FAST-Forward Phase III Randomised Controlled Trial of 1-Week Hypofractionated Breast Radiotherapy: 5-Year Results for Efficacy and Late Normal Tissue Effects

Background: FAST-Forward aims to identify a 5-fraction (Fr) schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week which is non-inferior for local cancer control and as safe as an international standard 15Fr regimen after primary surgery for early breast cancer. Five-year results are presented. Methods: FAST-Forward (ISRCTN19906132) randomised (1:1:1) patients with invasive carcinoma of the breast (pT1-3 pN0-1 M0) after breast conservation surgery or mastectomy to 40Gy in 15Fr (3 weeks), 27Gy or 26Gy in 5Fr (1 week) to whole breast/chest wall. Primary endpoint was ipsilateral breast tumour relapse (IBTR); assuming 2% 5-year incidence for 40Gy, non-inferiority was pre-defined as < 1.6% excess for 5Fr schedules (critical hazard ratio HR=1.81). Normal tissue effects (NTE) were assessed by clinicians, patients and photographs. Findings: 4096 consenting patients (1361 40Gy, 1367 27Gy, 1368 26Gy) were recruited November 2011-June 2014 from 97 UK centres. At 71 months median follow-up, 79 IBTR events were reported (40Gy: 31, 27Gy: 27, 26Gy: 21); HRs (95%CI) versus 40Gy/15Fr were 27Gy/5Fr: 0.86 (0.51,1.44), 26Gy/5Fr: 0.67 (0.38,1.16). Five-year incidence of IBTR after 40Gy was 2.1% (1.4,3.1); estimated absolute differences versus 40Gy/15Fr were -0.3% (-1.0,0.9) for 27Gy/5Fr (p=0.0022 for non-inferiority) and -0.7% (-1.3,0.3) for 26Gy/5Fr (p=0.00019). 5-year prevalence of any clinician-assessed moderate/marked breast NTE after 40Gy: 98/986 (9.9%), 27Gy: 155/1005 (15.4%), 26Gy: 121/1020 (11.9%). Across all clinician assessments from 1-5 years, odds ratios versus 40Gy/15Fr were 1.55 (1.32,1.83, p<0.0001) for 27Gy/5Fr and 1.12 (0.94,1.34, p=0.20) for 26Gy/5Fr. Patient and photographic assessments showed higher NTE risk for 27Gy versus 40Gy but not for 26Gy. Interpretation: 5-year local tumour incidence and NTE prevalence show 26Gy/5Fr in 1 week to be an effective and safe alternative to 40Gy/15Fr in 3 weeks for patients prescribed adjuvant local radiotherapy after primary surgery for early stage breast cancer. Trial Registration: ISRCTN19906132. Funding Statement: The FAST-Forward trial is funded by the National Institute for Health Research (NIHR) Health Technology Assessment Programme - HTA (UK) (09/01/47), with programme grants from Cancer Research UK to support the work of ICRCTSU (C1491/A15955; C1491/A25351). We acknowledge NHS funding to the NIHR Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research (London, UK). Declaration of Interests: JMB reports grants from NIHR HTA and grants from Cancer Research UK during the conduct of the study, and grants and non-financial support from Novartis (previously GSK), grants and non-financial support from Astra Zeneca, grants and non-financial support from Clovis Oncology, grants and non-financial support from Janssen-Cilag, grants and non-financial support from Merck Sharpe & Dohme, grants and non-financial support from Puma Biotechnology, grants and non-financial support from Pfizer, grants and non-financial support from Roche, grants from Medivation, outside the submitted work. DAW reports travel grants from Roche Pharmaceuticals, outside the submitted work. JSH, MAS and LS report grants from NIHR HTA and grants from Cancer Research UK, during the conduct of the study. CCK reports personal fees from Roche Pharmaceutical, outside the submitted work. AA, AMB, DJB, CC, CEC, MC, AG, PH, CM, ZN, NS, IS, JRY declare no competing interests. Ethics Approval Statement: FAST-Forward was approved by the national South East Coast Kent Research Ethics Committee (11/LO/0958) and local Research and Development offices of all participating centres.