Effect of Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast Radiotherapy on Local Recurrence and Survival: Long-term Results From the TARGIT-A Randomized Clinical Trial in Early Breast Cancer

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; 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

doi:10.1001/jamaoncol.2020.0249

Effect of Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast Radiotherapy on Local Recurrence and Survival: Long-term Results From the TARGIT-A Randomized Clinical Trial in Early Breast Cancer

Jayant S. Vaidya (Lead / Corresponding author), 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, Norman Williams, Ingrid Potyka, Nicholas Roberts, Marcelle Bernstein, Douglas Brown, Elena Sperk, Siobhan LawsMarc 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

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Abstract

Importance: Conventional adjuvant radiotherapy for breast cancer given daily for several weeks is onerous and expensive. Some patients may be obliged to choose a mastectomy instead, and some may forgo radiotherapy altogether. We proposed a clinical trial to test whether radiotherapy could be safely limited to the tumor bed.

Objective: To determine whether delayed second-procedure targeted intraoperative radiotherapy (TARGIT-IORT) is noninferior to whole-breast external beam radiotherapy (EBRT) in terms of local control.

Design, Setting, and Participants: In this prospective, randomized (1:1 ratio) noninferiority trial, 1153 patients aged 45 years or older with invasive ductal breast carcinoma smaller than 3.5 cm treated with breast conservation were enrolled from 28 centers in 9 countries. Data were locked in on July 3, 2019.

Interventions: The TARGIT-A trial was started in March 2000; patients were randomized after needle biopsy to receive TARGIT-IORT immediately after lumpectomy under the same anesthetic vs EBRT and results have been shown to be noninferior. A parallel study, described in this article, was initiated in 2004; patients who had their cancer excised were randomly allocated using separate randomization tables to receive EBRT or delayed TARGIT-IORT given as a second procedure by reopening the lumpectomy wound.

Main Outcomes and Measures: A noninferiority margin for local recurrence rate of 2.5% at 5 years, and long-term survival outcomes.

Results: Overall, 581 women (mean [SD] age, 63 [7] years) were randomized to delayed TARGIT-IORT and 572 patients (mean [SD] age, 63 [8] years) were randomized to EBRT. Sixty patients (5%) had tumors larger than 2 cm, or had positive nodes and only 32 (2.7%) were younger than 50 years. Delayed TARGIT-IORT was not noninferior to EBRT. The local recurrence rates at 5-year complete follow-up were: delayed TARGIT-IORT vs EBRT (23/581 [3.96%] vs 6/572 [1.05%], respectively; difference, 2.91%; upper 90% CI, 4.4%). With long-term follow-up (median [IQR], 9.0 [7.5-10.5] years), there was no statistically significant difference in local recurrence-free survival (HR, 0.75; 95% CI, 0.57-1.003; P = .052), mastectomy-free survival (HR, 0.88; 95% CI, 0.65-1.18; P = .38), distant disease-free survival (HR, 1.00; 95% CI, 0.72-1.39; P = .98), or overall survival (HR, 0.96; 95% CI, 0.68-1.35; P = .80).

Conclusions and Relevance: These long-term data show that despite an increase in the number of local recurrences with delayed TARGIT-IORT, there was no statistically significant decrease in mastectomy-free survival, distant disease-free survival, or overall survival.

Trial Registration: ISRCTN34086741, ClinicalTrials.gov Identifier: NCT00983684.

Original language	English
Article number	e200249
Number of pages	10
Journal	JAMA Oncology
Volume	6
Issue number	7
Early online date	2 Apr 2020
DOIs	https://doi.org/10.1001/jamaoncol.2020.0249
Publication status	Published - Jul 2020

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

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

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Vaidya, J. S., Bulsara, M., Saunders, C., Flyger, H., Tobias, J. S., Corica, T., Massarut, S., Wenz, F., Pigorsch, S., Alvarado, M., Douek, M., Eiermann, W., Brew-Graves, C., Williams, N., Potyka, I., Roberts, N., Bernstein, M., Brown, D., Sperk, E., ... Joseph, D. (2020). Effect of Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast Radiotherapy on Local Recurrence and Survival: Long-term Results From the TARGIT-A Randomized Clinical Trial in Early Breast Cancer. JAMA Oncology, 6(7), Article e200249. https://doi.org/10.1001/jamaoncol.2020.0249

@article{55d3b4ee4011478abb4c483e65c90aee,

title = "Effect of Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast Radiotherapy on Local Recurrence and Survival: Long-term Results From the TARGIT-A Randomized Clinical Trial in Early Breast Cancer",

abstract = "Importance: Conventional adjuvant radiotherapy for breast cancer given daily for several weeks is onerous and expensive. Some patients may be obliged to choose a mastectomy instead, and some may forgo radiotherapy altogether. We proposed a clinical trial to test whether radiotherapy could be safely limited to the tumor bed.Objective: To determine whether delayed second-procedure targeted intraoperative radiotherapy (TARGIT-IORT) is noninferior to whole-breast external beam radiotherapy (EBRT) in terms of local control.Design, Setting, and Participants: In this prospective, randomized (1:1 ratio) noninferiority trial, 1153 patients aged 45 years or older with invasive ductal breast carcinoma smaller than 3.5 cm treated with breast conservation were enrolled from 28 centers in 9 countries. Data were locked in on July 3, 2019.Interventions: The TARGIT-A trial was started in March 2000; patients were randomized after needle biopsy to receive TARGIT-IORT immediately after lumpectomy under the same anesthetic vs EBRT and results have been shown to be noninferior. A parallel study, described in this article, was initiated in 2004; patients who had their cancer excised were randomly allocated using separate randomization tables to receive EBRT or delayed TARGIT-IORT given as a second procedure by reopening the lumpectomy wound.Main Outcomes and Measures: A noninferiority margin for local recurrence rate of 2.5% at 5 years, and long-term survival outcomes.Results: Overall, 581 women (mean [SD] age, 63 [7] years) were randomized to delayed TARGIT-IORT and 572 patients (mean [SD] age, 63 [8] years) were randomized to EBRT. Sixty patients (5%) had tumors larger than 2 cm, or had positive nodes and only 32 (2.7%) were younger than 50 years. Delayed TARGIT-IORT was not noninferior to EBRT. The local recurrence rates at 5-year complete follow-up were: delayed TARGIT-IORT vs EBRT (23/581 [3.96%] vs 6/572 [1.05%], respectively; difference, 2.91%; upper 90% CI, 4.4%). With long-term follow-up (median [IQR], 9.0 [7.5-10.5] years), there was no statistically significant difference in local recurrence-free survival (HR, 0.75; 95% CI, 0.57-1.003; P = .052), mastectomy-free survival (HR, 0.88; 95% CI, 0.65-1.18; P = .38), distant disease-free survival (HR, 1.00; 95% CI, 0.72-1.39; P = .98), or overall survival (HR, 0.96; 95% CI, 0.68-1.35; P = .80).Conclusions and Relevance: These long-term data show that despite an increase in the number of local recurrences with delayed TARGIT-IORT, there was no statistically significant decrease in mastectomy-free survival, distant disease-free survival, or overall survival.Trial Registration: ISRCTN34086741, ClinicalTrials.gov Identifier: NCT00983684.",

author = "Vaidya, {Jayant S.} and Max Bulsara and Christobel Saunders and Henrik Flyger and Tobias, {Jeffrey S.} and Tammy Corica and Samuele Massarut and Frederik Wenz and Steffi Pigorsch and Michael Alvarado and Michael Douek and Wolfgang Eiermann and Chris Brew-Graves and Norman Williams and Ingrid Potyka and Nicholas Roberts and Marcelle Bernstein and Douglas Brown and Elena Sperk and Siobhan Laws and Marc S{\"u}tterlin 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 Michael Baum and David Joseph",

year = "2020",

month = jul,

doi = "10.1001/jamaoncol.2020.0249",

language = "English",

volume = "6",

journal = "JAMA Oncology",

issn = "2374-2437",

publisher = "American Medical Association",

number = "7",

}

Vaidya, JS, Bulsara, M, Saunders, C, Flyger, H, Tobias, JS, Corica, T, Massarut, S, Wenz, F, Pigorsch, S, Alvarado, M, Douek, M, Eiermann, W, Brew-Graves, C, Williams, N, Potyka, I, Roberts, N, Bernstein, M, Brown, D, Sperk, E, Laws, S, Sütterlin, M, 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, Baum, M & Joseph, D 2020, 'Effect of Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast Radiotherapy on Local Recurrence and Survival: Long-term Results From the TARGIT-A Randomized Clinical Trial in Early Breast Cancer', JAMA Oncology, vol. 6, no. 7, e200249. https://doi.org/10.1001/jamaoncol.2020.0249

Effect of Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast Radiotherapy on Local Recurrence and Survival: Long-term Results From the TARGIT-A Randomized Clinical Trial in Early Breast Cancer. / Vaidya, Jayant S. (Lead / Corresponding author); Bulsara, Max; Saunders, Christobel et al.
In: JAMA Oncology, Vol. 6, No. 7, e200249, 07.2020.

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

TY - JOUR

T1 - Effect of Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast Radiotherapy on Local Recurrence and Survival

T2 - Long-term Results From the TARGIT-A Randomized Clinical Trial in Early Breast Cancer

AU - Vaidya, Jayant S.

AU - Bulsara, Max

AU - Saunders, Christobel

AU - Flyger, Henrik

AU - Tobias, Jeffrey S.

AU - Corica, Tammy

AU - Massarut, Samuele

AU - Wenz, Frederik

AU - Pigorsch, Steffi

AU - Alvarado, Michael

AU - Douek, Michael

AU - Eiermann, Wolfgang

AU - Brew-Graves, Chris

AU - Williams, Norman

AU - Potyka, Ingrid

AU - Roberts, Nicholas

AU - Bernstein, Marcelle

AU - Brown, Douglas

AU - Sperk, Elena

AU - Laws, Siobhan

AU - Sütterlin, Marc

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 - Baum, Michael

AU - Joseph, David

PY - 2020/7

Y1 - 2020/7

N2 - Importance: Conventional adjuvant radiotherapy for breast cancer given daily for several weeks is onerous and expensive. Some patients may be obliged to choose a mastectomy instead, and some may forgo radiotherapy altogether. We proposed a clinical trial to test whether radiotherapy could be safely limited to the tumor bed.Objective: To determine whether delayed second-procedure targeted intraoperative radiotherapy (TARGIT-IORT) is noninferior to whole-breast external beam radiotherapy (EBRT) in terms of local control.Design, Setting, and Participants: In this prospective, randomized (1:1 ratio) noninferiority trial, 1153 patients aged 45 years or older with invasive ductal breast carcinoma smaller than 3.5 cm treated with breast conservation were enrolled from 28 centers in 9 countries. Data were locked in on July 3, 2019.Interventions: The TARGIT-A trial was started in March 2000; patients were randomized after needle biopsy to receive TARGIT-IORT immediately after lumpectomy under the same anesthetic vs EBRT and results have been shown to be noninferior. A parallel study, described in this article, was initiated in 2004; patients who had their cancer excised were randomly allocated using separate randomization tables to receive EBRT or delayed TARGIT-IORT given as a second procedure by reopening the lumpectomy wound.Main Outcomes and Measures: A noninferiority margin for local recurrence rate of 2.5% at 5 years, and long-term survival outcomes.Results: Overall, 581 women (mean [SD] age, 63 [7] years) were randomized to delayed TARGIT-IORT and 572 patients (mean [SD] age, 63 [8] years) were randomized to EBRT. Sixty patients (5%) had tumors larger than 2 cm, or had positive nodes and only 32 (2.7%) were younger than 50 years. Delayed TARGIT-IORT was not noninferior to EBRT. The local recurrence rates at 5-year complete follow-up were: delayed TARGIT-IORT vs EBRT (23/581 [3.96%] vs 6/572 [1.05%], respectively; difference, 2.91%; upper 90% CI, 4.4%). With long-term follow-up (median [IQR], 9.0 [7.5-10.5] years), there was no statistically significant difference in local recurrence-free survival (HR, 0.75; 95% CI, 0.57-1.003; P = .052), mastectomy-free survival (HR, 0.88; 95% CI, 0.65-1.18; P = .38), distant disease-free survival (HR, 1.00; 95% CI, 0.72-1.39; P = .98), or overall survival (HR, 0.96; 95% CI, 0.68-1.35; P = .80).Conclusions and Relevance: These long-term data show that despite an increase in the number of local recurrences with delayed TARGIT-IORT, there was no statistically significant decrease in mastectomy-free survival, distant disease-free survival, or overall survival.Trial Registration: ISRCTN34086741, ClinicalTrials.gov Identifier: NCT00983684.

AB - Importance: Conventional adjuvant radiotherapy for breast cancer given daily for several weeks is onerous and expensive. Some patients may be obliged to choose a mastectomy instead, and some may forgo radiotherapy altogether. We proposed a clinical trial to test whether radiotherapy could be safely limited to the tumor bed.Objective: To determine whether delayed second-procedure targeted intraoperative radiotherapy (TARGIT-IORT) is noninferior to whole-breast external beam radiotherapy (EBRT) in terms of local control.Design, Setting, and Participants: In this prospective, randomized (1:1 ratio) noninferiority trial, 1153 patients aged 45 years or older with invasive ductal breast carcinoma smaller than 3.5 cm treated with breast conservation were enrolled from 28 centers in 9 countries. Data were locked in on July 3, 2019.Interventions: The TARGIT-A trial was started in March 2000; patients were randomized after needle biopsy to receive TARGIT-IORT immediately after lumpectomy under the same anesthetic vs EBRT and results have been shown to be noninferior. A parallel study, described in this article, was initiated in 2004; patients who had their cancer excised were randomly allocated using separate randomization tables to receive EBRT or delayed TARGIT-IORT given as a second procedure by reopening the lumpectomy wound.Main Outcomes and Measures: A noninferiority margin for local recurrence rate of 2.5% at 5 years, and long-term survival outcomes.Results: Overall, 581 women (mean [SD] age, 63 [7] years) were randomized to delayed TARGIT-IORT and 572 patients (mean [SD] age, 63 [8] years) were randomized to EBRT. Sixty patients (5%) had tumors larger than 2 cm, or had positive nodes and only 32 (2.7%) were younger than 50 years. Delayed TARGIT-IORT was not noninferior to EBRT. The local recurrence rates at 5-year complete follow-up were: delayed TARGIT-IORT vs EBRT (23/581 [3.96%] vs 6/572 [1.05%], respectively; difference, 2.91%; upper 90% CI, 4.4%). With long-term follow-up (median [IQR], 9.0 [7.5-10.5] years), there was no statistically significant difference in local recurrence-free survival (HR, 0.75; 95% CI, 0.57-1.003; P = .052), mastectomy-free survival (HR, 0.88; 95% CI, 0.65-1.18; P = .38), distant disease-free survival (HR, 1.00; 95% CI, 0.72-1.39; P = .98), or overall survival (HR, 0.96; 95% CI, 0.68-1.35; P = .80).Conclusions and Relevance: These long-term data show that despite an increase in the number of local recurrences with delayed TARGIT-IORT, there was no statistically significant decrease in mastectomy-free survival, distant disease-free survival, or overall survival.Trial Registration: ISRCTN34086741, ClinicalTrials.gov Identifier: NCT00983684.

U2 - 10.1001/jamaoncol.2020.0249

DO - 10.1001/jamaoncol.2020.0249

M3 - Article

C2 - 32239210

SN - 2374-2437

VL - 6

JO - JAMA Oncology

JF - JAMA Oncology

IS - 7

M1 - e200249

ER -

Effect of Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast Radiotherapy on Local Recurrence and Survival: Long-term Results From the TARGIT-A Randomized Clinical Trial in Early Breast Cancer

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