Objective: To determine whether risk adapted intraoperative radiotherapy, delivered as a single dose during lumpectomy, can effectively replace postoperative whole breast external beam radiotherapy for early breast cancer.
Design: Prospective, open label, randomised controlled clinical trial.
Setting: 32 centres in 10 countries in the United Kingdom, Europe, Australia, the United States, and Canada.
Participants: 2298 women aged 45 years and older with invasive ductal carcinoma up to 3.5 cm in size, cN0-N1, eligible for breast conservation and randomised before lumpectomy (1:1 ratio, blocks stratified by centre) to either risk adapted targeted intraoperative radiotherapy (TARGIT-IORT) or external beam radiotherapy (EBRT).
Interventions: Random allocation was to the EBRT arm, which consisted of a standard daily fractionated course (three to six weeks) of whole breast radiotherapy, or the TARGIT-IORT arm. TARGIT-IORT was given immediately after lumpectomy under the same anaesthetic and was the only radiotherapy for most patients (around 80%). TARGIT-IORT was supplemented by EBRT when postoperative histopathology found unsuspected higher risk factors (around 20% of patients).
Main outcome measures: Non-inferiority with a margin of 2.5% for the absolute difference between the five year local recurrence rates of the two arms, and long term survival outcomes.
Results: Between 24 March 2000 and 25 June 2012, 1140 patients were randomised to TARGIT-IORT and 1158 to EBRT. TARGIT-IORT was non-inferior to EBRT: the local recurrence risk at five year complete follow-up was 2.11% for TARGIT-IORT compared with 0.95% for EBRT (difference 1.16%, 90% confidence interval 0.32 to 1.99). In the first five years, 13 additional local recurrences were reported (24/1140 v 11/1158) but 14 fewer deaths (42/1140 v 56/1158) for TARGIT-IORT compared with EBRT. With long term follow-up (median 8.6 years, maximum 18.90 years, interquartile range 7.0-10.6) no statistically significant difference was found for local recurrence-free survival (hazard ratio 1.13, 95% confidence interval 0.91 to 1.41, P=0.28), mastectomy-free survival (0.96, 0.78 to 1.19, P=0.74), distant disease-free survival (0.88, 0.69 to 1.12, P=0.30), overall survival (0.82, 0.63 to 1.05, P=0.13), and breast cancer mortality (1.12, 0.78 to 1.60, P=0.54). Mortality from other causes was significantly lower (0.59, 0.40 to 0.86, P=0.005).
Conclusion: For patients with early breast cancer who met our trial selection criteria, risk adapted immediate single dose TARGIT-IORT during lumpectomy was an effective alternative to EBRT, with comparable long term efficacy for cancer control and lower non-breast cancer mortality. TARGIT-IORT should be discussed with eligible patients when breast conserving surgery is planned.
Trial registration: ISRCTN34086741, NCT00983684.