Proton Craniospinal Irradiation for Leptomeningeal Metastasis

By Rajiv S. Magge, MD

Synopsis: Proton craniospinal irradiation (pCSI) demonstrated better overall survival and progression-free survival outcomes compared to involved-field radiotherapy (IFRT) for the treatment of leptomeningeal metastases in patients with non-small cell lung cancer and breast cancer.

Source: Yang JT, Yerramilli D, Pentsova E, et al. Proton craniospinal irradiation for patients with leptomeningeal metastasis. JAMA Oncol. 2025; Sep 4. doi: 10.1001/jamaoncol.2025.3007. [Online ahead of print].

Leptomeningeal disease (LMD), also known as leptomeningeal metastases or carcinomatous meningitis, represents the spread of cancer cells into the leptomeningeal space and remains a devastating complication of metastatic cancer. Tumor invasion into the cerebrospinal fluid (CSF) can cause severe multifocal neurologic morbidity, including hydrocephalus, seizures, cranial neuropathies, cerebellar dysfunction, radiculopathy, and cauda equina syndrome. Likely underdiagnosed, LMD is identified in approximately 5% of patients with metastatic solid tumors and carries a poor prognosis, with median overall survival typically ranging from two to four months. New targeted agents — including epidermal growth factor receptor (EGFR) inhibitors, such as osimertinib and lazertinib for EGFR-mutant non-small cell lung cancer (NSCLC), and human epidermal growth factor receptor (HER2) inhibitors, such as trastuzumab deruxtecan and tucatinib for HER2-positive breast cancer — demonstrate improved central nervous system (CNS) penetration and may transiently control LMD. However, for most patients, treatment options remain limited.

Involved-field radiation therapy (IFRT), such as whole-brain radiation therapy (WBRT) or focal spinal cord radiation therapy, has been used for symptom palliation but has not been shown to improve survival, likely because tumor cells can disseminate throughout the entire neuraxis, rendering local therapies inadequate. Craniospinal irradiation (CSI) allows treatment of the entire brain, spinal cord, and leptomeningeal space, but historically has been limited by substantial toxicity, including myelosuppression, fatigue, and neurocognitive impairment. Proton therapy, by contrast, offers more conformal dose delivery than conventional photon radiation, minimizing exposure to surrounding tissues, such as vertebral bone marrow, and thereby reducing some of the toxicities that traditionally have hindered whole-neuroaxis irradiation. Proton craniospinal irradiation (pCSI) has emerged as a novel therapeutic approach for diffuse LMD, but until recently its effect on survival outcomes had not been clearly established.

In this randomized, Phase II trial, Yang et al assigned patients with LMD from NSCLC and breast cancer to receive either pCSI or IFRT in a 2:1 ratio, stratified by histology and systemic disease status. Patients with other solid tumors were enrolled in an exploratory cohort and received pCSI only. The primary and secondary endpoints were CNS progression-free survival (CNS-PFS) and overall survival (OS), respectively. Among the primary cohort, 42 patients were randomized to pCSI and 21 patients were randomized to IFRT. The study was stopped early after an interim analysis demonstrated significant improvement in CNS-PFS with pCSI.

In the final analysis, patients in the pCSI group achieved a median CNS-PFS of 8.2 months, significantly longer than the 2.3 months seen with IFRT (P < 0.001). This translated into improved overall survival as well — 11.3 months vs. 4.9 months, respectively (P = 0.04). In their prior publication, the investigators reported similar rates of grade 3-4 treatment-associated adverse events (TAEs) between groups, with lymphopenia being the most common (10% with pCSI vs. 19% with IFRT).¹ Notably, the exploratory cohort of patients treated with pCSI for leptomeningeal spread from other cancer types demonstrated lower median CNS-PFS (5.8 months) and OS (7.0 months) compared with the NSCLC and breast cancer cohorts.

Commentary

This important study by Yang and colleagues demonstrates that pCSI significantly improves survival outcomes compared with IFRT in patients with LMD secondary to NSCLC and breast cancer — a major advance in a population with historically dismal prognosis. Previous use of palliative WBRT or focal spinal radiation therapy has provided symptomatic relief without clear survival benefit; this trial establishes that broader neuroaxis treatment with protons can meaningfully extend both CNS control and overall survival. Equally notable, the study confirms that proton-based delivery may mitigate the substantial toxicity that limited traditional photon CSI. The findings make pCSI an attractive treatment option for patients with good performance status (Karnofsky Performance Status ≥ 60) and controlled systemic disease, both of which remain key determinants of prognosis.

Nevertheless, several challenges persist. Proton therapy remains inaccessible to many patients because of its limited availability, high cost, and inconsistent insurance coverage. Continued refinement of bone marrow-sparing photon CSI techniques will, therefore, be critical, since these can be implemented at most radiation centers. Despite improved dosimetry, neurocognitive toxicity remains a concern, since the entire brain must remain within the treatment field. The ongoing development of CNS-penetrant systemic therapies ultimately may allow concurrent or alternative treatment of LMD while sparing patients from radiation-related toxicities. Additionally, the inferior outcomes observed among patients with other systemic cancers (e.g., ovarian, esophageal, melanoma, colorectal) highlight potential tumor-specific radio resistance and underscore the need for novel systemic agents capable of crossing the blood-CSF barrier.

As with any emerging therapy, limitations and logistical hurdles remain, but the results of this study are highly encouraging. The investigators should be commended for showing that pCSI can meaningfully prolong survival in selected patients with leptomeningeal metastases, offering a measure of hope for a condition that long has been regarded as uniformly fatal.

Rajiv S. Magge, MD, is Associate Professor of Clinical Neurology, Weill Cornell Medicine, Weill Cornell Brain Tumor Center.

Reference

1. Yang JT, Wijetunga NA, Pentsova E, et al. Randomized Phase II trial of proton craniospinal irradiation versus photo involved-field radiotherapy for patients with solid tumor leptomeningeal metastasis. J Clin Oncol. 2022;40(33):3858-3867.