A Brief Description of the TARGIT-A trial and the results published in the Lancet in 2010.
For most women with breast cancer, the standard treatment includes surgery, which removes the tumour with a margin of normal tissues (lumpectomy), and radiotherapy, which reduces the chances of the cancer coming back. Radiotherapy is usually given as a 3-6 weeks course (whole breast external beam radiotherapy -EBRT). A new development could significantly change the way breast cancer is treated.
Based on our clinical and pathological studies, we suggested in 1995 that radiotherapy restricted only to the tissues around the original tumour, and given at the time of surgery, may be as effective.
In the late 1990s, we designed a new device (called Intrabeam®) in collaboration with a specialist manufacturer, and developed the operative technique to deliver single-dose radiotherapy either during the lumpectomy or at a second operation soon afterwards. We called this novel approach TARGeted Intra-operative radioTherapy (TARGIT). In this technique, radiation is given directly to the site, the spherical device being placed where the lump was, and over half an hour, radiation is administered to the tissues that surrounded the tumour – the ‘tumour bed’, from within the breast.
In March 2000 we launched a large international randomised clinical study (TARGIT-A trial) that took 10 years to complete and directly compared the TARGIT approach with conventional EBRT given over 3-6 weeks. The TARGIT approach was to give single-dose TARGIT to every patient, and, if a higher than acceptable risk was found (for example many positive lymph nodes) whole breast EBRT was added. The control group consisted of whole breast EBRT over 3-6 weeks for every patient. Patients could also be entered in the trial after the tumour had been removed for example, at another hospital. For such patients, TARGIT was delivered by re-opening the wound as an additional surgical procedure.
It is important to recognise that the TARGIT-A trial compared TARGIT (with added whole breast EBRT as per the individual risk) vs. whole breast EBRT in all. In other words it compared risk-adjusted radiotherapy vs. whole-breast-radiotherapy-for-all. Within the trial, overall, 14% patients who received TARGIT also received EBRT. Amongst those who received TARGIT at the time of the first operation, 21% also received EBRT. Thus nearly 4 out of 5 such patients did not need any further radiotherapy.
In total, 2232 women from 28 centres in 9 countries participated in the trial: 1113 were allocated the TARGIT approach and 1119 the conventional radiotherapy approach. Our manuscript describing the results was fast tracked and published in The Lancet (online first on 5 June and in the print on 9 July 2010)1. We found that the local recurrence rates in the two groups were very low and similar at 4 years, by which time the greatest risk of local recurrence had passed (EBRT group 0.95% and TARGIT group 1.2%)*. We also found that the TARGIT approach had less radiotherapy related side effects.
We concluded in the Lancet that “For selected patients with early breast cancer, a single dose of radiotherapy delivered at the time of surgery by use of targeted intraoperative radiotherapy should be considered as an alternative to external beam radiotherapy delivered over several weeks”
Given the similar outcome and lower side effects, one cannot overemphasise the obvious advantages to the patient and the healthcare system of completing the radiotherapy in a single session at the time of the cancer operation; in addition the equipment is less expensive and there would be lower greenhouse gas emissions from avoiding 3-6 weeks’ of daily trips for EBRT.
*The statistics: The actual difference between the TARGIT and EBRT groups was 0.25% (10 times less than our original acceptable limit of 2.5%) at 4 years. As is usual while reporting clinical trials, not all patients have reached the follow up period of 4 years, so a standard statistical method was used to estimate a range around the 0.25% difference. This range, called 95% confidence interval, was -1% to +1.5%, which means that, with a 95% probability, at worst TARGIT is 1.5% worse than EBRT and at best TARGIT is 1% better than EBRT.
Photograph taken at the International Steering Committee and Data Monitoring Committee meeting at Barcelona on 25 March 2010
Contributors
JSV, MBa, and JST were responsible for trial concept, trial design, trial management, data interpretation, and writing of the report. DJJ, FW, 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 report. JSV and MA contributed to training and accreditation of centres, patient accrual and treatment, data collection, and writing of the report. JSV and NRW designed the statistical analysis plan and contributed to statistical analysis, trial coordination, data collection, data interpretation, and writing of the report. MBu and JSV did the statistical analyses and contributed to data interpretation and writing of the report. CS, TC, and LE contributed to trial design, patient accrual, patient treatment, data interpretation, and writing of the report. HLF, WE, MK, MR, and MS contributed to patient accrual, patient treatment, data collection, and data interpretation. MK contributed to trial management and accreditation of new centres. HLF, SM, WE, MK, JSV, JD, UKT, MS, MR, HMRH, and SP contributed to setting up their centres, patient accrual, treatment, data collection, and approval of the report. JSV and MM were involved with design and preclinical tests of the Intrabeam system. MM was involved with continuing quality assurance and dosimetry analysis, data collection, and approved the report. MF was involved with primary diagnosis and subsequent assessment of the histology from University College London Hospitals. AM reviewed the data generated from the trial and their interpretation and approved the report. All authors apart from HLF, MR, SP, and HMRH attended the ISC meetings as members. The authors take full responsibility for the report. The writing committee consisted of JSV,JST, MBu, FW, CS, MA, and DJJ, and was helped by the trial operations staff and their respective families.
TARGIT-A team
International Steering Committee: Jayant S Vaidya, David J Joseph, Jeffrey S Tobias, Max Bulsara, Frederik Wenz, Christobel Saunders, Michael Alvarado, Henrik L Flyger, Samuele Massarut, Wolfgang Eiermann, Mohammed Keshtgar, John Dewar, Uta Kraus-Tiefenbacher, Marc Sütterlin, Laura Esserman, Marinos Metaxas, Mary Falzon, April Matthews, Stephen Morris, Tammy Corica, Norman R Williams, Michael Baum. Carl Zeiss staff attended the meetings as observers. Data Monitoring Committee: Jack Cuzick, Alan Rodger, Hazel Thornton. Trial Operations Staff: London, UK: Michael Baum (director), Norman R Williams, Ingrid Potyka, Chris Brew-Graves, Cindy Li, Alexandra Sherley, Past: Joan Houghton, Christina Lennon, Olive Murphy; Mannheim, Germany: Anke Keller; Perth, WA, Australia: Tammy Corica, Celsete Lopez, Eva Vosikova. Targit Physics Group: Akbar Beiki-Ardakani (Toronto), Elvira Capra (Aviano), Annette Haworth (Melbourne), Peter Lanzon (Perth), Colin Mackay (Dundee), Marinos G Metaxas (London), Sonia Reccanello (Padova), Michael Ringor (Indiana), Giovanna Sartor (Aviano), Chris Stacey (London), Volker Steil (Mannheim), Fank Weigand (Carl Zeiss), Jayant S Vaidya (London), Alex Vitkin (Toronto), Norman Williams (London). Individual centre teams (in order of the date of randomisation of the first patient): University College London Hospital, London, UK (J S Vaidya, J S Tobias, M Baum, M Keshtgar, G Blackman, C Brew-Graves, M Douek, D D’Souza, M Falzon, E Harrison, C Kocjan, S Lakhani, M Metaxas, P Mulvey, S V Naidu, R Sainsbury, C Saunders, C Stacey, I Taylor); Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany (Frederik Wenz, E Blank, M Bohrer, S Clausen, B Hermann, R Hildenbrand, Anke Keller, Uta Kraus-Tiefenbacher, B Kuepper, A Marx, F Melchert, D Neumann, F Schneider, V Steil, M Suetterlin, M Trunk); Sir Charles Gairdner Hospital, Perth, WA, Australia (Christobel Saunders, David J Joseph, Sean Bydder, Sheryl Campbell, Joe Clarke, Tammy Corica, Annette Haworth, Rosemary Hedges, Robin Kane, Peter Lanzon, Celeste Lopez, Mandy Taylor, Eva Vosikova, Nik Zeps); Centro di Riferimento Oncologico, Aviano, Italy (Samuele Massarut, M Arcicasa, E Bidoli, E Cadiani, E Capra, M Oliva, T Perin, S Reccanello, M Roncadin, G Sartor, G Tabaro, M Trovo, R Volpe); Ninewells Hospital, Dundee, UK (J S Vaidya, J Dewar, C Ackland, D Adamson, K Armoogum, J Bosch, D Brown, S Edwards, J Gardner, A Gunning, M Hawkes, L Jordan, J Lindsay, G Little, V Walker, C Mackay, A Munro, J Parry, C Purdie, M Reis, A Thomson, R A B Wood); University of California, San Francisco Medical Center, San Francisco, CA, USA (Laura Esserman, Michael Alvarado, Alfred Au, Alison Bevan, Jay Connolly, Cheryl Ewing, Clark Fisher, Shelley Hwang, K Lane, Christina Minami, Michelle Oboite, Cathy Park, Jean Pouliot, Theadora Sakata); Frauenklinik vom Roten Kreuz, Munich, Germany (Wolfgang Eiermann, Beyhan Ataseven, C Becker, B Hoegel, P Kneschaurek, A Lackermeier, M Molls, Carsten Nieder, Steffi Pigorsch, J Rauch, Barbara Röper,Sabine Schill, Brigitte Werner, Christopher Wolf); University of Southern California, Los Angeles, CA, USA (Dennis R Holmes, Melvin Astrahan, Carryl Dubois, Jacqueline Majors, Sylvia Villegas Mendez, Afshin Rashtian, Ronald Rivera, Howard Silberman, Melvin Silverstein, Rashida Soni, Oscar E Streeter Jr, Lina Wang); Ospedale San Giuseppe di Empoli, Empoli, Italy (Gianmaria Fiorentini, Carli Ballola Adele, Rafaella Barca, Mauro Biancalani, Giampaolo Biti, Enrico Cellai, Antonella Compagnucci, Claudio Caponi, Vito Maria Fontanarosa, Roberta Ghezzi, Alessandro Ghirelli, Gloria Giustarini, Barbara Grilli Leonulli, Francesca Littori, Maurizio Pertici, Visna Petrina, Paola Raffaele, Francesca Righi, Serenella Russo, Michele de Simone, Gina Turrisi); Sankt Gertrauden-Krankenhaus, Berlin, Germany (Jens-Uwe Blohmer, Petra Feyer, J Gross, G Jautzke, K Luebbert, Michaela Platzer, Joerg Preussler, D Puppe, Esther Wiedemann); Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (Michael Henderson, David Blakey, Boon Chua, Ram Das, Roslyn Drummond, Annette Haworth, Penny Fogg, Stephen Fox, Jodi Lynch, Jane O’Brien, Catherine Poliness, Ann-Marie Power, David Speakman, Tina Thorpe, Melanie Walker); Ludwig Maximilians Universität, Munich, Germany (Wolfgang Janni, Ulrich Andergassen, C Balka, Darius Dian, Sylvia Dondl, Klaus Friese, Julia Jueckstock, Thomas Kirchner, Klaus Krimmel, Doris Mayr, Susanne Reinhard, Dr Schaffer, Christian Schindlbeck, Harald Sommer, Justus Well); Universität Frankfurt am Main, Frankfurt, Germany (M Kaufmann, H Boettcher, J Moog, Achim Rody, Claus Rödel, S Schopohl, Christian Weiss, Inge Fraunholz, Ulla Ramm, Martin-Leo Hansmann, R Strohmeier); Herlev/Rigs Hospitals, Copenhagen, Denmark (Henrik Flyger, Eva Balslev, Niels Bentzon, Paul Geertsen, Helle Holtveg, Claus Kamby, Niels Kroman, Faisal Mahmood, Fritz Rank, Birgitte Bruun Rasmussen, Lone Gry Schäfer, Peter Michael Vestlev, Vera Timmermans Wielenga, Eva Wilken); Medical University of Lublin, Lublin, Poland (Wojciech P Polkowski, Malgorzata Jankiewicz, Andrzej Kurylcio, Maria Mazurkiewicz, Jerzy Mielko, Krzysztof Paprota, Barbara Pawlowska-Wakowicz, Urszula Radwanska, Jaroslaw Romanek, Zofia Siezieniewska, Magdalena Skorzewska, Andrzej Stanislawek); Royal Free/Whittington Hospitals, London, UK (Mohammed Keshtgar, Jayant S Vaidya, Glen Blackman, R Chaudhuri, R Crooks, Tim Davidson, Ruth Hudson, Jawad Keshtgar, Vivienne Maidens, F Peters, Katherine Pigott, Su Ramachandra, Chris Stacey, Alan Wilson); Lafayette Surgical Clinic, Lafayette, IN, USA (Tom L Summer, Mario Contreras, Paul M DesRosiers, Irene Gordon, Cindy McDowell, M Ringer, Tammy Spurlock); Sentara Surgery Specialists, Hampton, VA, USA (Richard A Hoefer, Mary Berry, Donna Forrest, Arvind Mahatma, Michael Miller, Song Kang, Gregory J Lavalle, Deborah A Martinez, Sandra Piggee); Uniklinikum des Saarlandes, Homburg, Germany (Erich Solomayer, K Abel, S Baum, Rainer Allgayer, R M Bohle, Mustafa Deryal, J Fleckenstein, R Grobholz, Jeanett Koehn, Anja Martin-Riedheimer, Marcus Niewald, Markus Promnik, Christian Ruebe, W Schmidt); Princess Margaret Hospital, Toronto, ON, Canada (David McCready, A Beiki-Ardakani, John Cho, S Done, J Escallon, AW Fyles, W Levin, Alex Vitkin, Marie Vranic); Royal Hampshire County Hospital, Winchester, UK (Dick Rainsbury, Claire Birch, Lyn Booth, Caroline Cross, Alan Gately, Virginia Hall, Kevin Harris, Siobhan Laws, Sanjay Raj, Balvinder Shoker, Virginia Straker, Jennifer Wilson); Brust Zentrum Seefeld, Zurich, Switzerland (Christopher Rageth, Uwe Gneveckow, Elisabeth Grob, Guenther Gruber, Baerbel Papassotiropoulos, Barbara Tausch, C Tausch, Zsuszanna Varga, Iris Vergin); Universitäts Spital Zurich, Zurich, Switzerland (Claudia Hutzli, Yvonne Burgstaller, R Caduff, Daniel Fink, Guntram Kunz, Claudia Linsenmeier, Yousef Najafi, Eleftherios Samartzis, Ana-Maria Schmidt, Tino Streller, Z Varga, Madeleine Wick); St Olav’s Hospital, Trondheim, Norway (Steinar Lundgren, Anne Brit Abusland, Marianne Brekke, Dagrun Danielsen, Hans E Fjosne, Jomar Frengen, Kristen Helset, Jarle Karlsen, Petter Osthus, Hanne-Brit Grong Smethurst, Trond Strickert); University of Nebraska Medical Center, Omaha, NE, USA (James Edney, Aaron Sasson, Debra Spence, Robert Thompson, William W West, Sumin Zhou); Guy’s Hospital, London, UK (Michael Douek, Sarah Aldridge, A Kothari, Nick Beechey-Newman, Charles Deehan, Ian Fentiman, Hisham Hamed, Sarah Harris, Hardeep Johal, Sarah Pinder, Arnie Purushotham, Vernie Ramalingam, Chris Stacey); Vassar Brothers Medical Center, New York, NY, USA (Angela Keleher, Eileen Abate, Nicole Cappillino, Laszlo Csury, Edward Farhangi, Anne Kim, Sutini Ngadiman,
Dimitrios Papadopoulos, Dan Pavord, P Hank Schmidt, Camilo Torres); New York Medical College, New York, NY, USA (P Kelemen, Andrew Ashikari, Ulrich Hermato, Helen Li, Demetrious Makrides, Mike Malamed, Wanda Rivera, Yadita Samnarain, Alfred Tinger, Raphael Yankelevich, Yasmin Yusuf).
Conflicts of interest
JSV had received a research grant from Photoelectron Corp (1996–99), and from Carl Zeiss for supporting data management at the University of Dundee (Dundee, UK) and has subsequently received honoraria. MBa is on the scientific advisory board of Carl Zeiss and is paid monthly consultancy fees. FW has received a research grant from Carl Zeiss for supporting radiobiological research. Carl Zeiss sponsors most of the travel and accommodation for meetings of the ISC and DMC and when necessary for conferences where a presentation about targeted intraoperative radio- therapy is being made for all authors apart from LE, MR, WE, and HMRH. Carl Zeiss paid MM and AM honoraria for attending ISC meetings. MR, WE, and HMRH declare that they have no conflicts of interest.
Acknowledgments
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, 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. We thank Michael D O’Shea (Tessella, Abingdon, UK) for database development, Mo Thaha for help in data collection, and Hrisheekesh J Vaidya for help with figure 1A, as well as several contributors who have now left the individual centres. Travel and accommodation for meetings of the international steering committee and data monitoring committee were provided by Carl Zeiss. Funding for the TARGIT Trials Operations Office was provided by the NIHR Health Technology Assessment programme. Individual centres were self-financed. We thank all the patients who kindly participated in the trial.