Efficacy and safety of online adaptive magnetic resonance-guided fractionated stereotactic radiotherapy for brain metastases in non-small cell lung cancer (GASTO-1075): a single-arm, phase 2 trial

Abstract

Background: Brain metastases (BMs) in non-small cell lung cancer (NSCLC) are associated with poor prognosis and quality of life (QoL). This study aimed to evaluate the efficacy and safety of online adaptive MR-guided fractionated stereotactic radiotherapy (FSRT) using a 1.5 T MR-Linac in this subgroup of patients.

Methods: This single-arm phase 2 trial was conducted at Sun Yat-sen University Cancer Centre. Patients aged 18-75 years with NSCLC, 1-10 BMs, and an ECOG status of 0-1 were included. Key exclusion criteria included inability to undergo contrast-enhanced MRI and contraindications to bevacizumab. Patients received 30 Gy adaptive FSRT in 5 daily fractions under real-time MR guidance, with bevacizumab before (day 1) and after (day 21) FSRT. The primary endpoint was 1-year intracranial progression-free survival (IPFS); secondary endpoints included objective response rate (ORR), 1-year progression-free survival (PFS), 1-year overall survival (OS), treatment-related toxicities, and QoL. All enrolled patients were included in primary and safety analyses. This trial is registered with Clinicaltrials.gov, NCT04946019.

Findings: Between June 10th, 2021 and June 29th, 2023, 70 patients were assessed for eligibility and 55 patients were enrolled (median follow-up: 22.3 months). The median age was 58 years (IQR: 51-65), with 33% (18/55) female patients, and 82% (45/55) presenting with adenocarcinoma. The 1-year IPFS rate was 78.7% (95% CI, 68.2%-90.7%), with a median IPFS of 21.9 months (95% CI, 13.8-30.1 months). The 1-year PFS rate was 63.5% (95% CI: 51.8%-78.2%), and OS was 82.4% (95% CI: 72.6%-93.6%). The ORR reached 78% (95% CI: 65.0%-88.2%). Treatment-related toxicity was minimal, with only one case (2%) of grade 1 radiation necrosis. QoL improved steadily, with the Global Health Status score increasing from 65.67 ± 16.97 to 79.33 ± 8.79 at 6 months post FSRT (p < 0.0001).

Interpretation: Online adaptive FSRT using a 1.5 T MR-Linac has demonstrated effectiveness and good tolerability for BMs in patients with NSCLC. However, the relatively small sample size and short follow-up may affect result generalizability. Further randomised studies are warranted to confirm these findings and establish optimal treatment protocols.

Funding: The National Natural Science Foundation of China (Grant Number 82073328).

Keywords: Adaptive radiotherapy; Brain metastases; Fractionated stereotactic radiotherapy; MR-Linac; NSCLC.

Fig. 1

Flow diagram of patient enrollment.

Fig. 2

(A and B) Axial MRI slices from two patients illustrating changes in GTVs and perilesional edema over the course of treatment fractions. (A) The GTVs (green: baseline, red: fractions 1–5) demonstrated a marked reduction as treatment progressed. (B) The volumes of perilesional edema (purple: baseline, yellow: fractions 1–5) showed a significant decrease with continued treatment. For comparative analysis, baseline contours (fraction 0, Fx0) were co-registered to each daily MR scan. GTV, gross tumor volume.

Fig. 3

(A) Waterfall plot illustrating the response of target BMs. The dashed horizontal line indicates the 30% tumor shrinkage threshold required for a partial response. (B) Swimming plot depicting intracranial response, survival, and subsequent salvage treatments following fractionated stereotactic radiotherapy (FSRT) with the MR-Linac. (C) Magnetic resonance imaging (MRI) of a patient with a left frontal lobe BM demonstrated a partial response (PR) 2 months after FSRT with the MR-Linac, with the lesion remaining locally stable at the 1-year follow-up. BMs, brain metastases.

Fig. 4

Survival analyses of BMs patients received FSRT in MR-Linac. Kaplan–Meier survival curves for intracranial progression-free survival (A), progression-free survival (B), and overall survival (C). BMs, brain metastases.

Fig. 5

The score changes of health-related QoL metrics at 1, 3, and 6-months after treatment compared to baseline (A–C). QoL improved across most metrics, with the most significant improvements observed in symptomatic patients. Error bars represent the 95% CI. QoL, quality of life.

Fig. 6

(A) The baseline DCE images and ADC maps of two patients with NSCLC BMs, classified into high-K^trans and low-K^trans groups. (B) The high-K^trans BM lesion achieved partial response (PR) after FSRT, while the low-K^trans lesion remained stable disease (SD) during follow-up. FSRT, fractionated stereotactic radiotherapy; NSCLC, non-small cell lung cancer; BMs, brain metastases.