The Radiobiology of Proton Therapy: Challenges and Opportunities Around Relative Biological Effectiveness

Abstract

With the current UK expansion of proton therapy there is a great opportunity for clinical oncologists to develop a translational interest in the associated scientific base and clinical results. In particular, the underpinning controversy regarding the conversion of photon dose to proton dose by the relative biological effectiveness (RBE) must be understood, including its important implications. At the present time, the proton prescribed dose includes an RBE of 1.1 regardless of tissue, tumour and dose fractionation. A body of data has emerged against this pragmatic approach, including a critique of the existing evidence base, due to choice of dose, use of only acute-reacting in vivo assays, analysis methods and the reference radiations used to determine the RBE. Modelling systems, based on the best available scientific evidence, and which include the clinically useful biological effective dose (BED) concept, have also been developed to estimate proton RBEs for different dose and linear energy transfer (LET) values. The latter reflect ionisation density, which progressively increases along each proton track. Late-reacting tissues, such as the brain, where α/β = 2 Gy, show a higher RBE than 1.1 at a low dose per fraction (1.2-1.8 Gy) at LET values used to cover conventional target volumes and can be much higher. RBE changes with tissue depth seem to vary depending on the method of beam delivery used. To reduce unexpected toxicity, which does occasionally follow proton therapy, a more rational approach to RBE allocation, using a variable RBE that depends on dose per fraction and the tissue and tumour radiobiological characteristics such as α/β, is proposed.

Exploring the advantages of intensity-modulated proton therapy: experimental validation of biological effects using two different beam intensity-modulation patterns

“…The use of RBE 1.1 is increasingly questioned. Now, it is well known that proton RBE is a complex function of many physical and biological factors such as dose, cell and tissue types, beam quality, and biological endpoint [9][10][11] . Nevertheless, the spatially variable RBE has yet been applied clinically in the optimization of treatment plans.…”

MultiRBE: Treatment planning for protons with selective radiobiological effectiveness

“…These new findings (along with accumulated clinical experience) have triggered several reviews of the existing knowledge on proton RBE. While a few of them claim, in one way or another, that a variable RBE scheme should be implemented in clinical practice in the near future many others agree that current evidence still does not support such a change of paradigm and propose alternative solutions for the consideration of this effect . In fact, the conclusions of a recent “expert group” explicitly mention that “the clinical practice of using a fixed RBE of 1.1 cannot be abandoned based on high‐quality evidence favoring other values in specific situations,” although they call for further research as the increasing capability to accurately deliver the dose in the treatment will cause the proton Bragg peaks to be positioned more precisely at the same spot, resulting in repeated exposure of areas with elevated LET values.…”

Evolution of the Supermodel: Progress in Modelling Radiotherapy Response in Mice

“…This system allows the beam delivery to take place only during the stationary resting phase of the breathing cycle [64]. A small animal proton therapy device has also been achieved using a 50 MeV proton beam from an existing cyclotron to produce 2 mm collimated beam coupled to SARRP [65] that will offer new opportunities in proton therapy research [66]. Finally, most systems now include on-board integration of optical imaging methods, including bioluminescence imaging and tomography for tumour targeting and response monitoring [51,67].…”