Cautious Comments on the TARGIT-A Trial


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Thomas A. Buchholz, MD

Benjamin D. Smith, MD

Numerous randomized trials have demonstrated that whole-breast irradiation plays an important role after breast-conserving surgery for invasive breast cancer. A recent meta-analysis of these trials indicated that whole-breast irradiation decreased the risk of total breast cancer relapse events and improved overall survival.1 However, whole-breast irradiation requires 3 to 6 weeks of daily treatments, which can be a source of inconvenience and cost. Accordingly, new strategies to mitigate the prolonged treatment schedules are being investigated, including attempts to accelerate treatments by targeting only the tumor-bed region of the breast.

The most convenient of all such approaches is intraoperative radiation delivered as a single radiation fraction at the time of lumpectomy. This strategy has been studied with an intraoperative electron therapy approach by investigators in Milan, who conducted a phase III randomized trial and unfortunately reported a hazard ratio for the development of in-breast recurrence of 9.3 (95% confidence interval = 3.3–26.3) for treatment with intraoperative radiotherapy vs whole-breast irradiation.2

Early TARGIT-A Data

In the United Kingdom, investigators developed a similar intraoperative strategy, termed targeted intraoperative radiation therapy (TARGIT). In contrast with the Milan approach, targeted intraoperative radiation therapy uses an orthovoltage technique rather than electrons and prescribes a lower radiation dose. This approach served as a basis of the TARGIT-A trial, a randomized trial comparing single-fraction intraoperative radiation with or without whole-breast irradiation vs whole-breast irradiation.

The original results of the trial were published in 2010 after a median follow-up of only 2 years.3 Many felt that the publication of such early results was not particularly informative with respect to the primary outcome of in-breast recurrence, especially considering that cumulative incidence of in-breast recurrence rises slowly over a period of 10 or more years after diagnosis in patients with favorable breast cancer, such as those included in the TARGIT-A trial.

Updated Report

After the original study was analyzed in 2010, the investigators continued accrual for an additional 2 years. The new 2013 report from this trial by Vaidya and colleagues in The Lancet, reviewed in this issue of The ASCO Post, therefore includes a larger number of total patients but again has a very short median follow-up of 2.5 years.4

This time, however, even with this short follow-up, the authors found a statistically significantly higher in-breast recurrence risk in patients randomly assigned to targeted intraoperative radiation therapy, compared to the whole-breast irradiation arm. The absolute difference was small, although it is likely that this difference will continue to grow with additional follow up as the cumulative incidence of in-breast recurrence continues to rise.

It is also interesting that the authors present 5-year in-breast recurrence outcomes when the median follow-up is only half this period, but they choose not to show the tail end of the local recurrence curves, which are truncated at 5 years post-treatment. If patients have appropriately complied with follow-up, then we would expect that 10-year data already exist for those patients enrolled and treated in the years 2000 to 2002. Such data would be helpful to illuminate any long-term differences in risk of in-breast recurrence between targeted intraoperative radiotherapy and whole-breast irradiation.

A major theme of the current publication is the assertion that patients treated with intraoperative radiotherapy “prepathology” (at the time of lumpectomy) experienced rates of in-breast recurrence that were comparable to whole-breast irradiation. In contrast, patients treated with intraoperative radiotherapy performed as a second procedure “postpathology” experienced a higher risk of in-breast recurrence than patients treated with whole-breast irradiation.4

Study Limitations

It is important to note that there was no randomized component of timing of targeted intraoperative radiotherapy and that a number of potential biases may have contributed to these results. For example, one likely contributor to these outcomes was the much greater use of adjuvant whole-breast irradiation in the “prepathology” patients randomly assigned to targeted intraoperative radiotherapy, compared to the “postpathology” patients randomized to targeted intraoperative radiotherapy. One could thus interpret this study finding as illustrating that to achieve results similar to whole-breast irradiation, it is better to have 21.6% of intraoperative radiotherapy recipients also treated with whole-breast irradiation than to have only 3.6% of intraoperative radiotherapy recipients also treated with whole-breast irradiation.

A final important note concerning targeted intraoperative radiotherapy is the relatively low radiation dose, a concern raised by our group in a letter to The Lancet following the 2010 publication.5 With targeted intraoperative radiotherapy, only 5 Gy is delivered to the tissue that extends 1 cm beyond the tumor bed, and the dose rapidly drops off beyond 1 cm. This dose is markedly lower than the dose delivered with other partial-breast radiation techniques or with conventional whole-breast irradiation.

Due to the much smaller volume treated and the much lower dose delivered, we fear that the modest increase in risk of in-breast recurrence noted in patients randomized to intraoperative radiotherapy as compared to whole-breast irradiation will become more pronounced as the median follow-up of the study matures. Accordingly, we are hesitant to agree with the authors’ conclusion that targeted intraoperative radiotherapy should currently be considered as a standard of care. ■

Dr. Buchholz is Division Head and Dr. Smith is Associate Professor, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.

Disclosure: Dr. Smith receives research funding from Varian Medical Systems and ASCO’s Conquer Cancer Foundation.

References

1. Early Breast Cancer Trialists’ Collaborative Group: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707-1716, 2011.

2. Veronesi U, Orecchia R, Maisonneuve P, et al: Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): A randomised controlled equivalence trial. Lancet Oncol 14:1269-1277, 2013.

3. Vaidya JS, Joseph DJ, Tobias JS, et al: Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): An international, prospective, randomised, non-inferiority phase 3 trial. Lancet 376:91-102, 2010.

4. 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 8, 2013.

5. Smith BD, Buchholz TA, Kuerer HM: Intraoperative radiotherapy for early breast cancer (correspondence). Lancet 376:1141, 2010.


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