Title: Fast-Forward: a randomised clinical trial testing a 1-week course of curative whole breast radiotherapy against a standard 3-week schedule in terms of local cancer control and late adverse effects in women with early breast cancer
Funder: Department of Health and Social Care

Abstract: Design: Phase III randomised controlled trial. Setting: Hospital oncology departments. Strategy for Reviewing literature: i) Pubmed database searches using the following criteria: breast cancer, radiotherapy, fractionation, trials ii) Direct communication between international researchers Target population: Women with early breast cancer. Health technologies being assessed: Three different radiotherapy fractionation regimens:- 40Gy in 15 fractions over 3 weeks, 27Gy in 5 fractions over 1 week, 26Gy in 5 fractions over 1 week. Measurement of costs and outcomes: The primary endpoint is local tumour relapse in the irradiated breast (the only clinically relevant measure of radiotherapy effect). Secondary endpoints concentrate on adverse effects measured (as in the recent UK START and FAST trials) using photographic assessments of changes in breast appearance due to radiotherapy, physician assessments of early and late radiotherapy adverse effects, and patient self-assessments of symptoms and quality of life (standard instruments). The primary outcome measure for the health economic evaluation is the cost per quality-adjusted life year (QALY) gained from health resource usage and EQ5D health status. Sample size: 4000 patients, distributed evenly between the 3 randomised schedules, provides 80% power with 1-sided significance of 0.025 (to allow for one-sided hypothesis and multiple testing) to exclude an excess of 1.6% in the 5-year local relapse rate in each of the test schedules compared with control (assuming 2% local relapse rate at 5 years). Since local relapse rates are so low, and no measurable difference in local relapse between the two test schedules is expected, interim analyses will also combine the test schedules for comparison with the control for the primary endpoint. This combined analysis will enable an excess of 1.3% in the 5-year local relapse rate for the 1-week test schedules compared with the control to be detected should it unexpectedly exist. For the photographic, quality of life and health economic sub-studies 2196 patients will provide 80% power to enable a difference of 8% in the 5-year rates of late adverse effects to be detected between the test schedules (assuming 35% rate at 5 years). All estimates allow for 10% loss to follow-up or patients being unevaluable. Project timetables (including recruitment rate): The trial will continue until all patients have had 10 years follow up. The trial comprises three different stages subsequent to ethics approval: Set-up (months 0-6): Research + Development and sponsorship approval obtained. ICR-CTSU staff recruited. Quality Assurance undertaken at centres. Centre agreements signed. Recruitment (months 7-54): All 25 centres open to recruitment by the end of month 27. Recruitment of 4000 patients will be completed by month 54 with each of the 25 radiotherapy centres recruiting an average of 4 patients per month. Monitoring visits to all centres will be undertaken during the first 8 years of the trial. Follow-up (months 55-174): collection of follow up data, interim analysis, data checking, primary analysis and publication of tumour control and 5 year adverse event data at 96 months, and analysis of tumour control and late (10 year) adverse effects at 156 months. Final analysis, report writing and dissemination of results will be undertaken between months 156 and 174.

Lay abstract: Curative radiotherapy prescribed to women in the UK with early breast cancer currently delivers 15 treatments to a total dose of 40Gy over a 3-week period. This was adopted in response to NICE guidance based on a randomised comparison with the 5-week international standard published by our collaborative group in 2008. However it is possible that even fewer treatments can be given. This trial tests a 5-fraction schedule delivered in 1 week against the UK 15-fraction standard. If a treatment giving 5 fractions in 1 week is shown to be as effective and safe as the 3-week UK standard regimen, there will be obvious benefits for patients and for the health services. The research will be carried out by a collaboration involving at least 25 UK radiotherapy centres, including those which participated in the UK Standardisation of Radiotherapy (START) trials and who subsequently completed the FAST trial, a pilot study for the Fast-Forward trial proposed in this application. The Chief Investigator is based at the Royal Marsden Hospital and the Institute of Cancer Research at Sutton, where the Clinical Trials and Statistics Unit (ICR-CTSU) is also based. ICR-CTSU specialises in conducting trials in breast cancer and in trials evaluating new ways to deliver radiotherapy. Outcomes used to assess the success of the research include the rate of local cancer control as primary endpoint supplemented by a series of secondary endpoints, including breast appearance and patient self-assessments of symptoms and quality of life all at 10 years post randomisation. A prospective health economic evaluation will estimate the cost per quality-adjusted life year gained from health resource usage and a general health status questionnaire. The ethical issues are no different from those encountered in many clinical trials. The anticipation is that the new treatments will be at least as safe and effective as the current UK standard. There is a small risk that this will not be the case, and that the new treatments are either less safe, less effective or both. The patient information sheet explains these possibilities in detail, recognising that the 1-week schedule could be responsible for a 1% increase in local cancer relapse or a 1% increase in the rate of marked adverse effects. The team is well placed to carry out the research. The chief investigator and associated clinical trials unit have led the previous four randomised trials evaluating this approach, and most, if not all, radiotherapy departments bring experience from participation in these trials. This is a large randomised trial recruiting 4000 patients from up to 25 radiotherapy centres across the UK, with associated studies for quality of life and health economics. The trial will last almost 15 years since chronic adverse effects from radiotherapy continue to occur and deteriorate for many years after treatment. However, since data on late adverse effects of radiotherapy are not routinely collected, either in hospital information systems or patients’ clinical notes, it will still be necessary for the patient to attend follow-up visits for clinical and photographic assessments The staff needed to support a trial of this size, to ensure that it is conducted to the highest scientific and quality standards, include a trial manager, senior trial manager, data manager, quality of life manager, trial administrator, statistician and a database programmer, though not all these posts are full-time for the duration of the trial. Specialist support involving physics and radiography is also required to manage the quality assurance aspects of radiotherapy planning and delivery. This ensures that participating centres carry out the required radiotherapy planning and delivery within the tight constraints demanded by the protocol. As two-thirds of the patients on the trial will receive 5 fractions instead of the standard 15 fractions this trial will provide significant cost savings to the NHS.

Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS