Developing a head and neck cancer model to assess the effect of radiotherapy on tumour growth inhibition and regrowth
Fernando Ortega, David Orrell, Claire Villette, Hitesh Mistry, Frances Brightman, Jim Millen, Christophe Chassagnole
Physiomics plc, The Oxford Science Park, Oxford, UK
Introduction:
We have previously developed agent-based tumour models that successfully replicate and predict the effect of irradiation on tumour growth inhibition in a number of preclinical studies [1, 2]. These studies utilize different irradiation doses and regimes as well as combination with therapeutic agents with disparate mechanism of action. The primary outcome measure of these models was tumour size over time up to 1-2 months. Having achieved the translation of pre-clinical models for small molecules [3], we have considered how this radiotherapy model could be translated into a clinical setting to support development decision making.
Objectives:
Develop an enhanced model of radiotherapy treatment that is capable of predicting tumour shrinkage and regrowth in squamous cell carcinoma head and neck tumours in humans.
Methods:
Analysis of historical data from clinical trials in head and neck cancer [4,5] showed that i) the initial rate sum of longest diameter (SLD) shrinkage depends on the SLD before treatment where the largest initial SLD the faster the initial tumour shrinkage rate ii) the magnitude of the tumour shrinkage can not only be explained by depletion of the proliferative layer of the tumour iii) a significant proportion of tumours remained suppressed for years following treatment.
Results:
We used these findings to update and adapt the mathematical model to the clinical setting as well as to calibrate the model to describe the behaviour of head and neck tumours treated with radiotherapy alone. We assumed that the mechanism of action of radiotherapy at the cell cycle level is unaltered between preclinical and clinical model, i.e. only proliferative cell layer is depleted by DNA damage production. However, we hypothesized that the integrity of the growing layer plays a role in preventing the necrotic core from being degraded by biological or physical processes. Therefore, the death of viable cells leading to depletion of the growing layer indirectly contributes to the overall tumour size shrinkage through enhanced erosion of or leakage from the necrotic core.
The other major challenge was to develop a mechanism to reflect the wide variation in time to regrowth post-treatment. Literature evidence [6,7] suggested that this regrowth can be explained by variation in cellular doubling time and we were able to calibrate our modelled cell population using a distribution of doubling times that enabled the model to accurately predict regrowth profiles from literature.
Conclusions:
We were able to extend our mathematical model from a tool that explained and predicted the effect of radiotherapy on tumour growth inhibition in the preclinical space to one that describes both tumour growth inhibition and regrowth in the clinical space. We have used this model as the basis to predict the effects of different radiotherapy regimens as well as combinations with other therapeutic agents in a clinical setting. Thus, we have developed a platform that enables us to predict in head and neck the effect of radiotherapy alone or in combination with other procedures on tumour shrinkage and locoregional control. This approach can also be implemented to model other tumour types.
References:
[1] Fernandez, E. et al. Modeling the sequence-sensitive gemcitabine-docetaxel combination using the Virtual Tumor. in AACR 102nd Annual Meeting, Orlando, FL (2011).
[2] Fernandez, E. et al. Modelling and translating head and neck radiation therapy on all three levels: in vitro, in vivo and clinical. PAGE Meeting, Lisbon, Portugal (2016).
[3] Mistry, H. et al. Virtual Tumour Clinical development, part II: translational modelling of vemurafenib, selumetinib and docetaxel in metastatic melanoma. PAGE Meeting, Alicante, Spain (2014).
[4] https://clinicaltrials.gov/ct2/show/NCT00094081
[5] https://clinicaltrials.gov/ct2/show/NCT00415194
[6] Corvo, R et al. Potential doubling time in head and neck tumors treated by primary radiotherapy: Preliminary evidence for a prognostic significance in local control. International Journal of Radiation Oncology • Biology • Physics , Volume 27 , Issue 5 , 1165 - 1172
[7] Kotelnikov, VM et al. Cell kinetics of head and neck cancers. Clin Cancer Res May 1 1995 (1) (5) 527-537
