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

The INTRABEAM® Photon Radiotherapy System for the adjuvant treatment of early breast cancer: a systematic review and economic evaluation

Background: initial treatment for early breast cancer is usually either breast-conserving surgery (BCS) or mastectomy. After BCS, whole-breast external beam radiotherapy (WB-EBRT) is the standard of care. A potential alternative to post-operative WB-EBRT is intraoperative radiation therapy delivered by the INTRABEAM® Photon Radiotherapy System (Carl Zeiss, Oberkochen, Germany) to the tissue adjacent to the resection cavity at the time of surgery.Objective: to assess the clinical effectiveness and cost-effectiveness of INTRABEAM for the adjuvant treatment of early breast cancer during surgical removal of the tumour.Data sources: electronic bibliographic databases, including MEDLINE, EMBASE and The Cochrane Library, were searched from inception to March 2014 for English-language articles. Bibliographies of articles, systematic reviews, clinical guidelines and the manufacturer’s submission were also searched. The advisory group was contacted to identify additional evidence.Methods: systematic reviews of clinical effectiveness, health-related quality of life and cost-effectiveness were conducted. Two reviewers independently screened titles and abstracts for eligibility. Inclusion criteria were applied to full texts of retrieved papers by one reviewer and checked by a second reviewer. Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer, and differences in opinion were resolved through discussion at each stage. Clinical effectiveness studies were included if they were carried out in patients with early operable breast cancer. The intervention was the INTRABEAM system, which was compared with WB-EBRT, and study designs were randomised controlled trials (RCTs). Controlled clinical trials could be considered if data from available RCTs were incomplete (e.g. absence of data on outcomes of interest). A cost–utility decision-analytic model was developed to estimate the costs, benefits and cost-effectiveness of INTRABEAM compared with WB-EBRT for early operable breast cancer.Results: one non-inferiority RCT, TARGeted Intraoperative radioTherapy Alone (TARGIT-A), met the inclusion criteria for the review. The review found that local recurrence was slightly higher following INTRABEAM than WB-EBRT, but the difference did not exceed the 2.5% non-inferiority margin providing INTRABEAM was given at the same time as BCS. Overall survival was similar with both treatments. Statistically significant differences in complications were found for the occurrence of wound seroma requiring more than three aspirations (more frequent in the INTRABEAM group) and for a Radiation Therapy Oncology Group toxicity score of grade 3 or 4 (less frequent in the INTRABEAM group). Cost-effectiveness base-case analysis indicates that INTRABEAM is less expensive but also less effective than WB-EBRT because it is associated with lower total costs but fewer total quality-adjusted life-years gained. However, sensitivity analyses identified four model parameters that can cause a switch in the treatment option that is considered cost-effective.Limitations: the base-case result from the model is subject to uncertainty because the disease progression parameters are largely drawn from the single available RCT. The RCT median follow-up of 2 years 5 months may be inadequate, particularly as the number of participants with local recurrence is low. The model is particularly sensitive to this parameter.Conclusions and implications: a significant investment in INTRABEAM equipment and staff training (clinical and non-clinical) would be required to make this technology available across the NHS. Longer-term follow-up data from the TARGIT-A trial and analysis of registry data are required as results are currently based on a small number of events and economic modelling results are uncertai