Title: An international randomised controlled trial to compare targeted intra-operative radiotherapy (TARGIT) with conventional post-operative radiotherapy after conservative breast surgery for women with early stage breast cancer (The TARGIT-A trial)
Funder: Department of Health (England)

Abstract: Intrabeam® (originally developed in collaboration with the Photoelectron Corporation USA and now manufactured by Carl Zeiss Germany) is a miniature electron beam-driven X-ray 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 depending on the size of the tumour bed 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 TARGIT technique was first developed 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 allowing the device to be used in standard operating theatres. 20 Gy is delivered to the surface of the tumour bed in about 20 minutes after which the radiation is switched off the applicator removed and the wound closed in the normal way. The simplicity of this technique has several advantages over conventional external beam radiotherapy interstitial implantation of radioactive wires or conformal external beam radiotherapy - all the radiotherapy is delivered at the time of surgery and hence the patient does not need to return for up to 6 weeks of treatment. If this technique can be shown to produce local control at least as good as conventional external beam radiotherapy then the patient is spared the usual 4-6 weeks of post operative radiotherapy and radiotherapy resources are released for other patients.The first twenty-five cases were treated in a pilot study at UCL using TARGIT technique as a replacement for the boost dose of radiotherapy; full dose external beam treatment was subsequently given. A further series of 300 unselected patients where TARGIT was used as the boost has shown a very low 5-year actuarial recurrence rate of 1.52% along with favourable toxicity and cosmetic outcome results of individual cohorts. Specifically there have been no problems with normal wound healing or fibrosis even with the addition of external beam radiotherapy. A mathematical model of TARGIT developed recently 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. Since the launch of the TARGIT Trial other trials have been launched aimed at testing similar concepts. Trials testing index quadrant irradiation: ELIOT in Italy with a similar but more expensive technique NSABP trial in USA testing mainly IMRT or the balloon (Mammosite) technique the IMPORT- low trial in the UK using external beam radiotherapy. However the TARGIT technique remains unique in its biological technical and economical advantages. The randomised controlled TARGIT trial is a pragmatic trial that compares two treatment policies in patients with early breast cancer who have undergone local excision of a good prognosis tumour. The conventional policy is that each patient receives a radical course of external beam radiotherapy (EBRT with or without a boost) according to local treatment guidelines. The experimental policy is to give targeted intra-operative radiotherapy (IORT) in a single dose recognising that some (~10%) patients randomised to this treatment because of unfavourable features found subsequently in the pathological examination of the excised lesion will need to have external beam therapy in addition (without the boost which has been provided by the targeted dose). A nested study allows randomisation of patients to IORT or EBRT after the pathological examination of the removed lesion. Patients in this randomisation stratum who are allocated IORT will require a second surgical procedure for administration of the radiation. Individual trial centres may opt to use either or both of these strata for entry. The main objective of the trial regardless of the stratum followed is to compare local tumour control between the two policies.


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