1-week hypofractionated adjuvant whole-breast radiotherapy: towards a new standard?
Authors: Antonin Levy, Sofia Rivera
Journal: The Lancet (2020)

Hypofractionated radiotherapy delivers a higher dose (>2 Gy) per fraction than conventional radiotherapy, reducing overall treatment duration and associated costs. In women with early stage breast cancer, moderate hypofractionated (eg, 40–42·5 Gy per 15–16 fractions in 3–3·2 weeks) adjuvant whole-breast radiotherapy was shown to be non-inferior in terms of long-term tumour control and toxicities than the conventional schedule (50 Gy in 2 Gy daily fractions over 5 weeks).1Whelan TJ Pignol JP Levine MN et al.Long-term results of hypofractionated radiotherapy for breast cancer.N Engl J Med. 2010; 362: 513-520Crossref PubMed Scopus (1344) Google Scholar, 2Haviland JS Owen JR Dewar JA et al.The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials.Lancet Oncol. 2013; 14: 1086-1094Summary Full Text Full Text PDF PubMed Scopus (1017) Google Scholar Subsequently, moderate hypofractionation has become the preferred dose-fractionation scheme for many patients.1Whelan TJ Pignol JP Levine MN et al.Long-term results of hypofractionated radiotherapy for breast cancer.N Engl J Med. 2010; 362: 513-520Crossref PubMed Scopus (1344) Google Scholar, 2Haviland JS Owen JR Dewar JA et al.The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials.Lancet Oncol. 2013; 14: 1086-1094Summary Full Text Full Text PDF PubMed Scopus (1017) Google Scholar, 3Murray Brunt A Haviland JS Wheatley DA et al.Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.Lancet. 2020; (published online April 28.)https://doi.org/10.1016/S0140-6736(20)30932-6Summary Full Text Full Text PDF Scopus (482) Google Scholar In The Lancet, Adrian Murray Brunt and colleagues3Murray Brunt A Haviland JS Wheatley DA et al.Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.Lancet. 2020; (published online April 28.)https://doi.org/10.1016/S0140-6736(20)30932-6Summary Full Text Full Text PDF Scopus (482) Google Scholar report the 5-year results of a three-arm, multicentre, randomised controlled, phase 3, non-inferiority trial (FAST-Forward) in which 4096 patients with invasive carcinoma of the breast were randomly assigned to treatment with 40 Gy in 15 fractions over 3 weeks (n=1361), or moderate hypofractionated radiotherapy with 27 Gy in five fractions of 5·4 Gy over 1 week (n=1367) or 26 Gy in five fractions of 5·2 Gy over 1 week (n=1368). The primary endpoint was ipsilateral breast tumour relapse, and normal tissue effects were assessed by clinicians, patients, and photographs. The population mainly comprised lower-risk patients (2551 [62·3%] of 4096, aged ≥50 years, and grade 1 or 2 breast cancer). Both five-fraction schedules were not inferior to 40 Gy in 15 fractions (5-year cumulative incidence of ipsilateral breast tumour relapse was 1·7% [95% CI 1·2–2·6] for the 27 Gy group, 1·4% [0·9–2·2] for the 26 Gy group, and 2·1% [1·4–3·1] for the 40 Gy group). Of those with at least one annual clinical assessment of normal tissue effects available (3975 [97%] of 4096), any moderate or marked clinician-assessed normal tissue effects in the breast or chest wall at 5 years were reported for 155 (15·4%) of 1005 participants in the 27 Gy group, 121 (11·9%) of 1020 in the 26 Gy group, and 98 (9·9%) of 986 in the 40 Gy group, with a significant difference between 40 Gy and 27 Gy (p<0·0001) but not between 40 Gy and 26 Gy (p=0·20). Incidence of locoregional relapse, distant relapse, disease-free survival, and overall survival was not different.3Murray Brunt A Haviland JS Wheatley DA et al.Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.Lancet. 2020; (published online April 28.)https://doi.org/10.1016/S0140-6736(20)30932-6Summary Full Text Full Text PDF Scopus (482) Google Scholar Hence, should 26 Gy in five fractions be considered an effective and safe alternative to moderate hypofractionated whole-breast radiotherapy? These findings provide robust evidence that limits of hypofractionated radiotherapy in the breast were not reached by previous trials, and that longer-term follow-up is needed because both recurrence and radiotherapy toxicity might occur late. After 5 years of adjuvant endocrine treatment (3649 [89·1%] of patients in the present trial),3Murray Brunt A Haviland JS Wheatley DA et al.Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.Lancet. 2020; (published online April 28.)https://doi.org/10.1016/S0140-6736(20)30932-6Summary Full Text Full Text PDF Scopus (482) Google Scholar the risk of distant recurrence generally lasts for at least the subsequent 15 years.4Mamounas EP Bandos H Lembersky BC et al.Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2019; 20: 88-99Summary Full Text Full Text PDF PubMed Scopus (85) Google Scholar Increased risk of long-term side-effects might be noticed with increased doses per fraction, by contrast with data from the present study. The mean dose to the heart linearly increases the risk of a major coronary event (7·4% [95% CI 2·9–14·5] per Gy) and this risk continues for at least 20 years.5Darby SC Ewertz M McGale P et al.Risk of ischemic heart disease in women after radiotherapy for breast cancer.N Engl J Med. 2013; 368: 987-998Crossref PubMed Scopus (2653) Google Scholar Modern radiotherapy techniques (eg, intensity-modulated radiotherapy and breath hold) could restrict the dose delivered to the heart, but such techniques were not reported in the present study.3Murray Brunt A Haviland JS Wheatley DA et al.Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.Lancet. 2020; (published online April 28.)https://doi.org/10.1016/S0140-6736(20)30932-6Summary Full Text Full Text PDF Scopus (482) Google Scholar Breast size was also not described in this study and different normal tissue effects could be observed in patients with larger breasts.3Murray Brunt A Haviland JS Wheatley DA et al.Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.Lancet. 2020; (published online April 28.)https://doi.org/10.1016/S0140-6736(20)30932-6Summary Full Text Full Text PDF Scopus (482) Google Scholar, 6Donovan E Bleakley N Denholm E et al.Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy.Radiother Oncol. 2007; 82: 254-264Summary Full Text Full Text PDF PubMed Scopus (386) Google Scholar The results of Murray Brunt and colleagues might not be applicable in some biological subtypes of breast cancer and high-risk patients, particularly with larger tumours and positive nodes. A substudy of patients in FAST-Forward comparing 40 Gy in 15 fractions and 26 Gy in five fractions for patients requiring regional radiotherapy is ongoing.3Murray Brunt A Haviland JS Wheatley DA et al.Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.Lancet. 2020; (published online April 28.)https://doi.org/10.1016/S0140-6736(20)30932-6Summary Full Text Full Text PDF Scopus (482) Google Scholar A 2019 trial suggested non-inferiority of post-mastectomy moderate hypofractionated radiotherapy compared with conventional fractionation.7Wang SL Fang H Song YW et al.Hypofractionated versus conventional fractionated postmastectomy radiotherapy for patients with high-risk breast cancer: a randomised, non-inferiority, open-label, phase 3 trial.Lancet Oncol. 2019; 20: 352-360Summary Full Text Full Text PDF PubMed Scopus (203) Google Scholar Further trials comparing moderate hypofractionated to conventional lymph node radiotherapy are ongoing (NCT03127995, NCT02690636, NCT03829553, NCT04025164, NCT02912312, and NCT04228991). A boost of radiotherapy to the tumour bed is intended to decrease locoregional recurrence, but its benefit in patients who have received hypofractionated radiotherapy is less clear. In the present study, 1011 (24·7%) patients had a boost, which was delivered in conventional fractions (10 Gy in five fractions or 16 Gy in eight fractions).3Murray Brunt A Haviland JS Wheatley DA et al.Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.Lancet. 2020; (published online April 28.)https://doi.org/10.1016/S0140-6736(20)30932-6Summary Full Text Full Text PDF Scopus (482) Google Scholar This choice of boost dose per fraction is difficult to understand because the boost is doubling the treatment time, and as such, the authors could have provided a rational for a hypofractionated boost schedule. In summary, we concur with the authors that 26 Gy in five fractions over 1 week might be changing practice for low-risk patients with breast cancer who have had surgery, but long-term disease outcomes and subset analyses are eagerly awaited. During the coronavirus disease 2019 (COVID-19) pandemic, hypofractionation could restrict the exposure of health-care professionals and patients to COVID-19. In this context, a schedule of 26 Gy in five fractions has been endorsed by an international panel of experts.8Coles CE Aristei C Bliss J et al.International guidelines on radiotherapy for breast cancer during the COVID-19 pandemic.Clin Oncol (R Coll Radiol). 2020; 32: 279-281Summary Full Text Full Text PDF PubMed Scopus (177) Google Scholar Different shorter fractionation schedules will hopefully also be compared to determine the restrictions of hypofractionation. The FAST-Forward schedule could challenge accelerated-partial breast radiotherapy as the preferred therapy in similar populations, but expected long-term outcomes and subanalyses of accelerated-partial breast radiotherapy trials (IMPORT-LOW, NSABP-B39, and RAPID) will help in positioning these options. Ultrahypofractionation with stereotactic body radiotherapy has been tested as an alternative therapy in women with early breast cancer who have had surgery, have been carefully selected, and do not need nodal radiotherapy (NCT03643861, NCT01290835, NCT02685332, and NCT01162200). In the future, patients' selection for adjuvant radiotherapy will ideally integrate tumour9Sjöström M Chang SL Fishbane N et al.Clinicogenomic Radiotherapy classifier predicting the need for intensified locoregional treatment after breast-conserving surgery for early-stage breast cancer.J Clin Oncol. 2019; 37: 3340-3349Crossref PubMed Scopus (56) Google Scholar and healthy tissue biology.10Seibold P Webb A Aguado-Barrera ME et al.REQUITE: a prospective multicentre cohort study of patients undergoing radiotherapy for breast, lung or prostate cancer.Radiother Oncol. 2019; 138: 59-67Summary Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 11Azria D Riou O Castan F et al.Radiation-induced CD8 T-lymphocyte apoptosis as a predictor of breast fibrosis after radiotherapy: results of the prospective multicenter french trial.EBioMedicine. 2015; 2: 1965-1973Summary Full Text Full Text PDF PubMed Scopus (84) Google Scholar We declare no competing interests. Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks for local tumour control, and is as safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer. Full-Text PDF Open Access