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

Jayant S. Vaidya; Max Bulsara; Michael Baum; Frederik Wenz; Samuele Massarut; Steffi Pigorsch; Michael Alvarado; Michael Douek; Christobel Saunders; Henrik L. Flyger; Wolfgang Eiermann; Chris Brew-Graves; Norman R. Williams; Ingrid Potyka; Nicholas Roberts; Marcelle Bernstein; Douglas Brown; Elena Sperk; Siobhan Laws; Marc Sütterlin; Tammy Corica; 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; David J. Joseph; Jeffrey S. Tobias

doi:10.1136/bmj.m2836

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

Jayant S. Vaidya (Lead / Corresponding author), Max Bulsara, Michael Baum, Frederik Wenz, Samuele Massarut, Steffi Pigorsch, Michael Alvarado, Michael Douek, Christobel Saunders, Henrik L. Flyger, Wolfgang Eiermann, Chris Brew-Graves, Norman R. Williams, Ingrid Potyka, Nicholas Roberts, Marcelle Bernstein, Douglas Brown, Elena Sperk, Siobhan Laws, Marc SütterlinTammy Corica, 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, David J. Joseph, Jeffrey S. Tobias

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Abstract

Objective: To determine whether risk adapted intraoperative radiotherapy, delivered as a single dose during lumpectomy, can effectively replace postoperative whole breast external beam radiotherapy for early breast cancer.

Design: Prospective, open label, randomised controlled clinical trial.

Setting: 32 centres in 10 countries in the United Kingdom, Europe, Australia, the United States, and Canada.

Participants: 2298 women aged 45 years and older with invasive ductal carcinoma up to 3.5 cm in size, cN0-N1, eligible for breast conservation and randomised before lumpectomy (1:1 ratio, blocks stratified by centre) to either risk adapted targeted intraoperative radiotherapy (TARGIT-IORT) or external beam radiotherapy (EBRT).

Interventions: Random allocation was to the EBRT arm, which consisted of a standard daily fractionated course (three to six weeks) of whole breast radiotherapy, or the TARGIT-IORT arm. TARGIT-IORT was given immediately after lumpectomy under the same anaesthetic and was the only radiotherapy for most patients (around 80%). TARGIT-IORT was supplemented by EBRT when postoperative histopathology found unsuspected higher risk factors (around 20% of patients).

Main outcome measures: Non-inferiority with a margin of 2.5% for the absolute difference between the five year local recurrence rates of the two arms, and long term survival outcomes.

Results: Between 24 March 2000 and 25 June 2012, 1140 patients were randomised to TARGIT-IORT and 1158 to EBRT. TARGIT-IORT was non-inferior to EBRT: the local recurrence risk at five year complete follow-up was 2.11% for TARGIT-IORT compared with 0.95% for EBRT (difference 1.16%, 90% confidence interval 0.32 to 1.99). In the first five years, 13 additional local recurrences were reported (24/1140 v 11/1158) but 14 fewer deaths (42/1140 v 56/1158) for TARGIT-IORT compared with EBRT. With long term follow-up (median 8.6 years, maximum 18.90 years, interquartile range 7.0-10.6) no statistically significant difference was found for local recurrence-free survival (hazard ratio 1.13, 95% confidence interval 0.91 to 1.41, P=0.28), mastectomy-free survival (0.96, 0.78 to 1.19, P=0.74), distant disease-free survival (0.88, 0.69 to 1.12, P=0.30), overall survival (0.82, 0.63 to 1.05, P=0.13), and breast cancer mortality (1.12, 0.78 to 1.60, P=0.54). Mortality from other causes was significantly lower (0.59, 0.40 to 0.86, P=0.005).

Conclusion: For patients with early breast cancer who met our trial selection criteria, risk adapted immediate single dose TARGIT-IORT during lumpectomy was an effective alternative to EBRT, with comparable long term efficacy for cancer control and lower non-breast cancer mortality. TARGIT-IORT should be discussed with eligible patients when breast conserving surgery is planned.

Trial registration: ISRCTN34086741, NCT00983684.

Original language	English
Article number	m2836
Number of pages	16
Journal	BMJ
Volume	370
DOIs	https://doi.org/10.1136/bmj.m2836
Publication status	Published - 19 Aug 2020

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General Medicine

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1136/bmj.m2836Licence: CC BY

Final Published VersionFinal published version, 1.15 MBLicence: CC BY

Cite this

Vaidya, J. S., Bulsara, M., Baum, M., Wenz, F., Massarut, S., Pigorsch, S., Alvarado, M., Douek, M., Saunders, C., Flyger, H. L., Eiermann, W., Brew-Graves, C., Williams, N. R., Potyka, I., Roberts, N., Bernstein, M., Brown, D., Sperk, E., Laws, S., ... Tobias, J. S. (2020). 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, Article m2836. https://doi.org/10.1136/bmj.m2836

@article{8cfe12d5555640b29b75c4ad7d3f0c29,

title = "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",

abstract = "Objective: To determine whether risk adapted intraoperative radiotherapy, delivered as a single dose during lumpectomy, can effectively replace postoperative whole breast external beam radiotherapy for early breast cancer.Design: Prospective, open label, randomised controlled clinical trial.Setting: 32 centres in 10 countries in the United Kingdom, Europe, Australia, the United States, and Canada.Participants: 2298 women aged 45 years and older with invasive ductal carcinoma up to 3.5 cm in size, cN0-N1, eligible for breast conservation and randomised before lumpectomy (1:1 ratio, blocks stratified by centre) to either risk adapted targeted intraoperative radiotherapy (TARGIT-IORT) or external beam radiotherapy (EBRT).Interventions: Random allocation was to the EBRT arm, which consisted of a standard daily fractionated course (three to six weeks) of whole breast radiotherapy, or the TARGIT-IORT arm. TARGIT-IORT was given immediately after lumpectomy under the same anaesthetic and was the only radiotherapy for most patients (around 80%). TARGIT-IORT was supplemented by EBRT when postoperative histopathology found unsuspected higher risk factors (around 20% of patients).Main outcome measures: Non-inferiority with a margin of 2.5% for the absolute difference between the five year local recurrence rates of the two arms, and long term survival outcomes.Results: Between 24 March 2000 and 25 June 2012, 1140 patients were randomised to TARGIT-IORT and 1158 to EBRT. TARGIT-IORT was non-inferior to EBRT: the local recurrence risk at five year complete follow-up was 2.11% for TARGIT-IORT compared with 0.95% for EBRT (difference 1.16%, 90% confidence interval 0.32 to 1.99). In the first five years, 13 additional local recurrences were reported (24/1140 v 11/1158) but 14 fewer deaths (42/1140 v 56/1158) for TARGIT-IORT compared with EBRT. With long term follow-up (median 8.6 years, maximum 18.90 years, interquartile range 7.0-10.6) no statistically significant difference was found for local recurrence-free survival (hazard ratio 1.13, 95% confidence interval 0.91 to 1.41, P=0.28), mastectomy-free survival (0.96, 0.78 to 1.19, P=0.74), distant disease-free survival (0.88, 0.69 to 1.12, P=0.30), overall survival (0.82, 0.63 to 1.05, P=0.13), and breast cancer mortality (1.12, 0.78 to 1.60, P=0.54). Mortality from other causes was significantly lower (0.59, 0.40 to 0.86, P=0.005).Conclusion: For patients with early breast cancer who met our trial selection criteria, risk adapted immediate single dose TARGIT-IORT during lumpectomy was an effective alternative to EBRT, with comparable long term efficacy for cancer control and lower non-breast cancer mortality. TARGIT-IORT should be discussed with eligible patients when breast conserving surgery is planned.Trial registration: ISRCTN34086741, NCT00983684.",

author = "Vaidya, {Jayant S.} and Max Bulsara and Michael Baum and Frederik Wenz and Samuele Massarut and Steffi Pigorsch and Michael Alvarado and Michael Douek and Christobel Saunders and Flyger, {Henrik L.} and Wolfgang Eiermann and Chris Brew-Graves and Williams, {Norman R.} and Ingrid Potyka and Nicholas Roberts and Marcelle Bernstein and Douglas Brown and Elena Sperk and Siobhan Laws and Marc S{\"u}tterlin and Tammy Corica and Steinar Lundgren and Dennis Holmes and Lorenzo Vinante and Fernando Bozza and Montserrat Pazos and {Le Blanc-Onfroy}, Magali and G{\"u}nther Gruber and Wojciech Polkowski and Dedes, {Konstantin J.} and Marcus Niewald and Jens Blohmer and David McCready and Richard Hoefer and Pond Kelemen and Gloria Petralia and Mary Falzon and Joseph, {David J.} and Tobias, {Jeffrey S.}",

note = "{\textcopyright} Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2020",

month = aug,

day = "19",

doi = "10.1136/bmj.m2836",

language = "English",

volume = "370",

journal = "BMJ",

issn = "0959-8138",

publisher = "BMJ Publishing Group",

}

Vaidya, JS, Bulsara, M, Baum, M, Wenz, F, Massarut, S, Pigorsch, S, Alvarado, M, Douek, M, Saunders, C, Flyger, HL, Eiermann, W, Brew-Graves, C, Williams, NR, Potyka, I, Roberts, N, Bernstein, M, Brown, D, Sperk, E, Laws, S, Sütterlin, M, Corica, T, Lundgren, S, Holmes, D, Vinante, L, Bozza, F, Pazos, M, Le Blanc-Onfroy, M, Gruber, G, Polkowski, W, Dedes, KJ, Niewald, M, Blohmer, J, McCready, D, Hoefer, R, Kelemen, P, Petralia, G, Falzon, M, Joseph, DJ & Tobias, JS 2020, '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, vol. 370, m2836. https://doi.org/10.1136/bmj.m2836

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. / Vaidya, Jayant S. (Lead / Corresponding author); Bulsara, Max; Baum, Michael et al.
In: BMJ, Vol. 370, m2836, 19.08.2020.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer

T2 - TARGIT-A randomised clinical trial

AU - Vaidya, Jayant S.

AU - Bulsara, Max

AU - Baum, Michael

AU - Wenz, Frederik

AU - Massarut, Samuele

AU - Pigorsch, Steffi

AU - Alvarado, Michael

AU - Douek, Michael

AU - Saunders, Christobel

AU - Flyger, Henrik L.

AU - Eiermann, Wolfgang

AU - Brew-Graves, Chris

AU - Williams, Norman R.

AU - Potyka, Ingrid

AU - Roberts, Nicholas

AU - Bernstein, Marcelle

AU - Brown, Douglas

AU - Sperk, Elena

AU - Laws, Siobhan

AU - Sütterlin, Marc

AU - Corica, Tammy

AU - Lundgren, Steinar

AU - Holmes, Dennis

AU - Vinante, Lorenzo

AU - Bozza, Fernando

AU - Pazos, Montserrat

AU - Le Blanc-Onfroy, Magali

AU - Gruber, Günther

AU - Polkowski, Wojciech

AU - Dedes, Konstantin J.

AU - Niewald, Marcus

AU - Blohmer, Jens

AU - McCready, David

AU - Hoefer, Richard

AU - Kelemen, Pond

AU - Petralia, Gloria

AU - Falzon, Mary

AU - Joseph, David J.

AU - Tobias, Jeffrey S.

PY - 2020/8/19

Y1 - 2020/8/19

N2 - Objective: To determine whether risk adapted intraoperative radiotherapy, delivered as a single dose during lumpectomy, can effectively replace postoperative whole breast external beam radiotherapy for early breast cancer.Design: Prospective, open label, randomised controlled clinical trial.Setting: 32 centres in 10 countries in the United Kingdom, Europe, Australia, the United States, and Canada.Participants: 2298 women aged 45 years and older with invasive ductal carcinoma up to 3.5 cm in size, cN0-N1, eligible for breast conservation and randomised before lumpectomy (1:1 ratio, blocks stratified by centre) to either risk adapted targeted intraoperative radiotherapy (TARGIT-IORT) or external beam radiotherapy (EBRT).Interventions: Random allocation was to the EBRT arm, which consisted of a standard daily fractionated course (three to six weeks) of whole breast radiotherapy, or the TARGIT-IORT arm. TARGIT-IORT was given immediately after lumpectomy under the same anaesthetic and was the only radiotherapy for most patients (around 80%). TARGIT-IORT was supplemented by EBRT when postoperative histopathology found unsuspected higher risk factors (around 20% of patients).Main outcome measures: Non-inferiority with a margin of 2.5% for the absolute difference between the five year local recurrence rates of the two arms, and long term survival outcomes.Results: Between 24 March 2000 and 25 June 2012, 1140 patients were randomised to TARGIT-IORT and 1158 to EBRT. TARGIT-IORT was non-inferior to EBRT: the local recurrence risk at five year complete follow-up was 2.11% for TARGIT-IORT compared with 0.95% for EBRT (difference 1.16%, 90% confidence interval 0.32 to 1.99). In the first five years, 13 additional local recurrences were reported (24/1140 v 11/1158) but 14 fewer deaths (42/1140 v 56/1158) for TARGIT-IORT compared with EBRT. With long term follow-up (median 8.6 years, maximum 18.90 years, interquartile range 7.0-10.6) no statistically significant difference was found for local recurrence-free survival (hazard ratio 1.13, 95% confidence interval 0.91 to 1.41, P=0.28), mastectomy-free survival (0.96, 0.78 to 1.19, P=0.74), distant disease-free survival (0.88, 0.69 to 1.12, P=0.30), overall survival (0.82, 0.63 to 1.05, P=0.13), and breast cancer mortality (1.12, 0.78 to 1.60, P=0.54). Mortality from other causes was significantly lower (0.59, 0.40 to 0.86, P=0.005).Conclusion: For patients with early breast cancer who met our trial selection criteria, risk adapted immediate single dose TARGIT-IORT during lumpectomy was an effective alternative to EBRT, with comparable long term efficacy for cancer control and lower non-breast cancer mortality. TARGIT-IORT should be discussed with eligible patients when breast conserving surgery is planned.Trial registration: ISRCTN34086741, NCT00983684.

AB - Objective: To determine whether risk adapted intraoperative radiotherapy, delivered as a single dose during lumpectomy, can effectively replace postoperative whole breast external beam radiotherapy for early breast cancer.Design: Prospective, open label, randomised controlled clinical trial.Setting: 32 centres in 10 countries in the United Kingdom, Europe, Australia, the United States, and Canada.Participants: 2298 women aged 45 years and older with invasive ductal carcinoma up to 3.5 cm in size, cN0-N1, eligible for breast conservation and randomised before lumpectomy (1:1 ratio, blocks stratified by centre) to either risk adapted targeted intraoperative radiotherapy (TARGIT-IORT) or external beam radiotherapy (EBRT).Interventions: Random allocation was to the EBRT arm, which consisted of a standard daily fractionated course (three to six weeks) of whole breast radiotherapy, or the TARGIT-IORT arm. TARGIT-IORT was given immediately after lumpectomy under the same anaesthetic and was the only radiotherapy for most patients (around 80%). TARGIT-IORT was supplemented by EBRT when postoperative histopathology found unsuspected higher risk factors (around 20% of patients).Main outcome measures: Non-inferiority with a margin of 2.5% for the absolute difference between the five year local recurrence rates of the two arms, and long term survival outcomes.Results: Between 24 March 2000 and 25 June 2012, 1140 patients were randomised to TARGIT-IORT and 1158 to EBRT. TARGIT-IORT was non-inferior to EBRT: the local recurrence risk at five year complete follow-up was 2.11% for TARGIT-IORT compared with 0.95% for EBRT (difference 1.16%, 90% confidence interval 0.32 to 1.99). In the first five years, 13 additional local recurrences were reported (24/1140 v 11/1158) but 14 fewer deaths (42/1140 v 56/1158) for TARGIT-IORT compared with EBRT. With long term follow-up (median 8.6 years, maximum 18.90 years, interquartile range 7.0-10.6) no statistically significant difference was found for local recurrence-free survival (hazard ratio 1.13, 95% confidence interval 0.91 to 1.41, P=0.28), mastectomy-free survival (0.96, 0.78 to 1.19, P=0.74), distant disease-free survival (0.88, 0.69 to 1.12, P=0.30), overall survival (0.82, 0.63 to 1.05, P=0.13), and breast cancer mortality (1.12, 0.78 to 1.60, P=0.54). Mortality from other causes was significantly lower (0.59, 0.40 to 0.86, P=0.005).Conclusion: For patients with early breast cancer who met our trial selection criteria, risk adapted immediate single dose TARGIT-IORT during lumpectomy was an effective alternative to EBRT, with comparable long term efficacy for cancer control and lower non-breast cancer mortality. TARGIT-IORT should be discussed with eligible patients when breast conserving surgery is planned.Trial registration: ISRCTN34086741, NCT00983684.

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U2 - 10.1136/bmj.m2836

DO - 10.1136/bmj.m2836

M3 - Article

C2 - 32816842

SN - 0959-8138

VL - 370

JO - BMJ

JF - BMJ

M1 - m2836

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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

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