Simulating tumor volume dynamics in response to radiotherapy: Implications of model selection.

From the beginning of the usage of radiotherapy (RT) for cancer treatment, mathematical modeling has been integral to understanding radiobiology and for designing treatment approaches and schedules. There has been extensive modeling of response to RT with the inclusion of various degrees of biological complexity. In this study, we compare three models of tumor volume dynamics: (1) exponential growth with RT directly reducing tumor volume, (2) logistic growth with direct tumor volume reduction, and (3) logistic growth with RT reducing the tumor carrying capacity with the objective of understanding the implications of model selection and informing the process of model calibration and parameterization. For all three models, we: examined the rates of change in tumor volume during and RT treatment course; performed parameter sensitivity and identifiability analyses; and investigated the impact of the parameter sensitivity on the tumor volume trajectories. In examining the tumor volume dynamics trends, we coined a new metric - the point of maximum reduction of tumor volume (MRV) - to quantify the magnitude and timing of the expected largest impact of RT during a treatment course. We found distinct timing differences in MRV, dependent on model selection. The parameter identifiability and sensitivity analyses revealed the interdependence of the different model parameters and that it is only possible to independently identify tumor growth and radiation response parameters if the underlying tumor growth rate is sufficiently large. Ultimately, the results of these analyses help us to better understand the implications of model selection while simultaneously generating falsifiable hypotheses about MRV timing that can be tested on longitudinal measurements of tumor volume from pre-clinical or clinical data with high acquisition frequency. Although, our study only compares three particular models, the results demonstrate that caution is necessary in selecting models of response to RT, given the artifacts imposed by each model.

Forecasting Individual Patient Response to Radiation Therapy in Head and Neck Cancer With a Dynamic Carrying Capacity Model.

PURPOSE: To model and predict individual patient responses to radiation therapy. METHODS AND MATERIALS: We modeled tumor dynamics as logistic growth and the effect of radiation as a reduction in the tumor carrying capacity, motivated by the effect of radiation on the tumor microenvironment. The model was assessed on weekly tumor volume data collected for 2 independent cohorts of patients with head and neck cancer from the H. Lee Moffitt Cancer Center (MCC) and the MD Anderson Cancer Center (MDACC) who received 66 to 70 Gy in standard daily fractions or with accelerated fractionation. To predict response to radiation therapy for individual patients, we developed a new forecasting framework that combined the learned tumor growth rate and carrying capacity reduction fraction (δ) distribution with weekly measurements of tumor volume reduction for a given test patient to estimate δ, which was used to predict patient-specific outcomes. RESULTS: The model fit data from MCC with high accuracy with patient-specific δ and a fixed tumor growth rate across all patients. The model fit data from an independent cohort from MDACC with comparable accuracy using the tumor growth rate learned from the MCC cohort, showing transferability of the growth rate. The forecasting framework predicted patient-specific outcomes with 76% sensitivity and 83% specificity for locoregional control and 68% sensitivity and 85% specificity for disease-free survival with the inclusion of 4 on-treatment tumor volume measurements. CONCLUSIONS: These results demonstrate that our simple mathematical model can describe a variety of tumor volume dynamics. Furthermore, combining historically observed patient responses with a few patient-specific tumor volume measurements allowed for the accurate prediction of patient outcomes, which may inform treatment adaptation and personalization.