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.
BACKGROUND
5-year results of the UK Standardisation of Breast Radiotherapy (START) trials suggested that lower total doses of radiotherapy delivered in fewer, larger doses (fractions) are at least as safe and effective as the historical standard regimen (50 Gy in 25 fractions) for women after primary surgery for early breast cancer. In this prespecified analysis, we report the 10-year follow-up of the START trials testing 13 fraction and 15 fraction regimens.


METHODS
From 1999 to 2002, women with completely excised invasive breast cancer (pT1-3a, pN0-1, M0) were enrolled from 35 UK radiotherapy centres. Patients were randomly assigned to a treatment regimen after primary surgery followed by chemotherapy and endocrine treatment (where prescribed). Randomisation was computer-generated and stratified by centre, type of primary surgery (breast-conservation surgery or mastectomy), and tumour bed boost radiotherapy. In START-A, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 41·6 Gy or 39 Gy in 13 fractions over 5 weeks. In START-B, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 40 Gy in 15 fractions over 3 weeks. Eligibility criteria included age older than 18 years and no immediate surgical reconstruction. Primary endpoints were local-regional tumour relapse and late normal tissue effects. Analysis was by intention to treat. Follow-up data are still being collected. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779.


RESULTS
START-A enrolled 2236 women. Median follow-up was 9·3 years (IQR 8·0-10·0), after which 139 local-regional relapses had occurred. 10-year rates of local-regional relapse did not differ significantly between the 41·6 Gy and 50 Gy regimen groups (6·3%, 95% CI 4·7-8·5 vs 7·4%, 5·5-10·0; hazard ratio [HR] 0·91, 95% CI 0·59-1·38; p=0·65) or the 39 Gy (8·8%, 95% CI 6·7-11·4) and 50 Gy regimen groups (HR 1·18, 95% CI 0·79-1·76; p=0·41). In START-A, moderate or marked breast induration, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 39 Gy group than in the 50 Gy group. Normal tissue effects did not differ significantly between 41·6 Gy and 50 Gy groups. START-B enrolled 2215 women. Median follow-up was 9·9 years (IQR 7·5-10·1), after which 95 local-regional relapses had occurred. The proportion of patients with local-regional relapse at 10 years did not differ significantly between the 40 Gy group (4·3%, 95% CI 3·2-5·9) and the 50 Gy group (5·5%, 95% CI 4·2-7·2; HR 0·77, 95% CI 0·51-1·16; p=0·21). In START-B, breast shrinkage, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 40 Gy group than in the 50 Gy group.


CONCLUSIONS
Long-term follow-up confirms that appropriately dosed hypofractionated radiotherapy is safe and effective for patients with early breast cancer. The results support the continued use of 40 Gy in 15 fractions, which has already been adopted by most UK centres as the standard of care for women requiring adjuvant radiotherapy for invasive early breast cancer.


BACKGROUND
Cancer Research UK, UK Medical Research Council, UK Department of Health.
ICR-CTSU, Division of Clinical Studies, The Institute of Cancer Research, Sutton, UK; University of Southampton Clinical Trials Unit, Southampton, UK.
Joanne S
JS
Haviland
Gloucestershire Oncology Centre, Cheltenham General Hospital, Cheltenham, UK.
J Roger
JR
Owen
Department of Oncology, Ninewells Hospital, Dundee, UK.
John A
JA
Dewar
Department of Oncology, Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UK.
Rajiv K
RK
Agrawal
Department of Radiotherapy, Royal Berkshire NHS Foundation Trust, Reading, UK.
Jane
J
Barrett
Velindre Hospital NHS Trust, Cardiff, UK.
Peter J
PJ
Barrett-Lee
Department of Clinical Oncology, Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK.
H Jane
HJ
Dobbs
ICR-CTSU, Division of Clinical Studies, The Institute of Cancer Research, Sutton, UK.
Penelope
P
Hopwood
Department of Oncology, Nottingham University Hospitals NHS Trust, Nottingham, UK.
Pat A
PA
Lawton
Christie NHS Foundation Trust, Manchester, UK.
Brian J
BJ
Magee
ICR-CTSU, Division of Clinical Studies, The Institute of Cancer Research, Sutton, UK.
Judith
J
Mills
ICR-CTSU, Division of Clinical Studies, The Institute of Cancer Research, Sutton, UK.
Sandra
S
Simmons
ICR-CTSU, Division of Clinical Studies, The Institute of Cancer Research, Sutton, UK.
Mark A
MA
Sydenham
Marie Curie Research Wing for Oncology, Mount Vernon Hospital, Northwood, UK.
Karen
K
Venables
ICR-CTSU, Division of Clinical Studies, The Institute of Cancer Research, Sutton, UK.
Judith M
JM
Bliss
Division of Radiotherapy and Imaging, The Institute of Cancer Research, Sutton, UK; Royal Marsden NHS Foundation Trust, Sutton, UK. Electronic address: john.yarnold@icr.ac.uk.
John R
JR
Yarnold
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000401:mortality / Q000532:radiotherapy* / Q000628:therapy; D003131:Combined Modality Therapy; D019583:Dose Fractionation, Radiation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008408:Mastectomy; D015412:Mastectomy, Segmental; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000401:mortality / Q000532:radiotherapy* / Q000628:therapy; D009367:Neoplasm Staging; D017410:Practice Guidelines as Topic / Q000592:standards*; D011379:Prognosis; D018714:Radiotherapy, Adjuvant; D012015:Reference Standards; D015996:Survival Rate
D000970:Antineoplastic Agents