Modelling recurrence and second cancer risks induced by proton therapy.

In the past few years, proton therapy has taken the centre stage in treating various tumour types. The primary contribution of this study is to investigate the tumour control probability (TCP), relapse time and the corresponding secondary cancer risks induced by proton beam radiation therapy. We incorporate tumour relapse kinetics into the TCP framework and calculate the associated second cancer risks. To calculate proton therapy-induced secondary cancer induction, we used the well-known biologically motivated mathematical model, initiation-inactivation-proliferation formalism. We used the available in vitro data for the linear energy transfer (LET) dependence of cell killing and mutation induction parameters. We evaluated the TCP and radiation-induced second cancer risks for protons in the clinical range of LETs, i.e. approximately 8 $\mathrm{keV/\mu m}$ for the tumour volume and 1-3 $\mathrm{keV/\mu m}$ for the organs at risk. This study may serve as a framework for further work in this field and elucidates proton-induced TCP and the associated secondary cancer risks, not previously reported in the literature. Although studies with a greater number of cell lines would reduce uncertainties within the model parameters, we argue that the theoretical framework presented within is a sufficient rationale to assess proton radiation TCP, relapse and carcinogenic effects in various treatment plans. We show that compared with photon therapy, proton therapy markedly reduces the risk of secondary malignancies and for equivalent dosing regimens achieves better tumour control as well as a reduced primary recurrence outcome, especially within a hypo-fractionated regimen.