Start of cheaper technique for breast cancer is delayed in UK despite adoption elsewhereBMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h2874 (Published 26 May 2015) Cite this as: BMJ 2015;350:h2874
All rapid responses
Sarah Thornton’s response to Hawkes’ News article in BMJ 2015;350:h2874 is correct: the TARGIT-A trial analysis is immature for the reason she states. In addition, leading clinical trial statisticians, including the former Chair of the TARGIT-A Independent Data Monitoring Committee, point out that the TARGIT-A claims of non-inferiority are based on analyses that do not comply with widely accepted standards for demonstrating non-inferiority.1-3 Based on the published TARGIT-A 2014 data, Haviland estimates a 5% (1 in 20) chance of a 7% local relapse rate 5 years after Intrabeam, well above the trialists’ published upper estimate.2, 4
Haviland’s estimate is consistent with the only other randomised trial testing intraoperative radiotherapy, the Italian ELIOT trial, which reported a 4.4% 5-year local relapse rate 5 years after intraoperative radiotherapy, compared to 0.4% in the women allocated whole breast radiotherapy.5 The decision of ELIOT trialists to wait until half their patients had at least 6 years of follow up attracted much respect. Figure 2 in their Lancet Oncology manuscript suggests that the breast tumour relapse rate approximately doubles between 5 and 9 years of follow up, a trend that may continue beyond 9 years, making it impossible to exclude this worrying scenario being played out in the TARGIT-A trial. Recognition that ‘low risk’ breast cancer displays an exceptionally long natural history is the reason why another 5 current randomised trials testing alternatives to whole breast radiotherapy intend to wait until half of their 17,000 trial participants reach a minimum of 5 years follow up before publishing local cancer relapse data. In TARGIT-A, the issue of immature follow-up data is compounded by a failure to use standard statistical methods to adjust for patients with a short follow-up, thereby underestimating the relapse risk of patients surviving longer periods of time.
There is another concern, which relates to how TARGIT-A has interpreted the small, statistically nonsignificant, imbalance in the number of cardiac deaths favouring the intraoperative treatment.4 The trialists suggest that this imbalance is due to the damaging effects of whole breast radiotherapy. They cite research by Professor Darby of Oxford University to support their interpretation, but by misapplying her data, they overestimate cardiac risk after whole breast radiotherapy by a factor of about 10. Based on the Oxford data, external beam radiotherapy actually explains <1 of the 6 excess cardiac deaths in the TARGIT-A control group. This corrected estimate of true risk was confirmed by Professor Darby before our letters were submitted to the Lancet in May 2014, and conveyed to the TARGIT-A Chief Investigator.6 Despite this, TARGIT-A trialists continue to misrepresent cardiac risks in recent publications and in patient information sheets, a practice that has been recently criticised by UK patient advocates.7-9
Impartial observers, including funders, regulatory agencies, advocate groups and the National Institute for Health and Care Excellence (NICE) must wonder why the academic community has failed to take effective action, given serious concerns over the TARGIT-A trial. We have expressed these via cancer conferences, debates and correspondence in the scientific literature, but we have been reluctant to expose what we believe is a striking lack of effective trial oversight. As stated in recent correspondence, there are responsibilities that trial sponsors are expected to fulfil in accordance with the UK Research Governance Framework.10, 11 These include responsibilities, usually delegated to the Chief Investigator, to appoint a Trial Steering Committee (TSC) acting on behalf of the sponsor, here University College London (UCL), that ensures adherence to Good Clinical Practice. Medical Research Council 1998 Guidance explains how TSC membership should be limited to an independent Chair, at least two other independent members, one or two principal investigators and, where possible, a consumer representative. Trial coordinators, trial statistician and others are invited to attend as requested by the Chair. The TARGIT-A International Trial Steering Committee (ITSC) names 24 individuals, all closely involved in the trial.12 They include a Chair drawing monthly consultancy fees over an undisclosed number of years from Zeiss (manufacturer of the Intrabeam device), and 4 senior employees of the Zeiss corporation, including the Vice-President of Sales. While the TARGIT-A trial may not have been in breach of formal legal requirements, the 1998 MRC guidelines were already widely adopted in the UK. This defect, rectified as recently as 2014, represents a serious challenge to trial integrity.
In recent correspondence, we point to other aspects that the UK trial sponsor should have taken action over long ago.10 The Chair of the TARGIT-A ITSC has also been head of the clinical trials group that collects and analyses TARGIT-A trial data. This alone is a risky arrangement, but the trials group is located in the Division of Surgery, where the Chief Investigator is based. The 2014 TARGIT-A Lancet publication states that the Chief Investigator was one of two members responsible for the statistical analysis.4 The TARGIT-A trialists are experienced enough to know that these arrangements can be considered serious conflicts of interest. To restore international trust in the trial and secure the future of the TARGIT-A trial, we urge UCL to move the trial to the highly respected Cancer Research UK and UCL Clinical Trials Centre, where the database can undergo standard checks for completeness and accuracy, and future analyses can be professionally supervised.
If sponsors fail to implement the Research Governance Framework, we should not be surprised if patients bring the arguments into the public domain. In the USA, the advocate group California Health Collaborative has written to the Attorney General of the California State Department of Justice stating its concerns that the manufacturer of Intrabeam (Zeiss) is marketing intraoperative radiotherapy ahead of science, and that the manipulated data are putting breast cancer patients at risk. Thousands of women are now being treated out of trial worldwide.13 We believe that the premature and market-driven global implementation of Intrabeam represents a serious deviation from huge collaborative efforts over the past decades striving to establish evidence-based best practice for patients with early breast cancer. We are not claiming that TARGIT-A is inferior to standard breast radiotherapy; we are stating the simple fact that the data analyses presented so far, do not allow one to conclude that TARGIT-A is non-inferior to standard therapy within a margin tight enough to reassure breast cancer patients that the added convenience of intra-operative radiotherapy is worth the possible added risks. In conclusion, the TARGIT-A trial needs to mature in an environment that offers protection from market forces and guarantees long-term benefits from the huge investments by research volunteers and investigators.
1. Cuzick J. Radiotherapy for breast cancer, the TARGIT-A trial. Lancet. 2014;383(9930):1716.
2. Haviland JS, A'Hern R, Bentzen SM, Whelan T, Bliss JM. Radiotherapy for breast cancer, the TARGIT-A trial. Lancet. 2014;383:1116-7
3. Haviland JS, Bliss JM, Bentzen SM, Cuzick J. The TARGIT-A trial: understanding non-inferiority and survival analysis. Int J Radiation Oncology Biology Physics. 2015;in press
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. 2014;383:603-13
5. 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. 2013;14(13):1269-77
6. Yarnold J, Offersen BV, Olivotto I, Poortmans P, Sarin R. Radiotherapy for breast cancer, the TARGIT-A trial. Lancet. 2014;383:1717-8
7. Vaidya JS, Bulsara M, Wenz F, et al. Pride, Prejudice, or Science – attitudes towards the results of the TARGIT-A trial of targeted intraoperative radiotherapy for breast cancer. Int J Radiation Oncology Biology Physics. 2015;DOI: 10.1016/j.ijrobp.2015.03.022. Reference: ROB 22832
8. J S Vaidya and Whittington Health NHS. TARGeted Intraoperative radioTherapy (TARGIT) - a patient's guide. 2014
9. Kirby AM, Hanna GG, Wilcox M, MacKenzie M. Sense, Sensibility and Shared decision making- clear and accurate information is the cornerstone of our relationship with patients. Int J Radiation Oncology Biology Physics. 2015;in press
10. Yarnold J, Bentzen SM. Concerning the lack of regulatory oversight of the Targit-A trial. Int J Radiation Oncology Biology Physics. 2015;In press
Competing interests: No competing interests
We know that whole breast irradiation following breast conserving surgery decreases the risk of both total breast cancer recurrence over 10 years and death from breast cancer over 10-15 years ¹.
However, whole-breast irradiation requires 3-6 weeks of daily treatments so a method which would mitigate the long treatment schedule would be welcome. The clear proviso is, of course, that the new treatment would have to work at least as well as whole-breast irradiation.
Two recent trials which investigate accelerating treatment by targeting only the tumour-bed via intraoperative radiation delivered as a single fraction at the time of the lumpectomy are the ELIOT trial and the TARGIT-A trial.
The ELIOT trial² investigated the intraoperative approach of using electrons versus whole breast irradiation. It has a median follow up of 5.8 years. Unfortunately, the ELIOT trial reported a hazard ratio for the development of within-breast recurrence of 9.3 (95% confidence interval = 3.3 – 26.3) for treatment with intraoperative radiotherapy versus whole-breast irradiation.
The TARGIT-A trial investigated an intraoperative approach using an orthovoltage technique, comparing the intraoperative approach with whole- breast irradiation. This trial had a median follow up of only 2 years. Results after such a short follow up are unlikely to be informative given the cumulative incidence of recurrence increases beyond 2 years.
In an attempt to address this shortfall the TARGIT trial continued to accrue participants for an additional 2 years. This increased the median follow up to 2.5 years, but it remains a very short period on which to draw robust conclusions about likely rates of recurrence.
Indeed, it is hard to understand why the study authors chose to present 5 year recurrence outcomes for the trial when the median follow-up is only 2.5 years.
The short follow up is compounded by the finding in the extended study of a statistically higher within-breast recurrence risk in those patients assigned to the intraoperative radiation treatment. The absolute difference is small but, given the short follow up period, is likely to grow with additional follow up.
Longer follow up could be reported for the TARGIT-A trial. 10-year data for those patients that were treated in 2000 to 2002 will already exist if patients have complied with the study follow up protocols. The data would show any long term differences in risk of within-breast recurrence with intraoperative radiotherapy and whole breast radiation. The question is why this has not been done?
The TARGIT-A trial concluded that targeted intraoperative radiotherapy should now be considered as a standard of care. It is difficult to agree with this when the trial results seem disappointing.
Despite the trial findings, Intrabeam is being promoted heavily; the press coverage detailed on Dr. Vaidya’s own website bears testament to his efforts in this area³. Against this there is a less visible ground swell of concern amongst senior radiation oncology professionals and their representative bodies. It is to the credit of NICE that following their initial draft guidance in July 2014 it is now taking time to consider carefully these concerns before making its final recommendation.
¹ Early Breast Cancer Trialists’ Collaberative 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 trail. Lancet Oncol 14:1269-1277, 2013)
Competing interests: No competing interests
A heavy price is being paid, not only by breast cancer patients eligible for intraoperative treatment by the `single dose` INTRABEAM method, but also by all of us within the NHS, occasioned by the long delay in gaining final approval from the UK National Institute for Health and Care Excellence (NICE).Their draft guidance recommending INTRABEAM`s use was given in July 2014. We are now advised that their appraisal committee will meet in August to consider further information before making their recommendation. 
Yet evidence from TARGIT A trial results published in 2010  and from the 5 year follow-up published in June 2014  has been sufficient for other countries involved in that international trial to give enthusiastic approval for its supply and use.  But NICE`s delay, while it has been considering comments from `professional organisations`, and `further information`, has blighted its use here in the country where its development took place.
In consequence, eligible women in the UK denied this single, intraoperative treatment, are being obliged to endure the prolonged regimen of regular radiotherapy, (or even opt for mastectomy), and the expense, discomfort and delays that prolonged radiotherapy imposes on them.
The cost of this delayed approval in a cash-strapped NHS runs into £millions.
This unreasonable, excessive delay is unethical: all those involved in hindering the release of approval of this treatment should stop to consider the effect of their actions on the many who might benefit. NICE should take action to rapidly conclude this lamentable situation.
Independent Citizen Advocate for Quality in Research and Healthcare
Member of the Data Monitoring Committee of the TARGIT A trial
 Hawkes, N. Start of cheaper technique for breast cancer is delayed in UK despite adoption elsewhere. BMJ 2015;350:h2874
 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. Lancet2010;376:91-102.
 Viadya 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. Lancet2014;383:603-13.
Competing interests: I was a member of the Data Monitoring Committee of the Targit A Trial