Computational Modeling of Interstitial Fluid Pressure and Velocity in Non-small Cell Lung Cancer Brain Metastases Treated With Stereotactic Radiosurgery.

Background: Early imaging-based treatment response assessment of brain metastases following stereotactic radiosurgery (SRS) remains challenging. The aim of this study is to determine whether early (within 12 weeks) intratumoral changes in interstitial fluid pressure (IFP) and velocity (IFV) estimated from computational fluid modeling (CFM) using dynamic contrast-enhanced (DCE) MRI can predict long-term outcomes of lung cancer brain metastases (LCBMs) treated with SRS. Methods: Pre- and post-treatment T1-weighted DCE-MRI data were obtained in 41 patients treated with SRS for intact LCBMs. The imaging response was assessed using RANO-BM criteria. For each lesion, extravasation of contrast agent measured from Extended Tofts pharmacokinetic Model (volume transfer constant, Ktrans) was incorporated into a computational fluid model to estimate tumor IFP and IFV. Estimates of mean IFP and IFV and heterogeneity (skewness and kurtosis) were calculated for each lesion from pre- and post-SRS imaging. The Wilcoxon rank-sum test was utilized to assess for significant differences in IFP, IFV, and IFP/IFV change (Δ) between response groups. Results: Fifty-three lesions from 41 patients were included. Median follow-up time after SRS was 11 months. The objective response (OR) rate (partial or complete response) was 79%, with 21% demonstrating stable disease (SD) or progressive disease (PD). There were significant response group differences for multiple posttreatment and Δ CFM parameters: post-SRS IFP skewness (mean -0.405 vs. -0.691, p = 0.022), IFP kurtosis (mean 2.88 vs. 3.51, p = 0.024), and IFV mean (5.75e-09 vs. 4.19e-09 m/s, p = 0.027); and Δ IFP kurtosis (mean -2.26 vs. -0.0156, p = 0.017) and IFV mean (1.91e-09 vs. 2.38e-10 m/s, p = 0.013). Posttreatment and Δ thresholds predicted non-OR with high sensitivity (sens): post-SRS IFP skewness (-0.432, sens 84%), kurtosis (2.89, sens 84%), and IFV mean (4.93e-09 m/s, sens 79%); and Δ IFP kurtosis (-0.469, sens 74%) and IFV mean (9.90e-10 m/s, sens 74%). Conclusions: Objective response was associated with lower post-treatment tumor heterogeneity, as represented by reductions in IFP skewness and kurtosis. These results suggest that early post-treatment assessment of IFP and IFV can be used to predict long-term response of lung cancer brain metastases to SRS, allowing a timelier treatment modification.