Hypoxia dose painting in SBRT – the virtual clinical trial approach

Abstract

Background

Treating hypoxic tumours remains a challenge in radiotherapy as hypoxia leads to enhanced tumour aggressiveness and resistance to radiation. As escalating the doses is rarely feasible within the healthy tissue constraints, dose-painting strategies have been explored. Consensus about the best of care for hypoxic tumours has however not been reached because, among other reasons, the limits of current functional in-vivo imaging systems in resolving the details and dynamics of oxygen transport in tissue. Computational modelling of the tumour microenvironment enables the design and conduction of virtual clinical trials by providing relationships between biological features and treatment outcomes. This study presents a framework for assessing the therapeutic influence of the individual characteristics of the vasculature and the resulting oxygenation of hypoxic tumours in a virtual clinical trial on dose painting in stereotactic body radiotherapy (SBRT) circumventing the limitations of the imaging systems.

Material and methods

The homogeneous doses required to overcome hypoxia in simulated SBRT treatments of 1, 3 or 5 fractions were calculated for tumours with heterogeneous oxygenation derived from virtual vascular networks. The tumour control probability (TCP) was calculated for different scenarios for oxygenation dynamics resulting on cellular reoxygenation.

Results

A three-fractions SBRT treatment delivering 41.9 Gy (SD 2.8) and 26.5 Gy (SD 0.1) achieved only 21% (SD 12) and 48% (SD 17) control in the hypoxic and normoxic subvolumes, respectively whereas fast reoxygenation improved the control by 30% to 50%. TCP values for the individual tumours with similar characteristics, however, might differ substantially, highlighting the crucial role of the magnitude and time evolution of hypoxia at the microscale.

Conclusion

The results show that local microvascular heterogeneities may affect the predicted outcome in the hypoxic core despite escalated doses, emphasizing the role of theoretical modelling in understanding of and accounting for the dominant factors of the tumour microenvironment.

Keywords:

• Tumour hypoxia
• virtual clinical trial
• modelling
• dose painting
• SBRT
• SRT

Acknowledgements

The computations were partly enabled by resources provided by the National Academic Infrastructure for Supercomputing in Sweden (NAISS) and the Swedish National Infrastructure for Computing (SNIC) at ‘PDC Center for High Performance Computing, KTH Royal Institute of Technology’ partially funded by the Swedish Research Council through grant agreements no. 2022-06725 and no. 2018-05973.

Disclosure statement

No potential conflict of interest was reported by the authors.

The authors report there are no competing interests to declare.

Data available on request from the authors.

Additional information

Funding

Financial support from the Swedish Cancer Research Funds of Radiumhemmet (RaHFo) and the Swedish Research Council (project registration number 2020-04618) is also kindly acknowledged.