Neoadjuvant Stereotactic Radiotherapy for Brain Metastases: Systematic Review and Meta-Analysis of the Literature and Ongoing Clinical Trials

SIMPLE SUMMARY: The available treatment strategies for patients with brain metastases remain suboptimal, with current research focused on identifying therapies intended to improve patient outcomes while reducing the risk of treatment-related complications. Several studies have investigated the role of pre-operative neoadjuvant stereotactic radiotherapy, and have proposed it as a valid alternative to post-operative adjuvant stereotactic radiotherapy. The aim of our systematic review was to comprehensively analyze the current literature and ongoing clinical trials evaluating neoadjuvant stereotactic radiotherapy in patients with brain metastases, describing treatment protocols and related outcomes. Early evidence suggests that neoadjuvant stereotactic radiotherapy may offer rates of local control and overall survival comparable to those obtained with adjuvant postoperative SRS, but comparative studies are currently lacking. In addition, neoadjuvant stereotactic radiotherapy shows low rates of post-treatment radiation necrosis and leptomeningeal metastases. Ongoing clinical trials aim to evaluate long-term outcomes in large patient cohorts, with some focused on comparing neoadjuvant stereotactic radiotherapy to adjuvant stereotactic radiosurgery. ABSTRACT: Background: Brain metastases (BMs) carry a high morbidity and mortality burden. Neoadjuvant stereotactic radiotherapy (NaSRT) has shown promising results. We systematically reviewed the literature on NaSRT for BMs. Methods: PubMed, EMBASE, Scopus, Web-of-Science, Cochrane, and ClinicalTrial.gov were searched following the PRISMA guidelines to include studies and ongoing trials reporting NaSRT for BMs. Indications, protocols, and outcomes were analyzed using indirect random-effect meta-analyses. Results: We included 7 studies comprising 460 patients with 483 BMs, and 13 ongoing trials. Most BMs originated from non-small lung cell carcinoma (41.4%), breast cancer (18.7%) and melanoma (43.6%). Most patients had single-BM (69.8%) located supratentorial (77.8%). Patients were eligible if they had histologically-proven primary tumors and ≤4 synchronous BMs candidate for non-urgent surgery and radiation. Patients with primary tumors clinically responsive to radiotherapy, prior brain radiation, and leptomeningeal metastases were deemed non-eligible. Median planning target volume was 9.9 cm(3) (range, 2.9–57.1), and NaSRT was delivered in 1-fraction (90.9%), 5-fraction (4.8%), or 3-fraction (4.3%), with a median biological effective dose of 39.6 Gy10 (range, 35.7–60). Most patients received piecemeal (76.3%) and gross-total (94%) resection after a median of 1-day (range, 1–10) post-NaSRT. Median follow-up was 19.2-months (range, 1–41.3). Actuarial post-treatment rates were 4% (95%CI: 2–6%) for symptomatic radiation necrosis, 15% (95%CI: 12–18%) and 47% (95%CI: 42–52%) for local and distant recurrences, 6% (95%CI: 3–8%) for leptomeningeal metastases, 81% (95%CI: 75–87%) and 59% (95%CI: 54–63%) for 1-year local tumor control and overall survival. Conclusion: NaSRT is effective and safe for BMs. Ongoing trials will provide high-level evidence on long-term post-treatment outcomes, further compared to adjuvant stereotactic radiotherapy.