An international randomised controlled trial to compare TARGeted Intraoperative radioTherapy (TARGIT) with conventional postoperative radiotherapy after breast-conserving surgery for women with early-stage breast cancer (the TARGIT-A trial).

Abstract

BACKGROUND: Based on our laboratory work and clinical trials we hypothesised that radiotherapy after lumpectomy for breast cancer could be restricted to the tumour bed. In collaboration with the industry we developed a new radiotherapy device and a new surgical operation for delivering single-dose radiation to the tumour bed - the tissues at highest risk of local recurrence. We named it TARGeted Intraoperative radioTherapy (TARGIT). From 1998 we confirmed its feasibility and safety in pilot studies. OBJECTIVE: To compare TARGIT within a risk-adapted approach with whole breast external beam radiotherapy over several weeks (EBRT). DESIGN AND SETTING: The TARGIT-A trial was a pragmatic, prospective, international, multicenter, non-inferiority, non-blinded, randomised (1:1 ratio), clinical trial from 33 centres in 11 countries. Originally, randomisation occurred before initial lumpectomy (prepathology) and if allocated TARGIT, the patient received it during the lumpectomy. Subsequently, the postpathology stratum was added, in which randomisation occurred after initial lumpectomy, allowing potentially easier logistics and a more stringent case selection, but needed a reoperation to reopen the wound to give TARGIT as delayed procedure. Risk-adapted approach meant that in the experimental arm, if pre-specified unsuspected adverse factors were found postoperatively after receiving TARGIT, then EBRT was recommended. Pragmatically, this reflected how TARGIT would be practiced in the real world. PARTICIPANTS: Women who were >=45 years of age with unifocal invasive ductal carcinoma preferably <= 3.5cm in size; 3451 patients were recruited between March 2000 and June 2012. OUTCOMES: Primary: absolute difference in local recurrence, with a non-inferiority margin of 2.5%. Secondary: included toxicity, breast cancer specific and non-breast-cancer mortality. RESULTS: Values below are 5-year Kaplan-Meier rates for TARGIT vs. EBRT. There was no statistically significant difference in local recurrence between TARGIT and EBRT. TARGIT was non-inferior to EBRT overall (3·3%(2·1–5·1) vs. 1·3%(0·7–2·5),p=0.04,Pnoninferiority =0.00000012) and in the prepathology stratum(n=2298) when TARGIT was given concurrently with lumpectomy(2·1%(1·1–4·2) vs. 1·1%(0·5–2·5),p=0.31,Pnoninferiority =0.0000000013). With delayed TARGIT postpathology,(n=1153) the between-group difference was larger than 2·5% and non-inferiority was not established for this stratum((5·4%(3·0–9·7) vs. 1·7%(0·6–4·9),p=0.069,Pnoninferiority= 0.06640). The local-recurrence-free survival when TARGIT was given with lumpectomy was 93.9%(95%CI 90.9 – 95.9) vs. EBRT: 92.5%(95%CI 89.7 – 94.6),p=0.35. In a planned subgroup analysis, progesterone (PgR) receptor status was found to be the only predictor of outcome - hormone responsive patients (PgRpositive) had similar 5-year local recurrence with TARGIT during lumpectomy 1.4%(0.5-3.9) vs. EBRT 1.2%(0.5-2.9),p=0.77. Grade 3 or 4 radiotherapy toxicity was significantly reduced with TARGIT. Overall, breast cancer mortality was much the same between groups (2·6%[1·5–4·3] vs. 1·9%[1·1–3·2];p=0·56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1·4% [0·8–2·5] vs 3·5%[2·3–5·2];p=0·0086), attributable to fewer deaths from cardiovascular causes and other cancers, leading to a trend in reduced overall mortality in the TARGIT arm 37 deaths, 3·9%(2·7–5·8) vs. 51 deaths, 5·3%(3·9–7·3),p=0.099). Health economic analyses suggest that TARGIT was statistically significantly less costly than EBRT, produced similar QALYs, had a positive incremental Net Monetary Benefit that was borderline statistically significant from zero, and had a probability of over 90% of being cost-effective. There appears to be little uncertainty in the point estimates, based on deterministic and probabilistic sensitivity analyses. If TARGIT were given instead of EBRT in suitable patients, it might potentially reduce costs to the health care providers by £8 million to £9.1 million each year. This does not include environmental, patient and societal costs. LIMITATIONS: The number of local recurrences is small however, the number of events for local-recurrence-free survival is not small (59 vs. 61); Occurrence of only a few events implies that the treatments are effective and any difference is unlikely to be large. The follow up not all 3451 patients is 5 years, although the number required to answer the main trial question (n=585) have more than 5 years follow up. FUTURE WORK: We shall repeat the analyses with longer follow up. Although this may not change the primary result, the larger number of events may confirm the effect on mortality and allow more detailed subgroup analyses. The TARGIT-B trial is testing whether TARGIT-Boost is superior to EBRT boost. CONCLUSION: For patients with breast cancer (women who are 45 years of age and older with hormone sensitive invasive ductal carcinoma that is up to 3.5cm in size), TARGIT concurrent with lumpectomy within a risk-adapted approach is as effective, safer and less expensive alternative to postoperative EBRT. TRIAL REGISTRATION: ISRCTN34086741, ClinicalTrials.gov NCT00983684.