TARGIT-A randomised trial of Intrabeam TARGIT IORT for breast cancer

First publication of the main results (2010)

Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. 

The Lancet.  2010 ;376(9735):91-102.

5-year results and first analysis of survival (2014)

Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. 

The Lancet. 11 November 2013. doi:10.1016/s0140-6736(13)61950-9 

Full text PDF  Podcast

Full final 226 page report of the TARGIT-A trial of Intrabeam TARGIT IORT for HTA, NIHR, Department of Health, UK (2016)

 

An international randomised controlled trial to compare TARGeted Intraoperative radioTherapy (TARGIT) with conventional postoperative radiotherapy after breast-conserving surgery for women with early-stage breast cancer (the TARGIT-A trial). 

Health Technology Assessment 2016;20(73)

Recent peer reviewed publications are below: more are available here

TARGIT investigators at the – 10-year International Steering Committee meeting in 2010

What is TARGIT IORT for breast cancer?
  • The TARGIT technique uses the Intrabeam device for delivering precise and timely dose of intraoperative radiotherapy accurately to the tumour bed.

  • An academic insight led to the development of this device through a collaborative effort between University College London and the Photoelectron Corporation in 1990s.

  • It was first used on 2 July 1998 in the Middlesex Hospital, UCL, London. Intrabeam is currently manufactured by Carl Zeiss

  • The Intrabeam TARGIT IORT method has been rigorously tested in the randomised TARGIT-A trial in which patients  33 centres in 11 countries participated. Intrabeam TARGIT IORT given during the cancer operation was compared with the traditional radiation therapy given daily over several weeks after the operation.

  • By 2016, breast cancer centres in over 300 hospitals in 35 countries offer Intrabeam TARGIT IORT to suitable patients

What was done in the TARGIT-A trial?

  • The TARGIT-A trial was a randomised trial testing an individualised approach of radiation after lumpectomy for breast cancer.

  • The comparison in the TARGIT-A trial was between standard radiation therapy that is given over several weeks after a lumpectomy vs. a risk-adapted approach using single dose of TARGeted Intraoperative radioTherapy (TARGIT) using Intrabeam given at the time of lumpectomy.

  • The risk-adapted protocol recommended that if the patients who had received TARGIT IORT with Intrabeam were found to have high risk factors postoperatively, they also received whole breast radiation – which occurred in 15-20% of cases as expected in the protocol; otherwise, about 80% of such patients completed their treatment (surgery and radiation) during their lumpectomy.

  • The pre-specified non-inferiority margin was an absolute difference in local recurrence of breast cancer between TARGIT and EBRT of 2.5% — in simple terms, if the absolute difference in local recurrence between the two treatments being compared was less than 2.5%, they would be considered non-inferior to each other in terms of local control of breast cancer. Patient preference studies have suggests majority of patients consider such a 2.5% margin as appropriate.

  • Patients from 33 centres in 11 countries participated in the TARGIT-A trial (UK, USA, Germany, Italy, France Poland , Switzerland, Norway, Denmark, Canada and Australia) from 24 March 2000 to 25 June 2012. (map).

  • 2298 patients participated in the trial of immediate TARGIT-IORT vs EBRT from 2000 to 2012

  • 1153 patients participated in the trial of delayed TARGIT-IORT vs EBRT from 2004 to 2012. 

TARGIT-A Trial Design

In the randomised TARGIT-A trial, two policies of local radiation treatment are compared:

Eligible patients were recruited in one of the two trials based on the stage at which they are randomised:

The trial of immediate TARGIT-IORT vs EBRT - ie randomisation before the primary surgery (Prepathology)

 

This is the original method of entry into the TARGIT-A trial for a breast cancer patient. Once the decision to do a wide local excision (lumpectomy) is taken, and informed consent obtained, the randomisation takes place before surgery and if randomised to TARGIT, it is delivered to the fresh tumour bed immediately after lumpectomy for breast cancer. If at the postoperative pathology review, it is felt that they have a particularly high risk of local recurrence especially in other quadrants ( EIC, invasive lobular carcinoma or positive excision margins) then external beam radiotherapy can be added- all as part of the experimental arm of the trial. Centres could pre-specify additional such factors such as extensive lymphovascular invasion, multiple positive nodes, etc.

The trial of Delayed TARGIT-IORT vs EBRT - ie randomisation after lumpectomy has been done (Postpathology)

This separate parallel trial was started in 2004 to enable patients in whom the excision of the cancer had already been performed. This was logistically easier in some centres and theoretically allowed better case selection – although it required a second procedure to be performed. Randomisation in the Targit-A trial is performed after the the primary cancer is removed. Patients were randomly allocated to receive either conventional whole breast radiation therapy over several weeks (control arm), or  to receive TARGIT, single session intraoperative radiotherapy is given as a day-case operation in which the lumpectomy wound was re-opened and TARGIT-IORT was given. This procedure could be also performed under local anaesthetic.

What was found? Results of the TARGIT-A trial

  • In the trial of Immediate TARGIT vs EBRT when randomisation is before lumpectomy and TARGIT-IORT is given with lumpectomy, the 5-year local recurrence of breast cancer is similar to EBRT

  • In the trial of Delayed TARGIT vs EBRT, when randomisation is after lumpectomy and delayed TARGIT is given as a second procedure, the difference in local recurrence between TARGIT and EBRT was more than 2.5%

  • Breast cancer mortality with TARGIT were similar to EBRT

  • Mortality from other causes  was significantly lower with TARGIT due to fewer deaths from  cardiovascular causes and other cancers.

  • The results remain stable with longer follow up. The results were the same for the large number (1222) patients who were treated between 2000-2008 and had a median follow up of 5 years.

  • The TARGIT-A trial has a large number of patients (n=1222) with a median follow up of 5 years and even larger 2232 with a median follow up of nearly 4 years.

  • Therefore, these results can be relied upon to guide the application of TARGIT using Intrabeam in routine clinical practice in appropriate patients.

The TARGIT trial office has received its main funding from the Health Technology Assessment programme of the National Institutes of Health Research, Department of Health, UK for the TARGIT-A and TARGIT-B trials

First publication of the main results (2010)

Vaidya JS, Joseph DJ, Tobias JS, Bulsara M, Wenz F, Saunders C, Alvarado M, Flyger HL, Massarut S, Eiermann W, Keshtgar M, Dewar J, Kraus-Tiefenbacher U, Sutterlin M, Esserman L, Holtveg HM, Roncadin M, Pigorsch S, Metaxas M, Falzon M, Matthews A, Corica T, Williams NR, Baum M. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. The Lancet.  2010 ;376(9735):91-102.

5-year results and first analysis of survival (2014)

Vaidya JS, Wenz F, Bulsara M, Tobias JS, Joseph DJ, Keshtgar M, Flyger HL, Massarut S, Alvarado M, Saunders C, Eiermann W, Metaxas M, Sperk E, Sütterlin M, Brown D, Esserman L, Roncadin M, Thompson A, Dewar JA, Holtveg HMR, Pigorsch S, Falzon M, Harris E, Matthews A, Brew-Graves C, Potyka I, Corica T, Williams NR, Baum M. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. The Lancet. 11 November 2013. doi:10.1016/s0140-6736(13)61950-9   Full text PDF  Podcast 

 

Full 226 page report of the TARGIT-A trial for the HTA, National Institutes of Health Research, Department of Health, UK (2016)

Vaidya JS, Wenz F, Bulsara M, Tobias JS, Joseph DJ, Saunders C, Brew-Graves C, Potyka I, Morris S, Vaidya HJ, Williams NR, Baum M. An international randomised controlled trial to compare TARGeted Intraoperative radioTherapy (TARGIT) with conventional postoperative radiotherapy after breast-conserving surgery for women with early-stage breast cancer (the TARGIT-A trial). Health Technology Assessment 2016;20(73) TARGIT-A randomised clinical trial of TARGIT IORT using Intrabeam

Long-term outcomes of the trial of Delayed single-dose TARGIT-IORT vs EBRT for breast cancer (2020)

Jayant S. Vaidya, Max Bulsara, Christobel Saunders, Henrik Flyger, Jeffrey S. Tobias, Tammy Corica, Samuele Massarut, Frederik Wenz, Steffi Pigorsch, Michael Alvarado, Michael Douek, Wolfgang Eiermann, Chris Brew-Graves MSc, Norman Williams, Ingrid Potyka, Nicholas Roberts, Marcelle Bernstein , Douglas Brown, Elena Sperk, Siobhan Laws, Marc Sütterlin, Steinar Lundgren, Dennis Holmes, Lorenzo Vinante, Fernando Bozza, Montserrat Pazos, Magali Le Blanc-Onfroy, Günther Gruber, Wojciech Polkowski, Konstantin J. Dedes, Marcus Niewald, Jens Blohmer, David McCready, Richard Hoefer, Pond Kelemen, Gloria Petralia, Mary Falzon, Michael Baum, David Joseph
JAMA Oncol. doi:10.1001/jamaoncol.2020.0249 

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