An Immune Organ-At-Risk Model for Prediction of Radiation Induced Lymphopenia During Radiotherapy

Abstract

Purpose: Associations between radiation‐induced lymphopenia (RIL) and survival have been extensively reported in multiple solid tumors. However, the immune system is not considered an organ‐at‐risk (OAR) during radiation treatment planning. This study aimed to develop the framework of an immune OAR model that can be utilized to predict and minimize RIL in radiotherapy. Methods: Based on literature, a dynamic model composed of 9 differential equations was developed for lymphocyte trafficking among a 5‐compartment model of the immune system, consisting of circulating blood, bone marrow, spleen, lymph nodes/vessels, and circulating lymphocytes in nonlymphatic organs. Radiation dose to the circulating lymphocytes in each compartment was calculated based on the doses to fixed structures of the immune compartments, with a special approach to calculate dose to circulating blood. A RIL model was developed using an iterative algorithm to solve the differential equations, and using lymphocyte radiosensitivity and reproductivity as patient‐dependent variables. The model was tested in 51 upper patients who had weekly absolute lymphocyte counts (ALC) measured during radiotherapy. Results: The model fitted well with ALC measurements. The fitting was almost perfect for 20 patients, with sum of square of errors (SSE) between the measured and predicted ALCs < 0.5, fair to excellent for 27 patients, with SSE = 0.5˜4.0, and poor for 4 patients, with SSE > 4.0. The fitting also provided a method of in vivo estimation of radiosensitivity (α) for each patient. The α value ranged from 0.08 to 2.9 Gy−1, with a median of 0.40 Gy⁻¹ for the 51 patients, consistent with in vitro measured data of 0.41 Gy⁻¹ in the literature. Conclusion: We have presented an immune OAR model that has the potential to predict and be used to minimize RIL in radiotherapy. This model can be validated and further refined by a prospective clinical study to directly compare the in vitro and in vivo measurements of the radiosensitivity.