Brain Metastases

1.SRS alone versus adding whole-brain radiotherapy

Randomized trials established that WBRT added to SRS reduces distant intracranial failure but at a cognitive cost. Chang and colleagues (MD Anderson) found patients receiving SRS plus WBRT had significantly worse learning and memory at four months than SRS alone, and the trial was stopped early. The definitive cognition trial, N0574 (Brown, JAMA 2016), randomized patients with 1–3 metastases and found less cognitive deterioration at three months with SRS alone and no overall-survival difference, concluding SRS alone is the preferred strategy for limited brain metastases amenable to radiosurgery. The trade-off is more frequent distant brain failure with SRS alone, which is managed by serial MRI surveillance and salvage SRS rather than upfront WBRT in most patients.

2.From "limited" to multiple lesions

The historical limit of treating only a few metastases has eroded. JLGK0901, a large prospective observational study, showed that overall survival after SRS for 5–10 metastases was non-inferior to that for 2–4. CYBER-SPACE, which randomized planning MRI sequence rather than treatment strategy, treated patients with 1–10 untreated metastases with SRS in both arms and reported 77% freedom from a whole-brain radiotherapy indication at 12 months, supporting SRS with close surveillance as a way to defer whole-brain treatment. Aizer 2026 then randomized patients with 5–20 metastases (median 14) to SRS or hippocampal-avoidance WBRT with memantine and found lower symptom burden with SRS, equal survival, far better local control (3.2% vs 39.5% local recurrence) at the cost of more distant intracranial failure and more radionecrosis. Contemporary practice therefore weighs total intracranial tumor volume, lesion size/location, performance status, extracranial disease, expected survival, and feasibility of surveillance/salvage more heavily than a strict lesion count. A high count alone is no longer an automatic indication for WBRT, but neither is every high-count patient an SRS candidate.

3.After resection

For a resected metastasis, two randomized trials defined modern practice. Mahajan (MD Anderson, Lancet Oncology 2017) showed that postoperative cavity SRS improves local control versus observation. N107C/CEC.3 (Brown, Lancet Oncology 2017) showed that cavity SRS versus WBRT produces less cognitive decline with no overall-survival difference, establishing cavity SRS as a standard, less-toxic alternative to postoperative WBRT. Cavity SRS is technically harder than intact-lesion SRS: the target is larger and irregular, the dural/surgical margin must be considered, local control is somewhat lower than for small intact lesions, and there is a recognized risk of leptomeningeal disease after resection. Larger cavities are commonly hypofractionated (e.g., 3–5 fractions) to respect normal-brain tolerance. Alliance A071801 (ASTRO 2026, abstract) has now tested fractionated cavity SRS directly. In 242 patients with a resected metastasis ≥ 2 cm, 27 Gy / 3 (or 30 Gy / 5 for cavities ≥ 30 cc) improved 1-year surgical bed control over single-fraction SRS dosed by the N107C volume tiers (87% vs 81%, P = .046), with crude grade 1 or higher radionecrosis of 14% vs 10% and edema of 8% vs 9%. Median overall survival was also longer (29 vs 20 months, HR 0.69), but that was a secondary endpoint without a clear mechanism and is best read as hypothesis-generating. Three further qualifiers matter: the absolute local-control gain is modest, about 6 points; median cavity target volumes were moderate (16.5 vs 14.8 cc); and cavities from lesions under 2 cm were not studied, so single-fraction SRS remains reasonable after resection of smaller lesions and for patients who prefer one treatment. All figures come from the abstract, and the full paper is pending (see Dose Tables).

One inference is worth stating, and labeling as ours. The abstract does not report the single-fraction dose distribution, but the single-fraction median cavity of 14.8 cc falls in the N107C 15 Gy tier, so at least half of that arm likely received 15 Gy or less. The typical comparison was probably closer to 15 Gy × 1 against 27 Gy / 3 (BED₁₀ 37.5 vs 51.3 Gy) than to an 18–20 Gy single fraction, and part of the benefit may reflect a higher biologically effective dose rather than fractionation alone. Intact lesions treated within each arm point the same way (failure 4% vs 11%, P = .063), but that difference was not significant. Treat this as a reading of the median volume against the protocol tiers until the full paper reports delivered doses.

4.Preoperative SRS: an emerging alternative

Treating the intact metastasis with SRS before resection offers a smaller, better-defined target and may lower leptomeningeal-disease and radionecrosis rates. Prospective and matched-cohort data are encouraging, but selection bias remains important and phase III confirmation is not yet available. NRG-BN012 closed to accrual in October 2025; results are awaited. Preoperative SRS should therefore be presented as an emerging strategy at experienced centers, not as a proven replacement for postoperative cavity SRS.

5.Dose by size, and the radionecrosis problem

The dose table is only valid if the planning image still represents the lesion. Brain metastases can enlarge, shift, or declare additional lesions during the interval between diagnostic MRI and treatment. Use a dedicated stereotactic planning MRI as close to SRS as practical, ideally within 7 days; same-day imaging is ideal for frame-based Gamma Knife. Repeat sooner for large or rapidly growing targets, recent postoperative cavities, changing edema or corticosteroid use, or new neurologic findings. A several-week-old diagnostic scan may establish candidacy but should not silently become the treatment dataset.

Single-fraction marginal dose is anchored to the size-based RTOG 90-05 maximum tolerated doses, established in previously irradiated patients and best read as a ceiling: 24 Gy for lesions ≤ 20 mm, 18 Gy for 21–30 mm, and 15 Gy for 31–40 mm (the smallest lesions are commonly prescribed toward the upper end, ~20–24 Gy), with hypofractionation (e.g., 27 Gy/3 or 30 Gy/5) preferred for larger lesions and resection cavities to limit toxicity. For intact lesions this rests on retrospective series; NRG-BN013 (single-fraction vs 3-fraction SRS for intact metastases 1 to 3 cm) closed to accrual in 2026, with results awaited. The dominant late complication is radionecrosis, whose risk rises with the volume of brain (including the target) receiving 12 Gy (V12Gy) and with prior or concurrent therapy. Distinguishing radionecrosis from tumor recurrence on follow-up imaging is a recurring challenge addressed with serial MRI, perfusion and advanced sequences, and occasionally biopsy; management of symptomatic necrosis includes corticosteroids, bevacizumab, and, in selected cases, laser interstitial thermal therapy or surgery. Repeat SRS is a reasonable salvage option for local or distant failure in appropriately selected patients.

6.The randomized evidence, and what is still argued

Brain metastases are the best-randomized indication in cranial radiosurgery. The trials below define current practice; the debates that follow are genuinely open.

Open controversies:

• How many metastases is too many? JLGK0901 and the randomized Aizer 2026 trial support SRS well beyond the historic 1–4 threshold, but selection remains multidimensional: total volume, largest-lesion size, location, systemic prognosis, surveillance capacity, and treatment time all matter.
• Whole-brain avoidance versus distant failure. SRS alone preserves cognition and survival but accepts more new distant metastases; the bargain only holds when paired with surveillance MRI and a willingness to deliver salvage SRS.
• Resection cavity: postoperative versus preoperative SRS. Postoperative cavity SRS remains standard. Preoperative SRS is promising, and NRG-BN012 has closed to accrual, but randomized results are awaited.
• Timing with immunotherapy and targeted therapy. Concurrent SRS and CNS-active systemic therapy is common, but the optimal sequencing, the radionecrosis-versus-abscopal balance, and when to defer radiation in asymptomatic patients on effective systemic therapy remain unsettled.