Proton Craniospinal Irradiation vs Photon Involved-Field Radiotherapy for Solid Tumor Leptomeningeal Metastasis

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In an interim analysis of a single-institution phase II trial reported in the Journal of Clinical Oncology, Yang et al found that proton craniospinal irradiation (pCSI) improved central nervous system (CNS) progression-free survival vs standard-of-care photon involved-field radiotherapy (IFRT) in patients with solid tumor leptomeningeal metastases.

Study Details

In the open-label trial, 63 patients with metastases from non–small cell lung cancer (NSCLC) or breast cancer at Memorial Sloan Kettering Cancer Center were randomly assigned 2:1 between April 2020 and October 2021 to undergo pCSI (n = 42) or IFRT (n =21). Protocol radiotherapy was given at a dose of 10 daily fractions of 3 Gy.

Patients in the pCSI group received pencil-beam scanning proton therapy to the entire CNS compartment. Patients receiving photon IFRT, including whole-brain radiotherapy or focal spine radiotherapy, underwent three-dimensional planning to symptomatic sites. All patients received memantine prophylaxis.

The primary endpoint was CNS progression-free survival.

CNS Progression-Free Survival and Toxicity

At the planned interim analysis, median follow-up was 9.3 months (95% confidence interval [CI] = 7.8–17.6 months; range = 0–18.9 months). CNS progression had occurred in 12 (29%) of 42 patients in the pCSI group and 16 (76%) of 21 in the IFRT group. Death had occurred in 16 patients (38%) vs 14 patients (67%). Median CNS progression-free survival was 7.5 months (95% CI = 6.6 months–not reached) in the pCSI group vs 2.3 months (95% CI = 1.2–5.8 months) in the IFRT group (P < .001).


  • Proton craniospinal irradiation improved CNS progression-free survival vs photon involved-field radiotherapy.
  • An overall survival benefit was observed with proton craniospinal irradiation.

Median overall survival was 9.9 months (95% CI = 7.5 months–not reached) in the pCSI group vs 6.0 months (95% CI = 3.9 months–not reached) in the IFRT group (P = .029).

No treatment-related deaths were observed. There was no difference between groups in the incidence of grade 3 or 4 treatment-related adverse events (P = .19). Lymphopenia was the only grade 4 treatment-related adverse event in either group, occurring in four patients (10%) in the pCSI group and four (19%) in the IFRT group. Grade 3 treatment-related nonhematologic adverse events included fatigue (n = 1, 2%), pain (n = 1, 2%), and vomiting (n = 1, 2%) in the pCSI group and fatigue (n = 2, 10%), gait disturbance (n = 1, 5%), and headache (n = 1, 5%) in the IFRT group.

In an exploratory pCSI group including 35 patients with solid tumor histology other than NSCLC or breast cancer, median CNS progression-free survival was 5.8 months (95% CI = 4.4–9.1 months) and median overall survival was 6.6 months (95% CI = 5.4–11 months).

The investigators concluded, “Compared with photon IFRT, we found pCSI improved CNS progression-free survival and overall survival for patients with non–small cell lung cancer and breast cancer with leptomeningeal metastases with no increase in serious treatment-related adverse events.”

Jonathan T. Yang, MD, PhD, of the Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by grants from Cycle for Survival Equinox Innovation Initiative and National Cancer Institute. For full disclosures of the study authors, visit

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