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

BACKGROUND: Leptomeningeal metastasis (LM) involves cerebrospinal fluid (CSF) seeding of tumor cells. Proton craniospinal irradiation (pCSI) is potentially effective for solid tumor LM. We evaluated whether circulating tumor cells (CTCs) in the CSF (CTC(CSF)), blood (CTC(blood)), and neuroimaging correlate with outcomes after pCSI for LM. METHODS: We describe a single-institution consecutive case series of 58 patients treated with pCSI for LM. Pre-pCSI CTCs, the change in CTC post-pCSI (Δ (CTC)), and MRIs were examined. Central nervous system progression-free survival (CNS-PFS) and overall survival (OS) from pCSI were determined using Kaplan Meier analysis, Cox proportional-hazards regression, time-dependent ROC analysis, and joint modeling of time-varying effects and survival outcomes. RESULTS: The median CNS-PFS and OS were 6 months (IQR: 4–9) and 8 months (IQR: 5–13), respectively. Pre-pCSI CTC(CSF) < 53/3mL was associated with improved CNS-PFS (12.0 vs 6.0 months, P < .01). Parenchymal brain metastases (n = 34, 59%) on pre-pCSI MRI showed worse OS (7.0 vs 13 months, P = .01). Through joint modeling, CTC(CSF) was significantly prognostic of CNS-PFS (P < .01) and OS (P < .01). A Δ (CTC-CSF)≥37 cells/3mL, the median Δ (CTC-CSF) at nadir, showed improved CNS-PFS (8.0 vs 5.0 months, P = .02) and further stratified patients into favorable and unfavorable subgroups (CNS-PFS 8.0 vs 4.0 months, P < .01). No associations with CTC(blood) were found. CONCLUSION: We found the best survival observed in patients with low pre-pCSI CTC(CSF) and intermediate outcomes for patients with high pre-pCSI CTC(CSF) but large Δ (CTC-CSF). These results favor additional studies incorporating pCSI and CTC(CSF) measurement earlier in the LM treatment paradigm.