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. 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.

Complications of radiotherapy: improving the therapeutic index.

For every course of radiotherapy treatment, the potential benefit has to be weighed against the risk of normal tissue damage. Radiation-induced proctitis during and after radical radiotherapy for prostate cancer can be decreased by reducing both the size of the target volume and the margins required around this volume. In the future, target volumes could be reduced by both CT/MRI co-registration and dose painting using MR spectroscopy of choline and citrate in the prostate. Improved immobilisation and image-guided radiotherapy should allow reduced margins without compromising the effectiveness of treatment. Similarly, in breast radiotherapy treatment, lung and cardiac complications can be reduced by better patient positioning and ensuring that doses to the heart and lung are minimised during radiotherapy treatment planning. Cosmesis can be improved by using 3D breast planning techniques rather than the conventional 2D approach. These ongoing improvements and developments in radiotherapy treatment planning are leading to treatments which offer both better tumour volume coverage, and are minimising the risk of treatment-related complications. In time, these changes should allow the escalation in dose delivered to the tumour volume with the potential for increased cure rates.

Improvements in radiotherapy practice: the impact of new imaging technologies.

Improvements in imaging technology are impacting on every stage of the radiotherapy treatment process. Fundamental to this is the move towards computed tomography (CT) simulation as the basis of all radiotherapy planning. Whilst for many treatments, the definition of three-dimensional (3D) tumour volumes is necessary, for geometrically simple treatments virtual simulation may be more speedily performed by utilising the reconstruction of data in multiple imaging planes. These multi-planar reconstructions may be used to define both the treatment volumes (e.g. for palliative lung treatments) and the organs at risk to be avoided (e.g. for para-aortic strip irradiation). For complex treatments such as conformal radiotherapy (CFRT) and intensity-modulated radiotherapy (IMRT) where 3D volumes are defined, improvements in imaging technologies have specific roles to play in defining the gross tumour volume (GTV) and the planning target volume (PTV). Image registration technologies allow the incorporation of functional imaging, such as positron emission tomography and functional magnetic resonance imaging, into the definition of the GTV to result in a biological target volume. Crucial to the successful irradiation of these volumes is the definition of appropriate PTV margins. Again improvements in imaging are revolutionising this process by reducing the necessary margin (active breathing control, treatment gating) and by incorporating patient motion into the planning process (slow CT scans, CT/fluoroscopy units). CFRT and IMRT are leading to far closer conformance of the treated volume to the defined tumour volume. To ensure that this is reliably achieved on a daily basis, new imaging technologies are being incorporated into the verification process. Portal imaging has been transformed by the introduction of electronic portal imaging devices and a move is underway from two-dimensional (2D) to 3D treatment verification (cone beam CT, optical video systems). A parallel development is underway from off-line analysis of portal images to the incorporation of imaging at the time of treatment using image-guided radiotherapy. By impacting on the whole process of radiotherapy (tumour definition, simulation, treatment verification), these new imaging technologies offer improvements in radiotherapy delivery with the potential for greater cure rates and a minimum level of treatment side effects.