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

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 break these fundamental tenets, because death is informative, and its occurrence is unequal between the two arms of the trial. By artificially increasing the denominator, 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 disproportionately underestimate the local recurrence rates in the EBRT arm due mainly to more deaths in the EBRT arm, both overall and also after local recurrence. Therefore, there is an artificial increase in the efficacy of EBRT and an inflation of the difference between the two treatments. The European Definition for the Assessment of Time-to-event Endpoints in CANcer trials25Gourgou-Bourgade S Cameron D Poortmans P et al.Guidelines for time-to-event end point definitions in breast cancer trials: Results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials).Annal Oncol. 2015; 26: 873-879Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar and the American Standardized Definitions for Efficacy End Points26Hudis CA Barlow WE Costantino JP et al.Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: The STEEP system.J Clin Oncol. 2007; 25: 2127-2132Crossref PubMed Scopus (596) Google Scholar (American) guidelines clearly state that death and local recurrence should both be included as clinical events for assessing local treatments for breast cancer. As these principles were not followed in Ward et al's methods, there is a discrepancy between their estimates and the actual raw data, even at the 5-year point when there is complete follow-up of 2298 randomized patients.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 Their parametric model estimate is higher than the actual local recurrence rate for TARGIT (true figure 2.11% artificially raised to 2.9%) and lower than the actual rate for EBRT (true figure 0.95% artifically reduced to 0.6%). Consequently, this mismatch artifically inflates the difference by 190%, that is, their estimate is wrongly inflated to 2.3%, which is nearly double the real value of 1.21%. This bias brings into question the validity of their model. Notably, the real chance of remaining free of local recurrence at 5 years, the relevant outcome from the patient's point of view, is identical for TARGIT-IORT and EBRT (94.15% vs 94.19%).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 Ward et al's hypothetical data yield even stranger results at 10 years. Their upper 95% confidence limit is 4.3% for their 1.7% estimate of local recurrence rate with EBRT. So the upper 95% confidence interval is 4.3 minus 1.7 which is 2.6. Normally, the upper and the lower confidence intervals (1.96 times the standard error) are equally above and below the point estimate. Therefore, the lower 95% confidence limit has to be 1.7 minus 2.6, which is negative 0.9%. A negative local recurrence rate! The same anomaly is present for their 5-year estimate (their lower 95% CI is a local recurrence rate of 0.6 minus 1.3, which is negative 0.7%). Ward et al seem to simply truncate these negative values to 0%. Even if one accepts unusually asymetric 95% confidence limits, their lower 95% CI estimate of 0% for 5- and 10-year local recurrence rate in 1158 medium-risk patients with breast cancer is clearly unrealistic (in the TARGIT-A trial, 83% [1898] patients were <70 years, 20% [443] had grade 3 cancers, 19% [426] were estrogen or progesterone receptor negative, and 22% [488] had involved nodes).27Vaidya JS Bulsara M Baum M et al.Single-dose intraoperative radiotherapy during lumpectomy for breast cancer: An innovative patient-centred treatment.Br J Cancer. 2021; 124: 1469-1474Crossref PubMed Scopus (8) Google Scholar When such unrealistic estimates and confidence limits are generated by Ward et al's model, there can be little confidence in that model or its results. The real data are that at 5 years, 2.11% versus 0.95% of the initially recruited women had local recurrence with TARGIT-IORT and EBRT (an increase of 1.16%), but 3.68% versus 4.84% women died (a reduction of 1.16%).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 Kaplan-Meier estimates for local control (ie, chance of being free of local recurrence) at 5 years were 94.15% (92.6-95.4) and 94.19% (92.6-94.4) for TARGIT-IORT and EBRT,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 and breast preservation was 92.32% (90.59-93.74) and 91.64% (89.85-93.12). Over the 19 years of follow-up (median follow-up 9 years), the real raw data show that in the whole trial of 2298 patients, there were 25 (2.2 %) more invasive local recurrences but 21 (1.8%) fewer deaths in the TARGIT IORT arm compared with the EBRT arm.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 With a long-term follow-up (maximum 19 years, median 8.6 years), analysis of the actual data shows that there was no statistically significant difference between TARGIT-IORT and EBRT in terms of the chance of being free of any local recurrence (hazard ratio [HR], 1.13; 95% CI, 0.91-1.41; P = .28), of remaining mastectomy free (HR, 0.96; 95% CI, 0.78-1.19; P = .74), of remaining distant disease free (HR, 0.88; 0.69-1.12; P = .30), or of breast cancer mortality (HR, 1.12; 0.78-1.60; P = .54).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 between TARGIT-IORT and 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 irrespective of the tumor subtype,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 and even when supplemental EBRT was not used.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 Overall survival was improved with TARGIT-IORT for patients with grade 1 or grade 2 cancers (HR 0.72 (0.53-0.98), P = 0.0361)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 correct results for the proportion of patients who did not have local failure, that is, those who were free of local recurrence at 10 years, were as follows: TARGIT arm (those who received supplemental EBRT: 82.6%; those who did not receive supplemental EBRT: 84.5%) and EBRT arm (85.5%; log-rank P value = .51; Fig. 2). We acknowledge that local recurrence has been a popular traditional endpoint and has been used in many important studies. However, the pitfalls when estimating it are being increasingly recognized.24Fojo 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, 25Gourgou-Bourgade S Cameron D Poortmans P et al.Guidelines for time-to-event end point definitions in breast cancer trials: Results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials).Annal Oncol. 2015; 26: 873-879Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 26Hudis CA Barlow WE Costantino JP et al.Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: The STEEP system.J Clin Oncol. 2007; 25: 2127-2132Crossref PubMed Scopus (596) Google Scholar, 27Vaidya JS Bulsara M Baum M et al.Single-dose intraoperative radiotherapy during lumpectomy for breast cancer: An innovative patient-centred treatment.Br J Cancer. 2021; 124: 1469-1474Crossref PubMed Scopus (8) Google Scholar Deaths during follow-up cannot be ignored while estimating local recurrence, as the patient does of course needs to be alive to have the potential for local recurrence. If deaths are simply ignored, the results no longer represent what actually happens to patients, even more so when deaths form the more substantial proportion of events or are unequal between the treatments being compared. We strongly believe that presentation of the data should reflect what actually happens. The outcomes should be clinically relevant and should provide realistic information for our patients. Such complete and accurate information (Figs. 1 and 2) is essential for both patients and physicians to decide what kind of treatment will suit them best.