Why This Study Matters
Meningioma is the most common primary intracranial tumor, and most WHO grade 1 tumors behave indolently after gross total resection. But management of subtotally resected, recurrent, or higher-grade (WHO grade 2-3) disease has lacked long-term prospective evidence to guide clinicians. NRG Oncology RTOG 0539 was designed to test a risk-adapted strategy — observation for low-risk disease, radiotherapy for intermediate- and high-risk disease — and this analysis reports outcomes after a median follow-up exceeding 10 years, far beyond the trial's original 3-year primary endpoint.
Study Design
Phase: Phase II. Design: Prospective, multi-arm, risk-adapted (non-randomized) trial — patients were assigned to one of three risk cohorts based on WHO grade, extent of resection, and recurrence status, rather than randomized to treatment. Population: Adults (age 18 and older) with Zubrod Performance Status 0-1 and histologically confirmed newly diagnosed or recurrent unifocal WHO grade 1-3 meningioma of any resection extent. Of 244 patients consented, 165 were eligible and assigned to a risk cohort.
| Risk Cohort | Assignment Criteria | Treatment |
|---|---|---|
| Low-risk (n=60) | WHO grade 1 tumor after gross total or subtotal resection | Observation only |
| Intermediate-risk (n=52) | Recurrent grade 1 tumor, or newly diagnosed grade 2 tumor after gross total resection | Radiotherapy, 54 Gy in 30 fractions |
| High-risk (n=53) | Newly diagnosed grade 2 tumor after subtotal resection, newly diagnosed grade 3 tumor, or recurrent grade 2/3 tumor | Radiotherapy, 60 Gy in 30 fractions |
Primary Endpoint Results
Median follow-up was 12.1 years for the low-risk cohort, 12.0 years for the intermediate-risk cohort, and 11.1 years for the high-risk cohort. The 10-year cumulative incidence of disease progression was 8.9% in the low-risk cohort, 21.2% in the intermediate-risk cohort, and 39.3% in the high-risk cohort. Median progression-free survival was not reached for the low- and intermediate-risk cohorts; for the high-risk cohort, median PFS was 3.8 years. Median overall survival was likewise not reached for the low-risk (observed) or intermediate-risk (irradiated) cohorts, while the high-risk cohort's median OS was 11.2 years.
| Risk Cohort | 5-Year PFS | 10-Year PFS | 5-Year OS | 10-Year OS |
|---|---|---|---|---|
| Low-risk (n=60) | 89.4% | 85.2% | 98.3% | 94.1% |
| Intermediate-risk (n=52) | 85.6% | 72.2% | 95.9% | 84.7% |
| High-risk (n=53) | 44.7% | 42.5% | 59.7% | 51.1% |
On multivariable Cox proportional hazards modeling, both recurrent disease (versus initial diagnosis; HR 2.5, 95% CI 1.01-6.18, P=.047) and subtotal resection (versus gross total resection; HR 2.58, 95% CI 1.09-6.11, P=.031) were independently associated with worse PFS. For OS, recurrent disease (HR 2.86, 95% CI 1.06-7.70, P=.038) and subtotal resection (HR 3.38, 95% CI 1.28-8.91, P=.014) were likewise independent predictors of inferior outcomes.
Subgroup Analyses
The following comparisons are within-study subgroup findings reported directly in the trial's results, not benchmarks against external trials. In the low-risk cohort, extent of resection separated outcomes clearly (10-year PFS 88.0% after gross total resection versus 72.7% after subtotal resection). In the intermediate-risk cohort, recurrent grade 1 disease and newly diagnosed grade 2 disease after gross total resection had similar PFS, but overall survival favored the newly diagnosed grade 2 group (HR 0.30, 95% CI 0.09-1.04, P=.045). In the high-risk cohort, recurrent grade 2 or grade 3 disease fared consistently worse than newly diagnosed grade 2 or grade 3 disease.
| Comparison | Result |
|---|---|
| Low-risk: 10-yr PFS, gross total vs. subtotal resection | 88.0% vs. 72.7% |
| Low-risk: 10-yr OS, gross total vs. subtotal resection | 90.9% vs. 100% |
| Intermediate-risk: 5-/10-yr PFS, recurrent grade 1 vs. new grade 2 after GTR | 86.2%/67.0% vs. 85.4%/73.2% (P=.61) |
| Intermediate-risk: 5-/10-yr OS, recurrent grade 1 vs. new grade 2 after GTR | 93.3%/67.0% vs. 97.1%/91.0% (HR 0.30, P=.045) |
| High-risk: 5-/10-yr PFS, recurrent grade 2 vs. new grade 2 after STR | 30.0%/15.0% vs. 54.5%/54.5% |
| High-risk: 5-/10-yr PFS, recurrent grade 2 vs. new grade 3 | 30.0%/15.0% vs. 52.9%/52.9% |
| High-risk: 5-/10-yr PFS, recurrent grade 3 vs. new grade 3 | 40.0%/no patients at 10 yrs vs. 52.9%/52.9% |
Safety Profile
Grade 3 or higher radiotherapy-related adverse events occurred in 5 patients (9.6%) in the intermediate-risk cohort and 8 patients (15.1%) in the high-risk cohort, per the study abstract. On extended follow-up, the intermediate-risk group had two additional grade 3 toxicities newly reported (one auditory, one neurologic) plus one grade 4 toxicity (hemorrhage). In the high-risk group, one additional patient developed new adverse events, including multiple grade 3 toxicities (musculoskeletal, neurologic, and ocular). Functional outcomes — assessed via Zubrod performance status, Mini-Mental State Examination, and neurologic function score — remained stable over time across all three cohorts.
| Cohort | Grade 3+ RT-Related Toxicity |
|---|---|
| Low-risk (observation) | Not applicable — no radiotherapy administered |
| Intermediate-risk | 5 patients (9.6%) |
| High-risk | 8 patients (15.1%) |
Interpretation and Broader Context
NRG Oncology RTOG 0539 was a practice-defining clinical trial using an innovative risk-adapted strategy.
— Discussion, Journal of Clinical Oncology
These 10-year results support current consensus practice of observation after gross total resection for low-risk (WHO grade 1) meningioma, with consideration of radiotherapy after subtotal resection. They also support upfront radiotherapy for grade 2 meningioma after gross total resection pending results of ongoing de-escalation trials (NRG BN003 [NCT03180268] and ROAM/EORTC 1308). Outcomes for high-risk meningioma (recurrent or grade 3 disease) remain suboptimal even with modern surgery and radiotherapy to 60 Gy, underscoring an unmet need for more effective systemic or combined-modality approaches in this group.
Future directions: the authors note that as molecular classification of meningioma evolves, some histopathologically grade 1 tumors with high-risk molecular features may eventually be reclassified, which could refine future risk-adapted strategies. Ongoing de-escalation trials (NRG BN003, ROAM/EORTC 1308) will further inform management of grade 2 disease after gross total resection.
Ten-year follow-up of NRG Oncology RTOG 0539 validates a risk-adapted meningioma strategy that most centers already practice: observation after gross total resection for low-risk disease, and radiotherapy for intermediate- and high-risk disease. Low- and intermediate-risk patients did well, with 10-year overall survival of 94.1% and 84.7% respectively, while high-risk (recurrent or grade 3) disease remained difficult to control, with 10-year overall survival of just 51.1% despite radiotherapy to 60 Gy. Recurrent disease and subtotal resection were the two factors most consistently linked to worse outcomes, reinforcing the value of complete resection when it can be safely achieved. With grade 2 management after gross total resection still unsettled, ongoing de-escalation trials (NRG BN003, ROAM/EORTC 1308) are positioned to refine this risk-adapted framework further.