New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer

Abstract

Background: The TARGIT-A trial reported risk-adapted targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy for breast cancer to be as effective as whole-breast external beam radiotherapy (EBRT). Here, we present further detailed analyses.

Methods: In total, 2298 women (≥45 years, invasive ductal carcinoma ≤3.5 cm, cN0-N1) were randomised. We investigated the impact of tumour size, grade, ER, PgR, HER2 and lymph node status on local recurrence-free survival, and of local recurrence on distant relapse and mortality. We analysed the predictive factors for recommending supplemental EBRT after TARGIT-IORT as part of the risk-adapted approach, using regression modelling. Non-breast cancer mortality was compared between TARGIT-IORT plus EBRT vs. EBRT.

Results: Local recurrence-free survival was no different between TARGIT-IORT and EBRT, in every tumour subgroup. Unlike in the EBRT arm, local recurrence in the TARGIT-IORT arm was not a predictor of a higher risk of distant relapse or death. Our new predictive tool for recommending supplemental EBRT after TARGIT-IORT is at https://targit.org.uk/addrt . Non-breast cancer mortality was significantly lower in the TARGIT-IORT arm, even when patients received supplemental EBRT, HR 0.38 (95% CI 0.17-0.88) P = 0.0091.

Conclusion: TARGIT-IORT is as effective as EBRT in all subgroups. Local recurrence after TARGIT-IORT, unlike after EBRT, has a good prognosis. TARGIT-IORT might have a beneficial abscopal effect.

Trial registration: ISRCTN34086741 (21/7/2004), NCT00983684 (24/9/2009).

Conflict of interest statement

J.S.V. has received a research grant from Photoelectron Corp (1996–99) and from Carl Zeiss for supporting data management at the University of Dundee (Dundee, UK, 2004-2008) and has received honoraria. J.S.V., J.S.T., N.W., I.P., C.B.-G. and N.R. receive funding from HTA, NIHR, Department of Health for some activities related to the TARGIT trials. M.Ba. was briefly on the scientific advisory board of Carl Zeiss and was paid consultancy fees before 2010. F.W. 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 WE who declares that he has no conflicts of interest. The remaining authors declare no competing interests.

© 2021. The Author(s).

Figures

Fig. 1. Forest plot showing local recurrence-free survival and overall survival as per tumour subgroups.

Each box represents the amount of the data and horizontal lines show the 95% confidence interval. The dashed vertical line is through the hazard ratio for all patients.

Fig. 2. Subgroup analysis: overall survival in those with grade 1 or 2, n = 1797, and those with grade 3 cancers, n = 443.

In total, 80% of the patients had grade 1 or 2 cancers. Of those with grade 1 or 2 cancers vs. grade 3 cancers, 20 vs. 30% were node-positive, and 4 vs. 29% were ER-negative, respectively. There was no difference in the rate of additional EBRT given after TARGIT-IORT between these groups.

Fig. 3. TARGIT-IORT vs EBRT: Contrasting long-term outcome after local recurrence.

The hazard of distant metastasis (top left), breast cancer death (top right) and any death (bottom) —interaction with local recurrence as a time-dependent covariate. The hazards of patients who have local recurrence after EBRT as shown by the rising red line in each graph are significantly higher than those who have local recurrence after TARGIT-IORT, which in turn are the same as those without any local recurrence. Please note that these figures denote cumulative hazards of each interaction groups, whereas the curves in Fig. 4 are Kaplan–Meier estimates of cumulative incidences.

Fig. 4. Randomised comparison of non-breast cancer mortality showing signifcantly fewer deaths in patients randomised to TARGIT-IORT(top graph), and non-randomised comparisons to assess the contribution to the difference seen in the randomised comparison: because of the delivery of TARGIT-IORT (bottom left), and the avoidance of EBRT (bottom right).

Please note that 40% of patients in the 1158 EBRT arm also received a tumour-bed boost which was not given to those who had received TARGIT-IORT.