Biological Impact of Target Fragments on Proton Treatment Plans: An Analysis Based on the Current Cross-Section Data and a Full Mixed Field Approach

Abstract

Clinical routine in proton therapy currently neglects the radiobiological impact of nuclear target fragments generated by proton beams. This is partially due to the difficult characterization of the irradiation field. The detection of low energetic fragments, secondary protons and fragments, is in fact challenging due to their very short range. However, considering their low residual energy and therefore high LET, the possible contribution of such heavy particles to the overall biological effect could be not negligible. In this context, we performed a systematic analysis aimed at an explicit assessment of the RBE (relative biological effectiveness, i.e., the ratio of photon to proton physical dose needed to achieve the same biological effect) contribution of target fragments in the biological dose calculations of proton fields. The TOPAS Monte Carlo code has been used to characterize the radiation field, i.e., for the scoring of primary protons and fragments in an exemplary water target. TRiP98, in combination with LEM IV RBE tables, was then employed to evaluate the RBE with a mixed field approach accounting for fragments’ contributions. The results were compared with that obtained by considering only primary protons for the pristine beam and spread out Bragg peak (SOBP) irradiations, in order to estimate the relative weight of target fragments to the overall RBE. A sensitivity analysis of the secondary particles production cross-sections to the biological dose has been also carried out in this study. Finally, our modeling approach was applied to the analysis of a selection of cell survival and RBE data extracted from published in vitro studies. Our results indicate that, for high energy proton beams, the main contribution to the biological effect due to the secondary particles can be attributed to secondary protons, while the contribution of heavier fragments is mainly due to helium. The impact of target fragments on the biological dose is maximized in the entrance channels and for small α/β values. When applied to the description of survival data, model predictions including all fragments allowed better agreement to experimental data at high energies, while a minor effect was observed in the peak region. An improved description was also obtained when including the fragments’ contribution to describe RBE data. Overall, this analysis indicates that a minor contribution can be expected to the overall RBE resulting from target fragments. However, considering the fragmentation effects can improve the agreement with experimental data for high energy proton beams.

Integrating microdosimetric in vitro RBE models for particle therapy into TOPAS MC using the MicrOdosimetry-based modeliNg for RBE ASsessment (MONAS) tool

“…Because of the several LET definitions, it can be challenging to discern whether the value indicates the track average or the dose average. Additionally, different LET scorers are commonly used, and including only primary particles or both primary and secondary particles in the scorer can completely change the physical significance of the resulting values and the estimation of the biological effect (Grassberger and Paganetti 2011, Bellinzona et al 2021a, Kalholm et al 2021. This becomes particularly problematic in the out-of-field regions, where the radiation field is mixed, short-track particles can play a significant and LET may not accurately characterize the radiation quality (Grün et al 2019).…”

“…, 1 2 with α and β two radiobiological parameters that depend on the biological tissue and on the specific ionizing radiation. Despite the MKM has displayed notable consistency with experimental data obtained both in vitro and in vivo (Mein et al 2020), over time, numerous successive adaptations of the MKM have been developed in the literature, (Kase et al 2006, 2007, Sato et al 2006, Inaniwa et al 2010, Bellinzona et al 2021a, primarily aimed to address limitations of the original model in specific scenarios where its underlying assumptions were unsuitable. Currently, the MKM represents the standard model used to calculate the RBE in several carbon-ion therapy centers, (Mein et al 2020), and, along with the Local Effect Model (LEM), the MKM is one of the only two models currently used in clinics for this purpose.…”

Formalism of the NanOx biophysical model for radiotherapy applications

“…Let us note, however, that this approximation is not always verified, particularly when projectile or target fragmentation occurs. Indeed, it has been shown in the literature that even for proton beams target fragmentation modifies the biological dose calculation, especially in the entrance channel, while minor effects are expected in the Bragg peak region [45]. The impact of fragment species is currently not included in NanOx, but it may be investigated in future versions of the model along with low-energy ion irradiations.…”

Fragmentation Measurements in Particle Therapy: status and plans of the FOOT experiment

“…During hadrontherapy treatments, due to the interaction of ions with nuclear targets, also nuclear fragments are produced and, for a precise dose calculation, also their effect has to be considered [2]. Another field where fragmentation (of incoming ions, nuclear targets or both of them) plays a relevant role is the evaluation of absorbed dose in long term space missions with human crews.…”