Alvarado, M

Bernstein, M

Bulsara, M

Douek, M

Flyger, H

Holmes, D

Joseph, D

Massarut, S

Pigorsch, S

Saunders, C

Sperk, E

Tobias, JS

Vaidya, JS

Wenz, F

English

UCL Discovery

Journal Pre-proofTARGIT-IORT during lumpectomy for breast cancer - better for patients than otherPBI approachesJayant S. Vaidya, MD PhD, Max Bulsara, PhD, Elena Sperk, MD, Samuele Massarut,MD, Michael Douek, MD, Michael Alvarado, MD, Steffi Pigorsch, Dennis Holmes, MD,Marcelle Bernstein, Christobel Saunders, MD, Henrik Flyger, MD, David Joseph, MD,Frederik Wenz, MD, Jeffrey S. Tobias, MD, on behalf of the TARGIT-A investigatorsPII: S0360-3016(21)00199-1DOI: https://doi.org/10.1016/j.ijrobp.2021.01.059Reference: ROB 26913To appear in: International Journal of Radiation Oncology • Biology • PhysicsReceived Date: 26 January 2021Accepted Date: 26 January 2021Please cite this article as: Vaidya JS, Bulsara M, Sperk E, Massarut S, Douek M, Alvarado M, PigorschS, Holmes D, Bernstein M, Saunders C, Flyger H, Joseph D, Wenz F, Tobias JS, on behalf of theTARGIT-A investigators, TARGIT-IORT during lumpectomy for breast cancer - better for patients thanother PBI approaches, International Journal of Radiation Oncology • Biology • Physics (2021), doi:https://doi.org/10.1016/j.ijrobp.2021.01.059.This is a PDF file of an article that has undergone enhancements after acceptance, such as the additionof a cover page and metadata, and formatting for readability, but it is not yet the definitive version ofrecord. This version will undergo additional copyediting, typesetting and review before it is publishedin its final form, but we are providing this version to give early visibility of the article. Please note that,during the production process, errors may be discovered which could affect the content, and all legaldisclaimers that apply to the journal pertain.© 2021 Elsevier Inc. All rights reserved.TARGIT-IORT during lumpectomy for breast cancer - better for patients than other PBI approaches TARGIT-IORT during lumpectomy for breast cancer   Jayant S. Vaidya1 MD PhD, Max Bulsara2 PhD, Elena Sperk3 MD, Samuele Massarut4 MD, Michael Douek5 MD, Michael Alvarado6 MD, Steffi Pigorsch7, Dennis Holmes8 MD, Marcelle Bernstein9, Christobel Saunders10 MD, Henrik Flyger11 MD, David Joseph12 MD, Frederik Wenz13 MD, Jeffrey S. Tobias14 MD on behalf of the TARGIT-A investigators    1. Division of Surgery and Interventional Science, University College London, 43-45 Foley Street, London W1W 7JN, UK 2. Department of Biostatistics, University of Notre Dame, Fremantle, WA, Australia  3. Department of Radiation Oncology, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg, University, Heidelberg, Germany  4. Department of Surgery, Centro di Riferimento Oncologic  di Aviano (CRO) IRCCS, Aviano, Italy  5. Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK 6. Department of Surgery, University of California, San Francisco, CA, USA  7. Department of Gynaecology and Obstetrics, Red Cross H pital, Technical University of Munich, Munich, Germany 8. University of Southern California, John Wayne Cancer Institute & Helen Rey Breast Cancer Foundation, Los Angeles, CA School of Surgery, University of Western Australia, Crawley, WA, Australia 9. Patient advocate, London, UK  10. School of Surgery, University of Western Australia, Crawley, WA, Australia 11. Department of Breast Surgery, University of Copenhagen, Copenhagen, Denmark  12. Department of Radiation Oncology, Sir Charles Gairdne  Hospital, Perth, WA, Australia  13. University of Frieberg, Frieberg, Germany  14. Department of Clinical Oncology, University College London Hospitals, London, UK    Corresponding Author: Professor Jayant S Vaidya jayntvaidya@gmail.com  Author Responsible for Statistical Analysis: Professor Max Bulsara max.bulsara@nd.edu.au]  Conflict of Interest Statement for All Authors – uploaded forms  Funding Statement: There was no specific funding for this work. The TARGIT-A trial was initiated by an academic insight and collaboration with the industry was solely for the development of the device. The manufactrers 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 Londo, 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 co cept, design, analysis or writing of the manuscript.  [Data Availability Statement for this Work] – Not applicable  [Acknowledgements] – not specifically for this work   Journal Pre-proof 1TARGIT-IORT during lumpectomy for breast cancer - better for patients than other PBI approaches Dear Sir,   The authors of the Budapest randomised trial1 of partial breast irradiation (PBI) recruited a very low-risk patients (T1N0, Grade 1 or 2). Their small sample size (n=258) was a little more than 1/10th of the TARGIT-A randomised trial (n=2298) published in the BMJ2. Yet they fail to mention it. TARGIT-A compared risk-adapted single-dose targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy vs whole breast radiotherapy (EBRT). TARGIT-IORT achieved comparable long-term outcomes to EBRT for local control, distant control, breast preservation and breast-cancer mortality, along with a significant and substanti l reduction in non-breast-cancer mortality by 4.4% by 12 years (5.41% vs 9.85%,p=0.005). With this magnitude of survival benefit, a new cytotoxic agent would achieve high-profile rapid adoption!  They also fail to correctly cite the trial of delayed IORT (n=1153) reported in JAMAOncology3 4. Instead, they selectively refer to the hypothetical and erroneous statistics from a correspondence letter, without noting our robust rebuttal3 4 - their fundamental error was not recognising thatTARGIT-A was a non-inferiority trial. The median follow-up was 9 years (they wrongly state 5 years, and give an incorrect p-value in Table 4). They overlook that the 10-year local recurrence-free survival was not statistically different (80.16% vs 84.36%,p=0.052), and mastectomy-free survival was virtually identical (83.79% vs 83.82%,p=0.38). We repeatedly stress our strong preference for TARGIT-IORT during the initial lumpectomy2-4.   Then they fall prey to the temptation of comparing TARGIT-A with the PRIME-II trial of ‘no-radiotherapy’ vs EBRT. Unlike the wide eligibility for TARGIT-A (≥ 45 years, ≤3.5cm invasive ductal carcinoma), PRIME-II recruited only ultra-low risk patients ≥ 65 years. In fact, three-quarters of the TARGIT-A patients2 would not have been eligible for the PRIME-II trial because they were either too young or had node positive (22%), grade 3 (20%) or ER/PR negative (19%) disease! Yet, even in this ultra-low risk PRIME-II trial, the reduction i local control in the absence of radiotherapy was dramatic, with a local recurrence of 9.8% vs 0.9% at 10 years(SABCS 2020 https://www.abstractsonline.com/pp8/#!/9223/presentation/579). PRIME-II found no hint of a reduction in mortality- the benefit of avoiding radiation was perhaps nullified by the harm from the large increase in local relapse. On the other hand, when TARGIT-IORT is given during lumpectomy (higher-risk patients, much larger trial), there is no reduction in the patient’s chance of being free of local recurrence, preserving the breast, or Journal Pre-proof 2survival from breast cancer, AND there is a substantial reduction in deaths from cardiovascular causes and other cancers.   PBI whether with brachytherapy wires/balloon or external beam, is very cumbersome to patients, requiring several hospital visits or even an in-patient stay5. These approaches inevitably deliver significant scattered irradiation to the nearby organs at risk (OARs) such as the heart and the lung5. TARGIT-IORT involves much less travel, delivers the least dose to OARs, has reduced toxicity, less pain and improves quality of life and cosmetic outcome2 6 7. To quote many patients, single-dose TARGIT-IORT delivered during surgery is a “no-brainer”.   The elephant in the room is something we have naively touted as an advantage: TARGIT-IORT is a high-value treatment, saving substantial sums (e.g. $1.5 billion over 5 years in the US8 9) to the healthcare system. However, from the perspective of the healthcare provider, these savings result in a substantially lower income-str am for the department or the individual, compared with any other method of radiotherapy. These considerations may reverse with the introduction of a value-based system for remuneration.   As an editorial in this journal pointed out10, “Many careers have been built around fractionated radiation therapy for breast cancer, and it comprises a substantial proportion of the practice of the average contemporary r diation oncologist. Depending on your perspective, intraoperative radiation therapy is thus either a very serious threat or a quantum leap forward.”.   260 centres in 38 countries worldwide have already treated 45,000 patients with TARGIT-IORT, which is now included in several national and international guidelines (https://targit.org.uk/targit-iort-in-guidelines).    Journl Pre-proof 3References  1. Polgar C, Major T, Takacsi-Nagy Z, et al. Breast-Conserving Surgery Followed by Partial or Whole Brast Irradiation: Twenty-Year Results of a Phase 3 Clinical Study. International journal of radiation oncology, biology, physics 2020 doi: 10.1016/j.ijrobp.2020.11.006 [published Online First: 2020/11/14] 2. Vaidya JS, Bulsara M, Baum M, et al. 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:m2836. doi: 10.1136/bmj.m2836 [published Online First: 2020/08/19] 3. Vaidya JS, Bulsara M, Saunders C, et al. Effect of Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast Radiotherapy on Local Recurrence and Survival: Long-term Results From the TARGIT-A Randomized Clinical Trial in Early Breast Cancer. JAMA Oncol 2020;6(7):e200249. doi: 10.1001/jamaoncol.2020.0249 [published Online First: 2020/04/03] 4. Vaidya JS, Bulsara M, Baum M. Targeted Intraoperative Radiotherapy for Early Breast Cancer-Reply. JAMA Oncol 2020 doi: 10.1001/jamaoncol.2020.2730 [published Online First: 2020/08/14] 5. Vaidya JS, Bulsara M, Baum M, et al. Intraoperative radiotherapy for breast cancer: powerful evidence to change practice. Nature Reviews Clinical Oncology 2021 doi: 10.1038/s41571-021-00471-7 6. Coombs NJ, Coombs JM, Vaidya UJ, et al. Environme tal and social benefits of the targeted intraoperative radiotherapy for breast cancer: data from UK TARGIT-A trial centres and two UK NHS hospitals offering TARGIT IORT. BMJ open 2016;6(5):e010703. doi: 10.1136/bmjopen-2015-010703 7. Corica T, Nowak AK, Saunders CM, et al. Cosmesis and Breast-Related Quality of Life Outcomes After Int aoperative Radiation Therapy for Early Breast Cancer: A Substudy of the TARGIT-A Trial. International journal of radiation oncology, biology, physics 2016;96(1):55-64. doi: 10.1016/j.ijrobp.2016.04.024 8. Alvarado MD, Mohan AJ, Esserman LJ, et al. Cost-effectiveness analysis of intraoperative radiation herapy for early-stage breast cancer. Annals of surgical oncology 2013;20(9):2873-80. doi: 10.1245/s10434-013-2997-3 9. Vaidya A, Vaidya P, Both B, et al. Health economics of targeted intraoperative radiotherapy (TARGIT- IORT) for early breast cancer: a cost- effectiveness analysis in the United Kingdom. BMJ open 2017;7:e014944. doi: 10.1136/bmjopen-2016-014944 [published Online First: 17 Aug 2017] 10. Zietman A. Letters Regarding the TARGIT-A Trial: The Editor's Introduction. International journal of radiation oncology, biology, physics 2015;92(5):951-2. doi: 10.1016/j.ijrobp.2015.05.048  Journal Pre-proof

In Regard to Polgar et al

https://discovery.ucl.ac.uk/id/eprint/10122730/21/Vaidya%202021%20Red%20Journal%20re%20Budapest%20trial.pdf

In Regard to Polgar et al

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