Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 10-year efficacy and late normal tissue effects from a multicentre, open-label, non-inferiority, phase 3, randomised controlled trial and 5-year efficacy results from a randomised axillary substudy

BACKGROUND: FAST-Forward aimed to identify a 1-week adjuvant radiotherapy schedule for early-stage breast cancer that was as safe and efficacious as the standard 3-week schedule of 40 Gy in 15 fractions over 3 weeks. Primary analysis showed non-inferiority of 5-year ipsilateral breast recurrence for 26 Gy and 27 Gy in five fractions over 1 week, with 26 Gy also having similar results to 40 Gy for normal tissue effects. Here, we report 10-year outcomes of the FAST-Forward trial and 5-year efficacy outcomes of a substudy assessing the approach in patients requiring axillary treatment. METHODS: FAST-Forward is a multicentre, open-label, non-inferiority, phase 3, randomised controlled trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged 18 years or older with invasive carcinoma of the breast (pT1-3, pN0-1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients (in a 1:1:1 ratio with random permuted blocks, stratified by radiotherapy centre) to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was non-inferiority of ipsilateral breast recurrence at 5 years. Here, we report the planned 10-year analysis assessed in the intention-to-treat population (all participants who were randomly assigned and consented for use of data). We also report a planned intention-to-treat analysis of a subsequent substudy assessing 5-year efficacy of the same schedules in patients meeting the study criteria but requiring axillary treatment. The clinical trial was registered with ISRCTN (ISRCTN19906132); the main trial is complete, follow-up of the substudy cohort is ongoing. FINDINGS: Between Nov 24, 2011, and June 19, 2014, 4110 participants were enrolled in the main FAST-Forward trial. 23 withdrew consent for data use and were excluded and 4087 participants were included in the intention-to-treat population for this 10-year analysis. Participants were randomly assigned to 40 Gy (n=1358), 27 Gy (n=1362), or 26 Gy (n=1367). Median follow-up was 10·1 years (IQR 10·0-10·2). Ipsilateral breast recurrence was reported for 116 participants (45 in the 40 Gy group, 41 in the 27 Gy group, and 30 in the 26 Gy group), with 10-year cumulative incidence of 3·6% (95% CI 2·7-4·9) for the 40 Gy group, 2·9% (2·1-4·0) for the 27 Gy group, and 2·1% (1·5-3·1) for the 26 Gy group. 10-year clinician-reported moderate or marked breast or chest wall effects occurred in 100 (13·1%) of 765 participants in the 40 Gy group, 157 (19·3%) of 814 in the 27 Gy group, and 111 (14·4%) of 770 in the 26 Gy group. Between April 11, 2016, and Oct 2, 2018, 469 participants enrolled in the nodal substudy, 466 of which were included in intention-to-treat analyses. Median follow-up was 7·0 years (IQR 6·2-7·1) and 32 locoregional recurrences were reported. INTERPRETATION: Long-term follow-up confirms that 26 Gy in five fractions over 1 week is safe and efficacious for adjuvant radiotherapy to the breast or chest wall, supporting its use as a standard of care. Efficacy data for this schedule in the axillary nodal radiotherapy setting are reassuring; however, sample size limits precision of estimation for this subgroup on its own. FUNDING: UK National Institute for Health and Care Research.