Title: Choosing breast cancer radiotherapy that improves survival.
Funder: Department of Health and Social Care

Abstract: Background Breast cancer is the commonest cancer in women. Radiotherapy is currently recommended for around two thirds of women with breast cancer. It can reduce the risks of cancer recurrence and death but it can also increase the risks of heart disease, lung cancer and oesophageal cancer due to incidental irradiation of these organs. Aim To provide information for women with breast cancer, and their oncologists, on features of successful radiotherapy regimens which provide the most survival benefit, and the least long-term risk. This aim will be fulfilled under three objectives. Methods First, I will identify the dosimetric features of lymph node radiotherapy regimens that are associated with improved survival. This will inform which regimens should be recommended in clinical guidelines and used by clinicians, and which regimens should be avoided.I will use data on ~13,000 women who received 31 different lymph node radiotherapy regimens in 14 worldwide randomised trials within an Early Breast Cancer Trialists' Collaborative Group meta-analysis. I will link various regimen-specific dose measures with clinical outcomes to inform which provide the best outcomes. I will then systematically describe all lymph node regimens used worldwide (outside trials) during 2015-2018 and classify them according to whether they have these features.Second, I will provide contemporary estimates of the absolute survival benefits and risks from breast cancer radiotherapy to help women and oncologists make more informed choices about whether to proceed with radiotherapy for breast cancer. I will estimate radiation doses received by various organs from radiotherapy for breast cancer in Oxford Cancer Centre during 2018 using 3-dimensional radiotherapy plans. These doses will be combined with dose-response relationships and population-based mortality rates to estimate absolute risks from contemporary radiotherapy. Absolute benefits of radiotherapy will be estimated using rate ratios from published meta-analyses and population data. Third,I will systematically review, summarise and evaluate available information on clinical outcomes after published proton beam therapy regimens to inform UK practice. It will also inform which regimen should be used in a proposed UK proton breast trial. Timelines Data have been received for all studies, and pilot work has demonstrated the feasibility of each objective within three years.Impact and dissemination Information generated will help radiotherapy decisions in the clinic today. Oncologists will be helped to choose radiotherapy regimens that provide the most benefit in terms of survival from breast cancer, with the lowest long-term risks of heart disease and second cancers. It will provide information on the benefits and risks of tomorrow's radiotherapy, to help guide the breast cancer radiotherapy research agenda and the implementation of new techniques.My findings will be submitted for publication in open-access journals and presented at conferences where feedback will inform our work. PPI has both driven and informed this proposal. Continued PPI from national and international breast cancer groups, and breast cancer charities will ensure findings are accessible to patients and the general public.

Lay abstract: AimTo provide information for women with breast cancer, and their oncologists, on which types of radiotherapy have the greatest benefits and lowest risks. BackgroundBreast cancer is the commonest cancer in women. If detected early, it is usually cured by surgery. However, in some women undetectable cancer cells may remain, later causing cancer recurrence and death.Breast cancer sometimes spreads to lymph nodes in the neck, under the arm, and in the centre of the chest behind the breast bone. These lymph nodes can be the first place cancer travels before spreading around the body. Benefits of radiotherapy Radiotherapy to the breast, or chest (if the breast is removed) after surgery, reduces the risks of recurrence and breast cancer death. Radiotherapy to the lymph nodes can provide additional survival benefit. Risks of radiotherapy It is challenging to give radiotherapy to the breast, and even more so the lymph nodes, without neighbouring organs also receiving radiation dose. The greater the dose to the nearby heart, lungs and oesophagus, the greater the risks of radiation-induced heart disease, lung cancer, and oesophageal cancer, respectively. Therefore, oncologists may be cautious about giving radiotherapy, particularly if treating the lymph nodes. Balancing benefits and risks The benefits and risks of radiotherapy change as techniques improve. There are many different types of radiotherapy and it is difficult for oncologists to choose which provide the most benefit with the least risk.For example, since 2018, proton beam therapy has been available to UK NHS patients. Computer modelling studies suggest this alternative to standard x-ray radiotherapy might reduce the risks of radiotherapy for breast cancer. But whether this holds true when given to patients is unknown. We do not have up-to-date estimates on the absolute benefits and risks of modern breast cancer radiotherapy. Oncologists and patients need these to assess whether to proceed with radiotherapy.DesignThis research informs three choices: 1. Choosing between types of lymph node radiotherapyI will describe the features of successful lymph node radiotherapy to help oncologists choose techniques for clinical practice that provide the greatest survival benefit. I will do this by assessing outcomes from different types of lymph node radiotherapy used worldwide in randomised trials. 2. Choosing whether to have radiotherapy for breast cancer: when does the benefit outweigh the risk? I will calculate up-to-date estimates of the benefits and risks of typical UK breast cancer radiotherapy. This information will help women and oncologists make more informed choices about whether to proceed with radiotherapy for breast cancer. I will also compare these UK estimates with estimates worldwide. 3. Choosing between beam types for women with breast cancer: proton beam therapy instead of x-rays? We currently use X-ray radiotherapy. I will review current knowledge worldwide about using newly available proton beam therapy in breast cancer. This will help oncologists and patients understand whether it has a role in reducing the risks of UK radiotherapy and will inform design of a planned UK clinical trial. Patient and public involvementPPI representatives have expressed support for objective 1 and will be involved in communicating results.Independent Cancer Patients' Voice requested objective 2, advised on its UK focus, and will help communicate findings.For objective 3, Mairead Mackenzie agrees accurate information on proton beam therapy is needed before its introduction into UK practice and is actively involved in future trial design. DisseminationPublication in high-impact journals and presentation at national and international meetings will ensure results reach those writing radiotherapy guidelines, designing clinical trials and influencing policy. PPI, including liaison with breast cancer charities, will ensure results are shared with patients and the public.

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