Jayant S Vaidya1, Frederik Wenz2, Max Bulsara3, Jeffrey S Tobias4, David J Joseph5, Mohammed Keshtgar6, Henrik L Flyger7, Samuele Massarut8, Michael Alvarado9, Christobel Saunders10, Wolfgang Eiermann11, Marinos Metaxas12, Elena Sperk2, Marc Sütterlin13, Douglas Brown14, Laura Esserman9, Mario Roncadin15, Alastair Thompson14, John A Dewar16, Helle M R Holtveg7, Steffi Pigorsch17, Mary Falzon18, Eleanor Harris19, April Matthews20, Chris Brew-Graves12, Ingrid Potyka12, Tammy Corica5, Norman R Williams12, Michael Baum12. 1. Clinical Trials Group, Division of Surgery and Interventional Science, University College London, London, UK; Department of Surgery, Royal Free Hospital, London, UK; Department of Surgery, Whittington Hopsital, London, UK. Electronic address: jayant.vaidya@ucl.ac.uk. 2. Department of Radiation Oncology, University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany. 3. Department of Biostatistics, University of Notre Dame, Fremantle, WA, Australia. 4. Department of Clinical Oncology, University College London Hospitals, London, UK. 5. Department of Radiation Oncology, Sir Charles Gairdner Hospital, Perth, WA, Australia. 6. Department of Surgery, Royal Free Hospital, London, UK; Department of Surgery, Whittington Hopsital, London, UK. 7. Department of Breast Surgery, University of Copenhagen, Copenhagen, Denmark. 8. Department of Surgery, Centro di Riferimento Oncologia, Aviano, Italy. 9. Department of Surgery, University of California, San Francisco, CA, USA. 10. Department of Surgery, Sir Charles Gairdner Hospital, Perth, WA, Australia; School of Surgery, University of Western Australia, Perth, WA, Australia. 11. Department of Gynecology and Obstetrics, Red Cross Hospital, Munich, Germany. 12. Clinical Trials Group, Division of Surgery and Interventional Science, University College London, London, UK. 13. Department of Gynecology and Obstetrics, University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany. 14. Department of Surgery, Ninewells Hospital, Dundee, UK. 15. Department of Radiation Oncology, Centro di Riferimento Oncologia, Aviano, Italy. 16. Department of Radiation Oncology, Ninewells Hospital, Dundee, UK. 17. Department of Radiation Oncology, Technical University of Munich, Munich, Germany. 18. Department of Pathology, University College London Hospitals, London, UK. 19. Department of Radiation Oncology, East Carolina University Brody School of Medicine, Greenville, NC, USA. 20. Psychosocial Oncology Clinical Studies Group, National Cancer Research Institute, London, UK; Independent Cancer Patients' Voice, London, UK.
Abstract
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.
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.
Authors: Laura S Dominici; Monica Morrow; Elizabeth Mittendorf; Jennifer Bellon; Tari A King Journal: Curr Probl Surg Date: 2016-11-29 Impact factor: 1.909