Biological and Mechanical Synergies to Deal With Proton Therapy Pitfalls: Minibeams, FLASH, Arcs, and Gantryless Rooms

Proton therapy has advantages and pitfalls comparing with photon therapy in radiation therapy. Among the limitations of protons in clinical practice we can selectively mention: uncertainties in range, lateral penumbra, deposition of higher LET outside the target, entrance dose, dose in the beam path, dose constraints in critical organs close to the target volume, organ movements and cost. In this review, we combine proposals under study to mitigate those pitfalls by using individually or in combination: (a) biological approaches of beam management in time (very high dose rate “FLASH” irradiations in the order of 100 Gy/s) and (b) modulation in space (a combination of mini-beams of millimetric extent), together with mechanical approaches such as (c) rotational techniques (optimized in partial arcs) and, in an effort to reduce cost, (d) gantry-less delivery systems. In some cases, these proposals are synergic (e.g., FLASH and minibeams), in others theyare hardly compatible (mini-beam and rotation). Fixed lines have been used in pioneer centers, or for specific indications (ophthalmic, radiosurgery,…), they logically evolved to isocentric gantries. The present proposals to produce fixed lines are somewhat controversial. Rotational techniques, minibeams and FLASH in proton therapy are making their way, with an increasing degree of complexity in these three approaches, but with a high interest in the basic science and clinical communities. All of them must be proven in clinical applications

Fractionation effects in particle radiotherapy: implications for hypo-fractionation regimes.

The aim is to demonstrate the potential impact of changes in the value of the β parameter in the linear quadratic (LQ) model on the calculation of clinical relative biological effectiveness (RBE) values used for high linear energy transfer (LET) radiotherapy. The parameter RBE(min) is introduced into the LQ formulation to account for possible changes in the β radiosensitivity coefficient with changing LET. The model is used to fit fractionated data under two conditions, where RBE(min) = 1 and RBE(min) ≠ 1. Nonlinear regression and analysis of variance are used to test the hypothesis that the inclusion of a non-unity value of RBE(min) better predicts the total iso-effective dose required at low number of fractions for fast neutrons, carbon ions, π-meson and proton fractionation data obtained for various tissues from previous publications. For neutrons the assumption of RBE(min) ≠ 1 provided a better fit in 89% of the cases, whereas for carbon ions RBE(min) ≠ 1 provided a better fit only for normal tissue at the spread-out Bragg peak. The results provide evidence of the impact that variations in the β parameter may have when calculating clinically relevant RBE values, especially when using high doses per fraction (i.e. hypofractionation) of high-LET radiations

Fast neutron relative biological effects and implications for charged particle therapy.

In two fast neutron data sets, comprising in vitro and in vivo experiments, an inverse relationship is found between the low-linear energy transfer (LET) α/β ratio and the maximum value of relative biological effect (RBE(max)), while the minimum relative biological effect (RBE(min)) is linearly related to the square root of the low-LET α/β ratio. RBE(max) is the RBE at near zero dose and can be represented by the ratio of the α parameters at high- and low-LET radiation exposures. RBE(min) is the RBE at very high dose and can be represented by the ratio of the square roots of the β parameters at high- and low-LET radiation exposures. In principle, it may be possible to use the low-LET α/β ratio to predict RBE(max) and RBE(min, )providing that other LET-related parameters, which reflect intercept and slopes of these relationships, are used. These two limits of RBE determine the intermediate values of RBE at any dose per fraction; therefore, it is possible to find the RBE at any dose per fraction. Although these results are obtained from fast neutron experiments, there are implications for charged particle therapy using protons (when RBE is scaled downwards) and for heavier ion beams (where the magnitude of RBE is similar to that for fast neutrons). In the case of fast neutrons, late reacting normal tissue systems and very slow growing tumours, which have the smallest values of the low-LET α/β ratio, are predicted to have the highest RBE values at low fractional doses, but the lowest values of RBE at higher doses when they are compared with early reacting tissues and fast growing tumour systems that have the largest low-LET α/β ratios

Fast neutron relative biological effects and implications for charged particle therapy.

In two fast neutron data sets, comprising in vitro and in vivo experiments, an inverse relationship is found between the low-linear energy transfer (LET) α/β ratio and the maximum value of relative biological effect (RBE(max)), while the minimum relative biological effect (RBE(min)) is linearly related to the square root of the low-LET α/β ratio. RBE(max) is the RBE at near zero dose and can be represented by the ratio of the α parameters at high- and low-LET radiation exposures. RBE(min) is the RBE at very high dose and can be represented by the ratio of the square roots of the β parameters at high- and low-LET radiation exposures. In principle, it may be possible to use the low-LET α/β ratio to predict RBE(max) and RBE(min, )providing that other LET-related parameters, which reflect intercept and slopes of these relationships, are used. These two limits of RBE determine the intermediate values of RBE at any dose per fraction; therefore, it is possible to find the RBE at any dose per fraction. Although these results are obtained from fast neutron experiments, there are implications for charged particle therapy using protons (when RBE is scaled downwards) and for heavier ion beams (where the magnitude of RBE is similar to that for fast neutrons). In the case of fast neutrons, late reacting normal tissue systems and very slow growing tumours, which have the smallest values of the low-LET α/β ratio, are predicted to have the highest RBE values at low fractional doses, but the lowest values of RBE at higher doses when they are compared with early reacting tissues and fast growing tumour systems that have the largest low-LET α/β ratios

Fractionation effects in particle radiotherapy: implications for hypo-fractionation regimes.

The aim is to demonstrate the potential impact of changes in the value of the β parameter in the linear quadratic (LQ) model on the calculation of clinical relative biological effectiveness (RBE) values used for high linear energy transfer (LET) radiotherapy. The parameter RBE(min) is introduced into the LQ formulation to account for possible changes in the β radiosensitivity coefficient with changing LET. The model is used to fit fractionated data under two conditions, where RBE(min) = 1 and RBE(min) ≠ 1. Nonlinear regression and analysis of variance are used to test the hypothesis that the inclusion of a non-unity value of RBE(min) better predicts the total iso-effective dose required at low number of fractions for fast neutrons, carbon ions, π-meson and proton fractionation data obtained for various tissues from previous publications. For neutrons the assumption of RBE(min) ≠ 1 provided a better fit in 89% of the cases, whereas for carbon ions RBE(min) ≠ 1 provided a better fit only for normal tissue at the spread-out Bragg peak. The results provide evidence of the impact that variations in the β parameter may have when calculating clinically relevant RBE values, especially when using high doses per fraction (i.e. hypofractionation) of high-LET radiations