CNS
Both CNS readouts are meningioma RT dose questions: FIRESTORM tests escalation above standard postop dosing, while RTOG 0539 sets the mature risk-adapted benchmark where high-risk disease plateaus at 60Gy.
FIRESTORM
ForHigh-risk meningioma: WHO grade 2 STR or recurrent, postop RT
TL;DR5-yr PFS 65.8% vs 38.8% favoring dose-escalated RT (BED ≥79.2 Gy), HR 0.40; OS not improved.
The trade-off is the actionable read: escalating to BED ≥79.2 Gy (≈66 Gy/33 fx) roughly doubled 5-yr PFS (65.8% vs 38.8%) but tripled any-grade radionecrosis (33.9% vs 13.2%), with severe RN unchanged (5.1% vs 3.2%) and no OS gain. Benefit was largest after subtotal resection.
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Individual patient-level meta-analysis pooling 7 institutions, N=248 (59 DE-RT, 189 SD-RT). Retrospective, non-randomized; compared by Kaplan-Meier, Cox multivariable, and IPTW propensity analysis.
High-risk meningioma: 75.8% WHO grade 2, 41.5% recurrent (grade 3 the remainder), 75.2% subtotal resection.
DE-RT defined as biologically effective dose ≥79.2 Gy (equivalent 66 Gy/33 fx); SD-RT comparator conventionally fractionated 59.4 Gy/33 fx or 60 Gy/30 fx. Mixed photon/carbon vs photon-alone DE-RT showed no PFS difference (81.3% vs 92.0% at 3y, P=.34).
Primary: progression-free survival, DE-RT vs SD-RT. Also overall survival and CNS radionecrosis.
OS not improved despite the PFS gain: 5-yr OS 83.8% vs 68.4% (P=.056 UVA), non-significant on MVA (HR 0.66, P=.27) and IPTW (HR 0.77, P=.42).
| Endpoint | DE-RT | SD-RT |
|---|---|---|
| 3-yr PFS | 86.4% | 55.6% |
| 5-yr PFS | 65.8% | 38.8% |
| Adjusted HR (MVA) | 0.40 (0.24-0.69), P=.001 | ref |
| IPTW HR | 0.45 (0.24-0.83), P=.01 | ref |
| Radionecrosis | DE-RT | SD-RT |
|---|---|---|
| Any grade | 33.9% (20/59) | 13.2% (25/189) |
| Grade 3+ | 5.1% | 3.2% |
Any-grade radionecrosis higher with DE-RT (33.9% vs 13.2%, P=.001) but grade 3+ similar (5.1% vs 3.2%); most RN was low-grade.
Standard-dose postoperative meningioma RT (RTOG-0539 high-risk 60 Gy, EORTC-22042 60 Gy) sits at/below this cohort's SD-RT arm; the dose-response signal here motivates the ongoing randomized escalation question.
Retrospective non-randomized pooling: DE-RT allocation confounded, IPTW mitigates but cannot fully adjust. PFS gain without OS benefit; prior-RT and grade imbalance across arms.
Retrospective non-randomized IPD pooling; DE-RT allocation confounded despite IPTW. PFS-only gain, no OS benefit. Signal supports escalation but needs randomized confirmation.
In high-risk meningioma (WHO grade 2, subtotally resected or recurrent) receiving postoperative RT, this supports a higher dose (BED ≥79.2 Gy) for local control; it does not extend to gross-totally-resected grade 1 disease or establish an OS benefit.
- Randomized confirmation of dose-escalated RT for high-risk meningioma active A Trial of Increased Dose Intensity Modulated Proton Therapy (IMPT) for High-Grade Meningiomas Phase NAn=21 · primary completion 2027-08 · increased-dose IMPT for high-grade meningioman=90 · primary completion 2028-12 · proton dose-escalation, 5y RFS in grade II/III
- Whether the PFS gain translates to an OS benefit
- Optimal escalation technique and dose (photon vs particle) recruiting Long-term Cognitive and Functional Impact of Proton-therapy or Modern Fractionated Radiotherapy in Cavernous Sinus Meningioma: An Open-label Randomized 1:1 Phase III Study Phase NAn=160 · primary completion 2032-02 · randomized proton vs photon RT, phase 3
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Abstract
RTOG 0539 NCT00895622
ForWHO grade 1-3 meningioma, post-resection, newly diagnosed or recurrent
TL;DR10-yr PFS 72.2% intermediate-risk (54Gy) and 42.5% high-risk (60Gy) meningioma on adjuvant RT; low-risk observed 85.2%.
The RT read is patient selection: low-risk grade 1 (GTR/STR) observed carried only 8.9% 10-yr cumulative progression, backing omission, while intermediate-risk earns 54Gy/30fx adjuvant. High-risk 60Gy still leaves 39.3% 10-yr progression, marking the ceiling of adjuvant RT alone in grade 2/3 disease.
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Prospective phase 2, multi-institutional (NRG/RTOG), risk-adapted by WHO grade, extent of resection, and recurrence status. 244 consented, 165 protocol-treated. Central pathology review; data cutoff 8/15/2023.
Adults ≥18, Zubrod 0-1, histologically confirmed unifocal WHO grade 1-3 meningioma, any resection extent. Low-risk n=60, intermediate n=52, high-risk n=53.
Intermediate-risk 54 Gy and high-risk 60 Gy, both in 30 fractions, adjuvant. Low-risk received no RT (observation). No hypofractionation or SRS arm.
Primary (3-yr PFS) reported previously. This analysis reports long-term PFS, OS, and cumulative incidence of progression (competing-risk) at ~12-yr median follow-up.
Per-cohort 10-yr PFS, OS, and cumulative-incidence values are in the table above. Median PFS not reached for low- and intermediate-risk.
| Cohort (management) | 10-yr PFS | 10-yr OS | 10-yr cum. incidence progression |
|---|---|---|---|
| Low-risk, observed | 85.2% | 94.1% | 8.9% (3.2-18.2) |
| Intermediate, 54Gy | 72.2% | 84.7% | 21.2% (10.8-33.9) |
| High-risk, 60Gy | 42.5% | 51.1% | 39.3% (25.8-52.5) |
RT-attributable grade 3+ toxicity 9.6% (intermediate, 5/52) and 15.1% (high-risk, 8/53). The observed low-risk cohort carried no RT toxicity.
No randomised RT-vs-observation trial in grade 2 meningioma has reported. ROAM/EORTC-1308 and NRG-BN003 (GTR grade 2) remain open; RTOG 0539 is the prospective benchmark.
Each risk cohort is single-arm, no randomised RT-vs-observation comparison; modest per-cohort N (~50-60); grading predates molecular integration into WHO CNS grading.
Prospective multi-institutional risk-adapted phase 2, 12-yr mature f/u, sets RT patient-selection benchmark. Each cohort single-arm; no randomised RT-vs-observation comparison.
In newly diagnosed grade 1 meningioma after gross or subtotal resection, this supports observation over adjuvant RT; it does not soften the case for 54-60Gy in recurrent grade 1, grade 2, or grade 3 disease.
- Randomised confirmation of RT omission after GTR of grade 2 meningioma not yet Efficacy of Postoperative Radiotherapy for Atypical Meningioma Without Venous Sinus Invasion After Gross-total Resection Phase NAn=140 · primary completion 2028-01 · postop RT need after GTR of atypical WHO II
- Role of dose escalation or systemic therapy for high-risk (grade 3) disease active An Open-Label Phase II Study of Nivolumab or Nivolumab/Ipilimumab in Adult Participants With Progessive/ Recurrent Meningioma Phase 2n=40 · primary completion 2024-12 · nivo/ipi for progressive/recurrent WHO IIIrecruiting Combination of Everolimus and 177Lu-DOTATATE in the Treatment of Grades 2 and 3 Refractory Meningioma: a Phase IIb Clinical Trial Phase 2n=28 · primary completion 2026-03 · everolimus + Lu-DOTATATE, refractory WHO 2/3active A Trial of Increased Dose Intensity Modulated Proton Therapy (IMPT) for High-Grade Meningiomas Phase NAn=21 · primary completion 2027-08 · IMPT dose intensification for high-grade WHO II/IIIn=90 · primary completion 2028-12 · proton dose escalation 68-72 Gy, WHO II/III
- Molecular grading integration to refine risk stratification