Proton Craniospinal Irradiation for Patients With Leptomeningeal Metastasis

A Randomized Clinical Trial

Yang, Jonathan T. MD; PhD
Yerramilli, Divya MD; MBE
Pentsova, Elena MD
Wolden, Suzanne MD
Young, Robert J. MD
Correa, Denise D. PhD
Imber, Brandon S. MD
Wijetunga, N. Ari MD; PhD
Goglia, Alexander G. MD; PhD
Zhang, Zhigang PhD
Zheng, Junting MS
Baser, Raymond MS
Bernstein, Ashley CTN
Kratochvil, Leah BA
Xiao, Julie BS
Hattangadi-Gluth, Jona MD
Miller, Alexandra M. MD; PhD
Wilcox, Jessica A. MD
Betof Warner, Allison MD; PhD
Yu, Helena MD
Kris, Mark G. MD
Seidman, Andrew D. MD
Powell, Simon N. MD; PhD
Boire, Adrienne MD; PhD

¹Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
²Department of Radiation Oncology, New York University Grossman School of Medicine, New York, New York
³Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York
⁴Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
⁵Department of Radiation Oncology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill
⁶Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
⁷Department of Radiation Medicine and Applied Sciences, University of California, San Diego
⁸Department of Neurology, New York University Grossman School of Medicine, New York, New York
⁹Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
¹⁰Department of Medicine, Stanford University School of Medicine, Palo Alto, California
¹¹Human Oncology and Pathogenesis Program, Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, New York

Article Information

Accepted for Publication: June 9, 2025.

Published Online: September 4, 2025. doi:10.1001/jamaoncol.2025.3007

Corresponding Author: Jonathan T. Yang, MD, PhD, Department of Radiation Oncology, NYU Grossman School of Medicine, 160 E 34th St, New York, NY 10016 ([email protected]).

Author Contributions: Dr Yang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Yang, Pentsova, Wolden, Young, Zhang, Betof Warner, Seidman, Powell, Boire.

Acquisition, analysis, or interpretation of data: Yang, Yerramilli, Wolden, Young, Correa, Imber, Wijetunga, Goglia, Zhang, Zheng, Baser, Bernstein, Kratochvil, Xiao, Hattangadi-Gluth, Miller, Wilcox, Betof Warner, Yu, Kris, Boire.

Drafting of the manuscript: Yang, Yerramilli, Young, Correa, Wijetunga, Goglia, Zhang, Zheng, Xiao, Hattangadi-Gluth, Yu.

Critical review of the manuscript for important intellectual content: Yang, Yerramilli, Pentsova, Wolden, Young, Imber, Wijetunga, Goglia, Zhang, Zheng, Baser, Bernstein, Kratochvil, Hattangadi-Gluth, Miller, Wilcox, Betof Warner, Yu, Kris, Seidman, Powell, Boire.

Statistical analysis: Yang, Wijetunga, Goglia, Zhang, Zheng, Baser, Hattangadi-Gluth.

Obtained funding: Yang.

Administrative, technical, or material support: Yang, Yerramilli, Wolden, Wijetunga, Kratochvil, Xiao, Miller, Yu, Kris, Powell, Boire.

Supervision: Yang, Yerramilli, Wolden, Young, Miller, Wilcox, Seidman, Boire.

Other - Collection of patient adverse events: Bernstein.

Other - neurocognitive data collection and analysis: Correa.

Conflict of Interest Disclosures: Dr Yang reported personal fees from AstraZeneca, Kazia Therapeutics, and Plus Therapeutics as well as grants from AstraZeneca, Kazia Therapeutics, Debi pharm, Cantex Therapeutics, and Biocept outside the submitted work. Dr Young reported personal fees from Guerbet, ICON plc, NordicNeuroLab, Olea Medical, RadMD, Servier, and Turing Medical outside the submitted work. Dr Imber reported grants from AstraZeneca, Kazia, and Novartis as well as personal fees from GT Medical Technologies during the conduct of the study. Dr Zheng reported grants from the National Institutes of Health during the conduct of the study. Dr Miller reported personal fees from Modifi Bio, GSK, and SurvivorNet and grants from V Foundation outside the submitted work. Dr Wilcox reported personal fees from Physicians Education Resource outside the submitted work. Dr Betof Warner reported personal fees from Adaptimmune, Bristol Myers Squibb, cTRL Therapeutics, Genmab, Immatics, IO Biotech, Iovance Biotherapeutics, Immunocore, Novartis, Merck, Pfizer, and Replimune outside the submitted work as well as research funding from Bristol Myers Squibb, Immunocore, Iovance Biotherapeutics, Lyell Immunopharma, Obsidian Therapeutics, and Replimune. Dr Yu reported personal fees from AstraZeneca, Daiichi, Janssen, Amgen, BMS, Ipsen, Taiho, and Takeda outside the submitted work. Dr Kris reported personal fees from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Merck, and Sanofi and nonfinancial support from Genentech outside the submitted work. Dr Powell reported grants from AstraZeneca outside the submitted work. Dr Boire reported patents issued to Memorial Sloan Kettering Cancer Center. No other disclosures were reported.

Funding/Support: This study was supported by grants from Cycle for Survival Equinox Innovation Initiative Award and the National Institutes of Health/National Cancer Institute (P30-CA008748).

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Received April 08, 2025

Accepted June 09, 2025

JAMA Oncology Publish Ahead of Print, November 2025. | DOI: 10.1001/jamaoncol.2025.3007

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