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      New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer

      research-article
      1 , , 2 , 1 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 1 , 1 , 1 , 1 , 11 , 12 , 3 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 15 , 32
      British Journal of Cancer
      Nature Publishing Group UK
      Breast cancer, Radiotherapy, Surgical oncology

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          Abstract

          Background

          The TARGIT-A trial reported risk-adapted targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy for breast cancer to be as effective as whole-breast external beam radiotherapy (EBRT). Here, we present further detailed analyses.

          Methods

          In total, 2298 women (≥45 years, invasive ductal carcinoma ≤3.5 cm, cN0–N1) were randomised. We investigated the impact of tumour size, grade, ER, PgR, HER2 and lymph node status on local recurrence-free survival, and of local recurrence on distant relapse and mortality. We analysed the predictive factors for recommending supplemental EBRT after TARGIT-IORT as part of the risk-adapted approach, using regression modelling. Non-breast cancer mortality was compared between TARGIT-IORT plus EBRT vs. EBRT.

          Results

          Local recurrence-free survival was no different between TARGIT-IORT and EBRT, in every tumour subgroup. Unlike in the EBRT arm, local recurrence in the TARGIT-IORT arm was not a predictor of a higher risk of distant relapse or death. Our new predictive tool for recommending supplemental EBRT after TARGIT-IORT is at https://targit.org.uk/addrt. Non-breast cancer mortality was significantly lower in the TARGIT-IORT arm, even when patients received supplemental EBRT, HR 0.38 (95% CI 0.17–0.88) P = 0.0091.

          Conclusion

          TARGIT-IORT is as effective as EBRT in all subgroups. Local recurrence after TARGIT-IORT, unlike after EBRT, has a good prognosis. TARGIT-IORT might have a beneficial abscopal effect.

          Trial registration

          ISRCTN34086741 (21/7/2004), NCT00983684 (24/9/2009).

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          Most cited references23

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          Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.

          In early breast cancer, variations in local treatment that substantially affect the risk of locoregional recurrence could also affect long-term breast cancer mortality. To examine this relationship, collaborative meta-analyses were undertaken, based on individual patient data, of the relevant randomised trials that began by 1995. Information was available on 42,000 women in 78 randomised treatment comparisons (radiotherapy vs no radiotherapy, 23,500; more vs less surgery, 9300; more surgery vs radiotherapy, 9300). 24 types of local treatment comparison were identified. To help relate the effect on local (ie, locoregional) recurrence to that on breast cancer mortality, these were grouped according to whether or not the 5-year local recurrence risk exceeded 10% ( 10%, 25,000 women). About three-quarters of the eventual local recurrence risk occurred during the first 5 years. In the comparisons that involved little ( 10%) differences, however, 5-year local recurrence risks were 7% active versus 26% control (absolute reduction 19%), and 15-year breast cancer mortality risks were 44.6% versus 49.5% (absolute reduction 5.0%, SE 0.8, 2p<0.00001). These 25,000 women included 7300 with breast-conserving surgery (BCS) in trials of radiotherapy (generally just to the conserved breast), with 5-year local recurrence risks (mainly in the conserved breast, as most had axillary clearance and node-negative disease) 7% versus 26% (reduction 19%), and 15-year breast cancer mortality risks 30.5% versus 35.9% (reduction 5.4%, SE 1.7, 2p=0.0002; overall mortality reduction 5.3%, SE 1.8, 2p=0.005). They also included 8500 with mastectomy, axillary clearance, and node-positive disease in trials of radiotherapy (generally to the chest wall and regional lymph nodes), with similar absolute gains from radiotherapy; 5-year local recurrence risks (mainly at these sites) 6% versus 23% (reduction 17%), and 15-year breast cancer mortality risks 54.7% versus 60.1% (reduction 5.4%, SE 1.3, 2p=0.0002; overall mortality reduction 4.4%, SE 1.2, 2p=0.0009). Radiotherapy produced similar proportional reductions in local recurrence in all women (irrespective of age or tumour characteristics) and in all major trials of radiotherapy versus not (recent or older; with or without systemic therapy), so large absolute reductions in local recurrence were seen only if the control risk was large. To help assess the life-threatening side-effects of radiotherapy, the trials of radiotherapy versus not were combined with those of radiotherapy versus more surgery. There was, at least with some of the older radiotherapy regimens, a significant excess incidence of contralateral breast cancer (rate ratio 1.18, SE 0.06, 2p=0.002) and a significant excess of non-breast-cancer mortality in irradiated women (rate ratio 1.12, SE 0.04, 2p=0.001). Both were slight during the first 5 years, but continued after year 15. The excess mortality was mainly from heart disease (rate ratio 1.27, SE 0.07, 2p=0.0001) and lung cancer (rate ratio 1.78, SE 0.22, 2p=0.0004). In these trials, avoidance of a local recurrence in the conserved breast after BCS and avoidance of a local recurrence elsewhere (eg, the chest wall or regional nodes) after mastectomy were of comparable relevance to 15-year breast cancer mortality. Differences in local treatment that substantially affect local recurrence rates would, in the hypothetical absence of any other causes of death, avoid about one breast cancer death over the next 15 years for every four local recurrences avoided, and should reduce 15-year overall mortality.
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            Immunological Mechanisms Responsible for Radiation-Induced Abscopal Effect

            Radiotherapy has been used for over hundred years as a local tumor treatment. The occurrence of systemic anti-tumor effects manifesting as regression of tumors outside of the irradiated field (abscopal effect) was occasionally observed but deemed too rare and unpredictable to be a therapeutic goal. This has changed with the advent of immunotherapy. Remarkable systemic effects have been observed in patients receiving radiotherapy to control tumors that were progressing during immune checkpoint blockade, stimulating interest in using radiation to overcome primary and acquired cancer resistance to immunotherapy. Here we review the immunological mechanisms that are responsible for the ability of focal radiation to promote antitumor T cell responses that mediate tumor rejection and, in some cases, result in systemic effects.
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              Tumor Microenvironment as A “Game Changer” in Cancer Radiotherapy

              Radiotherapy (RT), besides cancer cells, also affects the tumor microenvironment (TME): tumor blood vessels and cells of the immune system. It damages endothelial cells and causes radiation-induced inflammation. Damaged vessels inhibit the infiltration of CD8+ T lymphocytes into tumors, and immunosuppressive pathways are activated. They lead to the accumulation of radioresistant suppressor cells, including tumor-associated macrophages (TAMs) with the M2 phenotype, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). The area of tumor hypoxia increases. Hypoxia reduces oxygen-dependent DNA damage and weakens the anti-cancer RT effect. It activates the formation of new blood vessels and leads to cancer relapse after irradiation. Irradiation may also activate the immune response through immunogenic cell death induction. This leads to the “in situ” vaccination effect. In this article, we review how changes in the TME affect radiation-induced anticancer efficacy. There is a very delicate balance between the activation of the immune system and the immunosuppression induced by RT. The effects of RT doses on immune system reactions and also on tumor vascularization remain unclear. A better understanding of these interactions will contribute to the optimization of RT treatment, which may prevent the recurrence of cancer.
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                Author and article information

                Contributors
                jayantvaidya@gmail.com
                Journal
                Br J Cancer
                Br J Cancer
                British Journal of Cancer
                Nature Publishing Group UK (London )
                0007-0920
                1532-1827
                25 May 2021
                25 May 2021
                3 August 2021
                : 125
                : 3
                : 380-389
                Affiliations
                [1 ]GRID grid.83440.3b, ISNI 0000000121901201, Division of Surgery and Interventional Science, , University College London, ; London, UK
                [2 ]GRID grid.266886.4, ISNI 0000 0004 0402 6494, Department of Biostatistics, , University of Notre Dame, ; Fremantle, WA Australia
                [3 ]GRID grid.411778.c, ISNI 0000 0001 2162 1728, Department of Radiation Oncology, , University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, ; Mannheim, Germany
                [4 ]GRID grid.418321.d, ISNI 0000 0004 1757 9741, Department of Surgery, , Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, ; Aviano, Italy
                [5 ]GRID grid.6936.a, ISNI 0000000123222966, Department of Radiation Oncology, , Red Cross Hospital, Technical University of Munich, ; Munich, Germany
                [6 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, Department of Surgery, , University of California, ; San Francisco, CA USA
                [7 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Nuffield Department of Surgical Sciences, , University of Oxford, ; Oxford, UK
                [8 ]GRID grid.1012.2, ISNI 0000 0004 1936 7910, School of Surgery, , University of Western Australia, ; Perth, WA Australia
                [9 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Department of Breast Surgery, , University of Copenhagen, ; Copenhagen, Denmark
                [10 ]GRID grid.6936.a, ISNI 0000000123222966, Department of Gynecology and Obstetrics, , Red Cross Hospital, Technical University of Munich, ; Munich, Germany
                [11 ]Patient advocate and writer, London, UK
                [12 ]GRID grid.416266.1, ISNI 0000 0000 9009 9462, Department of Surgery, , Ninewells Hospital, ; Dundee, UK
                [13 ]GRID grid.416128.8, ISNI 0000 0000 9300 7922, Department of Surgery, , Royal Hampshire County Hospital, ; Winchester, UK
                [14 ]GRID grid.7700.0, ISNI 0000 0001 2190 4373, Department of Gynecology and Obstetrics, , University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, ; Berlin, Germany
                [15 ]GRID grid.3521.5, ISNI 0000 0004 0437 5942, Department of Radiation Oncology, , Sir Charles Gairdner Hospital, ; Perth, WA Australia
                [16 ]GRID grid.5947.f, ISNI 0000 0001 1516 2393, Department of Oncology, St Olav’s University Hospital, & Department of Clinical and Molecular Medicine, , Norwegian University of Science and Technology (NTNU), ; Trondheim, Norway
                [17 ]GRID grid.42505.36, ISNI 0000 0001 2156 6853, John Wayne Cancer Institute & Helen Rey Breast Cancer Foundation, , University of Southern California, ; Los Angeles, CA USA
                [18 ]GRID grid.418321.d, ISNI 0000 0004 1757 9741, Department of Radiation Oncology, , Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, ; Aviano, Italy
                [19 ]Department of Surgery, Instituto Oncologico Veneto (IVO) IRCCS, Padoa, Italy
                [20 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, Department of Radiation Oncology, , University Hospital, Ludwig Maximilians Universitat, ; Munich, Germany
                [21 ]GRID grid.418191.4, ISNI 0000 0000 9437 3027, Oncologie radiothérapeute, , Institut de Cancérologie de l’Ouest, ; Nantes, France
                [22 ]Brust Zentrum Seefeld, Zurich, Switzerland
                [23 ]GRID grid.411484.c, ISNI 0000 0001 1033 7158, Department of Surgical Oncology, , Medical University of Lublin, ; Lublin, Poland
                [24 ]GRID grid.412004.3, ISNI 0000 0004 0478 9977, Breast Center, , Universitätsspital Zürich, ; Zurich, Switzerland
                [25 ]GRID grid.411937.9, Saarland University Medical Center, ; Homburg, Germany
                [26 ]GRID grid.6363.0, ISNI 0000 0001 2218 4662, Sankt Gertrauden-Krankenhaus, , and The Charité—Universitätsmedizin Berlin, ; Berlin, Germany
                [27 ]GRID grid.415224.4, ISNI 0000 0001 2150 066X, Princess Margaret Cancer Centre, ; Toronto, Canada
                [28 ]Sentara Surgery Specialists, Hampton, VA USA
                [29 ]GRID grid.260917.b, ISNI 0000 0001 0728 151X, Ashikari Breast Center, , New York Medical College, ; New York, NY USA
                [30 ]GRID grid.439749.4, ISNI 0000 0004 0612 2754, Department of Surgery, , University College London Hospitals, ; London, UK
                [31 ]GRID grid.439749.4, ISNI 0000 0004 0612 2754, Department of Pathology University College London Hospitals, ; London, UK
                [32 ]GRID grid.439749.4, ISNI 0000 0004 0612 2754, Department of Clinical Oncology, , University College London Hospitals, ; London, UK
                Author information
                http://orcid.org/0000-0003-1760-1278
                Article
                1440
                10.1038/s41416-021-01440-8
                8329051
                34035435
                f4c1f638-8f4c-44f2-bf52-10d32889e90b
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 9 October 2020
                : 26 April 2021
                : 13 May 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100000664, DH | NIHR | Health Technology Assessment Programme (NIHR Health Technology Assessment Programme);
                Award ID: HTA 07/60/49
                Award ID: HTA 10/04/07
                Award ID: HTA 14/49/13
                Award ID: HTA 10/04/07
                Award ID: HTA 14/49/13
                Award ID: HTA 07/60/49
                Award ID: HTA 10/04/07
                Award ID: HTA 14/49/13
                Award ID: HTA 07/60/49
                Award ID: HTA 10/04/07
                Award ID: HTA 14/49/13
                Award ID: HTA 07/60/49
                Award ID: HTA 10/04/07
                Award ID: HTA 14/49/13
                Award ID: HTA 07/60/49
                Award ID: HTA 10/04/07
                Award ID: HTA 14/49/13
                Award ID: HTA 07/60/49
                Award ID: HTA 10/04/07
                Award ID: HTA 14/49/13
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100003108, Federal Ministry of Health, Germany | Bundeszentrale für gesundheitliche Aufklärung (Federal Centre for Health Education);
                Award ID: FKZ 01ZP0508
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100002347, Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research);
                Award ID: FKZ 01ZP0508
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100000925, Department of Health | National Health and Medical Research Council (NHMRC);
                Categories
                Article
                Custom metadata
                © Springer Nature Limited 2021

                Oncology & Radiotherapy
                breast cancer,radiotherapy,surgical oncology
                Oncology & Radiotherapy
                breast cancer, radiotherapy, surgical oncology

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