A Challenging Setting, Strong Evidence: Proton Radiotherapy for Leptomeningeal Metastasis
In this article
Why Does It Matter?
Leptomeningeal metastasis (LM)is one of the most challenging conditions, particularly in patients with breast cancer and non-small cell lung cancer (NSCLC) . Average survival is often limited to just a few months. Until now, the most commonly used approach, photon-based involved-field radiotherapy (IFRT), could provide only partial benefit by irradiating symptomatic areas and was inadequate for protecting the entire central nervous system (CNS).
This is where proton craniospinal irradiation (pCSI) comes to the fore. Proton therapy, through its unique physical ability to deposit the beam's energy directly at the target, allows both the entire brain and the spinal cord to be irradiated safely at the same time. This enables more effective control of disease spread while reducing damage to healthy organs.
A critical milestone in LM treatment was a report in JAMA Oncologyin September 2025 of the first randomized Phase II clinical trial (Yang et al.) . This study showed that, compared with IFRT, pCSI significantly prolonged both central nervous system progression-free survival (8.2 months vs 2.3 months) and overall survival (11.3 months vs 4.9 months) . This represents the strongest evidence to date in LM treatment.
In addition, a report in Cancers in March 2025 of a large real-world analysis (Gal et al.) confirmed in a cohort of 38 patients that pCSI was feasible, safe, and effective . The study reported median CNS-PFS of 8.1 monthsand overall survival of 10.1 months ; the most common adverse effect was transient lymphopenia (42%).
We now have both randomized controlled evidence and real-world data . Together, these findings strongly suggest that proton irradiation may offer new hope in LM management, which was previously limited to palliative treatment.
Study Design
- A multicenter, open-label, Phase II randomized clinical trial in the US
- A total of 98 patients: 57% NSCLC, 43% breast cancer
- Randomization: 2:1 to pCSI (n=42) vs IFRT (n=21)
- Dose: 3 Gy × 10 fractions
- pCSI: Targeting the entire CNS compartment with proton pencil-beam irradiation
Primary Endpoint: Central nervous system progression-free survival (CNS-PFS)
Secondary Endpoint: Overall survival (OS)
📊 Findings
| Outcome | pCSI | IFRT | Statistics |
|---|---|---|---|
| Median CNS-PFS | 8.2 months (6.6–15.3) | 2.3 months (1.2–4.0) | P < .001 |
| Progression at month 6 | 22% | 88% | P < .001 |
| Median Overall Survival | 11.3 months (7.5–18.3) | 4.9 months (3.9–15.0) | P = .04 |
- Multivariable Analysis: pCSI: HR = 0.14 for CNS-PFS (P < .001), HR = 0.50 for OS (P = .03)
- Functional Benefit: A clear trend favoring pCSI was observed in activities of daily living.
🔑 In Summary
pCSI significantly prolongs both central nervous system progression-free survival and overall survival . These results can be considered among the strongest evidence obtained to date for treating leptomeningeal metastasis.
Clinical Implications
- pCSI instead of IFRTshould be seriously considered if available at the center.
- Coverage of the entire CNSprovides a marked advantage in diffuse leptomeningeal involvement.
- As access increases, pCSI may be expected to become the standard approach in the future.
📚 Sources
- Yang JT, Yerramilli D, Pentsova E, et al. Proton Craniospinal Irradiation for Patients With Leptomeningeal Metastasis: A Randomized Clinical Trial. JAMA Oncol. Published online September 4, 2025. doi:10.1001/jamaoncol.2025.3007
- Gal et al. Real-World Outcomes of Proton Craniospinal Irradiation in Patients With Leptomeningeal Metastasis. Cancers. 2025;17(6):1046.
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