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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Vaidya has received a research grant from Photoelectron Corp (1996-1999) and from Carl Zeiss for supporting data management at the University of Dundee (2004-2008) and has subsequently received honoraria. Drs Vaidya, Tobias, Williams, Potyka, Ms Brew-Graves, and Mr Roberts receive funding from Health Technology Assessment Programme, National Institute for Health Research (NIHR), Department of Health for some activities related to the TARGIT trials. Dr Baum was on the scientific advisory board of Carl Zeiss and was paid monthly consultancy fees briefly before 2010. Dr Wenz has received a research grant from Carl Zeiss for supporting radiobiological research. Carl Zeiss sponsors some of the travel and accommodation for meetings of the international steering committee and data monitoring committee and when necessary for conferences where a presentation about targeted intraoperative radiotherapy is being made for all authors apart from Dr Eiermann who declares that he has no conflicts of interest. No other conflicts are reported.

Figures

Figure 1.. Flowchart and CONSORT Diagram

EBRT indicates whole-breast external beam radiotherapy; MRI, magnetic resonance imaging; TARGIT-IORT, targeted intraoperative radiotherapy. A, Flowchart outlining recruitment to trial of delayed TARGIT-IORT vs EBRT. B, CONSORT diagram of participant randomization. aThe difference in number withdrawn was not statistically significant (P = .15). bAs per protocol, 31 of 581 patients (5.3 %) allocated to delayed TARGIT-IORT received EBRT after TARGIT-IORT. cTwo of 581 patients (0.3%) allocated to delayed TARGIT-IORT received EBRT and 8 of 572 (1.4%) allocated EBRT received TARGIT-IORT as well.

Figure 2.. Actual Follow-up and Expected Follow-up for the Trial of Delayed Second-Procedure TARGIT-IORT vs EBRT

EBRT indicates whole-breast external beam radiotherapy; TARGIT-IORT, targeted intraoperative radiotherapy.

Figure 3.. Twelve-Year Kaplan-Meier Curves Comparing Delayed Second-Procedure TARGIT-IORT vs EBRT

EBRT indicates whole-breast external beam radiotherapy; TARGIT-IORT, targeted intraoperative radiotherapy. In each of these Kaplan-Meier graphs, the blue lines represent delayed TARGIT-IORT with light blue shading indicating the 95% confidence intervals. The orange lines represent EBRT with light orange shading indicating the 95% confidence intervals.