2022 Top Story in Brain Cancer: Proton Craniospinal Irradiation for Leptomeningeal Disease

Leptomeningeal disease represents a unique form of disease spread to the CNS axis when cancer cells infiltrate the leptomeninges of the brain or spinal cord or the cerebrospinal fluid (CSF). This can occur when patients are diagnosed concurrently with brain metastases (approximately 1% to 12% of the time) or subsequently during the disease course (in 1% to 37% of patients).¹ Typically, the management of these patients involves CSF diversion approaches for those with symptomatic increased intracranial pressure, involved-field photon radiotherapy (IFRT), whole-brain radiotherapy (WBRT) with or without focal radiotherapy to symptomatic spinal segments, and systemic therapy (CNS-penetrating agents or intrathecal chemotherapy). From a systemic therapy standpoint, intrathecal therapy allows immediate delivery of the agent to the CSF; however, it is restricted to patients with a normal CSF flow. Even with these aggressive approaches used in well-selected patients, the outcomes remain modest, with a median duration of freedom from progression of 2.4 months and median overall survival (OS) of 5.5 months.² From a radiotherapy standpoint, a European survey of the members of the European Association of Neuro-Oncology (EANO) and the European Organisation for Research and Treatment of Cancer Brain Tumor Group revealed significant practice variations, with WBRT being performed always in 15.5% of cases, in cases of concomitant brain metastasis (48.0%), and in cases of nodular or bulky leptomeningeal disease (51.5%).³ Focal spine radiotherapy was performed for neurological symptoms only in 13.5% of patients and in 73.0% of those with neurological symptoms and MRI abnormalities.

Craniospinal irradiation (CSI) is a technique wherein the entire brain and spinal cord are irradiated, and it is commonly used in pediatric malignancies. Previous studies with photon CSI are limited to retrospective studies in selected patients with modest rates of treatment-related myelosuppression.⁴ In fact, in one recent series of 19 patients treated with photon CSI, 9 patients (47%) did not complete the treatment, the most common reason being grade 3/4 cytopenias that did not resolve even after radiotherapy treatment breaks.⁵ In fact, the current EANO–ESMO guidelines do not recommend CSI, given the risks of bone marrow toxicity, enteritis, and mucositis.⁶

Proton CSI is dosimetrically superior to photon CSI, and comparative studies have demonstrated a reduction in treatment-related nausea and vomiting, esophagitis, and hematologic toxicity (both nadir and 1-month post treatment) with proton CSI.⁷ In addition, a phase Ib study of proton CSI for patients with leptomeningeal disease demonstrated limited high-grade hematologic toxicities and promising disease control outcomes, with a median CNS progression-free survival (PFS) and overall survival (OS) of 7 and 9 months, respectively.⁸ This naturally led to a single-institution phase II randomized study of proton CSI versus photon IFRT for patients with non–small cell lung cancer or breast cancer leptomeningeal disease.⁹ At an interim analysis conducted by the data safety monitoring committee at a median follow-up at 9.3 months, 12 patients in the proton CSI group (n = 42) had experienced CNS progression and 16 patients had died compared with 16 patients with CNS progression and 14 patients who had died with photon IFRT (n = 21). The median CNS PFS was substantially and significantly prolonged with proton CSI (7.5 vs 2.3 months; P < .0001), as was the OS (9.9 vs 6.0 months; P = .029).

Although we await the final publication of the results from this study, this has led to an immediate change in our practice management of patients with leptomeningeal disease from solid tumors. For patients with poor performance status, lack of effective systemic therapies, or substantial disease burden, consideration of hospice or palliative photon IFRT is warranted. However, for those with better performance status and potential systemic therapy options, we have started offering proton CSI based on these practice-changing data until a confirmatory randomized controlled trial is open to accrual.