The TARGIT-A Randomized Trial: TARGIT-IORT Versus Whole Breast Radiation Therapy: Long-Term Local Control and Survival

Abstract

For assessing the efficacy of any cancer therapeutic approach, patients and clinicians want to know the chance of being free of disease as well as the likelihood of achieving long-term survival. Single-dose targeted intraoperative radiation therapy (TARGIT-IORT) during lumpectomy for patients with early breast cancer can avoid the inconvenience and toxicity of whole breast radiation therapy (external beam radiation therapy [EBRT]) and results in reduced pain, a better quality of life,1Sperk E Welzel G Keller A et al.Late radiation toxicity after intraoperative radiotherapy (IORT) for breast cancer: Results from the randomized phase III trial TARGIT A.Breast Cancer Res Treat. 2012; 135: 253-260Crossref PubMed Scopus (84) Google Scholar, 2Welzel G Boch A Sperk E et al.Radiation-related quality of life parameters after targeted intraoperative radiotherapy versus whole breast radiotherapy in patients with breast cancer: Results from the randomized phase III trial TARGIT-A.Radiat Oncol. 2013; 8: 9Crossref PubMed Scopus (57) Google Scholar, 3Andersen KG Gartner R Kroman N Flyger H Kehlet H. Persistent pain after targeted intraoperative radiotherapy (TARGIT) or external breast radiotherapy for breast cancer: A randomized trial.Breast. 2012; 21: 46-49Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 4Keshtgar MR Williams NR Bulsara M et al.Objective assessment of cosmetic outcome after targeted intraoperative radiotherapy in breast cancer: Results from a randomised controlled trial.Breast Cancer Res Treat. 2013; 140: 519-525Crossref PubMed Scopus (46) Google Scholar, 5Corica T Nowak AK Saunders CM et al.Cosmesis and breast-related quality of life outcomes after intraoperative radiation therapy for early breast cancer: A substudy of the TARGIT-A trial.Int J Radiat Oncol Biol Phys. 2016; 96: 55-64Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 6Corica T Nowak AK Saunders CM et al.Cosmetic outcome as rated by patients, doctors, nurses and BCCT.core software assessed over 5 years in a subset of patients in the TARGIT-A trial.Radiat Oncol. 2018; 13: 68Crossref PubMed Scopus (20) Google Scholar a cosmetically superior outcome, and requires less traveling by the patient.7Coombs NJ Coombs JM Vaidya UJ et al.Environmental and social benefits of the targeted intraoperative radiotherapy for breast cancer: Data from UK TARGIT-A trial centres and two UK NHS hospitals offering TARGIT IORT.BMJ Open. 2016; 6e010703Crossref PubMed Scopus (35) Google Scholar Scattered irradiation that accompanies EBRT has been shown to lead to second cancers (lung, esophagus, etc) and heart attacks, which are even more pronounced in smokers.8Hojris I Overgaard M Christensen JJ Overgaard J. Morbidity and mortality of ischaemic heart disease in high-risk breast- cancer patients after adjuvant postmastectomy systemic treatment with or without radiotherapy: Analysis of DBCG 82b and 82c randomised trials. Radiotherapy Committee of the Danish Breast Cancer Cooperative Group.Lancet. 1999; 354: 1425-1430Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar, 9Hojris I Sand NP Andersen J Rehling M Overgaard M. Myocardial perfusion imaging in breast cancer patients treated with or without post-mastectomy radiotherapy.Radiother Oncol. 2000; 55: 163-172Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 10Hojris I Andersen J Overgaard M Overgaard J. Late treatment-related morbidity in breast cancer patients randomized to postmastectomy radiotherapy and systemic treatment versus systemic treatment alone.Acta Oncol. 2000; 39: 355-372Crossref PubMed Scopus (115) Google Scholar, 11Taylor C Correa C Duane FK et al.Estimating the risks of breast cancer radiotherapy: Evidence from modern radiation doses to the lungs and heart and from previous randomized trials.J Clin Oncol. 2017; 35: 1641-1649Crossref PubMed Scopus (401) Google Scholar, 12Grantzau T Mellemkjaer L Overgaard J. Second primary cancers after adjuvant radiotherapy in early breast cancer patients: A national population based study under the Danish Breast Cancer Cooperative Group (DBCG).Radiother Oncol. 2013; 106: 42-49Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 13Lind PA Pagnanelli R Marks LB et al.Myocardial perfusion changes in patients irradiated for left-sided breast cancer and correlation with coronary artery distribution.Int J Radiat Oncol Biol Phys. 2003; 55: 914-920Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar With the substantially lower doses to organs at risk, TARGIT-IORT minimizes such risk compared with EBRT. In the large international TARGIT-A randomized trial (n = 2298),14Vaidya JS Bulsara M Baum M et al.Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial.BMJ. 2020; 370: m2836Crossref PubMed Scopus (103) Google Scholar15Vaidya JS Bulsara M Baum M et al.New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.Br J Cancer. 2021; 125: 380-389Crossref PubMed Scopus (15) Google Scholar as per the latest published results, breast cancer outcomes in patients randomized to TARGIT-IORT were comparable to patients randomized to whole breast postoperative radiotherapy (EBRT).14Vaidya JS Bulsara M Baum M et al.Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial.BMJ. 2020; 370: m2836Crossref PubMed Scopus (103) Google Scholar No difference was found in survival without local recurrence, survival without having a mastectomy, survival without distant disease, or breast cancer mortality.14Vaidya JS Bulsara M Baum M et al.Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial.BMJ. 2020; 370: m2836Crossref PubMed Scopus (103) Google Scholar The local control was comparable irrespective of the tumor subtype15Vaidya JS Bulsara M Baum M et al.New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.Br J Cancer. 2021; 125: 380-389Crossref PubMed Scopus (15) Google Scholar or when supplemental EBRT was not used. These are well illustrated in overlapping Kaplan-Meier curves drawn up to 12 years (Fig. 114Vaidya JS Bulsara M Baum M et al.Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial.BMJ. 2020; 370: m2836Crossref PubMed Scopus (103) Google Scholar and Fig. 215Vaidya JS Bulsara M Baum M et al.New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.Br J Cancer. 2021; 125: 380-389Crossref PubMed Scopus (15) Google Scholar).Fig. 2Kaplan-Meier plot of local recurrence-free survival for patients randomised to receive EBRT (purple line) along with patients randomised to receive TARGIT-IORT separated by those who received additional EBRT (blue line), and those who did not (pink line). No statistically significant difference was found between EBRT and the two latter groups.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Deaths from other causes were fewer in the TARGIT-IORT arm by 41% (reduced from 7.5% to 4.0% at 10 years),14Vaidya JS Bulsara M Baum M et al.Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial.BMJ. 2020; 370: m2836Crossref PubMed Scopus (103) Google Scholar a statistically significant and clinically meaningful benefit. In a subgroup analysis (with its usual caveats), overall survival was higher in the TARGIT-IORT arm by 4.4% at 12 years (Fig. 1)14Vaidya JS Bulsara M Baum M et al.Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial.BMJ. 2020; 370: m2836Crossref PubMed Scopus (103) Google Scholar,15Vaidya JS Bulsara M Baum M et al.New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.Br J Cancer. 2021; 125: 380-389Crossref PubMed Scopus (15) Google Scholar in patients with grade 1 and grade 2 cancers (n = 1797), which make up the majority of cases.15Vaidya JS Bulsara M Baum M et al.New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.Br J Cancer. 2021; 125: 380-389Crossref PubMed Scopus (15) Google Scholar Importantly, prognosis after the rare local recurrence after TARGIT-IORT was much better than after EBRT. As seen in the lower left panel of Figure 1, the hazard of death was 43% for those patients who had recurrence in the EBRT arm, substantially higher than the 9% hazard after local recurrence in the TARGIT-IORT arm or those without local recurrence.15Vaidya JS Bulsara M Baum M et al.New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.Br J Cancer. 2021; 125: 380-389Crossref PubMed Scopus (15) Google Scholar Multiple prospective nonrandomized studies have published their results of using TARGIT-IORT, with similar outcomes in over 3000 patients treated with TARGIT-IORT from France, Germany, Denmark, Switzerland, and others.16Sperk E. First per protocol analysis of the prospective phase II study of Intraoperative Radiotherapy (IORT) in elderly patients with small breast cancer: Targit E(lderly).Int J Radiat Oncol Biol Phys. 2019; 105: S8Abstract Full Text Full Text PDF Google Scholar, 17Mi Y Lv P Wang F et al.Targeted intraoperative radiotherapy is non-inferior to conventional external beam radiotherapy in Chinese patients with breast cancer: A propensity score matching study.Front Oncol. 2020; 10550327Crossref Scopus (7) Google Scholar, 18Manikhas A Oganesyn A Grinev I et al.Mid-term results of INTRABEAM intraoperative radiotherapy in St. Petersburg, Russia.J Clin Oncol. 2016; 34 (e12535-e35)Crossref Google Scholar, 19Wang X Feng K Wang W et al.Long-term outcomes of intraoperative radiotherapy for early-stage breast cancer in China: A multicenter real-world study.Cancer Commun (Lond). 2022; 42: 277-280Crossref PubMed Scopus (1) Google Scholar, 20Tallet A Racadot S Boher JM et al.The actual benefit of intraoperative radiation therapy using 50 kV x-rays in early breast cancer: A retrospective study of 676 patients.Breast J. 2020; 26: 2145-2150Crossref PubMed Scopus (11) Google Scholar, 21Lemanski C Bourgier C Draghici R et al.Intraoperative partial irradiation for highly selected patients with breast cancer: Results of the INTRAOBS prospective study.Cancer Radiother. 2020; 24: 114-119Crossref PubMed Scopus (10) Google Scholar By 2019, over 260 centers in 38 countries worldwide had treated over 45,000 patients with breast cancer with TARGIT-IORT (https://targit.org.uk).22Vaidya JS Vaidya UJ Baum M et al.Global adoption of single-shot targeted intraoperative radiotherapy (TARGIT-IORT) to improve breast cancer treatment – better for patients, better for health care systems.Front Oncol. 2022; 12786515Crossref Scopus (2) Google Scholar Ward et al23Ward MC, Bentzen SM, Fasola CE, et al. An estimate of local failure in the TARGIT-A trial of pre-pathology intraoperative radiation therapy for early breast cancer [e-pub ahead of print]. Int J Radiat Oncol Biol Phys. doi:10.1016/j.ijrobp.2021.12.161, accessed June 14, 2022.Google Scholar chose to look only at local recurrence, without accounting for deaths. But to develop a local recurrence, one needs to be alive. As a separate point, patients can and do die after local recurrence, especially after EBRT. As a consequence of this conceptual misunderstanding, we believe that their estimates are misleading. Ward et al23Ward MC, Bentzen SM, Fasola CE, et al. An estimate of local failure in the TARGIT-A trial of pre-pathology intraoperative radiation therapy for early breast cancer [e-pub ahead of print]. Int J Radiat Oncol Biol Phys. doi:10.1016/j.ijrobp.2021.12.161, accessed June 14, 2022.Google Scholar derived an inaccurately estimated set of “pure” local recurrences, which they calculated from the data extracted from our graphs in the BMJ paper14Vaidya JS Bulsara M Baum M et al.Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial.BMJ. 2020; 370: m2836Crossref PubMed Scopus (103) Google Scholar on the long-term outcomes after intraoperative radiotherapy (TARGIT-IORT, which is given using the Intrabeam (Carl Zeiss) device during lumpectomy) for early breast cancer in the TARGIT-A trial. They also assumed that risk-level for the cohort who received EBRT after TARGIT-IORT was the same as those randomized to EBRT, when in fact, this cohort included many more higher-risk cases (39% vs 20% node positive, 26% vs 15% lymphovascular invasion, 20% vs 10% positive margin, 24% vs 16% size >2 cm).15Vaidya JS Bulsara M Baum M et al.New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.Br J Cancer. 2021; 125: 380-389Crossref PubMed Scopus (15) Google Scholar The assumption of lower risk in this subgroup has meant that their estimate of local recurrence in the rest of the TARGIT-IORT arm (that did not receive supplemental EBRT) was erroneously inflated. Ward et al23Ward MC, Bentzen SM, Fasola CE, et al. An estimate of local failure in the TARGIT-A trial of pre-pathology intraoperative radiation therapy for early breast cancer [e-pub ahead of print]. Int J Radiat Oncol Biol Phys. doi:10.1016/j.ijrobp.2021.12.161, accessed June 14, 2022.Google Scholar calculated local recurrences by subtracting the overall survival probability from local recurrence-free survival probability. This method results in 2 separate and compounding errors. First, it only counts those patients who were alive after local recurrence and does not account for the fact that some patients who had local recurrence subsequently died. As a consequence, they underestimate the local recurrence numbers. This underestimate is substantial, and mainly in the EBRT arm because the hazard of death after local recurrence was 43% in the EBRT arm and only 9% in the TARGIT- IORT arm (Fig. 1, bottom panel).15Vaidya JS Bulsara M Baum M et al.New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.Br J Cancer. 2021; 125: 380-389Crossref PubMed Scopus (15) Google Scholar Second, Ward et al23Ward MC, Bentzen SM, Fasola CE, et al. An estimate of local failure in the TARGIT-A trial of pre-pathology intraoperative radiation therapy for early breast cancer [e-pub ahead of print]. Int J Radiat Oncol Biol Phys. doi:10.1016/j.ijrobp.2021.12.161, accessed June 14, 2022.Google Scholar completely ignore deaths while plotting their estimated cumulative local recurrence rates. This would work well if everyone's follow-up was the same and no one died, but this of course is never the case because patients are never recruited all at the same instant in any trial. Censoring is the workaround for this problem. Censored patients’ data are correctly used only until the point when last seen alive, with the assumption that they continue to have a risk of having local recurrence. But once patients are known to have died, this assumption is, of course, no longer true. In the quest for finding “pure” local failure, Ward et al23Ward MC, Bentzen SM, Fasola CE, et al. An estimate of local failure in the TARGIT-A trial of pre-pathology intraoperative radiation therapy for early breast cancer [e-pub ahead of print]. Int J Radiat Oncol Biol Phys. doi:10.1016/j.ijrobp.2021.12.161, accessed June 14, 2022.Google Scholar inappropriately censor dead patients. This results in spurious figures, as patients are assumed to be at risk of local recurrence even after they have died. Their method therefore results in biased, misleading, and incongruous results, as illustrated in Figure 3. In Figure 3, the right-hand graph (taken from Ward et al23Ward MC, Bentzen SM, Fasola CE, et al. An estimate of local failure in the TARGIT-A trial of pre-pathology intraoperative radiation therapy for early breast cancer [e-pub ahead of print]. Int J Radiat Oncol Biol Phys. doi:10.1016/j.ijrobp.2021.12.161, accessed June 14, 2022.Google Scholar) shows “1.7% people have local failure” in the EBRT arm. It implies that 98.3% are free of local failure. But the graph on the left shows that only 86% are actually alive at 10 years. Clearly, the right-hand graph, which implies that 98.3% are still alive without local recurrence, is unfounded and this method of estimating local failure is inaccurate. In their article in Lancet Oncology (2021), Fojo and Simon24Fojo T Simon RM. Inappropriate censoring in Kaplan-Meier analyses.Lancet Oncol. 2021; 22: 1358-1360Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar warn about this common mistake and emphasize that “censoring must be nonprognostic or noninformative, with individuals censored at any one time having a prognosis identical to that of all other patients alive at that time but not censored. Groups must be balanced both in terms of percentage of patients censored and the times of censoring.” Therefore, by censoring the dead, Ward et al23Ward MC, Bentzen SM, Fasola CE, et al. An estimate of local failure in the TARGIT-A trial of pre-pathology intraoperative radiation therapy for early breast cancer [e-pub ahead of print]. Int J Radiat Oncol Biol Phys. doi:10.1016/j.ijrobp.2021.12.161, accessed June 14, 2022.Google Scholar because death is and its is between the two of the trial. By the Ward et al23Ward MC, Bentzen SM, Fasola CE, et al. An estimate of local failure in the TARGIT-A trial of pre-pathology intraoperative radiation therapy for early breast cancer [e-pub ahead of print]. Int J Radiat Oncol Biol Phys. doi:10.1016/j.ijrobp.2021.12.161, accessed June 14, 2022.Google Scholar underestimate the local recurrence in the EBRT arm mainly to more deaths in the EBRT arm, both overall and also after local recurrence. Therefore, is an in the efficacy of EBRT and an of the difference between the two The for the of in S P et for point in breast cancer Results of the for the of in Oncol. 26: Full Text Full Text PDF PubMed Scopus Google Scholar and the for et for for efficacy in adjuvant breast cancer The Clin Oncol. PubMed Scopus Google Scholar that death and local recurrence both be included as clinical for assessing local for breast As were not in Ward et is a between their estimates and the actual even at the point when is follow-up of randomized JS Bulsara M Baum M et al.Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial.BMJ. 2020; 370: m2836Crossref PubMed Scopus (103) Google Scholar Their estimate is higher than the actual local recurrence for TARGIT to and lower than the actual for EBRT reduced to this the difference by that is, their estimate is to which is the of This the of their the chance of free of local recurrence at 5 the outcome from the point of is identical for TARGIT-IORT and EBRT vs JS Bulsara M Baum M et al.New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.Br J Cancer. 2021; 125: 380-389Crossref PubMed Scopus (15) Google Scholar Ward et data even results at 10 years. Their is for their estimate of local recurrence with EBRT. the is which is the and the lower times the are and the point Therefore, the lower has to be which is A local recurrence The same is for their estimate lower is a local recurrence of which is Ward et to to if one their lower estimate of for and local recurrence in patients with breast cancer is the TARGIT-A patients were 20% had grade were or and had JS Bulsara M Baum M et intraoperative radiotherapy during lumpectomy for breast cancer: An J Cancer. 2021; PubMed Scopus Google Scholar such estimates and are by Ward et can be in that or its The data are that at 5 versus of the recruited had local recurrence with TARGIT-IORT and EBRT of but versus of JS Bulsara M Baum M et al.Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial.BMJ. 2020; 370: m2836Crossref PubMed Scopus (103) Google Scholar The Kaplan-Meier estimates for local control chance of being free of local at 5 years were and for TARGIT-IORT and JS Bulsara M Baum M et al.New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.Br J Cancer. 2021; 125: 380-389Crossref PubMed Scopus (15) Google Scholar and breast was and the years of follow-up follow-up the data that in the whole trial of patients, were more local recurrences but fewer deaths in the TARGIT IORT arm compared with the EBRT JS Bulsara M Baum M et al.Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial.BMJ. 2020; 370: m2836Crossref PubMed Scopus (103) Google Scholar With a long-term follow-up analysis of the actual data shows that was no statistically significant difference between TARGIT-IORT and EBRT in terms of the chance of being free of any local recurrence P = of free P = of distant disease free P = or of breast cancer mortality P = JS Bulsara M Baum M et al.Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial.BMJ. 2020; 370: m2836Crossref PubMed Scopus (103) Google Scholar The local control was comparable between TARGIT-IORT and JS Bulsara M Baum M et al.Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial.BMJ. 2020; 370: m2836Crossref PubMed Scopus (103) Google Scholar irrespective of the tumor JS Bulsara M Baum M et al.New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.Br J Cancer. 2021; 125: 380-389Crossref PubMed Scopus (15) Google Scholar and even when supplemental EBRT was not JS Bulsara M Baum M et al.New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.Br J Cancer. 2021; 125: 380-389Crossref PubMed Scopus (15) Google Scholar survival was with TARGIT-IORT for patients with grade 1 or grade 2 cancers P = JS Bulsara M Baum M et al.New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.Br J Cancer. 2021; 125: 380-389Crossref PubMed Scopus (15) Google Scholar The results for the of patients who did not have local failure, that is, those who were free of local recurrence at 10 were as TARGIT arm who received supplemental those who did not receive supplemental and EBRT arm P = Fig. that local recurrence has been a and has been used in many the when estimating it are being T Simon RM. Inappropriate censoring in Kaplan-Meier analyses.Lancet Oncol. 2021; 22: 1358-1360Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, S P et for point in breast cancer Results of the for the of in Oncol. 26: Full Text Full Text PDF PubMed Scopus Google Scholar, et for for efficacy in adjuvant breast cancer The Clin Oncol. PubMed Scopus Google Scholar, JS Bulsara M Baum M et intraoperative radiotherapy during lumpectomy for breast cancer: An J Cancer. 2021; PubMed Scopus Google Scholar Deaths during follow-up be while estimating local recurrence, as the does of course needs to be alive to have the for local recurrence. deaths are the results no longer actually to patients, even more when deaths the more of or are between the being believe that of the data actually The outcomes be clinically and for our patients. and 1 and is for both patients and to of treatment

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