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

Abstract

Background Leptomeningeal metastasis (LM) involves 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 (CTCCSF), blood (CTCblood), and neuroimaging correlates 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 (ΔCTC), 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 CTCCSF<53/3mL was associated with improved CNS-PFS (12.0 vs 6.0 months, p<0.01). Parenchymal brain metastases (n=34, 59%) on pre-pCSI MRI showed worse OS (7.0 vs 13 months, p=0.01). Through joint modeling, CTCCSF was significantly prognostic of CNS-PFS (p<0.01) and OS (p<0.01). A ΔCTC-CSF≥37 cells/3mL, the median ΔCTC-CSF at nadir, showed improved CNS-PFS (8.0 vs 5.0 months, p=0.02) and further stratified patients into favorable and unfavorable subgroups (CNS-PFS 8.0 vs 4.0 months, p<0.01). No associations with CTCblood were found. Conclusion We found the best survival observed in patients with low pre-pCSI CTCCSF and intermediate outcomes for patients with high pre-pCSI CTCCSF but large ΔCTC-CSF. These results favor additional studies incorporating pCSI and CTCCSF measurement earlier in the LM treatment paradigm.

Randomized Phase II Trial of Proton Craniospinal Irradiation Versus Photon Involved-Field Radiotherapy for Patients With Solid Tumor Leptomeningeal Metastasis

“…45 In an exploratory analysis, we determined that baseline CTC count is a predictive biomarker of CNS control and survival in patients treated with pCSI, confirming our prior results. 23 Furthermore, although pCSI is associated with overall decrease in CTC count after treatment, increase in CTC count was observed after IFRT and was associated with poorer outcomes for these patients. Our results demonstrated that comprehensive treatment of the entire leptomeningeal compartment, such as with pCSI, is needed to reduce CSF LM burden.…”

“…This result is comparable with our prior publications of pCSI for solid tumor LM that predominantly included patients with NSCLC or breast cancer. 22,23 For the exploratory pCSI group including patients of other solid tumor histologies, a notably shorter CNS PFS was found. Although our study was not designed to compare the exploratory group to the randomized groups, the shorter CNS PFS in the exploratory group is likely because of the higher rate of systemic disease progression-related death (31%) compared with the randomized pCSI group (19%), as the CNS control was similar at 6 months for both groups (22% v 21%).…”

“…(B) Estimated effect of treatment on CSF CTC count assessed through joint modeling of longitudinal and survival outcomes with shared random effects and an unspecified baseline risk function. 23 From the linear mixed-model component of the joint model of overall survival, we reported the slope from a nonsignificant interaction between histology and treatment arm. Although pCSI was associated with a decreasing CTC count after treatment, increasing CTC count was observed after IFRT.…”

“…Pretreatment evaluations included history and physical examination; complete blood count, electrolytes, and renal and liver function tests; lumbar puncture for CSF assessment, including cytology and circulating tumor cell (CTC) using CellSearch platform 23 ; and contrast-enhanced magnetic resonance imaging of the neuroaxis. Protocol RT was delivered at a dose of 3 Gy × 10 daily fractions, with RT planning time ≤ 2 weeks per protocol.…”

“…We tested whether there was a significant interaction between baseline CTC count and treatment groups, and reported association of CTC count with CNS TTP, CNS PFS, and OS. We then analyzed CTC counts over time (baseline and after protocol therapy) as described previously with joint modeling of longitudinal and survival outcomes with shared random effects and an unspecified baseline risk function, 23 allowing modeling of a linear mixed-effect model that is then used as a predictor in a Cox proportional hazard model. The interpretation of the joint model coefficients reveals whether trends in CTC count over time are associated with outcomes.…”