Altered fractionation outcomes for hypoxic head and neck cancer using the HYP-RT Monte Carlo model.

OBJECTIVE: Altered fractionation radiotherapy is simulated on a set of virtual tumours to assess the total doses required for tumour control compared with clinical head and neck data and the doses required to control hypoxic vs well-oxygenated tumours with different radiobiological properties. METHODS: The HYP-RT model is utilised to explore the impact of tumour oxygenation and the onset times of accelerated repopulation (AR) and reoxygenation (ROx) during radiotherapy. A biological effective dose analysis is used to rank the schedules based on their relative normal tissue toxicities. RESULTS: Altering the onset times of AR and ROx has a large impact on the doses required to achieve tumour control. Immediate onset of ROx and 2-week onset time of AR produce results closely predicting average human outcomes in terms of the total prescription doses in clinical trials. Modifying oxygen enhancement ratio curves based on dose/fraction significantly reduces the dose (5-10 Gy) required for tumour control for hyperfractionated schedules. HYP-RT predicts 10×1.1 Gy per week to be most beneficial, whereas the conventional schedule is predicted as beneficial for early toxicity but has average-poor late toxicity. CONCLUSION: HYP-RT predicts that altered radiotherapy schedules increase the therapeutic ratio and may be used to make predictions about the prescription doses required to achieve tumour control for tumours with different oxygenation levels and treatment responses. ADVANCES IN KNOWLEDGE: Oxic and hypoxic tumours have large differences in total radiation dose requirements, affected by AR and ROx onset times by up to 15-25 Gy for the same fractionation schedule.

The HYP-RT hypoxic tumour radiotherapy algorithm and accelerated repopulation dose per fraction study.

The HYP-RT model simulates hypoxic tumour growth for head and neck cancer as well as radiotherapy and the effects of accelerated repopulation and reoxygenation. This report outlines algorithm design, parameterisation and the impact of accelerated repopulation on the increase in dose/fraction needed to control the extra cell propagation during accelerated repopulation. Cell kill probabilities are based on Linear Quadratic theory, with oxygenation levels and proliferative capacity influencing cell death. Hypoxia is modelled through oxygen level allocation based on pO(2) histograms. Accelerated repopulation is modelled by increasing the stem cell symmetrical division probability, while the process of reoxygenation utilises randomised pO(2) increments to the cell population after each treatment fraction. Propagation of 10(8) tumour cells requires 5-30 minutes. Controlling the extra cell growth induced by accelerated repopulation requires a dose/fraction increase of 0.5-1.0 Gy, in agreement with published reports. The average reoxygenation pO(2) increment of 3 mmHg per fraction results in full tumour reoxygenation after shrinkage to approximately 1 mm. HYP-RT is a computationally efficient model simulating tumour growth and radiotherapy, incorporating accelerated repopulation and reoxygenation. It may be used to explore cell kill outcomes during radiotherapy while varying key radiobiological and tumour specific parameters, such as the degree of hypoxia.

Monte Carlo radiotherapy simulations of accelerated repopulation and reoxygenation for hypoxic head and neck cancer.

OBJECTIVE: A temporal Monte Carlo tumour growth and radiotherapy effect model (HYP-RT) simulating hypoxia in head and neck cancer has been developed and used to analyse parameters influencing cell kill during conventionally fractionated radiotherapy. The model was designed to simulate individual cell division up to 10(8) cells, while incorporating radiobiological effects, including accelerated repopulation and reoxygenation during treatment. METHOD: Reoxygenation of hypoxic tumours has been modelled using randomised increments of oxygen to tumour cells after each treatment fraction. The process of accelerated repopulation has been modelled by increasing the symmetrical stem cell division probability. Both phenomena were onset immediately or after a number of weeks of simulated treatment. RESULTS: The extra dose required to control (total cell kill) hypoxic vs oxic tumours was 15-25% (8-20 Gy for 5 × 2 Gy per week) depending on the timing of accelerated repopulation onset. Reoxygenation of hypoxic tumours resulted in resensitisation and reduction in total dose required by approximately 10%, depending on the time of onset. When modelled simultaneously, accelerated repopulation and reoxygenation affected cell kill in hypoxic tumours in a similar manner to when the phenomena were modelled individually; however, the degree was altered, with non-additive results. Simulation results were in good agreement with standard linear quadratic theory; however, differed for more complex comparisons where hypoxia, reoxygenation as well as accelerated repopulation effects were considered. CONCLUSION: Simulations have quantitatively confirmed the need for patient individualisation in radiotherapy for hypoxic head and neck tumours, and have shown the benefits of modelling complex and dynamic processes using Monte Carlo methods.