	G2 New Dx, GTR	III	2017-O	159/163*	Obs v adjuvant RT	03180268
RTOGF 3523	Mening	Rec/Progressive	II	2025-O	7/153*	77Lu-DOTATATE v SOC	06955169
BN015	Mening	Clinical low risk; mol high-risk	III	O	0/212(A)* 0/252(B)*	RT v Obs	Developing
BN016	Mening	Clinical High-Risk	III	O	0/120*	RT +/- CDK4/6 inhibition	Developing
OTHERS
RTOG 7501	MDL/EPN	Peds Tumors	III	1974-84	233	No OS ↑ c̄ CCNU, VCR, and prednisone + RT	2319316
RTOG 7823	Various Recurrent	Peds Tumors	I/II	1980-85	29	Limited efficacy c̄ Misonidazole + re-RT	3756787

Table Abbreviations Key: AA = Anaplastic astrocytoma, AZQ = Aziridinylbenzoquinone,, AF =Accelerated fractionation, AB = Accelerated boost, ATRA = All trans-retinoic acid, AO = Anaplastic oligodendroglioma, Ph = Phase, MG = Malignant glioma, GBM = Glioblastoma, HGG = High grade glioma, OS = Overall survival, BCNU = Bis-chloroethylnitrosourea, MeCCNU = Methyl-cyclohexyl-chloroethylnitrosourea, DTIC = Dimethyl triazeno imidazole carboxamide, RT = Radiotherapy, IUDR = Iododeoxyuridine, HFRT = Hyperfractionated radiation therapy, rMG = Recurrent malignant glioma, SRS = Stereotactic radiosurgery, RhIFN-β = Recombinant human interferon beta, DE-3DCRT = Dose-escalated three-dimensional conformal radiotherapy, TMZ = Temozolomide, BEV = Bevacizumab, rGBM = recurrent glioblastoma, reRT = re-irradiation, Ipi = Ipilumimab, Nivo = Nivolumab, RTOGF = RTOG-Foundation, EGFR = Epidermal growth factor receptor, MGMT = O6-methylguanine-DNA methyltransferase, Toci = Tociluzimab, Atezo = Atezoluzimab, LGG = Low grade glioma, G2 = WHO grade 2; G3 = WHO grade 3; G4 = WHO grade 4 (Historical histologic terminology is preserved for trials conducted before adoption of the current WHO CNS classification), PCV = procarbazine, lomustine/CCNU, vincristine,, PFS = Progression-free survival, 1p/19q codel = 1p/19q codeletion, AG = Anaplastic glioma, MOA = Malignant oligoastrocytoma, IDH mut = Isocitrate dehydrogenase mutation, BM = Brain metastases, SCLC = Small cell lung cancer, PCI = Prophylactic cranial radiotherapy, SOC = Standard of care, NSCLC = Non-small cell lung cancer, BUDR = Bromodeoxyuridine, LS = Limited stage, NCF = Neurocognitive function, HA-WBRT = Hippocampal avoidant whole brain radiotherapy, HER2 = Human epidermal growth factor receptor, RR = Response rate, O = Ongoing, * = Projected total accrual goal, LMD = Leptomemingeal disease, CSI = Craniospinal irradiation, IF-RT = Involved-field radiotherapy, PCNSL = Primary central nervous system lymphoma, CR = Complete response, CHOD = Cyclophosphamide Adriamycin Vincristine dexamethasone, MTX = Methotrexate, Mening = Meningioma, NewlyDx = Newly diagnosed, GTR = Gross total resection, STR = subtotal resection, Obs = Observation, IMRT = Intensity modulated radiotherapy, 77Lu-DOTATATE = Lutetium77 DOTA-tyrosine-3-octreotate, CDK4/6 = Cyclin-Dependent Kinases 4 and 6, MDL = Medulloblastoma, EPN = Ependymoma, Peds = Pediatric, VCR = Vincristine

Collectively, these trials established the limitations of radiotherapy intensification in malignant gliomas. This set in motion three hypothesis, (a) innate resistance (later attributed to stem cells), (b) inadequate targeting of microscopic disease with legacy imaging (catalyzing advanced imaging-based targeting strategies), and (c) combinatorial approaches designed to eradicate microscopic disease potentially outside the radiotherapy field [8, 15]. These discouraged empiric dose escalation and redirected efforts toward methodological refinement, statistical model development to conduct more efficient trials, and improvements in centralized QA for precision radiotherapy techniques.

Methodological maturation: prognostic stratification and efficient phase II trials

As the limitations of radiotherapy intensification became apparent, other innovations were pursued. Large datasets enabled the creation of prognostic tools such as the RPA for gliomas, subsequently incorporated as a stratification variable. Several novel agents were tested in a series of highly efficient single arm phase II trials utilizing innovative designs harnessing legacy data for comparative purposes, thereby minimizing the requisite number of control patients, predating the modern concept of synthetic controls [16]. These trials included evaluation of hypoxic-cell targeting agents such as tirapazamine, anti-angiogenic agents such as thalidomide and tamoxifen, receptor-targeted approaches, etc [3, 17–20]. While most did not demonstrate sufficient improvement to justify phase III evaluation, this structured screening approach allowed efficient triage of candidate therapies and established a disciplined cooperative-group framework for early-phase therapeutic screening.

Chemoradiotherapy as the new SOC and expanding the role of TMZ

Early randomized studies evaluating Carmustine (bis-chloroethyl nitrosourea, BCNU) in combination with radiotherapy showed modest survival improvements, supporting combined-modality approaches [10]. The EORTC/NCI-Canada trial established TMZ as the new SOC for GBM, but its role in other gliomas remained ill-defined. RTOG was the first to investigate the role of TMZ in newly diagnosed anaplastic astrocytomas (AA, G3) in a large, randomized trial (RTOG 9813, 2017). OS was not improved with TMZ compared to nitrosourea, but the toxicity was more favorable, effectively establishing TMZ as the standard of care. Upon post-hoc analysis, isocitrate dehydrogenase (IDH) mutation was identified as a prognostic and predictive biomarker for the benefit of TMZ [21, 22]. The EORTC 26,053 − 22,054 “CATNON” (RTOG 0834, 2007) trial evolved from this experience, demonstrating that adjuvant TMZ significantly improved survival in patients with 1p/19q non-codeleted anaplastic glioma, with the benefit confined to IDH mutant tumors [23]. RTOG 0525 tested dose-dense TMZ which did not improve OS or PFS, and was associated with higher toxicity using a battery of tests including neurocognitive function, symptom burden and QOL, reinforcing the limitations of empiric TMZ intensification [3]. A more contemporary effort tested the combinatorial alkylator therapy approach of TMZ and lomustine which had demonstrated improved survival in a prior smaller trial; when tested in NRG-BN011 (2022), this benefit could not be recapitulated [24, 25].

In low grade [G2 astrocytoma and oligodendrogliomas (RTOG 9802, 2012), as well as G3 Oligodendrogliomas (RTOG 9402, 2006), PCV added to radiotherapy dramatically improved OS, establishing a new SOC [2, 26]. PCV was established as a categorical SOC in the same era as widespread adoption of TMZ across all grades of gliomas was occurring in the absence of meaningful evidence, and hence trials of TMZ in both high-risk low grade glioma [27] and oligodendroglioma [28] were conducted, setting the basis for definitive testing through the CODEL trial [29].

Novel systemic therapies for gliomas

Due to marked vascular proliferation inherent to GBM, angiogenesis inhibition emerged as a promising strategy. Early phase II studies of bevacizumab demonstrated radiographic responses and prolonged PFS, leading to regulatory approval in recurrent GBM (rGBM). RTOG 0825, evaluating the addition of bevacizumab to standard RT-TMZ demonstrated no improvement in OS (despite longer PFS) and was associated with worse PRO/QOL and NCF decline over time, highlighting the necessity of incorporating functional endpoints [5, 30]. RTOG/NRG efforts increasingly moved toward biomarker-selected trials, and trials using novel agents. Examples include RTOG 0627 (2018) evaluating the multi-targeted Src/PDGFR/c-KIT inhibitor dasatinib in target-selected patients with rGBM [31], and RTOG Foundation Study 3508 (2023), testing the EGFR-targeting antibody-drug conjugate depatuxizumab mafodotin (ABT-414) in EGFR-amplified newly diagnosed GBM [32]. Additionally, NRG-BN007 (2025) evaluated dual check point inhibition with ipilimumab plus nivolumab in patients with MGMT-unmethylated GBM [33], and NRG-BN011 tested dual alkylator therapy in MGMT-methylated GBM [26].

Advanced radiotherapeutic techniques and advanced imaging in glioma trials

With the advent of proton therapy, a novel opportunity for technology testing emerged. NRG established credentialing and standards for co-operative group proton trials, and 2 categorical trials for proton therapy in gliomas have been completed. NRG-BN005, a randomized phase II trial compared proton versus photon therapy for IDH-mutant grade 2–3 gliomas, with a primary focus on cognitive preservation, and results are pending. NRG-BN001 (2025) was a signal-seeking randomized phase II study evaluating dose-escalated/intensified RT (to 75 Gy) using photon IMRT or proton therapy versus standard-dose photon RT (60 Gy), testing the dual hypothesis of survival improvement through dose-intensification and lymphocyte-sparing. The trial met its phase 2 OS endpoint for the proton dose-escalation arm and a definitive phase 3 trial is in development, incorporating advanced imaging to identify appropriate boost volumes [34]. A recently launched trial, NRG-CC017, is testing the benefit of temporally modulated radiotherapy for neurofunctional preservation in GBM [35].

Integration of molecular stratification into cooperative group trials

RTOG/NRG trials established reflexive tissue collection, central pathology, and harmonized molecular marker testing, leading to subsequent biomarker-enriched designs. RTOG 9402 (2006), which randomized patients with anaplastic oligodendroglial tumors to radiotherapy alone or PCV followed by radiotherapy, provided seminal evidence supporting molecularly informed treatment selection. Long-term follow-up demonstrated that patients harboring 1p19q loss experienced significant survival benefit from PCV and further demonstrated the prognostic as well as predictive value of IDH mutations [22, 36]. This represented one of the earliest prospective validations of molecular stratification in neuro-oncology. RTOG 94 − 02 directly influenced subsequent classification systems and set a precedent for incorporating molecular biomarkers into eligibility criteria, stratification, and outcome interpretation in later CNS trials of lower grade gliomas.

Improving outcomes in rGBM

The very poor median survival of 6–9 months after recurrence for rGBM has historically limited generation of high-quality prospective evidence [37]. NRG Oncology/RTOG 1205 (2023), the first randomized trial evaluating the role of re-irradiation combined with bevacizumab versus bevacizumab alone in rGBM, demonstrated a significant improvement in PFS, thereby providing the first high-level evidence supporting the role of re-irradiation [38]. Building on these findings, next-generation cooperative group studies are incorporating advanced imaging, molecular stratification, and biologically guided treatment approaches to better define patient selection and optimize therapeutic strategies for rGBM. For example, NRG-BN010 evaluated FSRT with immune modulation (tocilizumab and atezolizumab) [39]. This illustrates a shift toward biologically informed trial designs (Fig. 1).

Fig. 1.

Highlights of RTOG/NRG glioma trials: key glioma trials and their major findings, with positive signals highlighted in the upper row in red, and practice-changing outcomes boxed in salmon; trials with negative results, but meaningful clinical practice relevance, are highlighted in grey in the lower row. These are presented in temporal sequence as far as possible

Section-2: Evolution of therapeutic paradigms in brain metastases and Leptomeningeal Disease (LMD)

Historical approach: WBRT as foundational treatment paradigm

For several decades, WBRT was the standard treatment for BM. Early RTOG studies established WBRT dose and fractionation balancing intracranial control and toxicity. Randomized trials established 30 Gy in 10 fractions and 37.5 Gy in 15 fractions as standard WBRT schedules with comparable outcomes [40]. Subsequent studies of dose escalation altered fractionation, radiosensitizers, chemotherapy, or targeted agents did not improve survival, highlighting the limitations of WBRT [8–11]. In parallel RTOG emphasized radiotherapy standardization and QA. Protocols incorporated centralized plan review and standardized target volume definitions to reduce interinstitutional variability. This QA framework supported later precision radiotherapy trials and complex multi-institutional CNS studies [41, 42].

Prognostic models

Recognition of heterogeneity among BM patients led to prognostic stratification tools. The RPA classification, derived from RTOG datasets, incorporated key clinical variables to define prognostic groups [43]. This enabled risk-adjusted interpretation of trial outcomes, including RTOG 9508. These findings informed subsequent prognostic models, and RTOG datasets helped validate the Graded Prognostic Assessment (GPA), which remains widely used.

Transition to SRS-based strategies

RTOG 9508 (2004) initiated a generation of trials that established SRS as the standard approach for many patients with BM [44]. JROSG 99 − 1 and NCCTG N0574 (2016) demonstrated that SRS alone preserved NCF without compromising OS despite high intracranial relapses, establishing it as a SOC [45, 46]. JLGK0901 and Aizer et al. further extended SRS beyond traditional lesion-number thresholds [47, 48]. Ongoing NRG-supported CE.7 is evaluating safety and efficacy of SRS in patients with up to 15 brain metastases, further expanding this paradigm [47, 49].

SRS is also being evaluated in small cell lung cancer (SCLC), traditionally managed with WBRT. NRG-CC009 is evaluating SRS vs. HA-WBRT in patients with SCLC and BM. The role of SRS in the postoperative setting has also evolved. Non-RTOG Randomized studies established postoperative SRS as SOC by preserving cognition by maintaining local control. Building upon this, NRG is evaluating preoperative SRS to reduce radionecrosis and iatrogenic LMD [50].

For larger lesions, FSRT may improve local control and reduce toxicity versus single-fraction SRS. NRG-BN013 is formally evaluating single versus fractionated radiosurgery in a randomized trial [51].

Stereotactic radiotherapy strategies have also extended to spinal metastases, where cooperative group trials have sought to define the role of stereotactic body radiotherapy (SBRT). RTOG 0631 found no clinical benefit for single-fraction SBRT over conventional radiotherapy for localized spine metastases; additional trials are ongoing [52].

Neurocognition, quality of life, and toxicity mitigation

As survival improved for selected patients with BM, preservation of NCF emerged as a central concern. A pivotal early trial, RTOG 0614 (2023), demonstrated that the NMDA receptor antagonist memantine could delay cognitive decline following WBRT, providing the first prospective evidence supporting pharmacologic neuroprotection in this setting [53].

Building on this, hippocampal-avoidance (HA) techniques aimed to reduce radiation dose to neural stem-cell niches, responsible for repopulating cells subserving memory function, culminated in NRG CC001, a randomized phase III trial evaluating HA WBRT plus memantine versus standard WBRT plus memantine. A significant reduction in the risk of cognitive failure was observed [54]. This also required the development of robust QA infrastructure, including standardized contouring atlases, credentialing processes, and real-time centralized review. These efforts were accompanied by extensive educational initiatives including dissemination of contouring guidelines, training modules, and real-time feedback, effectively training large numbers of radiation oncologists in the consistent application of hippocampal-sparing techniques. This combination of QA rigor and structured education was essential to ensure protocol compliance and has facilitated widespread adoption of HA in routine practice [55–57].

Subsequent NRG trials have continued to expand this strategy, including studies evaluating HA in prophylactic cranial irradiation (PCI) for SCLC (NRG CC003, 2025), as well as ongoing trials assessing focal and systemic therapy combinations aimed at further minimizing neurotoxicity [58] (Fig. 2).

Fig. 2.

Hippocampal avoidance whole brain radiotherapy. This figure illustrates the dosimetric differences between standard and hippocampal-avoidant whole brain radiotherapy, the rationale for this approach, and the clinical trial portfolio providing practice-changing evidence for this approach. [Created in BioRender. Associates, R. (2026)]

Section  3: LMD

LMD remains a major challenge because of poor prognosis, heterogenous presentation, and limited prospective data. Median OS ranges from 2 to 6 months, reflecting aggressive disease biology and the difficulty of treating the neuraxis. Cooperative group trials have been limited by rapid clinical deterioration and heterogenous primary tumor histologies. Radiotherapy has typically been delivered focally for symptomatic disease, with systemic and intrathecal therapies incorporated according to tumor type [59].

A recent phase II randomized trial demonstrated that proton craniospinal irradiation (CSI) significantly improved PFS and OS versus involved-field radiotherapy, representing a major advance in this disease [60]. A definitive trial evaluating proton CSI, NRG BN014 is underway.

BM and GBM account for the largest share of cooperative group trial enrollment, reflecting historical emphasis of RTOG/NRG CNS research (Figs. 3 and 4).

Fig. 3.

Highlights of RTOG/NRG BM and meningioma trials: (a) illustrates key BM trials and their major findings, with practice-changing outcomes/positive signals highlighted in red; trials with negative results, but meaningful clinical practice relevance is highlighted in grey presented in temporal sequence as far as possible. (b) illustrates trials based on risk groups in meningioma. Abbreviations: WBRT – whole brain radiotherapy, SRS- stereotactic radiosurgery, RT- radiotherapy, NCTN – National Clinical trial network, G- Grade, GTR – Gross total resection, STR- Subtotal Resection, Lo- low risk, O- observation, P-Phase, P2R- Phase 2 randomized, v-versus, rec- recurrent, Dx – diagnosis

Fig. 4.

Bar chart showing distribution of patients enrolled, accrued and planned for key RTOG and NRG Oncology trials. Enrollment totals were obtained from primary publications; current accrual was used for selected ongoing studies. For each disease category, the first and second databox represent patients enrolled in completed and ongoing trials, and the third box represents patients to be enrolled. Note the significant focus on the meningioma portfolio, representing a unique feature of any neuro-oncology focused clinical trials group

Section 4: PCNSL

PCNSL presents unique therapeutic challenges. Despite marked sensitivity to both chemotherapy and radiotherapy, survival has historically been very poor. Early cooperative group studies established high-dose WBRT as an effective modality, achieving high response rates but with significant neurotoxicity, particularly in older patients [61].

Subsequent high dose methotrexate-based chemotherapy regimens improved survival, allowing deferral or omission of WBRT. Recent NRG trials evaluated reduced dose WBRT following chemotherapy using a risk/response-based adaptive strategy strategies to balance disease control with neurotoxicity. RTOG 1114 demonstrated that lower dose consolidation radiotherapy optimizes disease control while mitigating long term cognitive decline [62, 63]. Trials incorporating low-dose WBRT with BTK inhibitors are under discussion.

Section 5: Meningioma

NRG Oncology/RTOG 0539 (2023) was a pioneering prospective phase II trial that stratified patients with meningioma into risk groups and evaluated risk-adapted radiotherapy approaches. The study demonstrated excellent PFS in intermediate-risk patients treated with postoperative radiotherapy, providing prospective evidence supporting adjuvant treatment. Importantly, RTOG 0539 incorporated centralized imaging review, standardized target volume delineation, and protocol-driven radiotherapy delivery, highlighting the importance of cooperative group infrastructure in achieving consistent outcomes across institutions [42]. The spin-off value of this trial is reflected in the current comprehensive portfolio of trials in accrual or deployment within NRG, including NRG-BN 003 (G2 observation versus RT following gross total resection), BN 015 (RT versus observation for molecular high-risk, clinical low-risk), BN 016 (clinical high risk meningioma treated with RT +/- CDK4/6 inhibitor), and the RTOG Foundation MOMENTUM-1- (post-RT recurrent high risk meningioma SOC versus ¹⁷⁷Lu-DOTATATE). Importantly, molecular imaging (DOTATATE-PET) is now incorporated.

Conclusion

We acknowledge that a number of limitations provide key learnings. Trials that do not succeed in meeting the primary end point do not necessarily reflect failure per se, but more an opportunity to allow better design of future clinical trials as well as an opportunity to study secondary end points. The key lessons from these trials that provide a roadmap for improving future clinical trial conduct include:

1. Enriching patient selection, particularly using molecular profiling to match tumor subtypes with appropriate therapies.

2. Realistic endpoint selection, including feasible assumptions regarding differences between standard and experimental arms.

3. Conservative accrual planning based on realistic enrollment expectations.

4. Recognition of accrual barriers in de-escalation trials, particularly in diseases with poor prognosis.

5. Central pathology, molecular marker, and real-time radiotherapy quality review for complex treatment techniques.

6. Conducting trials that are patient-centric, especially in terms of cognitive and quality of life and points.

RTOG and NRG Oncology CNS trials collectively demonstrate a clear evolution from foundational radiotherapy studies to increasingly sophisticated, biology-informed, and patient-centered investigations. Early efforts established standards for dose and fractionation, as well as evidence for integrated chemoradiotherapy approaches, while subsequent trials introduced methodological rigor through centralized QA and prognostic stratification. More recent studies incorporated molecular selection, refining therapeutic approaches despite limited success of many targeted strategies. Importantly, cooperative group trials have redefined endpoints by integrating NCF and QOL outcomes, particularly in BM, shifting the focus toward preservation of neurological function alongside disease control. The collaborative nature of NRG Oncology, supporting clinical trials within other groups, is also clear. Together, these advances reflect a transition toward coordinated, multidisciplinary precision care. Moving forward, the cooperative group model remains essential for advancing CNS oncology care through integration of molecular biomarkers, advanced imaging, and adaptive trial design.

Author contributions

Conceptualization and Supervision: M.P.M. conceived and supervised the study, provided critical intellectual oversight, guided the study design and interpretation of findings, and reviewed and approved the final manuscript. Literature Review, Investigation, Methodology, Manuscript Preparation and Final Review: K. S. drafted the initial manuscript. M.P.M. critically revised the manuscript for important intellectual content and approved the final version for submission. M.Y.C.P., M.A.V., M.G., A.C., D.P.C., A.B.L., D.R.R., E.P.S, M.M., Q.T.L., W.C., V.G., and M.P.M. contributed to manuscript review, interpretation of the literature, and approved the final version of the manuscript.

Funding

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number(s) U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), UG1CA189867 [National Cancer Institute Community Oncology Research Program (NCORP)] and Aurora NCORP Research Base grant (UG1CA189867). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethical approval

Ethics approval and informed consent were not required because this study is a white paper of previously published literature and did not involve individual patient-level data.

Competing interests

M.P.M.- Consultant/Honoraria: Mustang BioTech, Novocure, AIQ, BDT, GT Technologies, Chimerix, Telix; Patents: WARF; Proton PRDR; Leadership Roles: NRG Oncology Brain Tumor Committee Chair; NRG Oncology Board Member; NAPT Board Member; PCG Board Member; Mevion Technological Advisory BoardStock/Ownership:Pyrojas. K.S.- No COI. M.Y.C.P.- Consultant/Honoraria: NeuroTrials, LLC; Astellas Pharma; Leadership Roles: member of the NCI Head and Neck Steering Committee; member of the NCI Lymphoma Steering Committee; member of the Psychosis Risk Outcomes Compound Assessment Network (ProCAN) Data and Safety Monitoring Board (DSMB). M.A.V. - founder, director and Chief Technology Officer of Cerinfuse, of which I am the majority shareholder.  I am also founder, director, Chief Medical Officer and a shareholder of Reverix Therapeutics, Inc. M.G.- No COI. A.C.- No COI. D.P.C.- has received honoraria for advisory activities from Boston Scientific (2025) and Servier (2023). A.B.L.- Consultant/Advisor/Honoraria: Fore, GSK, GCAR, Immunicom, Modifibio, Nerviano Medical Sciences srl, Orbus, Deciphera, Rigel, Sapience, Servier. Stock: Moderna (divested). Travel/in-kind support: AnHeart/Nuvation, Fortrea, Gilead, GCAR, Immunicom, Incyte, Modifibio, MI&T srl, Orbus, Sapience, Servier, VBI. Editorial board (uncompensated): Neuro Oncology (current), Journal of Neuro-oncology (former). D.R.R.- has consulted with GammaTile, Tipping Point, Sirtex, Crinetics, Exelixis, Capvision, and SurvivorNet, is an inventor on patents pertaining to brain tumor treatment and risk-stratification and has served as an expert witness. E.P.S. - Has consulted and received institutional research funding from Novocure; has consulted for Telix, received research funding from SHY-Therapeutics, Purdue Pharma, Curtana, Duke Street Bio. M.M.- Deputy Group Chair and member of the Board of Directors of NRG Oncology; President and member of the Board of Directors of the RTOG Foundation; Research funding (last 5 years): Merck, Astra Zeneca, Genentech, Eli Lilly, Amgen, Consultancy and travel funding: Varian, Astra Zeneca, Caris. Q.T.L. - Leadership Roles: NRG Oncology/RTOGF group chair; Consultant/Honoraria: Merck, Johnson&Johnson; Research Grant: Merck. W.C.- Data Monitoring Committee Member: Amgen, Bristol Myers Squibb, AstraZeneca; Shareholder and Board Member: Lumonus; Shareholder: SeeTreat, Nanthealth; Limited Partner: Oncology Ventures Fund; Stock Options: Arterra AI. V.G.- Consultant/Honoraria: Servier, Novocure, AstraZeneca, GammaTile, Accuray, UpToDate; Leadership Roles: NRG Oncology Brain Tumor Committee Chair.