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The sparing of circulating lymphocytes is often presented as a potential mechanism to explain the FLASH effect. Indeed, modelling has shown that ultra-high dose rate (UHDR) irradiation could reduce the volume of blood irradiated compared to conventional irradiation. However, it is difficult to extrapolate these results to the whole recirculating lymphocyte pool, whose instantaneous fraction in blood is estimated to be about 2% and whose recirculation and homing patterns between lymphoid organs are complex. It has been shown that severe radiation-induced lymphopenia (RIL) is a negative prognostic factor to treatment outcome that occurs in up to 40% of patients treated with radio-chemotherapy for brain tumours, but whose mechanisms are still poorly understood. We therefore propose a new model to evaluate the dose received by circulating lymphocytes in brain tumours treated with IMRT using either conventional or UHDR irradiation, in order to study the lymphocyte-sparing effect of UHDR irradiation.

A Monte Carlo simulation based on the combination of 2 compartment models describing the complex dynamics of lymphocyte recirculation and blood flow was developed (Fig. 1). The same 6MV photon irradiation plan (30 fraction of 2Gy) was used with 2 different dose rates: conventional IMRT (6 beams per fraction, 15 sec per beam) or UHDR (1 beam per fraction, 0.02 sec per beam). The dose received by a lymphocyte was computed as follows: if, during the beam on time, the lymphocyte was in the brain compartment, it received a dose randomly sampled on the DVH associated with the beam and weighted by its passage time in the beam. The code was developed in Julia and simulations were carried out on 10e6 particles.

At the end of the treatment, the conventional IMRT irradiated 35% of the lymphocytes (dose > 0 Gy) at a mean dose of 50 ± 57mGy (Fig. 2). Note that most of the irradiated lymphocytes received very low doses, the median dose being 31mGy. The UHDR treatment irradiated 2.4% of the lymphocytes (dose > 0 Gy) at a mean dose of 0.73 ± 0.62Gy, with a median of 0.56Gy. In both cases, most of irradiated lymphocytes passed through the field only once during the entire treatment period.

This study is the first to model the dynamics of lymphocyte recirculation in the context of UHDR irradiation. Based on our results, the fraction of lymphocytes irradiated during UHDR brain irradiation is greatly reduced compared to conventional irradiation, but at the cost of a higher average dose for those receiving doses. Some previous studies have shown that almost all the blood is irradiated during conventional irradiation. Our results show on the contrary that only a fraction of the lymphocytes is irradiated, and at a very low dose. It should be noted that these results still need to be compared with experimental measurements. This work was supported by the French National Research Agency (N°ANR-21-RHU5-0005) within the FRANCE2030 investment plan.