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TARGIT: Targeted Intraoperative Radiotherapy with Low-Energy X-Rays for Breast Cancer

Summary and Comment |
November 21, 2013

TARGIT: Targeted Intraoperative Radiotherapy with Low-Energy X-Rays for Breast Cancer

  1. Henry Mark Kuerer, MD, PhD, FAC

Randomized trial with short follow-up raises questions about the efficacy of the technique.

  1. Henry Mark Kuerer, MD, PhD, FAC

For breast cancer patients undergoing lumpectomy, would targeted intraoperative radiotherapy (TARGIT) with low-energy x-rays delivered once at surgery be as effective as adjuvant external beam radiotherapy (ERBT) delivered over several weeks after surgery? To address this question, investigators previously reported short-term results of an international, randomized, noninferiority, phase III trial (TARGIT-A; Lancet 2010; 376:91), which compared the use of these two techniques in 3451 women (age, ≥45) with invasive ductal carcinoma. Now, the researchers report results at a slightly longer median follow-up of 29 months (interquartile range, 12–52 months).

The trial design was complex in that 2298 patients were randomized before lumpectomy and 1153 were randomized after lumpectomy. Moreover, for those receiving TARGIT in the group randomized after lumpectomy, the device was placed in the surgical cavity when the wound was reopened during a second procedure. Also, the study treatment was termed “risk-adapted” because additional EBRT was given after TARGIT in 15.2% of patients with adverse features on pathology.

The estimated 5-year risk for local recurrence in the conserved breast was higher with TARGIT than with EBRT (3.3% vs. 1.3%; P=0.042); this absolute difference of 2.0% fell within the prespecifed margin for noninferiority of 2.5%. However, breast cancer mortality was similar in both groups (2.6% and 1.9%, respectively). Grade 3 or 4 skin complications were extremely rare, occurring in only 17 patients, and were significantly less common in the TARGIT group.

Comment

Patients would obviously prefer to complete local therapy at the time of surgery rather than several weeks later. Targeted intraoperative radiotherapy is being used more often as standard practice in the U.S., despite a notable lack of long-term follow-up data, primarily due to the prestige of the journal publishing these results as well as perhaps patient interest and heavy marketing efforts in the competitive landscape of breast cancer care. Because the median follow-up for this study is only 29 months, it is unclear whether TARGIT actually decreases the risk for local recurrence or if the risk would be similar in the absence of any adjuvant radiotherapy for low-risk patients. Further, it is unclear how many of these patients, who were enrolled from 33 centers in 11 countries, were lost to follow-up. TARGIT may be effective, but it is too early to definitively endorse it as a safe and effective alternative to external beam radiotherapy.

Editor's note: Since the above commentary was published, other reviewers have written letters to the editor at The Lancet to question the validity of this study (Lancet 2014 May; 383:1716).

  • Disclosures for Henry Mark Kuerer, MD, PhD, FAC at time of publication Consultant / Advisory board Bayer Pharma AG Speaker's bureau AstraZeneca Grant / research support Susan G. Komen Foundation Leadership positions in professional societies Alliance for Clinical Trials in Oncology (Chair, Education Committee)

Citation(s):

Reader Comments (1)

Professor Jayant Vaidya MBBS MS DNB FRCS PhD Physician, Oncology, University College London
Competing Interests: We are the lead authors of the paper

Follow up: Firstly, the follow up is not short. The TARGIT-A trial has a substantial number of patients (n=1222) with a median follow up of 5 years. The whole trial (n=3451) includes the data from all these longer-term patients as well as the data of recently recruited patients – which may give an appearance that the follow up is short. Secondly, there was no significant loss to follow up. 93·7% [3234 of 3451] of patients were seen within the year before the datalock or had at least 5 years of follow up.
Most importantly, the results remain stable with longer follow up periods, even after restricting the analysis to the earliest patients (median follow up 5 years). Furthermore, the difference between the two treatments at 5 years is not expected to be different from that seen at 8 or 10 years, as seen in other similar trials (ELIOT and START-B). It has been repeatedly shown that the hazard of relapse of breast cancer peaks during the 2nd /3rd year – which is already well covered in the TARGIT-A trial follow up.

Effectiveness: We found that TARGIT concurrent with lumpectomy is effective in reducing local recurrence. Absence of radiotherapy increases local recurrence (7% at 5 years in CALGB trial). TARGIT given as a second procedure (postpathology) was not effective – this provided us with an internal control. The patients in the postpathology stratum (n=1153) were highly selected for favorable pathological entry criteria yet they showed a difference of 3·7% (5·4% vs 1·7%) in local recurrence, much the same as for patients in studies with a non-irradiated experimental group. In the larger (n=2298) prepathology stratum the difference was a non-significant 1·0%, suggesting that TARGIT is effective in reducing local recurrence when given concurrently with lumpectomy.
Reduced non-breast-cancer mortality: Importantly, there are significantly fewer non-breast-cancer deaths with TARGIT. The author appears to have missed this significant finding. Mortality from causes other than breast cancer - such as cardiovascular causes and other cancers was significantly reduced with TARGIT leading to a trend in lower overall mortality.

In brief, when TARGIT is given with lumpectomy, breast cancer outcomes (local recurrence or death) are not statistically different from whole breast radiotherapy; mortality from causes other than breast cancer is significantly lower - 1.3% with TARGIT and 4.4% with whole breast radiotherapy.
Hence the interpretation is valid: “TARGIT 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 EBRT.
We recognize that an opposition to the policy of limiting radiotherapy to the tumor bed rather than the whole breast in selected cases is not very different from the resistance to the change from mastectomy to lumpectomy 30 years ago. We hope that there will be enough clinicians with open minds who will embrace this approach of targeted intraoperative radiotherapy in the same way that breast conserving surgery for selected cases was adopted within a few years of the results of randomized trials were published.
Jayant S Vaidya, Frederik Wenz, Max Bulsara, Jeffrey S Tobias, David Joseph and Michael Baum

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