Proton Craniospinal Irradiation for Patiënten met Leptomeningeal Metastasis: A Gerandomiseerde Klinische studie.

IMPORTANCE: Leptomeningeal metastasis (LM) is associated with limited survival and few treatment options. Photon involved-field radiotherapy (IFRT) is the most common radiotherapy treatment for patients with LM from solid tumors. OBJECTIVE: To assess whether proton craniospinal irradiation (pCSI) would result in superior central nervous system progression-free survival (CNS-PFS) compared with IFRT. DESIGN, SETTING, AND PARTICIPANTS: A randomized, phase 2 trial of pCSI vs IFRT was conducted between April 16, 2020, and October 11, 2021, and included patients with non-small cell lung cancer and breast cancer with LM. Patients with other solid tumors were also enrolled in an exploratory pCSI cohort. INTERVENTION: For the randomized groups, after stratifying by histology and systemic disease status, patients were assigned (2:1) to pCSI or IFRT. MAIN OUTCOMES AND MEASURES: The primary end point was CNS-PFS. Secondary end points included overall survival (OS). RESULTS: Of 98 total patients, 72 individuals (73.5%) were female, and the median (IQR) age was 59 (50-65) years. A total of 42 and 21 patients were randomly assigned to pCSI and IFRT, respectively. At planned interim analysis, a significant benefit in CNS-PFS was observed with pCSI compared with IFRT, leading to the early discontinuation of the trial. In this final analysis, a significant benefit was continually observed in CNS-PFS with pCSI (median, 8.2 months; 95% CI, 6.6-15.3) vs IFRT (median, 2.3 months; 95% CI, 1.2-4.0; P < .001). A statistically significant and clinically meaningful OS benefit with pCSI (median, 11.3 months; 95% CI, 7.5-18.3) vs IFRT (median, 4.9 months; 95% CI, 3.9-15.0; P = .04) was also observed. For the exploratory pCSI cohort (n = 35), the median CNS-PFS was 5.8 months (95% CI, 4.4-9.1) and OS was 7.0 months (95% CI, 5.4-10.6). CONCLUSIONS AND RELEVANCE: This randomized clinical trial that assessed the optimal radiotherapy treatment for LM found improved CNS-PFS and OS with pCSI compared with IFRT. The results suggest that pCSI should be considered when available. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04343573.