Randomized Controlled Trial

. 2020 Aug 19:370:m2836.

doi: 10.1136/bmj.m2836.

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

Jayant S Vaidya¹, Max Bulsara², Michael Baum³, Frederik Wenz⁴, Samuele Massarut⁵, Steffi Pigorsch⁶, Michael Alvarado⁷, Michael Douek⁸, Christobel Saunders⁹, Henrik L Flyger¹⁰, Wolfgang Eiermann⁶, Chris Brew-Graves³, Norman R Williams³, Ingrid Potyka³, Nicholas Roberts³, Marcelle Bernstein¹¹, Douglas Brown¹², Elena Sperk⁴, Siobhan Laws¹³, Marc Sütterlin¹⁴, Tammy Corica¹⁵, Steinar Lundgren^{16

17}, Dennis Holmes¹⁸, Lorenzo Vinante¹⁹, Fernando Bozza²⁰, Montserrat Pazos²¹, Magali Le Blanc-Onfroy²², Günther Gruber²³, Wojciech Polkowski²⁴, Konstantin J Dedes²⁵, Marcus Niewald²⁶, Jens Blohmer²⁷, David McCready²⁸, Richard Hoefer²⁹, Pond Kelemen³⁰, Gloria Petralia³¹, Mary Falzon³², David J Joseph¹⁵, Jeffrey S Tobias

Affiliations

¹ Division of Surgery and Interventional Science, University College London, 43-45 Foley Street, London W1W 7JN, UK jayantvaidya@gmail.com.
² Department of Biostatistics, University of Notre Dame, Fremantle, WA, Australia.
³ Division of Surgery and Interventional Science, University College London, 43-45 Foley Street, London W1W 7JN, UK.
⁴ Department of Radiation Oncology, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
⁵ Department of Surgery, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.
⁶ Department of Gynaecology and Obstetrics, Red Cross Hospital, Technical University of Munich, Munich, Germany.
⁷ Department of Surgery, University of California, San Francisco, CA, USA.
⁸ Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
⁹ School of Surgery, University of Western Australia, Crawley, WA, Australia.
¹⁰ Department of Breast Surgery, University of Copenhagen, Copenhagen, Denmark.
¹¹ London, UK.
¹² Department of Surgery, Ninewells Hospital, Dundee, UK.
¹³ Department of Surgery, Royal Hampshire County Hospital, Winchester, UK.
¹⁴ Department of Gynaecology and Obstetrics, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
¹⁵ Department of Radiation Oncology, Sir Charles Gairdner Hospital, Perth, WA, Australia.
¹⁶ Department of Oncology, St Olav's University Hospital, Trondheim, Norway.
¹⁷ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁸ University of Southern California, John Wayne Cancer Institute & Helen Rey Breast Cancer Foundation, Los Angeles, CA, USA.
¹⁹ Department of Radiation Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.
²⁰ Instituto Oncologico Veneto, Padoa, Italy.
²¹ Department of Radiation Oncology, University Hospital, The Ludwig Maximilian University of Munich, Munich, Germany.
²² Radiotherapy-Oncology, Western Cancer Institute, Nantes, France.
²³ Breast Centre Seefeld, Zurich, Switzerland.
²⁴ Department of Surgical Oncology, Medical University of Lublin, Lublin, Poland.
²⁵ Breast Centre, University Hospital Zurich, Zurich, Switzerland.
²⁶ Saarland University Medical Center, Homberg, Germany.
²⁷ Sankt Gertrauden Hospital, Charité, Medical University of Berlin, Berlin, Germany.
²⁸ Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
²⁹ Sentara Surgery Specialists, Hampton, VA, USA.
³⁰ Ashikari Breast Center, New York Medical College, New York, NY, USA.
³¹ Department of Surgery, University College London Hospitals, London, UK.
³² Department of Pathology, University College London Hospitals, London, UK.

PMID: 32816842
PMCID: PMC7500441
DOI: 10.1136/bmj.m2836

Randomized Controlled Trial

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

Jayant S Vaidya et al. BMJ. 2020.

. 2020 Aug 19:370:m2836.

doi: 10.1136/bmj.m2836.

Authors

Affiliations

¹ Division of Surgery and Interventional Science, University College London, 43-45 Foley Street, London W1W 7JN, UK jayantvaidya@gmail.com.
² Department of Biostatistics, University of Notre Dame, Fremantle, WA, Australia.
³ Division of Surgery and Interventional Science, University College London, 43-45 Foley Street, London W1W 7JN, UK.
⁴ Department of Radiation Oncology, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
⁵ Department of Surgery, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.
⁶ Department of Gynaecology and Obstetrics, Red Cross Hospital, Technical University of Munich, Munich, Germany.
⁷ Department of Surgery, University of California, San Francisco, CA, USA.
⁸ Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
⁹ School of Surgery, University of Western Australia, Crawley, WA, Australia.
¹⁰ Department of Breast Surgery, University of Copenhagen, Copenhagen, Denmark.
¹¹ London, UK.
¹² Department of Surgery, Ninewells Hospital, Dundee, UK.
¹³ Department of Surgery, Royal Hampshire County Hospital, Winchester, UK.
¹⁴ Department of Gynaecology and Obstetrics, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
¹⁵ Department of Radiation Oncology, Sir Charles Gairdner Hospital, Perth, WA, Australia.
¹⁶ Department of Oncology, St Olav's University Hospital, Trondheim, Norway.
¹⁷ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁸ University of Southern California, John Wayne Cancer Institute & Helen Rey Breast Cancer Foundation, Los Angeles, CA, USA.
¹⁹ Department of Radiation Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.
²⁰ Instituto Oncologico Veneto, Padoa, Italy.
²¹ Department of Radiation Oncology, University Hospital, The Ludwig Maximilian University of Munich, Munich, Germany.
²² Radiotherapy-Oncology, Western Cancer Institute, Nantes, France.
²³ Breast Centre Seefeld, Zurich, Switzerland.
²⁴ Department of Surgical Oncology, Medical University of Lublin, Lublin, Poland.
²⁵ Breast Centre, University Hospital Zurich, Zurich, Switzerland.
²⁶ Saarland University Medical Center, Homberg, Germany.
²⁷ Sankt Gertrauden Hospital, Charité, Medical University of Berlin, Berlin, Germany.
²⁸ Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
²⁹ Sentara Surgery Specialists, Hampton, VA, USA.
³⁰ Ashikari Breast Center, New York Medical College, New York, NY, USA.
³¹ Department of Surgery, University College London Hospitals, London, UK.
³² Department of Pathology, University College London Hospitals, London, UK.

PMID: 32816842
PMCID: PMC7500441
DOI: 10.1136/bmj.m2836

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.

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Conflict of interest statement

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.

Figures

**Fig 1**
Flowchart outlining TARGIT-A recruitment and CONSORT (consolidated standards of reporting trials) diagram. *Difference in number withdrawn was statistically significant (P=0.002). †Crossovers: 65/1140 (5.7%) allocated TARGIT-IORT received EBRT, and 22/1158 (1.9%) allocated EBRT received TARGIT-IORT. ‡1027/1140 (91%) allocated TARGIT-IORT and 1065/1158 (92%) allocated EBRT received allocated treatment. §As per protocol, 241/1140 (21.1%) patients allocated TARGIT-IORT received EBRT after TARGIT-IORT. EBRT=external beam radiotherapy; TARGIT-IORT=targeted intraoperative radiotherapy

**Fig 2**
Completeness of follow-up. Curves for actual follow-up and how close they are to curves for expected follow-up. Expected is presumed equal to actual if patients have withdrawn or died. No significant difference in follow-up duration between TARGIT-IORT and EBRT (log rank P=0.22). EBRT=external beam radiotherapy; TARGIT-IORT=targeted intraoperative radiotherapy

**Fig 3**
Kaplan-Meier estimates and curves for the following outcomes for TARGIT-IORT versus EBRT in the TARGIT-A trial: local recurrence-free survival, invasive local recurrence-free survival, mastectomy-free survival, distant disease-free survival, breast cancer specific survival, non-breast cancer survival, and overall survival. Figures under titles are hazard ratios (95% confidence intervals) and log rank test P values. EBRT=external beam radiotherapy; TARGIT-IORT=targeted intraoperative radiotherapy

**Fig 4**
Kaplan-Meier curves showing differences in breast cancer mortality, non-breast cancer mortality, and overall mortality in TARGIT-A trial for TARGIT-IORT v EBRT. Figures under titles are hazard ratios (95% confidence intervals) and log rank test P values. EBRT=external beam radiotherapy; TARGIT-IORT=targeted intraoperative radiotherapy

**Fig 5**
Pictogram showing outcomes in TARGIT-A trial of TARGIT-IORT v EBRT for breast cancer. Complete follow-up is available for five years. Each dot represents a patient. Absolute numbers of patients who had local recurrences, distant disease, and died (TARGIT-IORT: 24/1140 local recurrences, 34/1140 distant disease, and 42/1140 deaths; EBRT: 11/1158 local recurrences, 31 distant disease, and 56/1158 deaths) are apportioned per 100 patients for each treatment type. At five years, one more local recurrence and one less death were reported per 100 patients. EBRT=external beam radiotherapy; TARGIT-IORT=targeted intraoperative radiotherapy

**Fig 6**
Amount of data in randomised trials of different techniques of partial breast irradiation for invasive breast cancer. 10# 8 days=10 fractions in eight days; EBRT=external beam radiotherapy; IMRT=intensity modulated radiotherapy; IORT=intraoperative radiotherapy; TARGIT-IORT=targeted intraoperative radiotherapy

See this image and copyright information in PMC

Comment in

Intraoperative radiotherapy for early breast cancer - insufficient evidence to change practice.
Sasieni PD, Sawyer EJ. Sasieni PD, et al. Nat Rev Clin Oncol. 2020 Dec;17(12):723-724. doi: 10.1038/s41571-020-00444-2. Nat Rev Clin Oncol. 2020. PMID: 33087894 Free PMC article.
Reply to 'Intraoperative radiotherapy for breast cancer: powerful evidence to change practice'.
Sasieni PD, Sawyer EJ. Sasieni PD, et al. Nat Rev Clin Oncol. 2021 Mar;18(3):188-189. doi: 10.1038/s41571-021-00472-6. Nat Rev Clin Oncol. 2021. PMID: 33495551 No abstract available.
Intraoperative radiotherapy for breast cancer: powerful evidence to change practice.
Vaidya JS, Bulsara M, Baum M, Alvarado M, Bernstein M, Massarut S, Saunders C, Sperk E, Wenz F, Tobias JS; TARGIT-A investigators. Vaidya JS, et al. Nat Rev Clin Oncol. 2021 Mar;18(3):187-188. doi: 10.1038/s41571-021-00471-7. Nat Rev Clin Oncol. 2021. PMID: 33495552 Free PMC article. No abstract available.
Single-dose intraoperative radiotherapy during lumpectomy for breast cancer: an innovative patient-centred treatment.
Vaidya JS, Bulsara M, Baum M, Tobias JS; TARGIT-A trial authors. Vaidya JS, et al. Br J Cancer. 2021 Apr;124(9):1469-1474. doi: 10.1038/s41416-020-01233-5. Epub 2021 Feb 2. Br J Cancer. 2021. PMID: 33531693 Free PMC article.

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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

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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

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