Title: PARABLE: Proton beAm theRApy in patients with Breast cancer: evaluating early and Late-Effects
Funder: Medical Research Council

Abstract: Aims: Proton Beam Therapy (PBT) is a type of radiation therapy. It uses protons (high-energy charged particles) rather than x-rays to treat cancer. PBT can be more accurately targeted than x-rays potentially reducing risks of side-effects in normal tissues such as the heart. We want to compare PBT with standard x-ray radiotherapy (RT) in breast cancer patients at higher risk of side-effects from RT. We aim to show that PBT reduces the predicted risk of long-term serious heart damage whilst not increasing other shorter term side effects such as skin changes._x000D_ Background: Around 33,000 breast cancer patients/year need RT as part of their treatment. A proportion (around 500/year) are less well served by standard RT due to the need to treat lymph nodes near the breast-bone. A person’s body shape can also make treatment difficult. This can result in less RT dose where needed (reducing the likelihood of cure), and/or unwanted dose to healthy tissue such as heart (increasing the risk of serious heart damage many years later). PBT has been used in other countries to treat breast cancer, but numbers are small with no direct comparison with RT._x000D_ PBT is different from RT as it delivers dose to a defined depth thereby giving better dose coverage where needed with less dose to heart. Increased skin and rib side effects have however been reported around 2 years after treatment, although this is mostly with older PBT techniques delivered over 5 weeks. UK standard RT is delivered over 3 weeks as clinical trials have shown this to be as good as 5 weeks with fewer side effects. The NHS has 2 PBT centres in Manchester (opened 2018) and London (opening 2021). We now have a unique opportunity to compare 3-week PBT with 3-week RT for this patient group with unmet need._x000D_ Design and methods: To confirm that PBT reduces rare but life-threatening side effects such as heart attacks compared with RT would need over 10,000 patients in a clinical trial lasting 15-20 years. This is not feasible and would mean large numbers of patients being exposed to less than optimal treatment in the meantime. We plan an efficient clinical trial using average heart dose, a short term predictor for later heart damage, to deliver a result much earlier. We will invite 192 breast cancer patients who have at least a 2 in 100 predicted lifetime risk of serious heart side effects from their planned RT to receive either PBT (Manchester/London) or RT (local centre). The choice of PBT or RT will be decided randomly by computer to minimise bias. We will compare average heart dose received with PBT to that received with RT and use symptoms reported by patients at 2 years after treatment to compare other side effects in and around the breast. Outcomes and side effects will be collected for 5 years and NHS databases will be used to collect even longer-term effects. We will assess whether patients accept randomisation and address any inequality of access._x000D_ Patient & Public Involvement (PPI): Patients as equal partners have contributed at all stages, including discussions at 7 national meetings and 2 patient focus groups. PPI has shaped the design by confirming that the main outcomes are important to patients, that 3-week PBT is acceptable and that outcome data should be collected beyond 5 years._x000D_ Communication of Results: We will present results at international conferences, publish in peer reviewed medical journals and produce lay summaries for a diverse audience together with our PPI partners.

Lay abstract: 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?_x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ 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. _x000D_ _x000D_ 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.

Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS