Neoadjuvant fractionated stereotactic radiotherapy followed by surgical resection for brain metastases: A multicenter, single arm phase II trial (NEO-TACTICS).

Abstract

2003 Background: Surgical resection followed by adjuvant radiotherapy for brain metastases (BM) is associated with unresolved challenges, including local recurrence (LR), leptomeningeal dissemination (LMD), radiation necrosis (RN), and cognitive decline. Preoperative stereotactic radiosurgery followed by surgical resection has been proposed as a novel strategy to address these limitations. This phase II trial evaluated the efficacy and safety of neoadjuvant fractionated stereotactic radiotherapy (FSRT) followed by surgical resection for BM. Methods: Patients with one index brain metastasis requiring surgical resection (2-5cm diameter) and up to three non-index metastases not requiring resection (< 2cm) were enrolled across 14 centers. All patients received neoadjuvant FSRT (30-35 Gy in 5 fraction) targeting the index lesion, followed by surgical resection. The primary endpoint was 6-month cumulative incidence of LR at the surgical site. Secondary endpoints included LMD, LR at 12 months, RN, distant brain failure (DBF), overall survival (OS), intracranial progression-free survival (IC-PFS), neurocognitive outcomes, and treatment-related adverse events. Results: Between June 2022 and August 2024, we enrolled 57 patients with 53 evaluable for response. The median age was 68 years (range 34-79). The median maximum diameter was 3.2 cm (range 2.0-4.9). The median follow-up duration was 11.9 months (range 1.3-14.7). The 6-month cumulative incidence of surgical site LR was 4.3% (95% CI: 0–10.1) (80%CI：0.4-8.1), and 4.0% (95%CI: 0-9.4) using competing risk analysis. LMD was not observed at either 6, 12 months. The 12-month cumulative incidence of LR was 16.4% (95% CI: 6.0–26.8). Symptomatic RN (≥ Gr 2) was not observed at either 6, 12 months, and asymptomatic RN occurred in 5.9% at 6 months and 8.0% at 12 months. DBF rates were 14.0% (95% CI: 4.4–23.6) at 6 months and 18.1% (95% CI: 7.4–28.8) at 12 months. Median OS rate was 86.3% (95%CI: 77.3-96.3) at 6 months, and 76.5% (95%CI: 65.7-89) at 12 months. IC-PFS rates were 72.5% (95% CI: 61.2-85.9) at 6 months and 64.4% (95% CI: 52.5-79.1) at 12 months. Neurocognitive function was largely preserved, with Mini-Mental State Examination (MMSE) decline ≥1 point observed in 15.4% at 6 months and 9.6% at 12 months, and decline ≥3 points in ≤ 4% at both time points. Adverse events from irradiation to surgery were acceptable (grade ≥2: 10.5%; grade ≥3: 5.3% (CTCAE version 5.0)). Conclusions: Neoadjuvant FSRT followed by surgical resection demonstrated excellent early local control, complete suppression of LMD, acceptable toxicity, and favorable cognitive preservation. This approach represents a promising alternative to postoperative FSRT for resectable brain metastases and warrants further comparative investigation. Clinical trial information: jRCT s042220014.