Alliance N0574

Background

Alliance N0574: Phase III, randomized, multicenter trial. 213 patients with 1–3 brain metastases randomized to SRS alone vs SRS + WBRT. WBRT 30 Gy in 12 fractions. Primary endpoint: HVLT-R total recall cognitive decline at 3 months (formal neurocognitive testing). Enrolled 2002–2013. This is the largest and most rigorous RCT of SRS ± WBRT evaluating neurocognition.

Interventions and follow up

Arm A: SRS alone (SRS dose: 18–24 Gy based on lesion diameter)
Arm B: SRS + WBRT (30 Gy in 12 fractions)
Primary endpoint: HVLT-R total recall cognitive failure at 3 months (≥1 SD decline from baseline)
mFollow up: Median 7.4 (SRS) and 6.0 months (SRS+WBRT)

Results

HVLT-R cognitive failure at 3 months: 63.5% (SRS alone) vs 91.7% (SRS+WBRT), P<.001
OS: Median 10.7 (SRS) vs 7.4 months (SRS+WBRT), hazard ratio 1.02 — not significant
1-year intracranial failure: 51.9% (SRS) vs 27.4% (SRS+WBRT), P<.001
Quality-adjusted survival: No significant difference

Adverse events

Main adverse events: Cognitive failure rates substantially higher across all tested domains with SRS+WBRT (HVLT-R delayed recall failure: 51% vs 20%). Executive function, processing speed, and fine motor control also worse with WBRT at 3 months. Acute WBRT toxicity: fatigue, alopecia. No grade 4-5 treatment toxicities.

Conclusions

SRS + WBRT produced significantly more cognitive deterioration than SRS alone at 3 months (91.7% vs 63.5%). OS was equivalent. Although WBRT reduced intracranial failure (27.4% vs 51.9% at 1 year), quality-adjusted survival was similar. This definitive trial established SRS alone as the preferred treatment for most patients with 1–3 BM, avoiding WBRT-associated neurocognitive harm.

Key Limitations

Key Limitations: Even SRS alone had a high cognitive failure rate (63.5%) — likely reflecting disease progression and other confounders. OS was similar between arms, suggesting that aggressive surveillance and salvage with additional SRS can maintain survival despite higher intracranial recurrence. The trial was not powered to detect OS differences. Patients with leptomeningeal disease, poor performance status, or extensive systemic disease were excluded.

Clinical Context

Alliance N0574 is the definitive phase III evidence base for current guidelines recommending SRS alone over SRS+WBRT for 1–3 BM. ASCO/ASTRO/SNO all now recommend SRS alone for most patients with 1–4 BM, reserving WBRT for patients with extensive BM burden, leptomeningeal disease, radiosurgery-resistant histologies, or poor prognosis. MRI surveillance every 2–3 months is required when omitting WBRT.

References

References: Brown PD et al, JAMA 2016 (Alliance N0574)