High Dose Rate and Fractionation to Reduce Radiation-Induced Lymphopenia: In Vivo Derivation of Lymphocyte Radiosensitivity Using Patient-Specific Blood Flow Simulations

Abstract

<h3>Purpose/Objective(s)</h3> Radiation induced lymphopenia (RIL) has recently gained attention due to its correlation with outcome/survival in a range of indications, particularly when combining radiotherapy (RT) with immunotherapy. The purpose of this study is to use a dynamic blood circulation model combined with observed lymphocyte depletion in patients to derive the in vivo lymphocyte radiosensitivity and study the effect of fast delivery techniques. <h3>Materials/Methods</h3> We evaluated weekly Absolute Lymphocyte Counts (ALC) during RT and follow-up (median 7 measurements per patient) in 17 patients with hepatocellular carcinoma (HCC) treated with RT alone in 15 fractions (fx) using conventional dose rates. We utilized HEDOS, a time-dependent, whole-body, blood flow computational framework, in combination with explicit liver blood flow modeling, to calculate the dose volume histogram for circulating lymphocytes. We utilized linear-quadratic cell survival and an exponential recovery model optimized for lymphocyte radiation sensitivity, α (and β using α/β=2), and the daily recovery source term. We investigated the impact of using a 5-fx treatment regimen (currently investigated in a randomized trial – NCT03186898) and increasing the dose rate to delivery times <<1s (FLASH). The primary endpoints of interest were relative ALC depletion measured at nadir and time to recovery of 80% of baseline ALC. <h3>Results</h3> The <i>in-vivo</i> derived patient-specific lymphocyte radiation sensitivity has a mean of 0.7 <i>Gy⁻¹</i> (range 0.28 – 1.23) after optimal fitting using conventional fractionation and dose rate. Simulating a 5-fx treatment regimen at the conventional dose rate reduces ALC depletion by 8% on average, with an interquartile range (IQR) from 3% to 16% and mean reduction in number of days until recovery by 26% (IQR 21 – 31%) both caused by the varying patient-specific lymphocyte radiosensitivity. Simulating the 15-fx regimen with FLASH dose rates leads to a 13% reduction (IQR 3 – 23%) in ALC depletion and a mean reduction in number of days until recovery by 9% (IQR 2 – 116%). Combining the shorter, 5-fx, treatment regimen with FLASH dose rates leads to a mean reduction in ALC depletion by 45% (IQR 41 – 56%) and mean reduction in time to ALC recovery by 67% (IQR 54 – 80%). <h3>Conclusion</h3> We developed a patient-specific computational framework to simulate lymphocyte depletion in patients receiving RT depending on fractionation and dose rate. We observed that increasing dose rate at the same fractionation reduced ALC depletion more significantly than reducing the number of fractions. High dose rates led to an increased sparing of lymphocytes when shortening the fractionation regimen, particularly for patients with radiosensitive lymphocytes at elevated risk.