Title: TARGIT-B: An international randomised controlled trial to compare targeted intra-operative radiotherapy boost with conventional external beam radiotherapy boost after lumpectomy for breast cancer in women with a high risk of local recurrence
Funder: Department of Health and Social Care

Abstract: DESIGN: A pragmatic multi-centre randomised clinical trial to test whether TARGeted Intraoperative radioTherapy as a tumour bed Boost (TARGIT-B) is superior in terms of local relapse within the treated breast compared with standard post-operative external beam radiotherapy boost in women undergoing breast conserving therapy who have a higher risk of local recurrence. Patients can be entered before the primary surgery or in a smaller proportion of cases, post-pathology. SETTING: Specialist breast units in UK, USA, Canada, Australia and Europe; 31 centres currently recruiting in the TARGIT-A trial and several are ready to join. TARGET POPULATION: Breast cancer patients suitable for breast conserving surgery, but with a high risk of local recurrence. Details of inclusion and exclusion are given in part 2. Briefly the patients should be either younger than 45 or if older, need to have certain pathological features that confer a high risk of local recurrence of breast cancer. HEALTH TECHNOLOGIES BEING ASSESSED. The TARGIT Technique: The Intrabeam® (Carl Zeiss, FDA approved and CE marked) is a miniature electron beam-driven source which provides a point source of low energy X-rays (50kV maximum) at the tip of a 3.2mm diameter tube. The radiation source is inserted into the tumour bed immediately after excision of the tumour and switched on for 20-35 minutes to provide intra-operative radiotherapy accurately targeted to the tissues that are at highest risk of local recurrence. The physics, dosimetry and early clinical applications of this soft x-ray device have been well studied (1;2). For use in the breast, the technique was first developed and piloted at University College London (3-5). The radiation source is surrounded by a spherical applicator, specially designed (and available in various sizes) to produce a uniform field of radiation at its surface, enabling delivery of an accurately calculated dose to a prescribed depth. It is inserted in the tumour bed and apposed to it with surgical sutures and/or other means. As the x-rays rapidly attenuate the dose to more distant tissues is reduced; this also allows it to be used in standard operating theatres. 20 Gy is delivered to the tumour bed surface in 20-35 minutes, after which the radiation is switched off, the applicator removed, and the wound closed in the normal way. This simple technique has potentially several advantages over convential external beam radiotherapy, interstitial implantation of radioactive wires or conformal external beam radiotherapy. The first pilot of twenty-five cases was at performed at UCL using TARGIT technique as a replacement for the boost dose of radiotherapy; full dose external beam treatment was subsequently given (3). The phase II study of 300 patients was published (6) and recently updated with long term data(7) along with favourable toxicity and cosmetic outcome results of individual cohorts (8-11). A mathematical model of TARGIT developed recently (funded by Cancer Research UK) suggests that it could be superior to conventional radiotherapy (12;13). Translational research has found that Targit impairs the surgical-trauma-stimulated proliferation and invasiveness of breast cancer cells (14). This effect of radiotherapy may act synergistically with its tumouricidal effect yielding a superior result. This technology has already being assessed (HTA Grant 07/60/49) and the first results were recently fast-tracked and published in the Lancet (15) in which we found that in the low-risk patients TARGIT yields a non-inferior outcome. MEASUREMENT OF COST AND OUTCOME: Patient assessments will be clinical examination (6 monthly x 3 years then yearly x 10 years) and mammography (yearly). with ulstrasound (if needed) . Primary outcome: histologically/cytologically proven local recurrence. Secondary: site of relapse in the breast, overall survival, local toxicity (RTOG and LENT SOMA criteria), cosmesis, quality of life, patient satisfaction and health economics.We will calculate the cost and cost-effectiveness of IORT versus EBRT, both as boost, from a NHS and personal social services (PSS) perspective. We will also assess costs to patients since EBRT is likely to impose additional time and travel costs to patients and families

Lay abstract: Despite advances in breast cancer treatments, a subgroup of patients, especially young women, remain at a significant risk of cancer returning in the breast (recurrence) after receiving the standard breast conserving surgery and post operative course of radiotherapy. In this group of patients, standard radiotherapy would have been given several months after surgery and would normally consist of a 3-5 week course of daily radiotherapy to the whole breast, as well as a shorter 5-8 day course to the tumour bed (the normal breast tissue immediately around the tumour); it is difficult to accurately aim the boost at the tumour bed. We developed a new radiotherapy technique- TARGeted Intraoperative radioTherapy (TARGIT), in 1998 and have accumulated considerable experience through worldwide collaboration in over 30 centres. With TARGIT, radiotherapy is delivered accurately to the tissues at highest risk of recurrence- the tumour bed- at the time of surgery in a single session. The long-term analysis of the first 300 patients treated with this technique found a remarkably low recurrence rate, less than half of the expected rate. We have also found laboratory evidence that could provide a biological explanation. Normally body fluid collects in the surgical wound and we found that this fluid stimulates cancer cells- but not when the patient had received TARGIT, suggesting that radiotherapy immediately after surgery is probably very important. Hence we have designed a randomised trial of 1796 patients to compare TARGIT boost with conventional boost to test its superiority. The research will be a global collaborative effort of over 30 centres co-ordinated from London. The primary outcome will be local recurrence of cancer at 5 years. We shall also be looking at breast appearance, patient satisfaction and quality of life, and whether or not the intervention represents good value for money to the NHS and to patients and families (cost and cost-effectiveness). The only ethical issue is the necessity of an additional procedure that might be required in a small proportion of patients who are found to be suitable for the trial after their primary operation is already performed, and who would otherwise not need a second operation. These patients would be at much higher risk of local recurrence even after routine radiotherapy (about 15-20%) and thus could potentially derive significant benefit from Targit-boost. The consenting physician/surgeon will carry out careful discussions about the risk of a second operation (which may not be significant in these patients who would usually be young and fit) vs. the possibility of a superior result and decision to enrol will be taken on an individual patient basis. We expect that these will constitute about less than 10% of cases. The team applying for the grant has pioneered the new approach, developed the technology and successfully administered multi-centre trials for over 20 years. The planned steering committee would bring together expertise in surgical oncology, radiation oncology, innovation, medical physics, patient advocacy and trial administration. This proposal to fund the work at this co-ordinating centre as the participating centres are self-financing and the equipment is already in place. Our team has also recently successfully analysed, presented and fast-tracked and published on-line, in the Lancet, the TARGIT-A study in low-risk women over the age of 45 years. In this trial our results show that giving a single dose of radiation with the TARGIT technique at the time of operation gives similar results as the usual several weeks' course of radiotherapy. We now wish to test whether in high risk women, TARGIT given accurately and immediately after surgery, as a boost to the tumour bed can improve the local control of breast cancer. Our vision is to tailor radiation treatment (risk-adjusted radiotherapy, rather than one-size-fits-all) for every women undergoing a lumpectomy for cancer so that it is focussed and minimised for low risk women and enhanced for high risk women so that the outcomes are ultimately better.

Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS