CCC publication: Classification of tolerable/intolerable mucosal toxicity of head-and-neck radiotherapy schedules with a biomathematical model of cell dynamics

Citation: Medical Physics. 2021 Mar 11. Online ahead of print
Author: Juan Pardo-Montero, Martín Parga-Pazos, John D Fenwick
Abstract: Purpose: To present a biomathematical model based on the dynamics of cell populations to predict the tolerability/intolerability of mucosal toxicity in head-and-neck radiotherapy.
Methods and materials: Our model is based on the dynamics of proliferative and functional cells populations in irradiated mucosa, and incorporates the three A's: Accelerated proliferation, loss of Asymmetric proliferation, Abortive divisions. The model consist of a set of delay differential equations, and tolerability is based on the depletion of functional cells during treatment. We calculate the sensitivity (sen) and specificity (spe) of the model in a dataset of 108 radiotherapy schedules, and compare the results with those obtained with three phenomenological classification models, two based on a Biologically Effective Dose (BED) function describing the tolerability boundary (Fowler and Fenwick), and one based on an Equivalent Dose in 2 Gy-fractions (EQD2 ) boundary (Strigari). We also perform a machine-learning-like cross-validation of all the models, splitting the database in two, one for training and one for validation.
Results: When fitting our model to the whole dataset we obtain predictive values (sen+spe) up to 1.824. The predictive value of our model is very similar to that of the phenomenological models of Fowler (1.785), Fenwick (1.806) and Strigari (1.774). When performing a k=2 cross-validation, the specificity and sensitivity in the validation dataset decrease for all models, from ~1.82 to ~1.55-1.63. For Fowler the worsening is higher, down to 1.49.
Conclusions: Our model has proved useful to predict the tolerability/intolerability of a dataset of 108 schedules. As the model is more mechanistic that other available models, it could prove helpful when designing unconventional dose fractionations, schedules not covered by datasets to which phenomenological models of toxicity have been fitted.
Keywords: classification; head-and-neck; linear-quadratic model; mucositis; radiotherapy.

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