Douglas Brown

Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial

BACKGROUND The TARGIT-A trial compared risk-adapted radiotherapy using single-dose targeted intraoperative radiotherapy (TARGIT) versus fractionated external beam radiotherapy (EBRT) for breast cancer. We report 5-year results for local recurrence and the first analysis of overall survival. METHODS TARGIT-A was a randomised, non-inferiority trial. Women aged 45 years and older with invasive ductal carcinoma were enrolled and randomly assigned in a 1:1 ratio to receive TARGIT or whole-breast EBRT, with blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy: randomisation occurred either before lumpectomy (prepathology stratum, TARGIT concurrent with lumpectomy) or after lumpectomy (postpathology stratum, TARGIT given subsequently by reopening the wound). Patients in the TARGIT group received supplemental EBRT (excluding a boost) if unforeseen adverse features were detected on final pathology, thus radiotherapy was risk-adapted. The primary outcome was absolute difference in local recurrence in the conserved breast, with a prespecified non-inferiority margin of 2·5% at 5 years; prespecified analyses included outcomes as per timing of randomisation in relation to lumpectomy. Secondary outcomes included complications and mortality. This study is registered with ClinicalTrials.gov, number NCT00983684. FINDINGS Patients were enrolled at 33 centres in 11 countries, between March 24, 2000, and June 25, 2012. 1721 patients were randomised to TARGIT and 1730 to EBRT. Supplemental EBRT after TARGIT was necessary in 15·2% [239 of 1571] of patients who received TARGIT (21·6% prepathology, 3·6% postpathology). 3451 patients had a median follow-up of 2 years and 5 months (IQR 12-52 months), 2020 of 4 years, and 1222 of 5 years. The 5-year risk for local recurrence in the conserved breast was 3·3% (95% CI 2·1-5·1) for TARGIT versus 1·3% (0·7-2·5) for EBRT (p=0·042). TARGIT concurrently with lumpectomy (prepathology, n=2298) had much the same results as EBRT: 2·1% (1·1-4·2) versus 1·1% (0·5-2·5; p=0·31). With delayed TARGIT (postpathology, n=1153) the between-group difference was larger than 2·5% (TARGIT 5·4% [3·0-9·7] vs EBRT 1·7% [0·6-4·9]; p=0·069). Overall, breast cancer mortality was much the same between groups (2·6% [1·5-4·3] for TARGIT vs 1·9% [1·1-3·2] for EBRT; p=0·56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1·4% [0·8-2·5] vs 3·5% [2·3-5·2]; p=0·0086), attributable to fewer deaths from cardiovascular causes and other cancers. Overall mortality was 3·9% (2·7-5·8) for TARGIT versus 5·3% (3·9-7·3) for EBRT (p=0·099). Wound-related complications were much the same between groups but grade 3 or 4 skin complications were significantly reduced with TARGIT (four of 1720 vs 13 of 1731, p=0·029). INTERPRETATION TARGIT concurrent with lumpectomy within a risk-adapted approach should be considered as an option for eligible patients with breast cancer carefully selected as per the TARGIT-A trial protocol, as an alternative to postoperative EBRT. FUNDING University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research.

Abstract S4-2: Targeted intraoperative radiotherapy for early breast cancer: TARGIT-A trial- updated analysis of local recurrence and first analysis of survival

Background TARGIT-A, an international phase 3 randomised trial (Lancet 2010;376:91–102) compared outcomes in patients undergoing breast conserving surgery followed by either whole breast external beam radiotherapy (EBRT) over several weeks, or a risk-adaptive approach using single dose targeted intra-operative radiotherapy (TARGIT). Risk-adaptive approach meant that if the final pathology report demonstrated unpredicted pre-specified adverse features, then EBRT was to be added to TARGIT. Method 3451 women aged 45 years or older with invasive ductal carcinoma were enrolled from 33 centres in 10 countries between 2000 and 2012. Randomisation to TARGIT or EBRT arm was done either before lumpectomy (pre-pathology) or after lumpectomy (postpathology). If allocated to TARGIT, patients in the pre-pathology group received it immediately after surgical excision under the same anaesthesia; patients in the post-pathology group received it as a subsequent procedure. We pre-specified that analysis would be performed overall as the primary analysis and for these groups separately as a secondary analysis. The primary outcome was ipsilateral within breast recurrence (IBR) with an absolute non-inferiority margin of 2.5% at 5 years and secondary outcome was survival. We performed exploratory analyses for loco-regional recurrence, ‘all recurrence’ (ipsilateral or contralateral breast, axilla or distant), distant recurrence, and causes of death. Results 1721 patients were randomly allocated to receive TARGIT and 1730 to EBRT. 1010 patients have a minimum 4 years follow up and 611 patients have minimum 5 years follow up. Primary events have increased from 13 to 34 since 2010. For the primary outcome of ipsilateral breast recurrence, the absolute difference at 5-years was 2.0%, which was higher with TARGIT and reached the conventional levels of statistical significance (p = 0.042), but was within the pre-specified non-inferiority margin; in prepathology the absolute difference in 5-year IBR was 1%; in postpathology it was 3.7%. For the secondary outcome, there was a non-significant trend for improved overall survival with TARGIT (HR = 0.70(0.46–1.07)) due to fewer non-breast cancer deaths (17 vs. 35, HR 0.47 (0.26–0.84)). Cardiovascular deaths were 1 vs. 10 and deaths from cancers other than breast were 7 vs.16. Conclusion The risk-adapted approach using single dose TARGIT has a slightly higher local recurrence rate than EBRT for the primary endpoint of IBR, but was within the preset non-inferiority boundary, with the prepathology apparently performing better than the postpathology stratum. In addition there was a trend for improved overall survival in the TARGIT arm due to fewer non-breast cancer deaths. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S4-2.

Abstract P1-01-27: SentiMAG multicentre trial*: Comparison of sentinel node biopsy identification rates using a magnetic tracer vs. standard technique. * UKCRN ID 12178 (UK); NTR 3283 (Netherlands)

Background: The SentiMAG Multicentre Trial, an international phase II paired equivalence trial, evaluated a new magnetic technique for sentinel node biopsy (SLNB) against the standard (radioisotope and patent blue dye; or radioisotope alone). The magnetic technique does not utilize radiation and provides both a colour change (brown dye) and a hand-held probe for node localization. The primary end-point of this trial was defined as the proportion of sentinel nodes detected with each technique (identification rate) and was found to be non-inferior with the magnetic when compared to the standard technique, in the primary analysis on 160 patients (95% vs 94%, 0.62% difference; 95% upper confidence limit 4.4%). The trial was extended to 350 patients in order to evaluate identification rates further with each technique and at each trial site. Methods: Women with breast cancer scheduled for SLNB, who were clinically and radiologically node negative, were recruited from 7 centres in the UK and the Netherlands. Sentinel node biopsy was undertaken after administration of both the magnetic and standard tracers (radioisotope +/- blue dye). To determine local identification rate with both techniques, a minimum of 30 cases were recruited at each site. Results: A total of 364 patients were recruited and 17 were excluded due to a breech of protocol (e.g: no radioisotope or magnetic dye given). SLNB procedures were undertaken on 347 patients. The overall identification rate was 96.3% (334/347) with the standard technique and 91.9% (319/347) with the magnetic technique (4.3% difference; 95% upper confidence limit 7.2%; 9.5% discordance). The identification rate was 93.4% (324/347) with the radioisotope alone (compared with magnetic technique 1.4% difference; 95% upper confidence limit 4.5%; 11.2% discordance). Identification rates with the standard technique at each site, ranged between 87% - 100% and with the magnetic technique between 84% - 100%. Of the 21% (72/347) of patients with lymph node involvement, 15% (51/347) had at least 1 macrometastasis and 6% (21/347), a micrometastasis only. Another 2% (8/347) had isolated tumour cells. Of 825 lymph nodes removed, 625 (76%) were true sentinel nodes identified with the standard technique. The lymph node retrieval rate was 2.38 nodes per patient overall, 1.80 nodes per patient with the standard technique and 1.83 nodes per patient with the magnetic technique. Conclusion: The magnetic technique is a feasible technique for SLNB, with an identification rate non-inferior to the radioisotope technique but inferior to the standard technique, within the non-inferiority margins setout for this trial. Variation exists in sentinel node identification rates between sites with both techniques. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-01-27.