Radiation therapy is widely used for treatments of malignant diseases. The search for the optimal radiation treatment approach for a specific case is a complex task, ultimately seeking to maximise the tumour control probability (TCP) while minimising the normal tissue complication probability (NTCP). Conventionally, standard curative treatments have been delivered with photons in daily fractions of 2 Gy over a period of approximately three to eight weeks. However, the interest in hypofractionated treatments and proton therapy have rapidly increased during the last decades. Given the same TCP for a photon and a proton plan, the proton plan selection could be made purely based on the reduction in NTCP. Such a plan selection system is clean and elegant but is not flawless. The nominal plans are typically optimised on a single three-dimensional scan of the patient trying to account for the treatment related uncertainties such as particle ranges, patient setup, breathing and organ motion. The comparison also relies on the relative biological effectiveness (RBE), which relates the doses required by photons and protons to achieve the same biological effect. The clinical standard of using a constant proton RBE of 1.1 does not reflect the complex nature of the RBE, which varies with parameters such as linear energy transfer (LET), fractionation dose, tissue type and biological endpoint.

These aspects of proton therapy planning have been investigated in this thesis through five individual studies. Paper I investigated the impact of including models accounting for the variability of the RBE into the plan comparison between proton and photon prostate plans for various fractionation schedules. In paper II, a method of incorporating RBE uncertainties into the robustness evaluation was proposed. Paper III evaluated the impact of variable RBE models and breathing motion for breast cancer treatments using photons and protons. In Paper IV, a novel optimisation method was proposed, where the number of protons stopping in critical structures is reduced in order to control the enhanced LET and the related RBE. Paper V presented a retrospective analysis with alternative treatment plans for intracranial cases with suspected radiation-induced toxicities.

The results indicate that the inclusion of variable RBE models and their uncertainties into the proton plan evaluation could lead to differences from the nominal plans made under the assumption of a constant RBE of 1.1 for both target and normal tissue doses. The RBE-weighted dose (D_RBE) for high α/β targets (e.g. head and neck (H&N) tumours) was predicted to be slightly lower, whereas the opposite was predicted for low α/β targets (e.g. breast and prostate) in comparison to the nominal D_RBE. For most normal tissues, the predicted D_RBE were often substantially higher, resulting in higher NTCP estimates for several organs and clinical endpoints. By combining uncertainties in patient setup, range and breathing motion with RBE uncertainties, comprehensive robustness evaluations could be performed. Such evaluations could be included in the plan selection process in order to mitigate potential adverse effects caused by an enhanced RBE. Furthermore, objectives penalising protons stopping in risk organ were proven able to reduce LET, RBE and NTCP for H&N and intracranial tumours. Such approach might be a future optimisation tool in order to further reduce toxicity risks and maximise the benefit of proton therapy.