Towards Achieving the Full Clinical Potential of Proton Therapy by Inclusion of LET and RBE Models

Abstract

Despite increasing use of proton therapy (PBT), several systematic literature reviews show limited gains in clinical outcomes, with publications mostly devoted to recent technical developments. The lack of randomised control studies has also hampered progress in the acceptance of PBT by many oncologists and policy makers. There remain two important uncertainties associated with PBT, namely: (1) accuracy and reproducibility of Bragg peak position (BPP); and (2) imprecise knowledge of the relative biological effect (RBE) for different tissues and tumours, and at different doses. Incorrect BPP will change dose, linear energy transfer (LET) and RBE, with risks of reduced tumour control and enhanced toxicity. These interrelationships are discussed qualitatively with respect to the ICRU target volume definitions. The internationally accepted proton RBE of 1.1 was based on assays and dose ranges unlikely to reveal the complete range of RBE in the human body. RBE values are not known for human (or animal) brain, spine, kidney, liver, intestine, etc. A simple efficiency model for estimating proton RBE values is described, based on data of Belli et al. and other authors, which allows linear increases in α and β with LET, with a gradient estimated using a saturation model from the low LET α and β radiosensitivity parameter input values, and decreasing RBE with increasing dose. To improve outcomes, 3-D dose-LET-RBE and bio-effectiveness maps are required. Validation experiments are indicated in relevant tissues. Randomised clinical studies that test the invariant 1.1 RBE allocation against higher values in late reacting tissues, and lower tumour RBE values in the case of radiosensitive tumours, are also indicated.

Why RBE must be a variable and not a constant in proton therapy

“…Also, the increase in a-radiosensitivity appears to be inversely related to the incident energy. Only the lower incident energy characteristics appear to be similar to the data of Belli et al, 8,12 where turnover occurs at an LET value of around 30.5 keV mm…”

“…This is especially relevant to proton irradiations in the central nervous system, which has low a/b ratios of 2 Gy and where the RBE is predicted to be the highest. 5,8,18,19 The analysis also shows that further in vitro and in vivo work may be helpful to define to what extent the RBE changes with dose per fraction in many different cell and tissue types. This can be ascertained from cell survival experiments which estimate a and b as accurately as possible, using large numbers of experiments to reduce the standard errors, in a wide panel of cells with different radiobiological characteristics.…”

“…Higher LET and RBE values will inevitably occur towards the end of SOBP range. 5,8,13 The detailed study of Britten et al, 13 where experiments were performed at different depth/ranges and LET values. The reported changes in the a radiosensitivity parameter with LET in human BED, biological effective dose.…”

“…[3][4][5][6][7][8] The decision to adopt this single value was made on the basis of some well-intended radiobiological experiments; it also followed previous decisions made in fast neutron therapy, principally in the UK, to use a single RBE value, despite extensive evidence that RBE varied with dose per fraction. [9][10][11] When these decisions were taken, the treatment planning systems could not have accommodated a variable RBE easily, and the easier alternative option of reallocating tissue tolerances was also not adopted owing to the necessary complexity and lack of three-dimensional dose distributions.…”

“…The points shown in Figure 1b are the published RBE values for a surviving fraction of 0.1: these fit on each curve almost exactly, although the curves are not fitted by using these points, thus increasing the overall confidence in the LQ model with modification by RBE max and RBE min interpretation (as given in the Appendix A and in other publications). 4,8,10,20 The K-S test statistic for goodness of fit approaches 1, the prediction accuracy being averaged at 0.998 6 0.002.…”