TARGIT-A trial of IORT for breast cancer – Adequate follow up for a large number of patients.

Click to access the PDF file: Adequacy of follow up duration in TARGIT-A trial of targeted intraoperative radiotherapy for breast cancer

Adequacy of follow up duration in the TARGIT-A trial 

In this short paper, we provide a detailed explanation about the follow-up of the TARGIT-A trial[1, 2] and clarify how it is long enough to be relied upon to guide the application of TARGIT using Intrabeam in routine clinical practice in appropriate patients. We have explained this in the correspondence columns of the Lancet (17 May 2014)

It may appear tempting to speculate that years in the future a difference in local recurrence will become apparent and the difference in mortality that we have already seen will go away, but neither our data nor previous trial results support this speculation, which ignores our understanding about the complex natural history of breast cancer and robust literature about the toxic effects of EBRT on other organs such as the heart.

Continuing to ignore the TARGIT-A trial data can potentially put a large proportion of breast cancer patients at a significant disadvantage. The temporal distribution of local recurrence shows that the first 2 to 3 year period covers the peak hazard of local recurrence after surgery[3, 4] (see figure 1 from SEER (Surveillance, Epidemiology and End Results) data base, Cheng et al[4].

More importantly, various local therapy trials (surgery and radiotherapy) have repeatedly shown that the effect of local therapy such as surgery or radiation is mainly seen in the first 5 years, with the peak of the hazard being bracketed by the first 2-3 years.

Screenshot 2014-06-21 05.57.31

Figure 1 is taken from 10 year follow up using data from SEER-Medicare showing that the peak hazard of recurrence is in the first 2-3 years[4].

Effect of radiothearpy is limited to the first 5 years

Figure 2: The effect of radiotherapy on local recurrence is only in the first 5 years and most of its benefit is already finished in the first 2-3 years. The difference between radiotherapy and no radiotherapy remains the same after the first 5 years

As seen in Figure 2, the lines representing local recurrence between radiotherapy and no-radiotherapy in Kaplan-Meier plots remain virtually parallel after 5 years in the US National Surgical Adjuvant Breast and Bowel Project NSABP B06[5](figure 2 left), NSABP B04[6], and the Oxford Overview[7] (latter two not shown).

The conclusion of the 25 year follow up of the Swedish trial of radiotherapy vs. no radiotherapy[8] was explicit: “Radiotherapy protects against recurrences during the first 5 years of follow-up..”- whatever difference was going to be seen at 25 years was already seen at 5 years[8] (figure 2 right). The biological rationale that adequately explains these observations are covered by Retsky et al [1] and further explored in greater detail with their relevance to the interpretation of the results of randomized controlled trials by Baum in 20139.

Statistically, it is inappropriate to use median follow up on its own without taking into account the absolute number of patients.

The TARGIT-A trial has a substantial number of patients (n=1222) with a median follow up of 5 years and 2232 patient had a median follow up close to 4 years.

As regards the number of patients (with a risk of recurrence similar to those in the TARGIT-A trial) that would have enough statistical power to prove non-inferiority in the TARGIT-A trial is much smaller because of the vanishingly low risk of recurrence. We had calculated that this number is 585 (table 6 of reference2). The TARGIT-A trial has many more patients than that with a 5-year follow up. We believe that clinicians and policy makers can rely on our published results1 and the results can be extrapolated to 10 years (figure 3).

Figure 3 shows comparative results of TARGIT vs. EBRT in the Prepathology stratum in which TARGIT was given during the initial lumpectomy. Over a 12-year period it shows no significant difference between the two randomised arms in terms of local recurrence or disease free survival

Figure 3 shows comparative results of TARGIT vs. EBRT in the Prepathology stratum in which TARGIT was given during the initial lumpectomy. Over a 12-year period it shows no significant difference between the two randomised arms in terms of local recurrence or disease free survival

Figure 3 shows comparative results of TARGIT vs. EBRT in the Prepathology stratum in which TARGIT was given during the initial lumpectomy. Over a 12-year period it shows no significant difference between the two randomised arms in terms of local recurrence or disease free survival

The primary outcome of the TARGIT-A trial was local control and the secondary outcome was survival. Therefore, the best composite parameter to assess the comparative benefit/harm and quality of life is diseases free survival. In the latest publication1 we concluded that the preferred method of delivery of TARGIT was during initial lumpectomy. There was no difference in the K-M estimates for disease-free survival with EBRT compared with TARGIT given during initial lumpectomy (p= 0.68). The diseases free survival at 5 years was TARGIT 91.6% (88.7-93.8) vs. EBRT 90.1% (86.8- 92.6); and at 10 years TARGIT 81.3% (71-88) and EBRT 71.2% (49-85).

The study of natural history of breast cancer and in particular its treatment with radiation therapy has repeatedly shown that the effect of radiation on local recurrence is only in the first few years -maximum in the first 2-3 years and none after the first 5 years. Therefore, in conclusion, there is already sufficient follow up data in the TARGIT-A trial for a large number of patients to allow us to derive reliable conclusions.

Professor Jayant S Vaidya, Professor of Surgery and Oncology, University College London United Kingdom

Professor Frederik Wenz, Professor of Radiation Oncology, University of Heidelberg, Mannheim, Germany

Professor Max Bulsara, Chair in Biostatistics University of Notre Dame, Fremantle, Australia

Professor Jeffrey S Tobias Professor of Cancer Medicine Department of Radiation Oncology University College London Hospital United Kingdom

Professor David Joseph Professor of Radiation Oncology Sir Charles Gairdener Hospital Perth, Australia

Professor Laura Esserman Professor of Surgery and Radiology, University of California San Francisco United States of America

Professor Michael Baum Emeritus Professor of Surgery, University College London United Kingdom

References

1. 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. The Lancet 2014 (e-pub 11 Nov 2013); 383(9917): 603-13 DOI:10.1016/ S0140-6736(13)61950-9.

2. 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. The Lancet 2010; 376(9735): 91-102.

3. Retsky MW, Demicheli R, Hrushesky WJ, Baum M, Gukas ID. Dormancy and surgery-driven escape from dormancy help explain some clinical features of breast cancer. APMIS 2008; 116(7-8): 730-41.

4. Cheng L, Swartz MD, Zhao H, et al. Hazard of recurrence among women after primary breast cancer treatment – a 10 year follow up using data from SEER-Medicare. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2012; 21(5).

5. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. NEnglJMed 2002; 347(16): 1233-41.

6. Fisher B, Jeong JH, Anderson S, Bryant J, Fisher ER, Wolmark N. Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. NEnglJMed 2002; 347(8): 567-75.

7. Early Breast Cancer Trialists’ Collaborative G. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. The Lancet 2005; 366(9503): 2087-106.

8. Wickberg A, Holmberg L, Adami HO, Magnuson A, Villman K, Liljegren G. Sector resection with or without postoperative radiotherapy for stage I breast cancer: 20-year results of a randomized trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2014; 32(8): 791-7.

9. Baum M. Modern concepts of the natural history of breast cancer: a guide to the design and publication of trials of the treatment of breast cancer Eur J Cancer. 2013 Jan;49(1):60-4. . European Journal of Cancer 2013; 49(1): 60-4.