Using proton beam therapy to reduce the toxicity of treatment for breast cancer

Abstract

Background and purpose Proton beam therapy (PBT) can deliver radiation dose that conforms more closely to the target than photon treatment, sparing organs­at-risk {OAR) thereby reducing late effects of radiotherapy (cardiac disease or second malignancy) in breast cancer survivors. Potential benefits are greater when conventional radiotherapy delivers higher mean heart dose (MHD) or dose to contralateral breast (CB) such as internal mammary nodal treatments or unfavourable anatomy e.g. pectus excavatum (PEx). In PBT the linear energy transfer (LET), increases steeply at the end-of-range and relates to the relative biological effectiveness (RBE). These physical differences from photons could have clinical implications for beam arrangement. The aims of this thesis were to identify which patients might benefit most from breast PBT, define beam arrangement(s) that minimise potential clinical risks of variable RBE and to develop eligibility and technical specifications for a randomised controlled trial of PBT versus photons (PARABLE). Methods OAR doses were compared between PBT and photon techniques for irradiating breast and nodal targets in PEx patients and those requiring a simultaneous integrated boost (SIB). Risks of developing a subsequent CB cancer were calculated. PBT plans using different beam arrangements were prepared. LET distributions and RBE-weighted doses were calculated using variable RBE models. Patients at greater risk of radiation-related cardiac disease were defined for inclusion into PARABLE considering age, pre-existing cardiac risks and MHD. A radiotherapy trial quality assurance (RTTQA) document was developed with multidisciplinary input. Results In PEx patients PBT reduced MHD by a mean of 3.4 Gy compared to volumetric modulated arc therapy and, in a mixed cohort, the median MHD contribution from a SIB was 0.3 Gy lower using PBT. In patients <40 years, PBT could decrease the risk of CB cancer six-fold. Higher LET was observed in OARs for single beam PBT plans. For PARABLE, a simplified model-based approach was developed for eligibility and RTTQA specifications agreed. Conclusions PBT has scope to reduce toxicity by reducing MHD, particularly in PEx patients. When using PBT, more than one beam is recommended. A MHD risk-adapted eligibility criterion and RTTQA document are in use in a national breast PBT trial.