Modeling long-term tumor growth and kill after combinations of radiation and radiosensitizing agents

Cardilin, Tim; Almquist, Joachim; Jirstrand, Mats; Zimmermann, Astrid; Lignet, Floriane; El Bawab, Samer; Gabrielsson, Johan

doi:10.1007/s00280-019-03829-y

Abstract

PurposeRadiation therapy, whether given alone or in combination with chemical agents, is one of the cornerstones of oncology. We develop a quantitative model that describes tumor growth during and after treatment with radiation and radiosensitizing agents. The model also describes long-term treatment effects including tumor regrowth and eradication.MethodsWe challenge the model with data from a xenograft study using a clinically relevant administration schedule and use a mixed-effects approach for model-fitting. We use the calibrated model to predict exposure combinations that result in tumor eradication using Tumor Static Exposure (TSE).ResultsThe model is able to adequately describe data from all treatment groups, with the parameter estimates taking biologically reasonable values. Using TSE, we predict the total radiation dose necessary for tumor eradication to be 110Gy, which is reduced to 80 or 30Gy with co-administration of 25 or 100mgkg(-1) of a radiosensitizer. TSE is also explored via a heat map of different growth and shrinkage rates. Finally, we discuss the translational potential of the model and TSE concept to humans.ConclusionsThe new model is capable of describing different tumor dynamics including tumor eradication and tumor regrowth with different rates, and can be calibrated using data from standard xenograft experiments. TSE and related concepts can be used to predict tumor shrinkage and eradication, and have the potential to guide new experiments and support translations from animals to humans.

Keywords

PK/PD; Oncology; Radiation therapy; Combination therapy; Turnover model; Interspecies scaling; Translational science

Published in

Cancer Chemotherapy and Pharmacology
2019, volume: 83, number: 6, pages: 1159-1173
Publisher: SPRINGER

SLU Authors

Gabrielsson, Johan
- Department of Animal Biosciences, Swedish University of Agricultural Sciences

Associated SLU-program

Translational and comparative medicine

UKÄ Subject classification

Pharmacology and Toxicology

Publication identifier

DOI: https://doi.org/10.1007/s00280-019-03829-y

Permanent link to this page (URI)

https://res.slu.se/id/publ/100225