In the randomized noninferiority TARGIT-A trial reported in The Lancet, Jayant S. Vaidya, PhD, FRCS, and Michael Baum, MD, FRCS, of University College London, and colleagues compared risk-adapted radiotherapy using single-dose targeted intraoperative radiotherapy vs fractionated external-beam radiotherapy in women with breast cancer.¹ Targeted intraoperative radiotherapy met the noninferiority margin for 5-year local recurrence among all patients and when given concurrently with lumpectomy but not when delayed until after lumpectomy (postpathology). Breast cancer mortality did not differ significantly between the two groups, but intraoperative radiotherapy was associated with reduced non–breast cancer mortality.

Study Details

In this open-label randomized trial, 3,451 women aged ≥ 45 years with invasive ductal carcinoma were randomly assigned to receive risk-adapted radiotherapy using single-dose targeted intraoperative radiotherapy (n = 1,721) or whole-breast external-beam radiotherapy according to standard schedules over several weeks (n = 1,730) at 33 centers in 11 countries between March 2000 and June 2012. Patients were stratified by center and by timing of intraoperative radiotherapy; randomization occurred either before lumpectomy (prepathology stratum, intraoperative radiotherapy given concurrent with lumpectomy, total n = 2,298) or after lumpectomy (postpathology stratum, intraoperative radiotherapy given subsequently by reopening the wound, total n = 1,153).

The risk-adapted strategy meant that as per protocol, patients in the targeted intraoperative radiotherapy group were to receive supplemental external-beam radiotherapy (excluding a boost) if deemed necessary based on final pathology; overall, 15.2% of the intraoperative radiotherapy group received external-beam radiotherapy, including 21.6% in the prepathology stratum and 3.6% in the postpathology stratum and there was no significant difference between strata in terms of timing of delivery of external-beam radiotherapy.

Overall, most cancers were small and had good prognosis; 87% were ≤ 2 cm, 85% were grade 1 or 2, 84% were node-negative, 93% were estrogen receptor–positive, and 82% were progesterone receptor–positive. Cancers were detected by screening in 69% of women. Nevertheless, there were a significant number of patients who had adverse prognostic factors such as positive nodes (n = 502) or grade 3 tumors (n – 459).

The primary outcome was the absolute difference in local recurrence in the conserved breast, with a prespecified noninferiority margin of 2.5% at 5 years. The current report consisted of 5-year results for local recurrence and the first analysis of overall survival.

Recurrence Rates

Overall, median follow-up was 2 years and 5 months in 3,451 patients, 4 years in 2,020, and 5 years in 1,222. The 5-year risk for local recurrence in the conserved breast was 3.3% in the intraoperative radiotherapy group vs 1.3% in the external-beam radiotherapy group (absolute difference = 2%, P = .042) among all patients, 2.1% vs 1.1% (absolute difference = 1.0%, P = .31) among patents in the prepathology stratum, and 5.4% vs 1.7% (absolute difference > 2.5%; P = .069) in the postpathology stratum. The rate of local recurrence in patients receiving intraoperative radiotherapy plus external-beam radiotherapy was 0.9% but did not differ significantly from that in patients receiving intraoperative radiotherapy alone.

Post hoc exploratory analyses showed no significant differences in 5-year rates of regional recurrence (1.1% vs 0.9%), distant recurrence (3.9% vs 3.2%), any other recurrence (4.9% vs 4.4%), or all recurrence (8.2% vs 5.7%). The difference in all recurrence was smaller in the prepathology stratum (6.9% vs 5.8%) than in the postpathology stratum (10.4% vs 5.4%), as was the difference in any recurrence other than local recurrence (4.8% vs 4.7% in prepathology stratum, 5.2% vs 3.7% in postpathology stratum). The difference in locoregional recurrence (4.2% vs 2.0%) was also smaller in the prepathology stratum (3.1% vs 2.0%) than in the postpathology stratum (6.2% vs 2.0%).

Mortality

Five-year mortality was 3.9% in the targeted intraoperative radiotherapy group vs 5.3% in the external-beam radiotherapy group (P = .099), with no significant difference in breast cancer mortality (2.6% vs 1.9%) but a significant advantage for intraoperative radiotherapy in non–breast cancer mortality (1.4% vs 3.5%, P =.0086), reflecting fewer deaths from cardiovascular causes and other cancers.

In the prepathology stratum, 5-year mortality was 4.6% vs 6.9% (P = .123), with no significant difference in breast cancer mortality (3.3% vs 2.7%, P = .72) and an advantage for intraoperative radiotherapy in non–breast cancer mortality (1.3% vs 4.4%, P = .016). In the postpathology stratum, 5-year mortality was 2.8% vs 2.3% (P =.674), with no significant difference in breast cancer mortality (1.2% vs 0.5%, P =.35) or non–breast cancer mortality (1.6% vs 1.8%, P =.32). Mortality in patients receiving intraoperative radiotherapy plus external-beam radiotherapy was high (8.0%), reflecting the poor prognostic features in this group.

Overall, there were 17 deaths in the intraoperative radiotherapy group and 35 in the external-beam radiotherapy group due to causes other than breast cancer (P =  .0086). These causes included other cancers in 8 intraoperative radiotherapy patients vs 16 external-beam radiotherapy patients and cardiovascular causes in 2 vs 11, including cardiac causes in 2 vs 8, stroke in 0 vs 2, and ischemic bowel disease in 0 vs 1.

Apart from deaths due to other cancers or cardiovascular causes, there were 7 additional deaths in the intraoperative radiotherapy group (2 due to diabetes, 1 to renal failure, 1 to liver failure, 1 to sepsis, 1 to Alzheimer’s disease, and 1 to unknown cause) and 8 additional deaths in the external-beam radiotherapy group (1 due to myelopathy, 1 to perforated bowel, 1 to pneumonia, 1 to old age, and 4 to unknown cause).

There were no significant differences between groups in wound-related complications, but external-beam radiotherapy was associated with a significantly greater frequency of grade 3 or 4 radiotherapy-related skin complications (0.8% vs 0.2%, P = .029).

The investigators concluded, “[Targeted intraoperative radiotherapy] concurrent with lumpectomy within a risk-adapted approach should be considered as an option for eligible patients with breast cancer carefully selected as per the TARGIT-A trial protocol, as an alternative to postoperative [external-beam radiotherapy].” ■

Disclosure: The study was supported by University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research. For full disclosures of the study authors, visit www.thelancet.com.

Reference

1. Vaidya JS, Wenz F, Bulsara M, et al: Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet. November 11, 2013.