Title: The NIHR FAST-Forward phase III randomised controlled trial of 1 week vs 3 weeks of curative whole breast radiotherapy in early breast cancer: 10 (Main trial) and 5 (Nodal Sub- Study) year outcomes
Funder: Department of Health and Social Care

Abstract: Patients diagnosed with early breast cancer are often recommended radiotherapy after surgery to lower the risk of cancer returning and of dying from breast cancer. Ongoing research is studying the best way to deliver radiotherapy. The NIHR HTA-funded FAST-Forward Trial tests 3 schedules of radiotherapy to the breast, 2 different doses each given on 5 days over 1 week compared with standard treatment given on 15 days over 3 weeks (“Main trial”). The Nodal Sub-study tests the same schedules in those also needing radiotherapy to the lymph nodes in the armpit. 5-year Main trial results published in April 2020 showed that the lower dose 1-week schedule gave similar results in terms of the cancer returning and side-effects to the standard 3-week treatment. Many UK centres adopted this 1-week schedule for the majority of patients but there remains uncertainty in the UK and worldwide about using this for all patients including those with higher risk disease, or those needing radiotherapy to the armpit. Previous trials have shown that long-term follow-up is needed to provide reassurance of the benefits and risks of new radiotherapy schedules. Beyond 5 years the risks of cancer returning in the breast continues and side-effects such as breast shrinkage and pain continue to occur; it is important to clinicians, patients and commissioners that long-term outcomes remain comparable between treatment schedules. Rare but serious side-effects such as lung, heart and nerve damage tend to appear later requiring longer follow-up to assess. Support is now requested to get that long-term trial follow-up. We have considered how best to collect 10-year data in the Main trial whilst minimising the burden on patients and hospitals post-COVID. Original funding covered 7-year data collection in the Main trial; further follow-up will formally consist of a 10-year assessment only. Centres may opt to see patients at 8 and 9 years but this is now optional for the trial. The Nodal Sub-study opened after the Main trial and has 3 years’ follow-up; further funding will allow assessments at years 4, 5 and 7 after which we will consider the best way to capture 10-year data. Breast cancer patients are usually discharged early from hospital follow-up so we need the trial to continue to get these data. Treating hospitals will record if a patient’s disease has come back. Information on side-effects will be recorded by the treating clinicians. We will also ask the patients via a survey at 5 years in the Nodal Sub-study and 10 years in the Main trial to tell us how the treatment has affected them. As discussed with patient representatives, we will expand the 10-year survey to include issues most relevant to the long-term impact of cancer and its treatment and will invite all trial participants to share their views. This will provide an invaluable and detailed picture of the long-term impact of radiotherapy, essential to inform future patients and their treating teams worldwide. Patient representatives have been partners in this research from the outset. In 2021 we worked with a group of trial participants to develop future aspects of FAST-Forward to ensure that we continue to collect information most relevant to patients and that we do this efficiently and with minimal burden. Our patient representatives will continue to support the trial management group offering their views, reviewing trial materials and optimising the sharing of future results to maximise impact.

Lay abstract: Research question: What is the long-term efficacy & toxicity of two 1-week radiotherapy (RT) schedules for early breast cancer compared with the standard 3-week schedule 5-10 years after treatment? Background: Meta-analyses confirm that RT after surgery for early breast cancer reduces local cancer relapse & breast cancer deaths. RCTs involving >7000 patients with long-term follow-up confirmed that hypofractionated RT (fewer larger fractions (Fr; daily doses)) can be at least as safe & effective as the historic standard of 50Gy in 25Fr (5 weeks) if a lower total dose is used. 40Gy in 15Fr (3 weeks) was adopted as UK standard in 2009. Further research into ultra-hypofractionated RT delivered in larger Fr in 1-week aims to reduce patient & healthcare burdens, maintaining excellent local tumour control without increasing toxicity. Trial design & progress to date: FAST–Forward is a UK-wide phase 3 randomised non-inferiority trial testing two 1-week schedules against the 3 week regimen. Patients with early breast cancer requiring adjuvant RT were randomly allocated (1:1:1) to 40Gy in 15Fr over 3 weeks, 27Gy or 26Gy in 5Fr over 1week to the whole breast or chest wall (Main trial) plus the regional lymph nodes (Nodal Sub-Study). Main trial recruited 4110 patients (2011-2014) and Nodal Sub-Study 469 patients (2016-2018). Primary endpoints were local relapse (Main trial) and patient-reported arm/hand swelling (Nodal Sub-Study). Secondary endpoints were late adverse effects assessed by patients & clinicians, cancer & survival outcomes. Primary results published in April 2020 showed non-inferiority for local cancer relapse for both 1-week schedules and no excess toxicity concern for 26Gy. Since i) half of local cancer relapses occur >5 years, ii) the incidence of moderate/severe adverse effects continues to increase > 5 years, and iii) nodal RT is increasingly preferred over axillary surgery, it is essential to patients & clinicians to confirm long-term balance of efficacy with minimal toxicity. Aims & objectives: To assess the 10-year efficacy & toxicity of 1-week 5Fr schedules of RT compared with standard 3-week 15Fr regimen after surgery for early breast cancer. To similarly assess 5 & 7-year outcomes in Nodal Sub-Study. Methods: The original NIHR funding enabled completion of 5 years’ follow-up in the Main trial. This funding application is to obtain data to 10 years for Main trial and 5-7 years for Nodal Sub-Study. The Main trial 10-year assessment will update the primary endpoint of local relapse and assess late effects reported by patients (including survivorship issues) & clinicians, secondary disease-related & survival outcomes. Co-development with trial patients has informed the 10-year PRO assessment. Nodal Sub-study will complete 5-year primary analysis. Timelines: Patients are in active follow-up between years 7-10 for Main trial & years 3-5 for Nodal Sub-Study. Results will be available in 2025. Impact & dissemination: Findings will be published in high impact journals, presented at international symposia and shared with patients and public by social and mainstream media. There is huge global interest in these longer-term results that will inform policy makers via definitive international guidelines, currently being held-back with concerns over potential long-term toxicity. Failure to report long-term efficacy & toxicity may prevent adoption of a 1-week schedule in many countries, disadvantaging patients.

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