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

Purpose. The sparing effect of ultra-high dose rate (FLASH) radiotherapy has been reported, but its potential to mitigate depletion of circulating blood and lymphocytes (CL) has not been investigated in pencil-beam scanning-based (PBS) proton therapy, which could potentially reduce the risk of radiation-induced lymphopenia.Material and methods. A time-dependent framework was used to score the dose to the CL during the course of radiotherapy. For brain patients, cerebral vasculatures were semi-automatic segmented from 3T MR-angiography data. A dynamic beam delivery system was developed capable of simulating spatially varying instantaneous dose rates of PBS treatment plans, and which is based on realistic beam delivery parameters that are available clinically. We simulated single and different hypofractionated PBS intensity modulated proton therapy (IMPT) FLASH schemes using 600 nA beam current along with conventionally fractionated IMPT treatment plan at 2 nA beam current. The dosimetric impact of treatment schemes on CL was quantified, and we also evaluated the depletion in subsets of CL based on their radiosensitivity.Results. The proton FLASH sparing effect on CL was observed. In single-fraction PBS FLASH, just 1.5% of peripheral blood was irradiated, whereas hypofractionated FLASH irradiated 7.3% of peripheral blood. In contrast, conventional fractionated IMPT exposed 42.4% of peripheral blood to radiation. PBS FLASH reduced the depletion rate of CL by 69.2% when compared to conventional fractionated IMPT.Conclusion. Our dosimetric blood flow model provides quantitative measures of the PBS FLASH sparing effect on the CL in radiotherapy for brain cancer. FLASH Single treatment fraction offers superior CL sparing when compared to hypofractionated FLASH and conventional IMPT, supporting assumptions about reducing risks of lymphopenia compared to proton therapy at conventional dose rates. The results also indicate that faster conformal FLASH delivery, such as passive patient-specific energy modulation, may further enhance the sparing of the immune system.

4D dosimetric-blood flow model: impact of prolonged fraction delivery times of IMRT on the dose to the circulating lymphocytes.

To investigate the impact of prolonged fraction delivery of modern intensity-modulated radiotherapy (IMRT) on the accumulated dose to the circulating blood during the course of fractionated radiation therapy. We have developed a 4D dosimetric blood flow model (d-BFM) capable of continuously simulating the blood flow through the entire body of the cancer patient and scoring the accumulated dose to blood particles (BPs). We developed a semi-automatic approach that enables us to map the tortuous blood vessels of the surficial brain of individual patients directly from standard magnetic resonance imaging data of the patient. For the rest of the body, we developed a fully-fledged dynamic blood flow transfer model according to the International Commission on Radiological Protection human reference. We proposed a methodology enabling us to design a personalized d-BFM, such it can be tailored for individual patients by adopting intra- and inter-subject variations. The entire circulatory model tracks over 43 million BPs and has a time resolution of∆t= 10-3s. A dynamic dose delivery model was implemented to emulate the spatial and temporal time-varying pattern of the dose rate during the step-and-shoot mode of IMRT. We evaluated how different configurations of the dose rate delivery, and a time prolongation of fraction delivery may impact the dose received by the circulating blood (CB).Our calculations indicate that prolonging the fraction treatment time from 7 to 18 min will augment the blood volume receiving any doseVD>0Gyfrom 36.1% to 81.5% during one single fraction. The results indicate that increasing the segment number has only a negligible effect on the irradiated blood volume, when the fraction time is kept identical. We developed a novel concept of customized 4D d-BFM that can be tailored to the hemodynamics of individual patients to quantify dose to the CB during fractionated radiotherapy. The prolonged fraction delivery and the variability of the instantaneous dose rate have a significant impact on the accumulated dose distribution during IMRT treatments. This impact should be considered during IMRT treatments design to reduce RT-induced immunosuppressive effects.

HEDOS-a computational tool to assess radiation dose to circulating blood cells during external beam radiotherapy based on whole-body blood flow simulations.

We have developed a time-dependent computational framework, hematological dose (HEDOS), to estimate dose to circulating blood cells from radiation therapy treatment fields for any treatment site. Two independent dynamic models were implemented in HEDOS: one describing the spatiotemporal distribution of blood particles (BPs) in organs and the second describing the time-dependent radiation field delivery. A whole-body blood flow network based on blood volumes and flow rates from ICRP Publication 89 was simulated to produce the spatiotemporal distribution of BPs in organs across the entire body using a discrete-time Markov process. Constant or time-varying transition probabilities were applied and their impact on transition time was investigated. The impact of treatment time and anatomical site were investigated using imaging data and dose distributions from a liver cancer and a brain cancer patient. The simulations revealed different dose levels to the circulating blood for brain irradiation compared to liver irradiation even for similar field sizes due to the different blood flow properties of the two organs. The volume of blood receiving any dose (V>0 Gy) after a single radiation fraction increases from 1.2% for a 1 s delivery time to 20.9% for 120 s delivery time for the brain cancer treatment, and from 10% (1 s) to 48.7% (120 s) for a liver cancer treatment. Other measures of the low-dose bath to the circulating blood such as the dose to small volumes of blood (D2%) decreases with longer delivery time. Furthermore, we demonstrate that the blood dose-volume histogram is highly sensitive to changes in the treatment time, indicating that dynamic modeling of blood flow and radiation fields is necessary to evaluate dose to circulating blood cells for the assessment of radiation-induced lymphopenia. HEDOS is publicly available and allows for the estimation of patient-specific dose to circulating blood cells based on organ DVHs, thus enabling the study of the impact of different treatment plans, dose rates, and fractionation schemes.

4D blood flow model for dose calculation to circulating blood and lymphocytes.

To better understand how radiotherapy delivery parameters affect the depletion of circulating lymphocytes in patients treated for intra-cranial tumors, we developed a computational human body blood flow model (BFM), that enables to estimate the dose to the circulating blood during the course of fractionated radiation therapy. A hemodynamic cardiovascular system based on human body reference values was developed to distribute the cardiac output to 24 different organs, described by a discrete Markov Chain. For explicit intracranial blood flow modeling, we extracted major cerebral vasculature from MRI data of a patient and complemented them with an extension network of generic vessels in the frontal and occipital lobes to guarantee even overall blood supply to the entire brain volume. An explicit Monte Carlo simulation was implemented to track the propagation of each individual blood particle (BP) through the brain and time-dependent radiation fields, accumulating dose along their trajectories. The cerebral model includes 1050 path lines and explicitly simulates more than 266 000 BP at any given time that are tracked with a time resolution of 10 ms. The entire BFM for the whole body contains 22 178 000 BP, corresponding to 4200 BP per ml of blood. We have used the model to investigate the difference between proton and photon therapy, and the effect of different dose rates and patient characteristics on the dose to the circulating blood pool. The mean dose to the blood pool is estimated to be 0.06 and 0.13 Gy after 30 fractions of proton and photon therapy, respectively, and the highest dose to 1% of blood was found to be 0.19 Gy and 0.34 Gy. The fraction of blood volume receiving any dose after the first fraction is significantly lower for proton therapy, 10.1% compared to 18.4% for the photon treatment plan. 90% of the blood pool will have received dose after the 11th fraction using photon therapy compared to the 21st fraction with proton therapy. Higher dose rates can effectively reduce the fraction of blood irradiated to low doses but increase the amount of blood receiving high doses. Patient characteristics such as blood pressure, gender and age lead to smaller effects than variations in the dose rate. We developed a 4D human BFM including recirculating to estimate the radiation dose to the circulating blood during intracranial treatment and demonstrate its application to proton- versus photon-based delivery, various dose rates and patient characteristics. The radiation dose estimation to the circulating blood provides us better insight into the origins of radiation-induced lymphopenia.