Invasive breast cancer: Targeted intraoperative radiotherapy during lumpectomy is better for patients than whole breast radiotherapy - whatever the ductal cancer subgroup.

The TARGIT-A randomised trial: TARGIT-IORT has excellent long-term outcomes, in all subgroups, and even after local relapse. A new decision-aid for additional radiotherapy. Reduced deaths seem attributable to avoidance of scatter radiation AND to delivery of TARGIT-IORT: a new data-led hypothesis.

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The long-term results of the TARGIT-A randomised trial confirmed that TARGIT-IORT is as effective and safer than whole breast radiotherapy.

Twenty-five years after its inception1, and 20 years after beginning of the TARGIT-A international randomised trial, there is robust evidence showing that risk-adapted single-dose targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy produces comparable breast cancer outcomes to post-operative whole breast external beam radiotherapy (EBRT). It also significantly reduces mortality from non-breast-cancer causes2,3. The original results in lay terms are explained in a short video

TARGIT-A trial for breast cancer - main results
Long term results of the randomised TARGIT-A trial of TARGIT-IORT during lumpectomy for breast cancer
BMJ 2020;370:m2836  https://www.bmj.com/content/370/bmj.m2836.full.pdf

A more detailed videos are available at Prof Vaidya's youtube channel e.g. https://youtu.be/s8mdLKOt784 

Further details about TARGIT-IORT are at https://targit.org.uk/


New results from the TARGIT-A trial


For the paper published today in the British Journal of Cancer (https://doi.org/10.1038/s41416-021-01440-8) we asked some pertinent questions. The answers are explained in the text and figures below, and this short video.


Who can have TARGIT-IORT, and who needs supplemental EBRT? 

One needs to remember that TARGIT-A trial was not limited to 'low-risk' patients. A substantial number of patients had tumours typically considered as 'high risk': 1898 (83%) were younger than 70 years, 366 (16%) had tumours >2 cm in size, 443 (20%) patients had grade 3 cancers, 488 (22%) patients had involved nodes and 426 (19%) had ER- or PgR-negative tumours.

This wide range of patients means that the results are widely applicable. Planned subgroup analysis found that a patient’s chance of living without a local recurrence was just as good with TARGIT-IORT and EBRT for all tumour subgroups (size, grade, ER, PgR, HER2, lymph node status, figure 1). For patients with grade 1 or 2 cancers, TARGIT-IORT improved overall survival by 4.4% (p=0.036).

 Forest plots showing that TARGIT-IORT is as effective as EBRT in all tumour subgroups
Improved survival with TARGIT-IORT in patients with Grade 1 or 2 cancers, with no detriment if Grade 3

NB There was no difference in the use of additional EBRT after TARGIT-IORT between Grade 1 or 2 and Grade 3

What was the outcome in patients who received just TARGIT-IORT? 

Analysis as per treatment received, showed that there was no difference in the local control with just TARGIT-IORT, TARGIT-IORT plus EBRT and EBRT 

No difference was seen between local control between the three groups -  TARGIT-IORT alone vs. TARGIT-IORT plus EBRT vs. EBRT
Supplementary figure 1: Kaplan-Meier plot of local recurrence-free survival of those randomised to receive EBRT (red line) along with those randomised to receive TARGIT-IORT separated by those who received additional EBRT (purple line) and those who did not (blue line). No statistically significant difference was found between EBRT and the two latter groups. 

How can we decide who gets additional whole breast radiotherapy after TARGIT-IORT?

Most patients in the TARGIT-A trial who had high-risk features did not receive supplemental EBRT after TARGIT-IORT as part of the risk-adapted approach. For example, supplemental EBRT was not given to 78% of Grade 3, not given to 82% of ER-negative and not given to 63% of node-positive patients.

The decision regarding use of supplemental EBRT was made for the individual patient by the treating multidisciplinary team, particularly bearing in mind the main indications of unexpected lobular cancer and positive margins, together with the patient's needs and personal preferences. We therefore created a decision-aid (https://targit.org.uk/addrt) for helping clinicians decide about recommending supplemental EBRT after TARGIT-IORT.


Guideline for using TARGIT-IORT for breast cancer

Together with the original findings, these data support an evidence-based guideline recommending routine use of risk-adapted single-dose TARGIT-IORT during lumpectomy for patients with early breast cancer. The sole selection criterion is that they should fulfil the eligibility criteria for the TARGIT-A trial  (>=45 years, invasive ductal carcinoma up to 3.5cm in size); their treatment can be tailored using the decision-aid (https://targit.org.uk/addrt)


Do all local recurrences have the same implications?

Unlike the well-known poorer prognosis faced by patients who develop a local recurrence after lumpectomy and whole breast radiotherapy, local recurrence in the TARGIT-IORT arm did not adversely affect long-term outcome. For example, 64% of patients who had local recurrence within 5-years after EBRT died (7/11), compared with only 13% in the TARGIT-IORT arm (3/24). In figure 3 the poor outcome in those with local recurrence after EBRT is in stark contrast with those who with local recurrence after TARGIT-IORT, who fare no worse than those without local recurrence - a biologically interesting finding of high statistical (p=0.003) and clinical significance.

Long-term outcome is excellent even after local recurrence if TARGIT-IORT is given, but is poor if EBRT is given

For patients and clinicians, this finding is of great importance. Firstly the chance of remaining free of local recurrence with TARGIT-IORT is just as good as EBRT, but even if one does get a local recurrence after TARGIT-IORT, the outlook in terms of distant disease and survival is much better than if one gets it after EBRT. 


Are deaths reduced by avoiding EBRT as well as by giving TARGIT-IORT?

This interesting biological insight relates to the substantially reduced non-breast-cancer mortality with TARGIT-IORT (HR 0.59, p=0.005, a reduction of 4.4% at 12 years from 9.85% to 5.41%)2,3. As seen in figure 4, it comes from the natural experiment: in the TARGIT-A trial, 20% of patients allocated TARGIT-IORT also received EBRT (n=241) as per protocol-specified post-operatively findings (e.g. unsuspected invasive lobular carcinoma, positive margins). If the reduced non-breast-cancer mortality was solely due to avoidance of the scattered irradiation from EBRT then these 241 patients would not benefit. But they did! As seen in the figure 2, non-breast-cancer mortality was significantly lower even in the 241 patients who received TARGIT-IORT plus supplemental EBRT, HR 0.38 (95%CI 0.17 to 0.88) p=0.0091. This drug-like benefit starts soon after randomisation and echoes other data4-15. It strengthens the hypothesis that TARGIT-IORT, interacting with the systemic effects of surgical trauma, exerts a beneficial abscopal / immunomodulatory protective effect against deaths from cardiovascular causes, lung problems and other cancers, opening the door to a new therapeutic avenue.

The avoidance of scattered irradiation from EBRT as well as the delivery of TARGIT-IORT during lumpectomy both seem to contribute to the reduced non-breast- cancer mortality seen in the TARGIT-A trial

In summary

We found (https://doi.org/10.1038/s41416-021-01440-8) that TARGIT-IORT is effective in all tumour subtypes amongst patients eligible for the TARGIT-A trial i.e., 45 years or older with invasive ductal carcinoma <=3.5cm. Post-operatively, our online tool (https://targit.org.uk/addrt) can help decide about supplemental EBRT, which will be recommended in a small proportion of cases. Patients can be reassured that a local recurrence after TARGIT-IORT, unlike after EBRT, does not detract from an excellent long-term prognosis. The reduced mortality from other causes possibly results from absence of scattered irradiation and presence of a systemic abscopal effect of TARGIT-IORT during lumpectomy.


45,000 patients in 260 centres in 38 countries have already received TARGIT-IORT16. Many more should now be offered this effective, convenient, safer, cosmetically superior and less expensive treatment that is much preferred by patients2,3.


Further reading: https://targit.org.uk/publications, and https://targit.org.uk 

TARGIT-A TRIAL AUTHORS

  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

Author affiliations

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

References

1                Vaidya, J. S., Vyas, J. J., Chinoy, R. F., Merchant, N., Sharma, O. P. & Mittra, I. Multicentricity of breast cancer: whole-organ analysis and clinical implications. British journal of cancer 74, 820-824 (1996).

2                Vaidya, J. S., Bulsara, M., Baum, M., Wenz, F., Massarut, S., Pigorsch, S. 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 370, m2836 (2020). https://www.bmj.com/content/370/bmj.m2836.full.pdf

3                Vaidya, J. S., Bulsara, M., Baum, M. & Tobias, J. S. Single-dose intraoperative radiotherapy during lumpectomy for breast cancer: an innovative patient-centred treatment. British journal of cancer 10.1038/s41416-020-01233-5 (2021). https://rdcu.be/ckK3B

4                Belletti, B., Vaidya, J. S., D'Andrea, S., Entschladen, F., Roncadin, M., Lovat, F. et al. Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding. Clinical cancer research : an official journal of the American Association for Cancer Research 14, 1325-1332 (2008).

5                Vaidya, J. S., Bulsara, M., Wenz, F., Massarut, M., Joseph, D., Tobias, J. S. et al. The Lower Non-Breast Cancer Mortality With TARGIT in the TARGIT-A Trial Could Be a Systemic Effect of TARGIT on Tumor Microenvironment. International journal of radiation oncology, biology, physics 87, S240 (2013).

6                Vaidya, J. S., Bulsara, M. & Wenz, F. Ischemic heart disease after breast cancer radiotherapy. New England Journal of Medicine 368, 2526-2527 (2013).

7                Veldwijk, M. R., Zhang, B., Wenz, F. & Herskind, C. The biological effect of large single doses: a possible role for non-targeted effects in cell inactivation. PLoS One 9, e84991 (2014).

8                Vaidya, J. S., Wenz, F., Bulsara, M., Tobias, J. S., Joseph, D., Saunders, C. et al. An international randomised controlled trial to compare targeted intra-operative radiotherapy (TARGIT) with conventional post-operative radiotherapy after conservative breast surgery for women with early stage breast cancer (The TARGIT-A trial). Health technology assessment 20 (2016).

9                Kolberg, H. C., Loevey, G., Akpolat-Basci, L., Stephanou, M., Fasching, P. A., Untch, M. et al. Targeted intraoperative radiotherapy tumour bed boost during breast-conserving surgery after neoadjuvant chemotherapy. Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al] 193, 62-69 (2017).

10              Vaidya, J. S. The Systemic Effects of Local Treatments (Surgery and Radiotherapy) of Breast Cancer. In: M. Retsky & R. Demichelli (eds). Perioperative Inflammation as Triggering Origin of Metastasis Development  10.1007/978-3-319-57943-6  Ch. 11, 227-236 (Nature, Springer, 2017).

11              Rodriguez-Ruiz, M. E., Vanpouille-Box, C., Melero, I., Formenti, S. C. & Demaria, S. Immunological Mechanisms Responsible for Radiation-Induced Abscopal Effect. Trends Immunol 39, 644-655 (2018).

12              Chicas-Sett, R., Morales-Orue, I., Castilla-Martinez, J., Zafra-Martin, J., Kannemann, A., Blanco, J. et al. Stereotactic Ablative Radiotherapy Combined with Immune Checkpoint Inhibitors Reboots the Immune Response Assisted by Immunotherapy in Metastatic Lung Cancer: A Systematic Review. Int J Mol Sci 20 (2019).

13              Cifarelli, C. P., Brehmer, S., Vargo, J. A., Hack, J. D., Kahl, K. H., Sarria-Vargas, G. et al. Intraoperative radiotherapy (IORT) for surgically resected brain metastases: outcome analysis of an international cooperative study. J Neurooncol 145, 391-397 (2019).

14              Jarosz-Biej, M., Smolarczyk, R., Cichon, T. & Kulach, N. Tumor Microenvironment as A "Game Changer" in Cancer Radiotherapy. Int J Mol Sci 20 (2019).

15              Welsh, J., Bevelacqua, J. J., Dobrzyński, L., S A R, M., S.A.R., Farjadian, S. H. & Mortazavi, S. M. J. Abscopal Effect Following Radiation Therapy in Cancer Patients: A New Look from the Immunological Point of View. J Biomed Phys Eng 10, 537-542 (2020).

16              Vaidya, J. S., Vaidya, U. J., Baum, M., Bulsara, M., Joseph, D., Tobias, J. S. et al. Global adoption of single-shot targeted intraoperative radiotherapy (TARGIT-IORT) to improve breast cancer treatment – better for patients, better for health care systems. UCL preprint https://doi.org/10.14324/000.wp.10121050 (2021).

Professor Jayant S Vaidya

Professor of Surgery and Oncology, University College London