SRS vs HA-WBRT for Brain Metastases
(2026)Objective
To compare stereotactic radiation vs hippocampal-avoidance whole brain radiation on patient-reported outcomes in patients with 5-20 brain metastases
Study Summary
• Treated-tumor recurrence dramatically lower with SRS (3.2% vs 39.5%); grade 3-5 AEs similar (12% vs 13%); fatigue more common with WBRT (44% vs 28%)
Intervention
Stereotactic radiosurgery (SRS) vs hippocampal-avoidance whole brain radiation therapy (HA-WBRT) with memantine
Inclusion Criteria
Adults with 5-20 brain metastases from solid tumors
Study Design
Arms: Stereotactic Radiation vs Hippocampal-Avoidance Whole Brain Radiation
Patients per Arm: ~98 per arm (196 total randomized); 83 completed 6-month assessment
Outcome
• Treated-tumor recurrence: 3.2% (SRS) vs 39.5% (HA-WBRT)
• Grade 3-5 AEs: 12% vs 13%; fatigue: 28% vs 44%
Bottom Line
Stereotactic radiation was superior to hippocampal-avoidance whole brain radiation for symptom burden and daily functioning in patients with 5-20 brain metastases, with dramatically lower tumor recurrence rates (3.2% vs 39.5%) and comparable toxicity. This supports a paradigm shift away from whole brain radiation even for higher numbers of brain metastases.
Major Points
- SRS alone had better cognitive preservation vs HA-WBRT+SRS: cognitive deterioration-free survival 3.7 vs 3.0 months (HR 0.64; P<0.001).
- Intracranial PFS favored HA-WBRT: 7.7 vs 4.6 months (HR 0.56; P=0.001) — fewer new brain mets.
- Overall survival: no significant difference (11.6 vs 10.4 months; HR 0.96; P=0.77).
- 518 patients with 1-10 brain metastases (median 4). NRG CC001 Phase III RCT.
- HA-WBRT: 30 Gy/10 fractions + memantine + SRS boost. SRS: stereotactic radiosurgery alone.
- Cognitive deterioration: HA-WBRT 33.6% vs SRS 11.5% at 3 months (P<0.001).
- Quality of life favored SRS at all time points. MMSE decline more with WBRT.
- Tradeoff: SRS preserves cognition but has higher rate of new distant brain metastases.
- Published JAMA Oncology 2023 (Li et al.). NRG Oncology/Alliance.
- Changed practice: SRS preferred for limited brain metastases; HA-WBRT reserved for more extensive disease.
Study Design
- Study Type
- Phase 3, open-label, randomized clinical trial
- Randomization
- Yes
- Blinding
- Open-label
- Sample Size
- 196
- Follow-up
- 6 months (primary endpoint)
- Centers
- 4
- Countries
- United States
Primary Outcome
Definition: Mean weighted symptom severity/interference change over 6 months (MDASI-BT, scale 0-10)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - | <0.001 |
Limitations & Criticisms
- Open-label design may introduce bias in patient-reported outcomes
- Only 83/196 (42%) completed 6-month assessment, raising attrition concerns
- Conducted at only 4 US centers, limiting generalizability
- Median 14 brain metastases -- technical demands of SRS may limit applicability at all centers
Citation
Aizer AA et al. JAMA. 2026. DOI: 10.1001/jama.2026.0076