FLASH radiotherapy sparing effect on the circulating lymphocytes in pencil beam scanning proton therapy: impact of hypofractionation and dose rate

Antje Galts1, Abdelkhalek Hammi1

1 TU Dortmund University, Dortmund, Germany

Physics in medicine and biology, 69(2), 10.1088/1361-6560/ad144e.



What was your motivation for initiating this study?

The use of fractionated radiotherapy significantly reduces the counts of circulating immune cells in the blood (CB) due to their high radiosensitivity, which is a phenomenon known as radiation-induced lymphopenia. Such lymphopenia has been shown to affect adversely the prognosis of various solid tumours. Furthermore, when immunotherapy is combined with radiation therapy, the reduced count of CB might undermine the potential synergistic benefits.

Ultra-high dose rate radiotherapy (FLASH-RT) has emerged as a promising alternative that may minimise peripheral blood irradiation and better preserve CB compared with fractionated radiotherapy. Despite some investigations into the effects of FLASH-RT on immune cells, the impact of dynamic proton delivery by gantry and the complex vascular structures of target organs have not been fully explored. Motivated by this omission, we aimed to develop the first dynamic framework to investigate the potential sparing effect of proton FLASH-RT compared with fractionated intensity-modulated proton therapy (IMPT) in brain cancer.


What were the main challenges during the work?

The dosimetric framework that was used in this study to calculate the accumulated dose to the CB during radiotherapy required details of the dynamic beam delivery specific to the IMPT treatment plan. It also needed a detailed spatiotemporal mapping of the continuous flow of blood particles through the brain as the treated organ.

A major obstacle that we encountered was the restricted access to proprietary treatment planning systems and patient data. Consequently, for this study, we had to rely entirely on open-source tools, such as the MatRad toolkit, publicly available patient databases and accessible information regarding parametrisation of commercially available cyclotrons.

It was also challenging to simulate cerebral blood flow due to the limited spatial and contrast resolutions of standard imaging data, such as CT and MRI scans, which are inadequate to reconstruct the full-scale vasculature, including small blood vessels. This limitation was overcome by using MR angiography data to extract the tortuous cerebral vessels and developing fractal-like arborisation approaches to model accurately the complex vasculature bifurcation.


What is the most important finding of your study?

During the treatment of a small target volume in the brain, proton FLASH-RT spared CB 27 times more efficiently than the conventional fractionated IMPT treatment. Despite this significant protective effect, it's important to highlight that the application of a single fractionated FLASH-RT still resulted in the depletion of approximately one-third of the CB that would be killed during the application of the corresponding fractionated IMPT plan. This finding underscores the nuanced trade-off between the volume of peripheral blood irradiated and the fraction of CB that receives high doses.


What are the implications of this research?

The study has revealed that the use of rapid delivery techniques and proton FLASH-RT has a sparing effect on the patient’s circulating immune cells when compared with fractionated treatment approaches. This finding may pave the way to the reduction of immune suppression during cancer therapy, which is particularly beneficial to enhance the effectiveness of concurrent immunotherapy.

Consequently, building on these findings, we are exploring alternative proton delivery techniques that can achieve high dose rates, such as alternating single-field treatments and conformal FLASH-RT, based on passive patient-specific energy modulation.

Recognition of the lymphocyte compartment as an organ at risk represents a transformative perspective with significant promise. It leads us towards the optimisation of radiotherapy strategies as we aim not only to target cancer cells but also to minimise the patient’s risk of radiation-induced lymphopenia. This approach might improve treatment outcomes.


Abdelkhalek Hammi

Department of Physics, TU Dortmund University