Effect of Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast Radiotherapy on Local Recurrence and Survival
Authors: 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
Journal: JAMA Oncology (2020)

<h3>Importance</h3> 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. <h3>Objective</h3> 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. <h3>Design, Setting, and Participants</h3> 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. <h3>Interventions</h3> 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. <h3>Main Outcomes and Measures</h3> A noninferiority margin for local recurrence rate of 2.5% at 5 years, and long-term survival outcomes. <h3>Results</h3> 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;<i>P</i> = .052), mastectomy-free survival (HR, 0.88; 95% CI, 0.65-1.18;<i>P</i> = .38), distant disease-free survival (HR, 1.00; 95% CI, 0.72-1.39;<i>P</i> = .98), or overall survival (HR, 0.96; 95% CI, 0.68-1.35;<i>P</i> = .80). <h3>Conclusions and Relevance</h3> 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. <h3>Trial Registration</h3> ISRCTN34086741, ClinicalTrials.gov Identifier:NCT00983684