PARABLE: Proton beAm theRApy in patients with Breast cancer: evaluating early and Late-Effects

Research question: Compared with standard radiotherapy (RT) for women with breast cancer, does Proton Beam Therapy (PBT) reduce mean heart dose (a validated biomarker of serious heart toxicity many years later) without increasing shorter-term side effects? Background: Around 500 UK breast cancer patients/year have increased risk of RT-induced heart toxicity due to the position of their heart in relation to the internal mammary nodes and/or their body shape. This can require compromises with RT that may increase risk of serious heart damage and/or reduce chance of cancer cure. PBT could be beneficial as it delivers dose to a specific depth to enable less dose to the heart whilst allowing full dose to the breast and nodes. This better dose distribution would maintain or even improve cancer outcomes. However, increased skin and rib side effects have been reported, mostly with earlier PBT techniques delivered over 5 weeks. UK standard RT for breast and nodes is delivered over 3 weeks, shown in clinical trials to be as good as 5 weeks RT but with less toxicity. With 2 NHS PBT centres in Manchester (open) and London (opening 2021), we have a unique opportunity to test PBT against RT both delivered in 3 weeks, in this important subgroup of patients with unmet need. Aims & objectives: PARABLE aims to show that PBT reduces predicted risk of late serious heart toxicity with no increase in other shorter-term side effects. PARABLE’s specific objectives are: (i) Change international practice for breast PBT early with a primary outcome analysis at 2 years’ follow-up (ii) Improve understanding of PBT biological models through a mechanistic study with potential benefit for all cancer patients needing PBT. Methods: PARABLE is a phase III multi-centre RCT testing 3-week PBT versus standard RT. Eligible breast cancer patients requiring RT with >=2% risk of RT-induced late heart toxicity will be randomised to PBT or standard RT at their local RT centre. Co-primary outcome measures are mean heart dose and patient-reported normal tissue toxicity in the breast (EORTC QLQ-BR23 breast symptoms score) at 2 years. Secondary longer-term outcomes include further patient and clinician-assessed toxicities up to 5 years identified as important to patients, plus recurrence and survival. 192 patients (1:1 allocation) provide 91% power overall to show a difference in mean heart dose of >1Gy and non-inferiority of PBT in 2-year patient-reported breast symptoms (<10-point clinically significant difference). Mechanistic outcomes are change in median lung CT Hounsfield Units from baseline to 2 years and differences in planned and delivered doses. Timelines for delivery: Grant start date: Month 1; trial will open to recruitment in Month 7; internal pilot will complete in 16 (9 months after accrual opens) and recruitment will finish in Month 36. Primary and mechanistic study analyses will be completed by Q4 2026. Follow-up will continue to 5 years after treatment. Anticipated impact & dissemination: PARABLE seeks to generate internationally practice-changing evidence for PBT in breast cancer patients underserved by current RT. Findings from the embedded mechanistic study are expected to have considerable impact for all future cancer patients requiring PBT. Results will be presented at international conferences and published in open access high-impact peer-reviewed medical journals with lay summaries produced with PPI partners.