Survival and hematologic toxicity after whole-brain radiotherapy, photon craniospinal irradiation, and proton craniospinal irradiation for solid-tumor leptomeningeal disease: a systematic review

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BACKGROUND: Leptomeningeal disease (LMD) from solid tumors carries poor prognosis and substantial neurologic morbidity. Radiotherapy is used for palliation and disease control, but outcomes across whole-brain radiotherapy (WBRT), photon craniospinal irradiation (CSI), and proton CSI remain incompletely defined. METHODS: We conducted a PRISMA-based systematic review of PubMed-indexed studies reporting radiotherapy outcomes for adult solid-tumor LMD. Studies were categorized as photon WBRT/non-CSI, photon CSI, or proton CSI. Primary outcomes were median overall survival (OS) and progression-free survival (PFS), including CNS-PFS or intracranial PFS when reported. Grade ≥ 3 hematologic and non-hematologic toxicities were extracted when available. RESULTS: Thirty-two unique studies/reports were included: 21 photon WBRT/non-CSI, 6 photon CSI, and 6 proton CSI studies. The median of reported median OS values were 4.5 months for photon WBRT/non-CSI, 4.1 months for photon CSI, and 10.7 months for proton CSI. Median PFS was 3.9 months for photon WBRT/non-CSI and 4.6 months for proton CSI; no extractable median PFS was available for photon CSI. Among studies with extractable denominators, crude pooled grade ≥ 3 hematologic toxicity was 2.8% for photon WBRT/non-CSI, 80.0% for photon CSI, and 59.4% for proton CSI; however, toxicity reporting was limited and heterogeneous. CONCLUSION: Proton CSI cohorts had numerically longer reported survival, but cross-study comparisons are limited by heterogeneity, treatment-era and selection differences, and systemic therapy exposure. These findings do not establish superiority over photon CSI and warrant prospective comparative evaluation.