Lancet Oncol. 2013-10-01
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.
Abstract
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.
Findings
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.
Interpretation
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.
Funding
Cancer Research UK, UK Medical Research Council, UK Department of Health.
Related Questions
What is the maximum dose that you would give to residual unresectable gross disease in the axilla in the setting of recurrent breast cancer s/p ALND?
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Is active rheumatoid arthritis (RA) a contraindication to hypofractionated breast irradiation?
Active RA with some sort of skin manifestation may make me consider delaying/deferring RT, but it would not change what fractionation I use.Here is recent data that shows no difference in toxicity across various fractionation schemes in patients with CVD.
In a patient with a history of prior BCS+RT for early stage breast cancer who is now s/p repeat lumpectomy for a low risk in-breast recurrence, what dose/fractionation regimens are appropriate for reirradiation?
PBI using IMRT to 1.5 Gy BID to 45 Gy like phase 2 RTOG.If declines, can do once a day conventional fractionation to 45-50.4 Gy.
When offering palliative radiation for breast cancer, what dose/fractionation do you prefer and in what subset of patients do you believe derive the most benefit?
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Given COVID-19, is there a good hypofractionated regimen for postmastectomy radiation for locally advanced breast cancer?
In light of COVID-19, we offer 2.66 x 16 PMRT with comprehensive RNI. This regimen is under study in ALLIANCE A221505, commonly known as RT-CHARM. Primary endpoint is reconstruction complications at 2 years. We discuss with reconstructed patients (most all will take if offered). Routinely given to u...
When treating patients with hypofractionated radiation to the breast in 16 fractions do you typically treat 4 or 5 days a week?
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Is it safe to hypofractionate for whole breast RT in patients with a BRCA 1/2 or CHEK2 mutation to chose to have breast conservation for early stage breast cancer or DCIS?
There is no evidence that hypofractionation compared to conventional fractionation results in higher acute or long term toxicities in patients who have these mutations. Since a majority of these patients may also be in a younger age group many clinicians may appropriately feel uncomfortable in offer...
Is there an age cutoff you use to determine when you will offer standard vs hypofractionated breast radiation in early stage breast cancer?
About 20% of patients in both START A and START B were under the age of 50, and these were huge trials. As such, I don't see a compelling reason not to treat younger women with hypofractionation. To put it another way, I don't think we have good reason to believe that schedules that are designed to ...
Are there situations where you would use hypofractionated radiotherapy for Stage III breast cancer?
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Do you avoid hypofractionated regimen for Grade 3 early stage breast cancer?
The Canadian finding was unexpected and likely not reproducible. Not sure if it will hold up in longer follow-up. START did not find that and I would not withhold hypofractionation based on grade. Whether the boost makes a difference based on grade is pure speculation at this point, but I tend to bo...
Do you recommend hypofractionated/Canadian fractionation for in-situ ductal cancer?
The same pretzel logic used to deny hypo fractionation to patients with DCIS was used in the 80's to deny them breast conservation. It is not only reasonable to extrapolate the data from over 7000 patients with early stage invasive breast cancer on the British and Canadian trials, it is necessary fo...
Can I treat breast nodal volumes with hypofractionation?
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