Central Nervous System — Board Review Summary

PART I — BRAIN METASTASES: CNS-ACTIVE SYSTEMIC THERAPY, SRS, AND WHEN TO HOLD RT

When Is It Safe to Withhold Radiation?

ScenarioKey dataPractical takeaway
Symptomatic melanoma brain metastasesCheckMate 204: symptomatic pts had median intracranial PFS only 1.2 months; Australian randomized phase II reported intracranial response only 6% in symptomatic ptsUpfront local therapy is recommended for symptomatic brain mets even when CNS-active systemic therapy exists
ALK+ NSCLC, asymptomatic small-volume brain metsCROWN: lorlatinib produced 82% intracranial response, 71% intracranial CR; at 5 years median time to intracranial progression was not reachedReasonable to defer RT initially in carefully selected asymptomatic patients with strong CNS-active targeted therapy options
HER2+ breast cancerHER2CLIMB supports intracranial activity of tucatinib-based therapy, but CNS response may be less dependable if tolerance is poor or dose reduction is neededFavor SRS when likelihood of durable drug response is low or systemic therapy cannot be maintained
Board pearl: modern systemic therapy does not eliminate the need for local CNS therapy. The key distinction is symptomatic / eloquent / hemorrhagic / large / edematous disease versus small, asymptomatic, non-eloquent metastases in a patient starting a highly CNS-active regimen with reliable follow-up.

Standard of Care for Limited Brain Metastases

N0574 established SRS alone as the preferred approach over SRS + WBRT for limited brain metastases. In patients with 1-3 metastases, cognitive decline at 3 months occurred in 63% with SRS alone vs 92% with SRS + WBRT (p<0.001), with better QOL in the SRS arm and no OS difference.
Aizer JAMA 2026 extended level I evidence to patients with 5-20 brain metastases (median 14). SRS improved symptom burden and interference with daily function relative to HA-WBRT, with mean MDASI-BT change -0.32 vs +0.74 (difference -1.06, 95% CI -1.54 to -0.58, p<0.001).

How "Limited" Has Evolved

  • There is now level I evidence supporting SRS for up to 20 lesions.
  • Best candidates generally have lesions <3 cm, ideally <2 cm.
  • Life expectancy matters; the slide specifically references the Brain Met GPA framework.
  • SRS remains especially attractive when cognitive preservation is a priority.

Brain Met SRS Planning Pearls

MRI: ideally within 1 week, thin-slice 1 mm sequences.
PTV: ≤2 mm, ideally ≤1 mm.
Single-fraction dose for lesions <2 cm: 20-24 Gy x 1.
Single-fraction brain V12: keep ≤10 cc.
Conformity index: <2.0, ideally around 1.0-1.2.
Immobilization: include intrafraction motion assessment.

Latest Metastasis-Directed Addition After SRS

Tumor treating fields after SRS for NSCLC brain metastases modestly prolonged intracranial progression (HR 0.72) but did not improve QOL, neurocognition, or OS. This is not a new routine standard.

PART II — RESECTED METASTASES, RADIATION NECROSIS, AND WBRT

Postoperative SRS Is Preferred Over WBRT

N107C randomized patients with one resected metastasis and showed that postoperative SRS improved cognitive deterioration-free survival vs WBRT (3.7 vs 3.0 months, HR 0.47, p<0.0001), with no OS difference. This is the key trial supporting cavity SRS after resection.
Mahajan et al. randomized completely resected 1-3 brain metastases to postoperative SRS vs observation. At 12 months, local recurrence-free rate was 72% vs 43% (HR 0.46, p=0.015), confirming that postoperative SRS improves local control even after GTR.

Postoperative SRS Volume Design

Register pre-op MRI for reference.
GTV: entire resection cavity; include the adjacent surgical tract for deep lesions; exclude edema.
If there was pre-op dural involvement: consider a 5 mm margin beyond the pre-op tumor, which often favors fractionated SRS.
CTV: up to 2 mm, excluding barriers like bone, air, falx, and tentorium.
PTV: optional symmetric 1 mm.

Challenging Post-op Cavities

ScenarioCommon regimenPlanning limit
Larger / irregular postoperative cavities24-27 Gy / 3 fxBrain + target V20Gy <20 cc
Very challenging cavities / fractionated cavity SRS30-32.5 Gy / 5 fxBrain + target V24Gy <20 cc

What’s Coming

  • Alliance A071801: postoperative SRS vs FSRS.
  • NRG-BN012: preoperative vs postoperative SRS.
  • ROADS interim analysis: early signal favored Cs-131 collagen tiles over postsurgical stereotactic RT for surgical-bed recurrence-free survival, but this is still evolving.

Radiation Necrosis: Diagnosis

There is no single SOC imaging test that definitively distinguishes recurrence from treatment effect.
Consider:
  • serial anatomic MRI morphology
  • "soap bubble" vs solid / nodular pattern
  • advanced imaging such as perfusion MRI
  • clinical symptoms
Amino-acid PET remains investigational in this setting.

Radiation Necrosis: Symptomatic Management

SeverityManagement
Mild symptomaticBoswellia 4200-4800 mg/day; vitamin E 1000 IU/day + pentoxifylline 800 mg/day; dexamethasone 4-8 mg/day
Severe / steroid-refractory / progressiveEscalate to bevacizumab, LITT, or surgery depending on symptoms, mass effect, accessibility, and diagnostic certainty

Whole Brain RT for Select Patients

NRG-CC001 supports HA-WBRT + memantine for patients with extensive brain metastases who are ineligible for SRS but have reasonable life expectancy. Hippocampal constraints shown on the slide were D100% ≤9 Gy and Dmax ≤16 Gy.
Conventional WBRT still has a role when HA-WBRT is not feasible, especially with leptomeningeal disease or substantial tumor involving the hippocampal region. The slide also highlights parotid sparing V20 <25% to reduce acute xerostomia.

PART III — GLIOBLASTOMA AND MOLECULAR GLIOBLASTOMA

WHO 2021 Classification Changes the Definition of GBM

Molecular glioblastoma refers to IDH-wildtype glioma without classic histologic grade 4 features but with molecular hallmarks such as TERT promoter mutation, +7/-10 copy number pattern, or EGFR amplification. The lecture treats these tumors like GBM for RT purposes, often to 60 Gy, while noting that molecular classification continues to evolve.

Standard Treatment Framework

  • For most fit patients <70 years: 60 Gy with concurrent and adjuvant temozolomide remains standard.
  • This includes molecular GBM.
  • Selected older patients with good performance status may still be treated similarly.

Elderly Patients with GBM

Perry NEJM 2017 randomized patients age 65+ to hypofractionated RT alone vs RT + concurrent/adjuvant TMZ. Using 40.05 Gy / 15 fx, median OS improved from 7.6 to 9.3 months (HR 0.67, p<0.001) with similar QOL. This is the modern high-yield regimen for older fit patients.

When to Consider TMZ Alone

  • Confirmed MGMT methylated
  • Multifocal disease where RT fields would be very large
  • Tumor not causing mass effect that demands a more rapid cytotoxic approach

When to Use Very Short-Course RT

5 Gy x 5 RT alone may be reasonable for patients who otherwise might receive hospice / best supportive care: very impaired patients, those unlikely to improve substantially, or those for whom longer treatment would create undue burden.

GBM Planning Principles

MRI timing: ideally within 2 weeks of planning; up to 3 weeks may still be usable.
Use both: T1 post-contrast and T2/FLAIR; always review the pre-op MRI.
GTV: cavity + residual enhancement + bulky non-enhancing disease.
CTV: GTV + 1-2 cm, anatomically constrained.
Evidence note: no OS difference was found between larger historic RTOG-style vs smaller EORTC-style volumes.

Common Pitfalls

  • Planning MRI too old (≥4 weeks)
  • CTV not anatomically constrained
  • Failure to cover expected pathways of spread
  • Under-treatment of bulky non-enhancing disease
  • Failure to inspect adjacent FLAIR and multifocal disease
  • For supratentorial tumors, letting CTV drift below the tentorium or into cavernous sinus without direct disease extension

Molecular GBM Margin Nuance

Because molecular GBM is often more non-enhancing, the lecture notes that one may consider a somewhat tighter 1-1.5 cm CTV margin in selected cases, while still prescribing 60 Gy.

PART IV — IDH-MUTANT LOWER-GRADE GLIOMA

High-Risk Grade 2 LGG: Chemoradiation Standard

RTOG 9802 is the key board trial for high-risk low-grade glioma. Patients age ≥40 or with STR/biopsy received RT alone 54 Gy or RT followed by PCV x 6. Long-term follow-up showed a major OS benefit with chemoradiation, with median OS commonly cited as about 13.3 vs 7.8 years.
RTOG 0424 was a single-arm phase II study using 54 Gy + TMZ followed by TMZ x12 in high-risk LGG. Three-year OS was 73.5% vs a historical 54% benchmark (p<0.001), with median OS about 8.2 years.

Role of RT in Grade 2 Glioma

  • EORTC 22845: early RT improves PFS but not OS versus delayed / salvage RT.
  • RT improves seizure control.
  • RT does not increase malignant transformation risk.
  • Lower-dose RT around 50 Gy is standard and is comparable to ~60 Gy with less toxicity.

When to Treat Grade 2 Disease

  • Incomplete resection or biopsy only
  • Location difficult to salvage surgically, including brainstem
  • Neurologic symptoms
  • Not a good candidate for watch-and-wait or unreliable follow-up

INDIGO and Vorasidenib

INDIGO established vorasidenib as a new option for residual or recurrent non-enhancing IDH-mutant grade 2 glioma in carefully selected patients. The phase III trial showed a clear PFS benefit, commonly quoted as about 27.7 vs 11.1 months, and delayed the next intervention. The slide emphasizes that this is most relevant for patients who might otherwise have been observed.

Grade 3 IDH-Mutant Glioma Treatment Paradigm

IDH-mutant grade 3 astrocytoma: RT then adjuvant TMZ.
IDH-mutant grade 3 oligodendroglioma: RT then PCV or TMZ; CODEL results remain pending.
This is one of the most board-relevant places where histology + molecular subtype directly change the post-RT chemotherapy plan.

Planning and Dose for Grade 2-3 IDHm Glioma

SubtypeCTV marginDose
Grade 2 IDHm oligodendroglioma1 cm50.4 Gy (range 45-54 Gy)
Grade 2 IDHm astrocytoma1-1.5 cm54 Gy (range 50-54 Gy)
Grade 3 IDHm oligodendroglioma1 cm57 Gy / 30 to 59.4 Gy / 33
Grade 3 IDHm astrocytoma1-1.5 cm57 Gy / 30 to 59.4 Gy / 33
LGG planning pearl: acquire high-resolution 3D T2 FLAIR and avoid excessive hot spots, generally keeping them <107-110%.

PART V — MENINGIOMA

WHO 2021 Molecular Reclassification Matters

TERT promoter mutation or CDKN2A/B homozygous deletion upgrades meningioma to WHO grade 3. That is a very testable modern pathology point.

RTOG 0539 Risk Groups

Risk groupDefinitionTreatment / result
Low riskNew grade 1, GTR or STR3y PFS 91%; 10y PFS 85%
Intermediate riskNew grade 2 after GTR or recurrent grade 1 any EOR54 Gy; 3y PFS 93.8%; no grade 3 AEs
High riskGrade 3 any EOR, recurrent grade 2 any EOR, or new grade 2 after STR60 Gy high-dose region + 54 Gy low-dose region; 3y PFS 58.8%

Planning Tools

Use: CT bone window, MRI T1 post-contrast, T2-weighted and skull-base fat-sat sequences.
Emerging helper: DOTATATE PET, since most meningiomas express somatostatin receptor.

CTV Margin Rules to Memorize

GradeCTV principle
Grade 1No CTV margin
Grade 20.5-1 cm generous dural margin; up to 5 mm into brain parenchyma for microscopic brain invasion
Grade 31-2 cm CTV

Management Framework

  • Grade 1: observe after GTR; after STR, either close surveillance or RT depending on symptoms, growth risk, and salvage options.
  • Grade 2 after GTR: multidisciplinary discussion about adjuvant RT, generally around 54-59.4 Gy.
  • Grade 2 after STR: RT generally recommended; common dose 60 Gy, with some retrospective series using highly conformal 66-70 Gy.
  • Grade 3: adjuvant RT even after GTR; standard dose about 60 Gy.

What’s Coming

  • MOMENTUM-1: [177Lu]Lu-DOTA-TATE for progressive grade 1-3 intracranial meningioma.
  • NRG-BN015: postop RT vs observation in clinically low-risk but molecularly high-risk meningioma.
  • NRG-BN003: observation vs RT after GTR for grade 2 meningioma.

PART VI — BRAIN TUMOR RE-IRRADIATION

Clinical Selection

Typical minimum interval: at least 6 months from prior RT, ideally ≥1 year.
Consider:
  • symptoms and urgency
  • duration and quality of prior response
  • functional consequences of severe complications
  • whether concurrent bevacizumab is appropriate

Technical Principles

  • Have a standard departmental process.
  • Acquire prior DICOMs whenever possible and review 3D cumulative dose.
  • Assess image-registration quality carefully; soft tissue changes can make composite dose estimation unreliable.
  • Account for tissue recovery assumptions when estimating cumulative dose.

Planning Pearls

Use tight margins: 0-5 mm CTV.
Be especially cautious with medial tumors, where cumulative dose to the contralateral hemisphere can produce bilateral deficits.
Cumulative EQD2, with an explicit tissue-recovery assumption, is very helpful in complex re-irradiation planning. The example slide used a 50% assumed tissue recovery model.

CROSS-CUTTING HIGH-YIELD POINTS

  • Symptomatic brain metastases still need upfront local therapy, even in the era of CNS-active systemic agents.
  • Deferring RT is most defensible in carefully selected asymptomatic patients with strong CNS-active drugs and reliable follow-up.
  • N0574 made SRS alone standard over SRS + WBRT for 1-3 brain mets because of cognitive preservation.
  • Level I evidence for SRS now extends to up to 20 lesions in selected patients.
  • Single-fraction SRS for lesions <2 cm: 20-24 Gy; keep V12 ≤10 cc.
  • Post-op cavity management: postoperative SRS is preferred over WBRT and better than observation for local control.
  • Post-op FSRS doses: 24-27 Gy / 3 or 30-32.5 Gy / 5 for larger or riskier cavities.
  • Radiation necrosis diagnosis remains multimodal; there is no single definitive SOC test.
  • Mild RN options: Boswellia, vitamin E/pentoxifylline, dexamethasone.
  • HA-WBRT + memantine is preferred for many patients with extensive brain mets who are not SRS candidates.
  • Hippocampal constraints: D100% ≤9 Gy, Dmax ≤16 Gy.
  • GBM standard: 60 Gy / 30 + concurrent/adjuvant TMZ, including molecular GBM.
  • Elderly GBM standard: 40.05 Gy / 15 + TMZ for fit older patients.
  • TMZ alone in elderly GBM is most reasonable when MGMT is methylated and RT is impractical or low-yield.
  • Very short-course GBM RT: 25 Gy / 5 is a real option near the hospice threshold.
  • High-risk LGG: RTOG 9802 established RT -> PCV as the OS-improving standard.
  • INDIGO made vorasidenib relevant for residual / recurrent non-enhancing grade 2 IDHm glioma.
  • Grade 3 IDHm astrocytoma generally gets RT then TMZ; grade 3 oligodendroglioma gets RT then PCV or TMZ pending CODEL.
  • Meningioma WHO 2021: TERT promoter mutation or CDKN2A/B homozygous deletion upgrades to grade 3.
  • Meningioma margins: grade 1 no CTV; grade 2 0.5-1 cm along dura; grade 3 1-2 cm.
  • Re-irradiation: wait at least 6 months when possible, use tight margins, and think in composite EQD2 rather than isolated plan doses.

CONSOLIDATED DOSE TABLE

Clinical settingDose / planning ruleUse case
Limited intact brain metastasis, <2 cm20-24 Gy x 1Standard single-fraction SRS
Post-op cavity, larger / irregular24-27 Gy / 3 fxFractionated postop SRS
Post-op cavity, very challenging30-32.5 Gy / 5 fxLarger cavity / dural involvement / FSRS
Single-fraction SRS constraintBrain V12 ≤10 ccNecrosis mitigation
FSRS cavity constraintBrain + target V20Gy (3 fx) or V24Gy (5 fx) <20 ccPost-op FSRS planning
HA-WBRT hippocampiD100% ≤9 Gy; Dmax ≤16 GyNRG-CC001 style planning
Conventional WBRT parotidsParotid V20 <25%Reduce acute xerostomia
Standard GBM60 Gy / 30 fxFit adults, including molecular GBM
Elderly GBM + TMZ40.05 Gy / 15 fxModern standard for older fit patients
Very short-course GBM RT25 Gy / 5 fxPoor performance / near-hospice scenario
Grade 2 IDHm oligodendroglioma50.4 GyCommon definitive / adjuvant dose
Grade 2 IDHm astrocytoma54 GyCommon definitive / adjuvant dose
Grade 3 IDHm oligodendroglioma57 Gy / 30 to 59.4 Gy / 33RT before PCV/TMZ
Grade 3 IDHm astrocytoma57 Gy / 30 to 59.4 Gy / 33RT before TMZ
Intermediate-risk meningioma54 GyRTOG 0539 group 2
High-risk meningioma60 GyRTOG 0539 high-dose region
High-risk meningioma low-dose region54 GyRTOG 0539 group 3 low-dose region
Re-irradiation marginCTV 0-5 mmTight composite-dose planning

KEY LANDMARK TRIALS (memorize)

TrialDiseaseOne-line takeaway
CheckMate 204Melanoma brain metsSymptomatic patients do poorly on IO alone; supports upfront local therapy
CROWNALK+ NSCLC brain metsLorlatinib has very high intracranial activity and can justify deferred RT in selected asymptomatic patients
N05741-3 brain metastasesSRS alone preserves cognition and QOL compared with SRS + WBRT
Aizer 20265-20 brain metastasesSRS outperformed HA-WBRT for symptom burden in selected multi-metastasis patients
N107CResected brain metastasisPost-op SRS beats WBRT for cognitive preservation without sacrificing OS
Mahajan 2017Resected 1-3 brain metastasesPost-op SRS improves local control compared with observation
NRG-CC001WBRT candidatesHA-WBRT + memantine is the modern preferred WBRT approach when feasible
Perry 2017Elderly GBM40.05 Gy / 15 + TMZ improves OS over RT alone
Wick / MalmstromElderly GBMSupport TMZ-alone selection in MGMT-methylated / RT-unfavorable patients
RTOG 9802High-risk LGGRT -> PCV confers a major OS benefit
RTOG 0424High-risk LGG54 Gy + TMZ showed favorable survival vs historical controls
EORTC 22845Grade 2 gliomaEarly RT improves PFS and seizure control, not OS
INDIGOIDHm grade 2 gliomaVorasidenib delays progression and time to next intervention
RTOG 0539MeningiomaRisk-stratified outcomes framework for grade / recurrence / extent of resection
MOMENTUM-1MeningiomaEmerging radioligand study in progressive intracranial meningioma
NRG-BN003 / BN015MeningiomaCritical ongoing postop RT vs observation trials in grade 2 / molecularly high-risk disease
NRG-BN001Newly diagnosed GBMDose intensification remains investigational; standard-dose chemoradiation still anchors care
NRG-CC017uMGMT GBMTemporally modulated pulsed RT is an important ongoing phase III concept