Critiques of TARGIT-A

The results of the TARGIT-A trial have been questioned in letters to the editors of the Lancet2-6 and the British Medical Journal.7,8


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“The premature analysis of the trial data is definitely a major criticism of the trial,” Joanne S. Haviland, MSc, of the University of Southampton in Southampton, United Kingdom, told Cancer Therapy Advisor. In addition, Haviland said that her opinion is that, “the actual method of analysis is also flawed,” and, along with her colleagues, has suggested that a survival analysis would be more appropriate instead of noninferiority with binomial proportions.2,9

The TARGIT-A investigators calculated noninferiority using binomial proportions, which equally weighs the data from the analyzed population and does not account for differences in follow-up time.1,10,11

Another criticism is that the occurrence of other cancers, as well as stroke and bowel ischemia as cardiovascular events, were reported, because according to some, 6,8 they are unlikely to be a result of EBRT.

In 2015, the TARGIT-A investigators published a point-by-point rebuttal to the above and other criticisms, including new data analyses and figures to further support their findings.11

“We have done four different types of analyses and all of them give the same answer; local and distant control of breast cancer, and breast cancer survival with TARGIT IORT local control is not statistically different from those achieved by EBRT, particularly when given during lumpectomy,” professor Jayant S. Vaidya, FRCS, PhD, of the University College London in London, United Kingdom and one of the lead TARGIT-A investigators told Cancer Therapy Advisor.

However, similar criticisms as stated above have also been published in response to the rebuttal.9,12 Haviland maintains that, “The TARGIT authors have repeatedly failed to address concerns raised by the many published responses. We believe that they should conduct a proper and appropriate noninferiority analysis or allow an independent analysis of their data.”

Select Patient Population

The questions about the TARGIT-A trial have recently come to the forefront in the United States after the California Chronic Care Coalition (CCCC), California Health Collaborative, and Carrie’s TOUCH, all patient advocacy groups, publicly announced their letter asking California Attorney General Kamala Harris to investigate the advertising and increased use of TARGIT IORT.13 Liz Helms, the president and CEO of CCCC told Cancer Therapy Advisor, “Our ultimate goal is for there to be transparent communication and patient education about the ongoing controversy over the data and efficacy of IORT as a treatment option.”

RELATED: Adding Onartuzumab to Triple-Negative Breast Cancer Treatment Fails to Show Clinical Benefit

Michael Alvarado, MD, one of the TARGIT-A investigators, of the University of California San Francisco (UCSF) Medical Center told Cancer Therapy Advisor that if the issue is that, “women aren’t getting informed or maybe people are utilizing the technology in the wrong patient population—if that is the case, then I would be the first to go with you to talk to these places that are using it on the wrong patients.”

In addition, Dr. Alvarado stated that TARGIT IORT should be used on protocol and in a controlled manner in the right patient population.

“Those patients are postmenopausal, estrogen-positive cancer, grade 1 or 2, lymph node–negative, HER2-negative, and less than 2.5 or 3 cm.”

Ongoing Studies

The TARGIT-A investigators continue to collect data from participating centers in a registry. For example, at UCSF about 260 women have been enrolled in the registry, and worldwide, more than 260 centers offer TARGIT IORT and more than 8,000 patients have received this treatment. Future analyses of these data will provide further information regarding the safety and efficacy of IORT.

Anthony Zietman, MD, FASTRO, and Editor-in-Chief of the International Journal of Radiation Oncology Biology Physics summarized the debate in an editorial, “Depending on your perspective, intraoperative radiation therapy is thus either a very serious threat or a quantum leap forward.”14

References

  1. Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiation for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomized trial. Lancet. 2014;383(9917):603-613.
  2. Haviland JS, A’Hern R, Bentzen SM, et al. Radiotherapy for breast cancer, the TARGIT-A trial. Lancet. 2014;383(9930):1716-1717.
  3. Cuzick J. Radiotherapy for breast cancer, the TARGIT-A trial. Lancet. 2014;383(9930):1716.
  4. Mackenzie P, Fyles A, Chung C. Radiotherapy for breast cancer, the TARGIT-A trial. Lancet. 2014;383(9930):1717.
  5. Yarnold J, Offersen BV, Olivotto I, et al. Radiotherapy for breast cancer, the TARGIT-A trial. Lancet. 2014;383(9930):1717-1718.
  6. Harness JK, Silverstein MJ, Wazer DE, et al. Radiotherapy for breast cancer, the TARGIT-A trial. Lancet. 2014;383(9930):1719.
  7. Thornton S. Re: start of cheaper technique for breast cancer is delayed in UK despite adoption elsewhere. BMJ. 2015;350:h2874.
  8. Yarnold J, Brentzen SM, Brunt AM, et al. Re: start of cheaper technique for breast cancer is delayed in UK despite adoption elsewhere. BMJ. 2015;350:h2874.
  9. Haviland JS, Bliss JM, Bentzen SM, et al. In regard to Vaidya et al. Int J Radiation Oncol Biol Phys. 2015;92(5):954-955.
  10. Vaidya JS, Joseph DJ, Tobias JS, et al. Targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomized, non-inferiority phase 3 trial. Lancet. 2010;376(9735):91-102.
  11. Vaidya JS, Bulsara M, Wenz F, et al. Pride, prejudice, or science: attitudes towards the results of the TARGIT-A trial of targeted intraoperative radiation therapy for breast cancer. Int J Radiation Oncol Biol Phys. 2015;92(3):491-497.
  12. Wazer DE, Hepel JT, Riker AI, et al. In regard to Vaidya et al. Int J Radiation Oncol Biol Phys. 2015;92(5):954-955.
  13. BusinessWire. Use of IORT for Breast Cancer Treatment Questioned by California Chronic Care Coalition and California Health Collaborative. 2015. Available at: http://www.businesswire.com/news/home/20150708005508/en/IORT-Breast-Cancer-Treatment-Questioned-California-Chronic#.VakPGflViko. Accessed July 15, 2015.
  14. Zeitman A. Letters regarding the TARGIT-A trail: the Editor’s introduction. Int J Radiation Oncol Biol Phys. 2015;92(5):952-963.