TARGIT-Boost is an international randomised clinical trial designed to test the hypothesis that the tumour bed boost delivered as a single dose of targeted intraoperative radiotherapy (TARGIT-B) is superior to the conventional course of external beam radiotherapy boost (EBRT-Boost), especially in women with high risk of local recurrence. It is a pragmatic trial in which each participating centre can use the local predefined inclusion/exclusion criteria for entry into the trial. Only centres with access to the Intrabeam® (Carl Zeiss) are eligible to enter patients into the trial.

Eligible patients are those with a higher risk of local recurrence after breast conserving surgery.

After giving consent patients are randomised to either TARGIT Boost or EBRT Boost. All patients will receive whole breast EBRT. They may receive any other adjuvant treatments as deemed necessary. The protocol recommends that patients be followed at six monthly intervals for three years and then annually.

The primary endpoint is ipsilateral breast recurrence rate. Secondary endpoints are relapse-free survival, site of recurrence, overall survival (breast-cancer specific and non-breast cancer deaths) patient satisfaction and quality of life.

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. For use in the breast, the technique was first developed and piloted at University College London. 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. The phase II study of 300 patients was published and recently updated with long term data along with favourable toxicity and cosmetic outcome results of individual cohorts. A mathematical model of TARGIT developed recently (funded by Cancer Research UK) suggests that it could be superior to conventional radiotherapy. Translational research has found that TARGIT impairs the surgical-trauma-stimulated proliferation and invasiveness of breast cancer cells. This effect of radiotherapy may act synergistically with its tumouricidal effect yielding a superior result. 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. The cost and cost-effectiveness of TARGIT versus EBRT, both as boost, will be calculated from a NHS and personal social services (PSS) perspective. Costs directly incurred by patients will also be assesed, since EBRT as a boost is likely to impose additional time and travel expense to patients and families.

Inclusion Criteria:

At least one of these criteria must be satisfied:

1. Less than 46 years of age

2. More than 45 years of age, but with one of the following poor prognostic factors:

   1. lymphovascular invasion
   2. gross nodal involvement (not micrometastasis)
   3. more than one tumour in the breast but still suitable for breast conserving surgery through a single specimen

3. More than 45 years of age, but with at least two of the following poor prognostic factors

   1. ER and/or PgR negative
   2. Grade 3 histology
   3. Positive margins at first excision

4. Those patients with large tumours which have responded to neo-adjuvant chemo- or hormone therapy in an attempt to shrink the tumour and are suitable for breast conserving surgery as a result.

5. Lobular carcinoma or Extensive Intraductal Component (EIC)

6. A list (one to many) of high risk factors are present (as predefined in the policy document) that give a high risk of local recurrence.

7. Patients with either HER2 positive or HER2 negative can be included.

Exclusion Criteria:

1. Bilateral breast cancer at the time of diagnosis.
2. Patients with any severe concomitant disease that may limit their life expectancy
3. Previous history of malignant disease does not preclude entry if the expectation of relapse-free survival at 10 years is 90% or greater (e.g., non-melanoma skin cancer, CIN, etc).
4. No more than 30 days can have elapsed between last breast cancer surgery (not axillary) and randomisation for patients in the post-pathology stratification unless part of a specific clinical trial that addresses the question of timing or tumour bed can be reliably identified, e.g., by ultrasound.