Clinical trial of proton craniospinal irradiation for leptomeningeal metastases

Abstract

Background Leptomeningeal metastases (LM) are associated with limited survival and treatment options. While involved-field radiotherapy is effective for local palliation, it lacks durability. We evaluated the toxicities of proton craniospinal irradiation (CSI), a treatment encompassing the entire central nervous system (CNS) compartment, for patients with LM from solid tumors. Methods We enrolled patients with LM to receive hypofractionated proton CSI in this phase I prospective trial. The primary end point was to describe treatment-related toxicity, with dose-limiting toxicity (DLT) defined as any radiation-related grade ≥ 3 non-hematologic toxicity or grade ≥ 4 hematologic toxicity according to CTCAE that occurred during or within 4 weeks of completion of proton CSI. Secondary end points included CNS progression-free survival (PFS) and overall survival (OS). Results We enrolled 24 patients between June 2018 and April 2019. Their median follow-up was 11 months. Twenty patients were evaluable for protocol treatment-related toxicities and 21 for CNS PFS and OS. Two patients in the dose expansion cohort experienced DLTs consisted of Grade 4 lymphopenia, Grade 4 thrombocytopenia, and/or Grade 3 fatigue. All DLTs resolved without medical intervention. The median CNS PFS was 7 months (95% CI 5-13) and the median OS was 8 months (95% CI 6 to not reached). Four patients (19%) were progression free in the CNS for more than 12 months. Conclusions Hypofractionated proton CSI using proton therapy is a safe treatment for patients with LM from solid tumors. We saw durable disease control in some patients.

Quantitative cerebrospinal fluid circulating tumor cells are a potential biomarker of response for proton craniospinal irradiation for leptomeningeal metastasis

“…We evaluated a prospectively collected consecutive case series of 58 patients who were treated with pCSI between January 2018 and December 2020; 21 of the patients were enrolled in a phase I trial evaluating the safety of pCSI (NCT03520504). 19 Patients were diagnosed with LM using radiographic criteria on MRI and/or positive CSF cytology (45 patients). 6 For each patient, we collected the patient demographics, treatment history, radiation dose and fractionation, and pre- and post-pCSI MRI studies.…”

“… 18 We have therefore evaluated and demonstrated that proton craniospinal irradiation (pCSI) can achieve therapeutic radiation doses with relatively few side effects. 19 Currently, there are no established biomarkers of response of LM-directed therapies. We aimed to understand whether neuroimaging, CTCs in the blood, or CTCs in the CSF correlate with clinical outcomes in patients with LM treated with pCSI.…”

Advances in the diagnosis, evaluation, and management of leptomeningeal disease

“…Though prospective data and direct comparisons of proton versus photon radiation are lacking, use of proton RT may lead to lower radiation exposure decrease toxicities such as myelosuppression. 46 …”

Management of brain metastases in lung cancer: evolving roles for radiation and systemic treatment in the era of targeted and immune therapies

“…While irradiation of the entire craniospinal axis is not typically recommended due to concern for significant myelosuppression and neurotoxicity, newer techniques using protons can potentially improve the tolerability of craniospinal irradiation. 22 Intrathecal methotrexate and cytarabine have also been studied in leptomeningeal disease from solid tumors but are only modestly effective and are limited by side-effects including chemical meningitis. 23 Additionally, systemic therapies with intracranial activity, such as pemetrexed, bevacizumab, and targeted therapies, now offer better-tolerated, potentially more effective alternatives beyond intrathecal chemotherapy and WBRT, as discussed below.…”