Proton relative biological effectiveness (RBE): a multiscale problem

Abstract

Proton radiotherapy is undergoing rapid expansion both within the UK and internationally, but significant challenges still need to be overcome if maximum benefit is to be realised from this technique. One major limitation is the persistent uncertainty in proton relative biological effectiveness (RBE). While RBE values are needed to link proton radiotherapy to our existing experience with photon radiotherapy, RBE remains poorly understood and is typically incorporated as a constant dose scaling factor of 1.1 in clinical plans. This is in contrast to extensive experimental evidence indicating that RBE is a function of dose, tissue type, and proton linear energy transfer, among other parameters. In this article, we discuss the challenges associated with obtaining clinically relevant values for proton RBE through commonly-used assays, and highlight the wide range of other experimental end points which can inform our understanding of RBE. We propose that accurate and robust optimization of proton radiotherapy ultimately requires a multiscale understanding of RBE, integrating subcellular, cellular, and patient-level processes.

MultiRBE: Treatment planning for protons with selective radiobiological effectiveness

“…While the evidence supporting variable proton RBE due to increased LET in in-vitro and animal studies is solid, [5][6][7]69 the first reports of statistically significant data in human subjects (although using subclinical endpoints) were published only recently. A study in 34 ependymoma patients found a correlation between incidence of post-treatment image changes in magnetic resonance and both dose and LET.…”

Comparison of Proton and Photon Beam Irradiation in Radiation-Induced Intestinal Injury Using a Mouse Model

“…PBT is increasingly used in clinical settings worldwide. However, there are also increasing concerns about its biological uncertainty [6,7,8,18,19,20,21]. Heavy ions, such as carbon ions, consider RBE variations in treatment planning.…”

The impact of proton LET/RBE modeling and robustness analysis on base-of-skull and pediatric craniopharyngioma proton plans relative to VMAT

“…The design of base-of-skull IMPT plans which are biologically robust, physically robust and clearly superior to VMAT in terms of OAR sparing, is non-trivial. Worldwide, considerable effort is being applied to the development of new methods for (i) robust IMPT optimization based on physical and biological parameters and (ii) IMPT robustness analyses [48]. ‘Worst case’ uncertainty scenarios (as employed in the commercial TPS we used) are sometimes criticized for being overly conservative [48]: stochastic or probabilistic approaches form an active area of research and a viable alternative [12].…”

“…Further work however could usefully investigate the accuracy of the analytical LET d script provided by Varian under a range of clinical circumstances. The suitability, or otherwise, of averaged LET as a surrogate for biological effect also warrants further investigation [48].…”

“…Worldwide, considerable effort is being applied to the development of new methods for (i) robust IMPT optimization based on physical and biological parameters and (ii) IMPT robustness analyses [48]. 'Worst case' uncertainty scenarios (as employed in the commercial TPS we used) are sometimes criticized for being overly conservative [48]: stochastic or probabilistic approaches form an active area of research and a viable alternative [12]. To date, relatively little research has been performed on robust optimization and robustness reporting in photon therapy [49,50]: additional work in this area could facilitate fairer dosimetric comparisons between treatment modalities.…”