Whole brain radiotherapy combined with intrathecal liposomal cytarabine for leptomeningeal metastasis—a safety analysis and validation of the EANO-ESMO classification

Abstract

Background Although there is no proven standard therapy for leptomeningeal metastases (LM), treatment often includes intrathecal chemotherapy combined with whole brain radiation therapy (WBRT). Little is known about the toxicity of such combination therapies. We performed a retrospective safety analysis for the combination of intrathecal liposomal cytarabine with WBRT in patients with LM and validated the EANO-ESMO (European Association of Neuro-oncology—European Society for Medical Oncology) classification in this unique cohort. Methods Treatment toxicities in patients diagnosed with LM between 2004 and 2014 were retrospectively analyzed according to RTOG (Radiation Therapy Oncology Group) toxicity criteria and NCI CTCAE V5.0 (National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0). Diagnostic criteria and treatment response as assessed by EANO-ESMO classification were correlated with survival by Kaplan–Meier analysis and Breslow test. Results In all, 40 patients with LM who were treated with combined WBRT and intrathecal cytarabine, were identified. Ten patients (25%) experienced adverse events ≥grade 3 according to RTOG toxicity criteria; in 22 patients (55%) NCI CTCAE ≥grade 3 were detected. Median overall survival was 124 days. Median time to neurological progression was 52 days. Patients with positive cerebrospinal fluid (CSF) cytology (n = 26) showed worse prognosis compared to patients with negative CSF cytology (n = 14; mOS (median overall survival) 84 days versus 198 days, p = 0.006, respectively). The EANO-ESMO response assessment was significantly associated with survival: “stable” (n = 7) mOS 233 days, “response” (n = 10) mOS 206 days, “progression” (n = 17) mOS 45 days, “suspicion of progression” (n = 6) mOS 133 days; overall, p < 0.001. Conclusions In this retrospective analysis, combined treatment of WBRT and intrathecal liposomal cytarabine shows an acceptable safety profile and may indicate a trend towards improved efficacy. The EANO-ESMO classification for diagnosis and treatment response predicts survival.

Brain Metastases and Leptomeningeal Disease

“…The EANO-ESMO classification has been shown to have prognostic value in retrospective cohorts of patients. 64,65 It may also be used to guide therapeutic decisions. 64…”

“… 63 This classification is based on the results of clinical, imaging, and CSF cytology assessments, which are the three current pillars for the diagnosis of leptomeningeal metastases. The EANO-ESMO classification has been shown to have prognostic value in retrospective cohorts of patients 64,65 . It may also be used to guide therapeutic decisions 64 …”