Intended for healthcare professionals

  1. Research
  2. Long term survival and...
  3. Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial
CCBY Open access
Research

Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial

BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m2836 (Published 19 August 2020) Cite this as: BMJ 2020;370:m2836

Linked Opinion

Targeted intraoperative radiotherapy for early breast cancer—new evidence challenges traditional treatment
  1. Jayant S Vaidya, professor of surgery and oncology1,
  2. Max Bulsara, professor of biostatistics2,
  3. Michael Baum, professor emeritus of surgery1,
  4. Frederik Wenz, professor of radiation oncology3,
  5. Samuele Massarut, director4,
  6. Steffi Pigorsch, consultant radiation oncologist5,
  7. Michael Alvarado, professor of surgery6,
  8. Michael Douek, professor of surgical sciences and breast cancer7,
  9. Christobel Saunders, professor of surgical oncology8,
  10. Henrik L Flyger, head9,
  11. Wolfgang Eiermann, professor of gynaecological oncology and surgery5,
  12. Chris Brew-Graves, director of operations1,
  13. Norman R Williams, deputy director1,
  14. Ingrid Potyka, senior clinical operations manager1,
  15. Nicholas Roberts, trial coordinator1,
  16. Marcelle Bernstein, patient advocate10,
  17. Douglas Brown, consultant breast surgeon11,
  18. Elena Sperk, associate professor of radiation oncology3,
  19. Siobhan Laws, consultant oncoplastic surgeon12,
  20. Marc Sütterlin, professor of surgery and gynaecology13,
  21. Tammy Corica, clinical research coordinator14,
  22. Steinar Lundgren, professor15 16,
  23. Dennis Holmes, consultant breast surgeon17,
  24. Lorenzo Vinante, consultant radiation oncologist18,
  25. Fernando Bozza, consultant surgeon19,
  26. Montserrat Pazos, consultant radiation oncologist20,
  27. Magali Le Blanc-Onfroy, consultant radiation oncologist21,
  28. Günther Gruber, consultant radiation oncologist22,
  29. Wojciech Polkowski, professor of surgery23,
  30. Konstantin J Dedes, consultant breast surgeon24,
  31. Marcus Niewald, professor of radiation oncology25,
  32. Jens Blohmer, professor of surgery and gynaecology26,
  33. David McCready, consultant surgeon27,
  34. Richard Hoefer, consultant surgeon28,
  35. Pond Kelemen, clinical associate professor of surgery29,
  36. Gloria Petralia, consultant surgeon30,
  37. Mary Falzon, consultant pathologist31,
  38. David J Joseph, professor of radiation oncology14,
  39. Jeffrey S Tobias, professor of radiation oncology
  1. 1Division of Surgery and Interventional Science, University College London, 43-45 Foley Street, London W1W 7JN, UK
  2. 2Department of Biostatistics, University of Notre Dame, Fremantle, WA, Australia
  3. 3Department of Radiation Oncology, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
  4. 4Department of Surgery, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
  5. 5Department of Gynaecology and Obstetrics, Red Cross Hospital, Technical University of Munich, Munich, Germany
  6. 6Department of Surgery, University of California, San Francisco, CA, USA
  7. 7Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
  8. 8School of Surgery, University of Western Australia, Crawley, WA, Australia
  9. 9Department of Breast Surgery, University of Copenhagen, Copenhagen, Denmark
  10. 10London, UK
  11. 11Department of Surgery, Ninewells Hospital, Dundee, UK
  12. 12Department of Surgery, Royal Hampshire County Hospital, Winchester, UK
  13. 13Department of Gynaecology and Obstetrics, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
  14. 14Department of Radiation Oncology, Sir Charles Gairdner Hospital, Perth, WA, Australia
  15. 15Department of Oncology, St Olav’s University Hospital, Trondheim, Norway
  16. 16Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
  17. 17University of Southern California, John Wayne Cancer Institute & Helen Rey Breast Cancer Foundation, Los Angeles, CA, USA
  18. 18Department of Radiation Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
  19. 19Instituto Oncologico Veneto, Padoa, Italy
  20. 20Department of Radiation Oncology, University Hospital, The Ludwig Maximilian University of Munich, Munich, Germany
  21. 21Radiotherapy-Oncology, Western Cancer Institute, Nantes, France
  22. 22Breast Centre Seefeld, Zurich, Switzerland
  23. 23Department of Surgical Oncology, Medical University of Lublin, Lublin, Poland
  24. 24Breast Centre, University Hospital Zurich, Zurich, Switzerland
  25. 25Saarland University Medical Center, Homberg, Germany
  26. 26Sankt Gertrauden Hospital, Charité, Medical University of Berlin, Berlin, Germany
  27. 27Princess Margaret Cancer Centre, Toronto, Ontario, Canada
  28. 28Sentara Surgery Specialists, Hampton, VA, USA
  29. 29Ashikari Breast Center, New York Medical College, New York, NY, USA
  30. 30Department of Surgery, University College London Hospitals, London, UK
  31. 31Department of Pathology, University College London Hospitals, London, UK
  32. 31Department of Clinical Oncology, University College London Hospitals, London, UK
  1. Correspondence to: J S Vaidya jayantvaidya{at}gmail.com (or @jsvaidya on Twitter)
  • Accepted 17 June 2020

Abstract

Objective To determine whether risk adapted intraoperative radiotherapy, delivered as a single dose during lumpectomy, can effectively replace postoperative whole breast external beam radiotherapy for early breast cancer.

Design Prospective, open label, randomised controlled clinical trial.

Setting 32 centres in 10 countries in the United Kingdom, Europe, Australia, the United States, and Canada.

Participants 2298 women aged 45 years and older with invasive ductal carcinoma up to 3.5 cm in size, cN0-N1, eligible for breast conservation and randomised before lumpectomy (1:1 ratio, blocks stratified by centre) to either risk adapted targeted intraoperative radiotherapy (TARGIT-IORT) or external beam radiotherapy (EBRT).

Interventions Random allocation was to the EBRT arm, which consisted of a standard daily fractionated course (three to six weeks) of whole breast radiotherapy, or the TARGIT-IORT arm. TARGIT-IORT was given immediately after lumpectomy under the same anaesthetic and was the only radiotherapy for most patients (around 80%). TARGIT-IORT was supplemented by EBRT when postoperative histopathology found unsuspected higher risk factors (around 20% of patients).

Main outcome measures Non-inferiority with a margin of 2.5% for the absolute difference between the five year local recurrence rates of the two arms, and long term survival outcomes.

Results Between 24 March 2000 and 25 June 2012, 1140 patients were randomised to TARGIT-IORT and 1158 to EBRT. TARGIT-IORT was non-inferior to EBRT: the local recurrence risk at five year complete follow-up was 2.11% for TARGIT-IORT compared with 0.95% for EBRT (difference 1.16%, 90% confidence interval 0.32 to 1.99). In the first five years, 13 additional local recurrences were reported (24/1140 v 11/1158) but 14 fewer deaths (42/1140 v 56/1158) for TARGIT-IORT compared with EBRT. With long term follow-up (median 8.6 years, maximum 18.90 years, interquartile range 7.0-10.6) no statistically significant difference was found for local recurrence-free survival (hazard ratio 1.13, 95% confidence interval 0.91 to 1.41, P=0.28), mastectomy-free survival (0.96, 0.78 to 1.19, P=0.74), distant disease-free survival (0.88, 0.69 to 1.12, P=0.30), overall survival (0.82, 0.63 to 1.05, P=0.13), and breast cancer mortality (1.12, 0.78 to 1.60, P=0.54). Mortality from other causes was significantly lower (0.59, 0.40 to 0.86, P=0.005).

Conclusion For patients with early breast cancer who met our trial selection criteria, risk adapted immediate single dose TARGIT-IORT during lumpectomy was an effective alternative to EBRT, with comparable long term efficacy for cancer control and lower non-breast cancer mortality. TARGIT-IORT should be discussed with eligible patients when breast conserving surgery is planned.

Trial registration ISRCTN34086741, NCT00983684.

Footnotes

  • Contributors: JSV, MBa, and JST were responsible for trial concept, trial design, trial management, data interpretation, and writing of the manuscript. FW, DJJ, JST, MBa, and JSV contributed to trial concept, trial design, trial management, training and accreditation of centres, patient accrual and treatment, data collection, data interpretation, and writing of the manuscript. JSV, FW, JST, MBa, SM, HLF, MD, ES, MS, and MA contributed to training and accreditation of centres, patient accrual and treatment, data collection, and writing of the manuscript. JSV, MBa, MBu, and NRW designed the statistical analysis plan and contributed to statistical analysis, trial coordination, data collection, data interpretation, and writing of the manuscript. CS and TC contributed to trial design, patient accrual, patient treatment, data interpretation, and writing of the manuscript. WE, MD, LV, FB, MP, GG, WP, KJD, MN, JB, GP, and MS contributed to patient accrual, patient treatment, data collection, and data interpretation. SM, WE, SP, JSV, ES, MS, MLB, DH, SLa, SLu, DM, RH, PK, and DB contributed to setting up their centres, patient accrual, treatment, and data collection. JSV was involved with design and preclinical tests of the Intrabeam system. CB-G, NR, and IP contributed to training, trial coordination, trial management, data collection, and writing of the manuscript. MF advised about pathological aspects of the trial. MBe reviewed the results and their interpretation, provided patient perspective and contributed to the manuscript. The authors take full responsibility for the manuscript. The initial draft was written by JSV, MBu, JST, and MBa, who revised it by following comments from all other authors and are the guarantors. The chief investigator/corresponding author and the trial statistician had access to all data sent by the trial centre for analysis; all authors were responsible for decision to submit the manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: The trial was initiated by an academic insight and collaboration with the industry was solely for the development of the device. The manufacturers of the Intrabeam device (Carl Zeiss) did not have any part in concept, design, or management of the trial, or in data analysis, data interpretation, or writing of the report. The study was sponsored by University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre. Funding was provided by UCLH Charities, National Institute for Health Research (NIHR) Health Technology Assessment programme (HTA 07/60/49), Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research (BMBF) FKZ 01ZP0508. The infrastructure of the trial operations office in London, UK was supported by core funding from Cancer Research Campaign (now Cancer Research UK) when the trial was initiated. The funding organisations had no role in concept, design, analysis or writing of the manuscript.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme, Ninewells Cancer Campaign, National Health and Medical Research Council, German Federal Ministry of Education and Research (BMBF), and Cancer Research Campaign (now Cancer Research UK) for the submitted work; JSV has received a research grant from Photoelectron Corp (1996-99) and from Carl Zeiss for supporting data management at the University of Dundee (Dundee, UK, 2004-2008), and has received honorariums. JSV, JST, NRW, IP, CBG, and NR receive funding from HTA, NIHR, Department of Health and Social Care for some activities related to the TARGIT trials. MBa was briefly on the scientific advisory board of Carl Zeiss and was paid consultancy fees before 2010. FW has received a research grant from Carl Zeiss for supporting radiobiological research. Carl Zeiss sponsors some of the travel and accommodation for meetings of the international steering committee and data monitoring committee and when necessary for conferences where a presentation about targeted intraoperative radiotherapy is being made for all authors apart from WE who declares that he has no conflicts of interest. All other authors declare that they have no conflicts of interest.

  • Ethical approval: The study received ethics approval from the joint University College London and University College London Hospital committees of ethics of human research (99/0307).

  • Data sharing: University College London is supportive of data sharing and will endeavour to assist in requests for data sharing. All requests for data sharing will adhere to the UCL Surgical and Interventional Trials Unit (SITU) data sharing agreement policy. These data will be held at UCL on secure servers and cannot be released to any third parties. All requests for access to the data and statistical code will be formally requested through the use of a SITU data request form which will state the purpose, analysis and publication plans together with the named collaborators. All requests are dealt with on a case-by-case basis. All requests will be logged and those successful will have a data transfer agreement which will specify appropriate security and privacy agreements, and acknowledgment of the TARGIT Trialists’ Group, investigators, the sponsor, and funders.

  • The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

  • Dissemination to participants and related patient and public communities: We plan to widely disseminate the published paper. We shall use all modern media and engage patients and our own institutional public relations departments.

http://creativecommons.org/licenses/by/4.0/

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.

View Full Text
Back to top