Relating the proton relative biological effectiveness to tumor control and normal tissue complication probabilities assuming interpatient variability in α/β

Abstract

Background: Proton therapy uses a constant relative biological effectiveness (RBE) of 1.1. The use of variable RBE values has been suggested but is currently not feasible due to uncertainties. The impact of variable RBE has solely been studied using dosimetric indices. This work elucidates the impact of RBE variations on tumor control and normal tissue complication probabilities (TCP/NTCP). Methods: Models to estimate TCP and NTCP were used in combination with an empirical proton RBE model. Variations in outcome as a function of linear-quadratic model parameters for cellular radiosensitivity were determined for TCP in prostate and ependymoma. In addition, NTCP analysis was done for brainstem necrosis. Results: Considering a variable proton RBE as a dose-modifying factor for prescription doses and dose constraints is misleading, as TCP/NTCP do not simply scale with RBE. The dependency of RBE on a/b cannot be interpreted independent of TCP/NTCP because variations in radiosensitivity affect both photon and proton treatments. Assuming interpatient variability in radiosensitivity results in lower TCP for patients with low a/b. In proton therapy, the magnitude of TCP variations is reduced due to an RBE increase as a/b decreases. The TCP in proton therapy is less affected by interpatient variability in a/b. On the other hand, patients with a lower a/b would have a lower complication probability, which is counteracted by an increase in RBE as a/b decreases. Toxicities in proton therapy would be more affected by a/b variations compared to photon therapy. Conclusions: Assessment of variable RBE in proton therapy should be based on TCP and NTCP. Potential interpatient variability in radiosensitivity causes a smaller variance in TCP but a larger variance in NTCP for proton patients. The relative TCP as a function of a/b was found to be higher than the RBE, whereas the relative NTCP was lower than a calculated RBE.

Proton Relative Biological Effectiveness – Uncertainties and Opportunities

“…However, it is difficult to assess RBE effects in patients because of patient variability in tissue radiosensitivity [68, 69]. …”

“…When analyzing the impact of (α/β) x on TCP, one needs to consider that not only the RBE but also the TCP depends on (α/β) x [69]. Assuming interpatient variability in linear-quadratic radiosensitivity parameters for a given tumor type, one might expect a lower TCP for patients with low average (α/β) x .…”

“…Consequently, toxicities in proton therapy would be more affected by variations in (α/β) x compared with photon therapy [69]. While this does not imply an overall higher risk for side effects from proton therapy, it does suggest wider distribution of the severity of toxicities.…”

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.…”

LET-weighted doses effectively reduce biological variability in proton radiotherapy planning

“…While these models broadly agree on overall trends in proton RBE for cell survival, they have seen limited translation to the clinic. In part, this is because these models depend on both the α/β ratio of the target tissue as well as model-specific fitting parameters which carry significant uncertainties and potential inter-patient variability, which translates into significant uncertainties in predicted RBE [9][10][11]. Furthermore, these models are based on cell survival endpoints that may not be relevant for normal tissue toxicities.…”