Title: Extended follow up of the TARGIT-A trial
Funder: Department of Health and Social Care

Abstract: Breast cancer remains the commonest female malignancy. Today, majority of patients can avoid a mastectomy and be treated with surgical excision of the tumour, surgery to the axillary lymph nodes followed by external beam radiotherapy given over several weeks of daily treatments. Increased public awareness and the widespread screening means that most patients present with small tumours. While the conventional whole breast radiotherapy remains an effective treatment, our own laboratory work and its clinical correlation[1, 2] has suggested that radiation to the whole breast may not be necessary in all cases, and radiotherapy to the tissue only around the tumour within a more individualised risk-adapted approach may be as effective. The rationale is that microscopic tumour foci are found away from the tumour site but their growth does not appear to be affected by giving or omitting whole breast radiotherapy and most early in-breast recurrences occur at the site of the original tumour site. Thus it makes sense to focus radiation to the tumour bed. With this academic insight, the TARGIT (TARGeted Intraoperative radioTherapy) technique using INTRABEAM™ was developed by us in collaboration with the manufacturers Carl Zeiss Surgical, Oberkochen, Germany. TARGIT allows the patient to receive a single dose of radiotherapy as soon as the primary tumour is excised, during the same anaesthetic[1-4]. Its advantages include: delivering the radiation immediately, accurately aimed at the tumour bed under direct vision, thus avoiding a “geographical miss”; sparing of vital organs (particularly the heart); decreased costs to the healthcare providers . The device can be used in an unmodified operating theatre. The first results[5,6] of the TARGIT-A trial which compared a risk-adapted approach using TARGIT vs. conventional radiotherapy given over several weeks found that TARGIT given at the time of lumpectomy within a risk-adapted approach achieves much the same results in terms of breast cancer control (locally and systemically). Furthermore, patients in the TARGIT arm had a significantly lower mortality from causes other than breast cancer due to fewer deaths from cardiovascular causes and other cancers. Several small studies have shown its encouraging results in terms of its use in special circumstances[7, 8], quality of life[9], cosmetic outcome[10, 11], health economics[12, 13] and patient preference[14-16]. Although these results are convincing enough for the treatment to be adopted world over (over 20,000 women have now had this treatment in over 300 centres in over 35 countries), it is essential that all the 3451 patients are followed up over a longer period of time and data analysed as per the protocol. As the last patient was randomised in 2012 the proposed extension will enable the collection of at least five years of follow-up on all patients. As per the latest published update there were 34 local recurrences and 88 deaths. A larger number of events would undoubtedly accumulate over the next 5 years and would allow for a more detailed analysis of the outcomes. Although it is unlikely that overall non-inferiority in terms of local recurrence will change, new data will help ascertain the reduction in non-breast-cancer mortality and enable meaningful subgroup analyses for fine tuning of patient selection criteria. We expect these new data will significantly influence wider and enthusiastic adoption of this approach that will be greatly welcomed by patients.

Lay abstract: Breast cancer remains the commonest female malignancy. Today, majority of patients can avoid removal of the whole breast and can instead have removal of just the cancerous lump, checking the glands under the arm. This is normally followed by radiation (x-ray) treatment given over several weeks of daily treatments in the radiotherapy centre at the hospital. Increased public awareness and the NHS national screening programme means that now patients find their cancers at an early stage. While the usual long course of radiotherapy to the whole breast after lumpectomy remains an effective treatment, our own laboratory work[1, 2] and clinical trial data have suggested that radiation to the whole breast may not be necessary in all cases, particularly when the cancer is small and of a ‘good’ type. This is because if the cancer comes back in the breast, it most commonly comes back around the site of the original cancer. Therefore, it was hypothesised that radiation focussed to the tissue only around the tumour may be as effective. With this academic insight, the TARGIT (TARGeted Intraoperative radioTherapy) technique using INTRABEAM™ was developed by us in collaboration with the manufacturers. TARGIT treatment allows the patient to have her radiotherapy as soon as the the cancerous lump is removed, during the same anaesthetic[1-4]. The radiation treatment is completed at the same time as the lumpectomy to remove the cancer and the radiation is delivered precisely where required. Vital organs (particularly the heart) are spared and the device can be used in a standard operating theatre. Finally, it is also be less expensive to the tax-payer. A large clinical trial - the TARGIT-A trial – in which 3451 patients from 33 centres in 11 countries participated, compared the TARGIT treatment given during the operation (i.e., just one treatment) with conventional radiotherapy (15 to 30 doses given every day for 3-6 weeks). The results published in a high-profile journal showed that compared with conventional external beam radiotherapy given over several weeks, TARGIT given at the time of lumpectomy within a risk-adapted individualised approach achieves much the same results in terms of breast cancer control. Furthermore, there were significantly fewer deaths from causes other than breast cancer because of fewer heart attacks and other cancer deaths. Several smaller studies have shown its encouraging results for its use in special circumstances, quality of life, cosmetic outcome, health economics, and patient preference. Although the results until now are convincing enough for the treatment to be adopted by many (over 20,000 women have now had this treatment in over 300 centres in 35 countries), further follow-up appears necessary for wider adoption of this technique. The proposed extension to the TARGIT A Trial will enable an analysis after all patients have completed five years of follow-up. Fortunately until now there were only a few patients in the trial who had a local recurrence (34 out of 3451); longer follow up will mean larger number of recurrences that would allow for a more detailed analysis which would improve how we can select patients for whom this treatment is best suited. Even more importantly it would enable us to confirm (or not) the reduction in non-breast-cancer mortality with this approach. These new results would stimulate wider adoption of this approach that will be greatly welcomed by patients.

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