Despite 50 years of intensive clinical and laboratory research, multiple single-arm and retrospective studies, and 8 randomized controlled trials (RCTs), the prognosis for patients with leptomeningeal metastases (LM) remains appalling. More recently, potentially paradigm-changing insights into the cellular and molecular anatomy of the leptomeningeal space, and the genomic underpinnings of tumors metastasizing to the cerebrospinal fluid (CSF), coupled with novel therapeutic strategies have resulted in a renaissance of interest in this disease. To maximize the impact of further research, we reviewed the patient-level data from all 8 RCTs. Using a PRISMA-compliant search with multiple databases, 8 qualifying RCTs were identified. Study-specific information regarding patient demographics, enrollment, treatment, and response outcomes were recorded using structured data extraction tools. De-identified patient-level data was acquired from study sponsors or was extracted from Kaplan Meier curves. Summary statistics were calculated using a random effects model and inverse variance technique. Eight randomized phase III studies conducted between 1987 and 2019 were identified. These studies accrued 429 patients (mean 53.5/study) from 161 institutions. Average study duration was 4.8 years; MTX, Ara-C, Thiotepa, DepoCyt, and systemic therapy were investigated. Five of 8 studies included Depocyt (no longer available). Median overall survival was 31.5 weeks. Only 4 studies provided class I evidence for OS and only 2 for PFS. All other studies and endpoints provided class III or IV evidence. Challenges to accrual, reasons for loss to follow-up, specific patient characteristics, multiple outcomes, and outcomes for specific patient subsets were all analyzed. The design and conduct of RCTs for leptomeningeal metastases, accrual, retention, treatment selection, and outcomes have been disappointing. The nature and reasons for these failures should help improve study efficiency and reliability for future trials.
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