Variations in the RBE for Cell Killing Along the Depth-Dose Profile of a Modulated Proton Therapy Beam

Abstract

Considerable evidence now exists to show that that the relative biological effectiveness (RBE) changes considerably along the proton depth-dose distribution, with progressively higher RBE values at the distal part of the modulated, or spread out Bragg peak (SOBP) and in the distal dose fall-off (DDF). However, the highly variable nature of the existing studies (with regards to cell lines, and to the physical properties and dosimetry of the various proton beams) precludes any consensus regarding the RBE weighting factor at any position in the depth-dose profile. We have thus conducted a systematic study on the variation in RBE for cell killing for two clinical modulated proton beams at Indiana University and have determined the relationship between the RBE and the dose-averaged linear energy transfer (LETd) of the protons at various positions along the depth-dose profiles. Clonogenic assays were performed on human Hep2 laryngeal cancer cells and V79 cells at various positions along the SOBPs of beams with incident energies of 87 and 200 MeV. There was a marked variation in the radiosensitivity of both cell lines along the SOBP depth-dose profile of the 87 MeV proton beam. Using Hep2 cells, the D(0.1) isoeffect dose RBE values (normalized against (60)Co) were 1.46 at the middle of SOBP, 2.1 at the distal end of the SOBP and 2.3 in the DDF. For V79 cells, the D(0.1) isoeffect RBE for the 87 MEV beam were 1.23 for the proximal end of the SOBP: 1.46 for the distal SOBP and 1.78 for the DDF. Similar D(0.1) isoeffect RBE values were found for Hep2 cells irradiated at various positions along the depth-dose profile of the 200 MeV beam. Our experimentally derived RBE values were significantly correlated (P = 0.001) with the mean LETd of the protons at the various depths, which confirmed that proton RBE is highly dependent on LETd. These in vitro data suggest that the RBE of the proton beam at certain depths is greater than 1.1, a value currently used in most treatment planning algorithms. Thus, the potential for increased cell killing and normal tissue damage in the distal regions of the proton SOBP may be greater than originally thought.

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

“…(a) a further analysis of the data of Britten et al 13 to find the relationship between RBE and dose per fraction at various depths in the beam. The published radiosensitivities of the control and test cells were used to provide the limit of RBE at high dose (RBE max ) and limit of RBE at low dose (RBE min ) values, which were then used in Equation (A7) of the Appendix A to provide the RBE plots.…”

“…Fast neutron experiments are appropriate for the simulation of proton RBE in the Bragg peak region, since most of the ionization occurs due to the formation of recoil protons. Examples are provided in the fast neutron data [16][17][18] and the proton data of Britten et al, 13 where a increases with LET to a much greater extent than b. The maximum RBE is then given by a H /a L, found at very low doses, since the a radiosensitivity parameter dominates cell killing at low doses.…”

“…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.…”

“…Another potentially misleading aspect is the definition of the boundary between "low" and "high" LET, which can be misleading in the case of protons where elevations in RBE can occur at what are deemed to be low LET values (from 1 to 10 keV mm 21 ). 12,13 In the present article, high LET will refer to any LET which exceeds the control low LET value which should be in the 0.5-1.5 keV mm 21 range, since there is a steep increase in RBE beyond this value, and more so in the case of protons than other ions 12,13 where the gradient of RBE with LET is less marked.…”

“…Methods: The reasons for a variable proton RBE are enumerated, with qualitative and quantitative arguments. The heterogeneous data sets collated by Paganetti et al (2002) and the more homogeneous data of Britten et al (2013) are further analyzed using linear regression fitting and RBE-inclusive adaptations of the linear-quadratic (LQ) radiation model. …”