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Effect of Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast Radiotherapy on Local Recurrence and Survival

Effect of Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast Radiotherapy on Local... IMPORTANCE Conventional adjuvant radiotherapy for breast cancer given daily for several Supplemental content weeks is onerous and expensive. Some patients may be obliged to choose a mastectomy instead, and some may forgo radiotherapy altogether. We proposed a clinical trial to test whether radiotherapy could be safely limited to the tumor bed. OBJECTIVE To determine whether delayed second-procedure targeted intraoperative radiotherapy (TARGIT-IORT) is noninferior to whole-breast external beam radiotherapy (EBRT) in terms of local control. DESIGN, SETTING, AND PARTICIPANTS In this prospective, randomized (1:1 ratio) noninferiority trial, 1153 patients aged 45 years or older with invasive ductal breast carcinoma smaller than 3.5 cm treated with breast conservation were enrolled from 28 centers in 9 countries. Data were locked in on July 3, 2019. INTERVENTIONS The TARGIT-A trial was started in March 2000; patients were randomized after needle biopsy to receive TARGIT-IORT immediately after lumpectomy under the same anesthetic vs EBRT and results have been shown to be noninferior. A parallel study, described in this article, was initiated in 2004; patients who had their cancer excised were randomly allocated using separate randomization tables to receive EBRT or delayed TARGIT-IORT given as a second procedure by reopening the lumpectomy wound. MAIN OUTCOMES AND MEASURES A noninferiority margin for local recurrence rate of 2.5% at 5 years, and long-term survival outcomes. RESULTS Overall, 581 women (mean [SD] age, 63 [7] years) were randomized to delayed TARGIT-IORT and 572 patients (mean [SD] age, 63 [8] years) were randomized to EBRT. Sixty patients (5%) had tumors larger than 2 cm, or had positive nodes and only 32 (2.7%) were younger than 50 years. Delayed TARGIT-IORT was not noninferior to EBRT. The local recurrence rates at 5-year complete follow-up were: delayed TARGIT-IORT vs EBRT (23/581 [3.96%] vs 6/572 [1.05%], respectively; difference, 2.91%; upper 90% CI, 4.4%). With long-term follow-up (median [IQR], 9.0 [7.5-10.5] years), there was no statistically significant difference in local recurrence-free survival (HR, 0.75; 95% CI, 0.57-1.003; P = .052), mastectomy-free survival (HR, 0.88; 95% CI, 0.65-1.18; P = .38), distant disease-free survival (HR, 1.00; 95% CI, 0.72-1.39; P = .98), or overall survival (HR, 0.96; 95% CI, 0.68-1.35; P = .80). CONCLUSIONS AND RELEVANCE These long-term data show that despite an increase in the Author Affiliations: Author number of local recurrences with delayed TARGIT-IORT, there was no statistically significant affiliations are listed at the end of this article. decrease in mastectomy-free survival, distant disease-free survival, or overall survival. Corresponding Author: Jayant S. TRIAL REGISTRATION ISRCTN34086741, ClinicalTrials.gov Identifier: NCT00983684 Vaidya, MBBS, MS, DNB, PhD, Division of Surgery and Interventional Science, University College London, 43-45 Foley St, London W1W 7JN, JAMA Oncol. 2020;6(7):e200249. doi:10.1001/jamaoncol.2020.0249 United Kingdom (jayantvaidya@ Published online April 2, 2020. Corrected on May 21, 2020. gmail.com). (Reprinted) 1/10 Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 07/11/2021 Research Original Investigation Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast External Beam Radiotherapy for Early Breast Cancer n 2018, there were 2 million new cases of breast cancer di- agnosed worldwide and 626 000 deaths. Most patients are Key Points I suitable for treatment with breast-conserving surgery and Question For early breast cancer, is 5-year local control with adjuvant radiotherapy, rather than total mastectomy. The delayed second-procedure targeted intraoperative radiotherapy TARGIT-A randomized clinical trial (accrual from 2000-2012) (TARGIT-IORT) noninferior to whole-breast postoperative external compared risk-adapted TARGeted intraoperative radio- beam radiotherapy (EBRT), and how do long-term outcomes compare? therapy (TARGIT-IORT) during the initial surgical excision of 2-5 the cancer with conventional whole-breast external beam Findings In this randomized clinical trial including 1153 2,6,7 radiotherapy (EBRT) over several weeks. The results of participants, delayed second-procedure TARGIT-IORT was not this trial demonstrated noninferiority particularly when noninferior to EBRT at 5-year complete follow-up; however, long-term (median 9 years) mastectomy-free survival, distant TARGIT-IORT was delivered at the time of initial excision of disease-free survival, and overall survival were not different. cancer. In 2004, 4 years after accrual began in the main Meaning For early breast cancer, delayed second-procedure TARGIT-A trial, and at the request of potentially high-volume single-dose TARGIT-IORT given by reopening the lumpectomy wound had similar long-term mastectomy-free and overall survival centers, we sought and received additional ethics approval and compared with EBRT despite higher local recurrence. opened a parallel study. This was previously referred to as “postpathology stratum” and recruited 1153 patients using a separate randomization table. Patients were randomized af- ter their initial surgery to have either conventional fraction- ing of delayed TARGIT-IORT in the operation theater. A po- ated whole-breast radiotherapy (n = 572), or to undergo a fur- tential benefit was that the inclusion criteria could be made ther operation to deliver delayed radiotherapy to the wound more selective, choosing the patients with better prognosis (n = 581) by reopening the original incision. This trial was ini- based on the full histopathologic results that would be avail- tiated mainly because of the convenience of easier schedul- able after tumor excision. For example, the knowledge of the Figure 1. Flowchart and CONSORT Diagram Flowchart outlining recruitment to trial of delayed TARGIT-IORT vs EBRT Eligibility: Age ≥45 years Primary tumor already excised Unifocal invasive ductal carcinoma preferably ≤3.5 cm, cN0-N1 (MRI not required) Suitable for breast-conserving surgery 1153 Randomized 581 Randomized to delayed 572 Randomized to conventional radiotherapy TARGIT-IORT delivered as a single dose to the Standard fractionated EBRT over 3-6 weeks tumor bed with intrabeam to the reopened tumor bed as a second procedure B CONSORT diagram EBRT indicates whole-breast external 1153 Patients enrolled and randomized after excision of tumor beam radiotherapy; MRI, magnetic resonance imaging; TARGIT-IORT, targeted intraoperative radiotherapy. A, Flowchart outlining recruitment to 581 Randomized to delayed second-procedure TARGIT-IORT 572 Randomized to EBRT trial of delayed TARGIT-IORT vs EBRT. B, CONSORT diagram of participant 2 Withdrawn from further follow-up 6 Withdrawn from further follow-up randomization. The difference in number 12 Did not receive allocated treatment 18 Did not receive allocated treatment withdrawn was not statistically b b 2 Received EBRT 8 Received TARGIT-IORT and EBRT significant (P = .15). 0 Did not receive TARGIT-IORT or EBRT 3 Did not receive TARGIT-IORT or EBRT As per protocol, 31 of 581 patients 10 Had a mastectomy 7 Had a mastectomy (5.3 %) allocated to delayed TARGIT-IORT received EBRT after 569 Received allocated treatment 554 Received allocated treatment TARGIT-IORT. 538 Received delayed TARGIT-IORT 554 Received EBRT Two of 581 patients (0.3%) 31 Received TARGIT-IORT plus EBRT allocated to delayed TARGIT-IORT received EBRT and 8 of 572 (1.4%) 581 Included in analysis 572 Included in analysis allocated EBRT received TARGIT-IORT as well. 2/10 JAMA Oncology July 2020 Volume 6, Number 7 (Reprinted) jamaoncology.com Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 07/11/2021 Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast External Beam Radiotherapy for Early Breast Cancer Original Investigation Research Table 1. Patient and Tumor Characteristics Table 1. Patient and Tumor Characteristics (continued) a a No. (%) No. (%) Delayed Delayed TARGIT-IORT EBRT TARGIT-IORT EBRT b b Characteristic (n = 581) (n = 572) P value Characteristic (n = 581) (n = 572) P value Age, y Chemotherapy ≤50 30 (5.2) 23 (4.02) Received 26 (4.5) 14 (2.5) 51-60 166 (28.6) 171 (29.9) Did not receive 553 (95.5) 546 (97.5) 61-70 302 (52.0) 284 (49.7) Unknown 2 (0.3) 12 (2.1) >70 83 (14.3) 94 (16.4) Abbreviations: DCIS, ductal carcinoma in situ; EBRT, whole-breast external Pathologic tumor size, mm beam radiotherapy; ER, estrogen receptor; PgR, progesterone receptor; TARGIT-IORT, targeted intraoperative radiotherapy. ≤10 294 (51.0) 290 (51.8) For percentage calculation, the denominator for unknown percentages is the 11-20 249 (43.2) 243 (43.4) total number randomized (581 and 572) and the denominator for each >20 33 (5.7) 27 (4.8) category is the total number of known cases. Unknown 5 (0.9) 12 (2.1) P values are given for differences between TARGIT-IORT and EBRT, calculated using a χ test for known values. Grade 1 305 (56.5) 339 (63.8) 2 204 (37.8) 159 (29.9) microscopically measured tumor size, grade, and nodal sta- 3 31 (5.7) 33 (6.2) tus could be used to select a much lower-risk patient popula- Unknown 41 (7.1) 41 (7.2) tion before randomization. Margin This delayed procedure was performed at a median (IQR) Free 539 (92.9) 520 (92.4) of 37 (29-51) days after the initial excision as a second surgical DCIS only 16 (2.8) 18 (3.2) procedure in the operation theater, rather than immediate in- Invasive 25 (4.3) 25 (4.5) traoperative radiotherapy given during the initial cancer op- Unknown 1 (0.2) 9 (1.6) eration. This article describes the long-term outcomes of this Lymphovascular invasion parallel study. Absent 536 (94.7) 533 (96.6) Present 30 (5.3) 19 (3.4) Unknown 15 (2.6) 20 (3.5) Methods Lymph nodes involved 0 543 (93.6) 537 (95.2) The TARGIT-A trial was a pragmatic, prospective, interna- 1-3 34 (5.9) 26 (4.6) tional, multicenter, open label, randomized, phase 3 trial that >3 3 (0.5) 1 (0.2) compared the policy of risk-adapted TARGIT-IORT vs the con- Unknown 1 (0.2) 8 (1.4) ventional policy of whole-breast EBRT. The trial protocol (https:// ER status njl-admin.nihr.ac.uk/document/download/2006598) and the details of sample size calculations, the process of random Positive 569 (98.3) 550 (97.9) 6,7 allocation, have been previously described. The trial protocol Negative 10 (1.7) 12 (2.1) is available in Supplement 1. The study received ethics approval Unknown 2 (0.3) 10 (1.7) from the joint University College London and University College PgR status London Hospital committees of ethics of human research. Positive 440 (81.8) 423 (82.0) Negative 98 (18.2) 93 (18.0) Participants Unknown 43 (7.4) 56 (9.8) Women were eligible to participate in the delayed TARGIT- ERBB2 status IORT trial if their breast cancer was already excised. They Positive 30 (5.4) 33 (6.0) needed to be aged 45 years or older with unifocal breast can- Negative 526 (94.6) 515 (94.0) cer on examination and conventional imaging. Pragmati- Unknown 25 (4.3) 24 (4.2) cally, we permitted individual centers to prespecify the final Method of presentation postoperative histopathologic criteria that would make pa- Screen detected 420 (73.6) 395 (70.5) tients eligible for randomization and these were prespecified Symptomatic 151 (26.4) 165 (29.5) in the center’s treatment policy document. Because most cen- Unknown 10 (1.7) 12 (2.1) ters specified criteria for eligibility: aged 50 years or older, grade Endocrine therapy 1 or 2 disease, and uninvolved nodes, only 5% of patients in Received 336 (58.0) 334 (59.4) the trial had any adverse prognostic criteria. All patients gave Did not receive 243 (42.0) 228 (40.6) .63 informed written consent and needed to be available for regu- lar follow-up for at least 10 years. Follow-up clinical examina- Unknown 2 (0.3) 10 (1.8) tion was at least every 6 months for the first 5 years and an- (continued) nually thereafter, including a mammogram once per year. jamaoncology.com (Reprinted) JAMA Oncology July 2020 Volume 6, Number 7 3/10 Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 07/11/2021 Research Original Investigation Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast External Beam Radiotherapy for Early Breast Cancer Figure 2. Actual Follow-up and Expected Follow-up for the Trial of Delayed Second-Procedure TARGIT-IORT vs EBRT 40 EBRT/actual EBRT/expected Delayed TARGIT-IORT (actual) Delayed TARGIT-IORT (expected) 0 2 46 8 10 12 Years No. at risk EBRT/actual 572 560 550 526 379 167 63 EBRT/expected 572 563 555 543 406 180 74 EBRT indicates whole-breast external Delayed TARGIT-IORT (actual) 581 570 562 542 402 197 83 beam radiotherapy; TARGIT-IORT, Delayed TARGIT-IORT (expected) 581 574 567 555 417 208 88 targeted intraoperative radiotherapy. Random allocation was in a 1:1 ratio, to receive either single- tions of local recurrence rate at 5-year complete follow up dose delayed TARGIT-IORT or EBRT as per standard sched- should not cross 2.5% in absolute terms. ules over several weeks, with randomization blocks stratified Kaplan-Meier graphs were displayed as recommended by by center. The flow diagram and CONSORT diagram are given Pocock et al, who recommend that the x-axis of these graphs in Figure 1A and B. should be extended until 10% to 20% of patients are at risk of The concept and the delayed TARGIT-IORT technique have an event. The log-rank test was used to compare the differ- 3-5,8-11 been described previously and enabled these patients to ence between survival functions and to obtain P values. have their radiotherapy in 1 sitting, albeit by undergoing a sec- ond procedure, usually under a general anesthetic. Radia- Main Outcomes and Measures tion was given over 20 to 50 minutes delivering 20 Gy to the The cause of death was specified by the center. If the cause was surface of the tumor bed attenuating to 5 to 7 Gy at 1-cm depth. specified as a non–breast cancer event and no distant disease The patients in the conventional arm underwent stan- was recorded, it was defined as a non–breast cancer death. If dard EBRT, which always included fractionated whole-breast the death was recorded by the center to be related to breast radiotherapy for 3 to 6 weeks, with or without an EBRT tu- cancer, or as per convention, if breast cancer was present at mor bed boost, as determined by local criteria prespecified by the time of death, or if the cause of death was recorded as un- the collaborating center. known or uncertain, it was presumed to be a breast cancer death. Statistical Analysis Figure 1B shows the CONSORT diagram, which describes The statistical analysis plan (Supplement 1) was signed off on the treatment received in each of the randomized arms. The by the chair of the independent steering committee and an in- reference date for completeness was May 2, 2018, 8 years af- dependent senior statistician before the unblinded data were ter the first data lock. A patient was considered as having com- sent to the trial statistician for the current analysis. It speci- plete follow-up if they were seen for the specified duration of fied the primary outcome as local recurrence-free survival. This follow-up, had died, or had withdrawn from the trial. As the 13 14 outcome, consistent with the DATECAN and STEEP guide- last patient was randomized in 2012, the statistical analysis plan lines, estimates the chance of a patient being alive without lo- specified that the 5-year follow-up would be considered com- cal recurrence and therefore included local recurrence or death plete if 95% of patients had complete follow-up. It also speci- as events, ie, patients who had died were not censored. The fied that 10-year follow-up would be considered complete if other outcomes included mastectomy-free survival, distant dis- the patient had at least 10 years of follow-up, had been seen ease-free survival, overall survival, breast cancer mortality and within 1 year of the reference date, or had died or withdrawn; non–breast cancer mortality. Statistical analysis was per- the 10-year follow-up would be considered complete if this was formed using established methods, using STATA statistical soft- achieved by 90% of patients. Because there was no specific trial ware (versions 15.0 and 16.0, STATA Corp) for data compila- funding for individual centers, return of follow-up relied on 13-15 tion, validation, and analysis. Data analysis took place individual investigators and their teams’ efforts, enthused by between September 11, 2019 to January 15, 2020. the trial-center team. The trial statistician and the chief inves- In the original protocol, noninferiority was specified as tigator produced reports of completeness of follow up using being achieved if the difference in 5-year local recurrence rate blinded databases on a regular basis. As recommended by the did not cross a stringent margin of 2.5%. However, we have ap- independent steering committee, the database was un- plied an even more rigorous criterion since 2013: that the up- blinded for analysis once the prespecified goals for complete- per 90% CI of the absolute difference in the binomial propor- ness of follow up were achieved. The reference date for analy- 4/10 JAMA Oncology July 2020 Volume 6, Number 7 (Reprinted) jamaoncology.com Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 07/11/2021 Follow-up, % Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast External Beam Radiotherapy for Early Breast Cancer Original Investigation Research Table 2. Twelve-Year Kaplan-Meier Estimates of Outcomes Measures for TARGIT-IORT vs EBRT Delayed TARGIT-IORT (n = 581) EBRT (n = 572) Significance test for the full follow-up Kaplan-Meier estimates Kaplan-Meier estimates Outcomes Events (95% CI) Events (95% CI) HR (95% CI) P value for log rank Local recurrence-free survival Estimate 0.75 (0.57-1.003) .052 5-y 41 92.87 (90.44-94.70) 19 96.63 (94.77-97.84) 10-y 98 80.16 (76.19-83.54) 72 84.36 (80.51-87.51) 12-y 106 75.30 (70.13-79.72) 79 78.38 (72.32-83.27) Invasive local recurrence-free survival Estimate 0.75 (0.56-1.002) .051 5-y 38 93.39 (91.03-95.15) 17 96.99 (95.20-98.12) 10-y 95 80.68 (76.73-84.02) 68 85.15 (81.35-88.23) 12-y 103 75.87 (70.72-80.24) 75 79.23 (73.23-84.04) Mastectomy-free survival Estimate 0.88 (0.65-1.18) .38 5-y 39 93.24 (90.87-95.02) 23 95.93 (93.93-97.27) 10-y 82 83.79 (80.14-86.83) 75 83.82 (79.94-87.01) 12-y 92 77.80 (72.57-82.16) 79 80.44 (75.16-84.71) Distant disease-free survival Estimate 1.00 (0.72-1.39) .98 5-y 26 95.49 (93.44-96.90) 18 96.80 (94.97-97.97) 10-y 62 87.50 (84.13-90.19) 62 86.91 (83.37 89.74) 12-y 71 81.98 (76.91-86.04) 67 82.18 (76.44-86.65) Overall survival Estimate 0.96 (0.68-1.35) .80 5-y 19 96.70 (94.87-97.88) 13 97.69 (96.06-98.65) 10-y 56 88.62 (85.35-91.19) 56 87.77 (84.22-90.56) 12-y 65 83.13 (78.11-87.10) 59 84.72 (79.52-88.70) Breast cancer mortality Estimate 0.81 (0.43-1.52) .50 5-y 9 1.58 (0.82-3.01) 4 0.72 (0.27-1.90) 10-y 20 3.79 (2.45-5.83) 16 3.50 (2.11-5.77) 12-y 21 4.39 (2.77-6.93) 17 4.63 (2.52-8.43) Mortality from other causes Estimate 1.02 (0.68-1.55) .89 5-y 10 1.75 (0.95-3.23) 9 1.60 (0.84-3.06) 10-y 36 7.90 (5.69-10.90) 40 9.05 (6.62-12.31) 12-y 44 13.05 (9.35-18.05) 42 11.17 (7.78-15.88) Abbreviations: EBRT, whole-breast external beam radiotherapy; HR, hazard ratio; TARGIT-IORT, targeted intraoperative radiotherapy. Each of these survival measures include death as an event. sis was 3 July 2019, so that all events up until 2 July 2019 were included for analysis. The chief investigator/corresponding au- Results thor and the trial statistician (J.S.V. and Ma.B.) had access to all data sent by the trial center for analysis; all authors were Overall, 581 women were randomized to delayed TARGIT- responsible for the decision to submit the article. Since the last IORT and 572 to EBRT. The patient and tumor characteristics analysis, the trial oversight has been provided by an indepen- are given in Table 1 and were well matched between the ran- dent steering committee, appointed by the Health Technol- domization arms. Most patients were estrogen receptor posi- ogy Assessment program of the National Institute of Health Re- tive (1119 [98%]), ERBB2 negative (1041 [94%]); 670 patients search, Department of Health, United Kingdom. (58%) received endocrine therapy, and 40 (3.5%) received che- jamaoncology.com (Reprinted) JAMA Oncology July 2020 Volume 6, Number 7 5/10 Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 07/11/2021 Research Original Investigation Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast External Beam Radiotherapy for Early Breast Cancer Figure 3. Twelve-Year Kaplan-Meier Curves Comparing Delayed Second-Procedure TARGIT-IORT vs EBRT A B Local recurrence-free survival Distant disease-free survival 100 100 EBRT EBRT 80 80 Delayed TARGIT-IORT Delayed TARGIT-IORT 60 60 40 40 20 20 HR, 0.75 (95% CI, 0.57-1.003); log-rank P = .052 HR, 1.00 (95% CI, 0.72-1.39); log-rank P = .98 0 0 0 2 46 8 10 12 0 2 46 8 10 12 Years Years No. at risk No. at risk Delayed TARGIT-IORT 581 567 544 513 378 178 78 Delayed TARGIT-IORT 581 565 557 538 399 193 81 EBRT 572 559 547 520 370 161 57 EBRT 572 559 546 519 374 165 61 C D Mastectomy-free survival Overall survival 100 100 EBRT EBRT 80 80 Delayed TARGIT-IORT Delayed TARGIT-IORT 60 60 40 40 20 20 HR, 0.88 (95% CI, 0.65-1.18); log-rank P = .38 HR, 0.96 (95% CI, 0.68-1.35); log-rank P = .78 0 0 0 2 46 8 10 12 0 2 46 8 10 12 Years Years No. at risk No. at risk Delayed TARGIT-IORT 581 563 545 521 387 186 78 Delayed TARGIT-IORT 581 570 562 542 402 197 83 EBRT 572 557 543 517 367 159 57 EBRT 572 560 550 526 379 167 63 EBRT indicates whole-breast external beam radiotherapy; TARGIT-IORT, 95% confidence intervals. The orange lines represent EBRT with light orange targeted intraoperative radiotherapy. In each of these Kaplan-Meier graphs, the shading indicating the 95% confidence intervals. blue lines represent delayed TARGIT-IORT with light blue shading indicating the motherapy. The completeness of follow-up is demonstrated conserving surgery occurs predominantly in the index 17,18 in Figure 2. quadrant, despite the fact that more than 60% of patients At 5-year complete follow-up, the local recurrence rates suitable for breast conserving surgery are known to have mi- 17-19 were TARGIT-IORT, 23 (including 3 DCIS) of 581 (3.96%) vs croscopic foci of the disease outside the index quadrant. EBRT, 6 (including 2 DCIS) of 572 (1.05%), giving a difference The delayed TARGIT-IORT approach was proposed mainly of 2.9% with its upper 90% CI of 4.4, which crossed the non- for logistical reasons. It allowed better planning of operation inferiority margin of 2.5%. theaters as well as theoretically stricter selection of patients Kaplan-Meier estimates and log-rank P values for de- with low-risk disease based on final histopathologic analysis layed TARGIT-IORT vs EBRT are given in Table 2 and Figure 3. results. It also allowed using TARGIT-IORT in patients com- The median follow-up was 9 years and the differences be- ing to a cancer center after having had their cancer excised in tween delayed TARGIT-IORT and EBRT were not statistically a smaller or remote hospital. Concordant with the results of significant for local recurrence-free survival, invasive local re- our 2013 analysis, with mature follow-up (5 years complete fol- currence-free survival, mastectomy-free survival, distant dis- low-up with a median of 9 years) delayed TARGIT-IORT was ease-free survival, breast cancer mortality, non–breast can- found not to be noninferior to EBRT in terms of local control, cer mortality, and overall survival. No patients had uncontrolled with the upper 90% confidence limit of the 2.9% absolute dif- local recurrence at the time of death. ference in the 5-year local recurrence rate being 4.4%, which is above our stringent 2.5% noninferiority margin. This noninferiority margin of 2.5% was decided after con- siderable thought, and is much more stringent than the 7% Discussion margin set in the in the ELIOT trial, the only other trial to our The TARGIT-A trial was originally conceived because of the knowledge of intraoperative radiotherapy. We believe that clinicopathologic observation that local recurrence after breast- it is important to consider how much the absolute differ- 6/10 JAMA Oncology July 2020 Volume 6, Number 7 (Reprinted) jamaoncology.com Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 07/11/2021 Survival, % Survival, % Survival, % Survival, % Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast External Beam Radiotherapy for Early Breast Cancer Original Investigation Research ences seen in the trial matter to the patient. When consider- had already occurred and fibrosis was setting in by the time ing treatments for patients with early breast cancer, local re- the delayed TARGIT-IORT was delivered (median, 37 days currence has been given great importance because of the later). A limitation of the study was that we did not antici- perceived risk of consequent mastectomy, the danger of dis- pate a change in surgical practice in later years, such that tant disease, and the potentially lower survival. The long- the tumor bed was approximated after tumor excision term data show that there was no impairment of mastectomy- rather than leaving a cavity. The resultant scarring could free survival, distant disease-free survival, or overall survival, have made it difficult to accurately locate the primary up to 12 years from randomization (Figure 3). Moreover, qual- tumor bed. Given the rapid attenuation of dose, with dis- ity of life studies have shown that despite having a second pro- tance from the applicator surface, adequate dose may not cedure, the quality of life and patient-reported outcomes, such have reached the original tumor bed. Finally, one can also as cosmesis, breast-related quality of life, and breast pain, have speculate that the additional surgical trauma owing to the 21,22 been demonstrated to be superior with TARGIT-IORT, and necessary second procedure in every case of delayed TARGIT-IORT could stimulate residual cancer cells. Not- this approach is preferred by patients even in the face of a hy- 23,24 pothetically higher local recurrence risk. These findings withstanding these theoretical reasons, the final judgments may mitigate some of the patient concerns, and results of must be based on the long-term outcomes data. further patient preference research would help these discussions. Conclusions Limitations The reasons for higher local recurrence with delayed Partial breast irradiation was heralded as a new standard at second-procedure TARGIT-IORT may be multifactorial. the time of the first publication of the TARGIT-A trial and sev- First, the propensity of tumor recurrence in the index quad- eral other supporting clinical trials have since been pub- rant could be owing to a tumor promoting effect of the lished: including the ELIOT trial, interstitial 25-27 30 31,32 microenvironment of the surgical wound, a risk that has wire-brachytherapy, and partial breast EBRT. Based on been shown to be beneficially manipulated by TARGIT-IORT the randomized evidence of immediate TARGIT-IORT, which 25,27,28 6,7,33 to the fresh tumor bed, but perhaps not when has been shown to be an effective alternative to EBRT, it TARGIT-IORT is given as a delayed second procedure. Sec- is clear that the preferred timing of using TARGIT-IORT is im- ond, the surgical procedure of lumpectomy has changed. mediately—during the initial surgical excision of breast can- Early on in the trial, the tissues around the tumor bed were cer. However, when immediate TARGIT-IORT has not been pos- often not approximated after lumpectomy, and the tumor sible, the long-term data presented in this article may help bed remained easily identifiable as a fluid-filled cavity at inform discussions by clinicians and patients who wish to avoid the time of the second procedure, although some healing a prolonged postoperative course of EBRT. ARTICLE INFORMATION University, Germany (Wenz, Sperk); Red Cross Blanc-Onfroy); Brust Zentrum Seefeld, Zurich, Hospital, Department of Gynecology and Zurich, Switzerland (Gruber); Department of Accepted for Publication: January 16, 2020. Obstetrics, Technical University of Munich, Munich, Surgical Oncology, Medical University of Lublin, Open Access: This is an open access article Germany (Pigorsch, Eiermann); Department of Lublin, Poland (Polkowski); Breast Center, distributed under the terms of the CC-BY License. Surgery, University of California, San Francisco Universitätsspital Zürich, Zurich, Switzerland © 2020 Vaidya JS et al. JAMA Oncology. (Alvarado); Nuffield Department of Surgical (Dedes); Saarland University Medical Center, Published Online: April 2, 2020. Sciences, University of Oxford, Oxford, United Homberg, Germany (Niewald); Sankt doi:10.1001/jamaoncol.2020.0249 Kingdom (Douek); Patient Advocate and Writer, Gertrauden-Krankenhaus, and The Charité – London, United Kingdom (Bernstein); Department Universitätsmedizin Berlin, Berlin, Germany Correction: This article was corrected on May 21, of Surgery, Ninewells Hospital, Dundee, United (Blohmer); Princess Margaret Cancer Centre 2020, to change the liscensing type to open access Kingdom (Brown); Department of Surgery, Royal Toronto, Toronto, Ontario, Canada (McCready); CC-BY type and to correct an error in Figure 1B. Hampshire County Hospital, Winchester, United Sentara Surgery Specialists, Hampton, Virginia Author Affiliations: Division of Surgery and Kingdom (Laws); University Medical Center (Hoefer); Ashikari Breast Center, New York Medical Interventional Science, University College London, Mannheim, Department of Gynecology and College, New York, New York (Kelemen); London, United Kingdom (Vaidya, Bulsara, Obstetrics, Medical Faculty Mannheim, Heidelberg Department of Surgery, University College London Brew-Graves, Williams, Potyka, Roberts, Baum); University, Germany (Sütterlin); Department of Hospitals, London, United Kingdom (Petralia); Department of Biostatistics, University of Notre Oncology, St Olav’s University Hospital, Trondheim, Department of Pathology, University College Dame, Fremantle, West Australia, Australia Norway (Lundgren); Department of Clinical and London Hospitals, London, (Bulsara); University of Western Australia School of Molecular Medicine, Norwegian University of United Kingdom (Falzon). Surgery, West Australia, Australia (Saunders); Science and Technology (NTNU), Trondheim, Author Contributions: Professors Vaidya and Department of Breast Surgery, University of Norway (Lundgren); Helen Rey Breast Cancer Bulsara had full access to all of the data in the study Copenhagen, Copenhagen, Denmark (Flyger); Foundation, John Wayne Cancer Institute, and take responsibility for the integrity of the data Department of Clinical Oncology, University College University of Southern California, Los Angeles and the accuracy of the data analysis. London Hospitals, London, United Kingdom (Holmes); Department of Radiation Oncology, Study concept and design: Vaidya, Saunders, Tobias, (Tobias); Department of Radiation Oncology, Sir Centro di Riferimento Oncologico di Aviano (CRO) Corica, Wenz, Douek, Eiermann, Blohmer, Charles Gairdner Hospital, Perth, West Australia, IRCCS, Aviano, Italy (Vinante); Instituto Oncologico Baum, Joseph. Australia (Corica, Joseph); Department of Surgery, Veneto, Padoa, Italy (Bozza); University Hospital, Acquisition, analysis, or interpretation of data: Centro di Riferimento Oncologico di Aviano (CRO) Department of Radiation Oncology, Ludwig All authors. IRCCS, Aviano, Italy (Massarut); University Medical Maximilians Universitat, Munich, Germany (Pazos); Drafting of the manuscript: Vaidya, Bulsara, Center Mannheim, Department of Radiation Oncologue radiothérapeute, Institut de Saunders, Tobias, Douek, Roberts, Holmes, Oncology, Medical Faculty Mannheim, Heidelberg Cancérologie de l’Ouest, Nantes, France (Le jamaoncology.com (Reprinted) JAMA Oncology July 2020 Volume 6, Number 7 7/10 Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 07/11/2021 Research Original Investigation Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast External Beam Radiotherapy for Early Breast Cancer Baum, Joseph. Sarpong, Jack Grierson, Neil McCartan, Charlie Darius Dian, Sylvia Dondl, Klaus Friese, Julia Critical revision of the manuscript for important Mizon, Mortez Ali, Cindy Li, Alex Shirley, Joanna Jueckstock, Thomas Kirchner, Klaus Krimmel, Doris intellectual content: Vaidya, Saunders, Flyger, Hadley, Fatima Akbar, Muhammad Hammed, Daryl Mayr, Susanne Reinhard, Dr Schaffer, Christian Tobias, Corica, Massarut, Wenz, Pigorsch, Alvarado, Hagan, Olive Murphy, Tina Lennon, Joan Houghton; Schindlbeck, Harald Sommer, Justus Well: Ludwig Douek, Eiermann, Brew-Graves, Williams, Potyka, Surgical Interventional Trials Unit, Division of Maximilians Universität, Munich, Germany; M Roberts, Bernstein, Brown, Sperk, Laws, Sutterlin, Surgery and Interventional Science, University Kaufmann, H Boettcher, J Moog, Achim Rody, Claus Lundgren, Holmes, Vinante, Bozza, Pazos, College London. Jayant S Vaidya, Jeffrey S Tobias, Rödel, S Schopohl, Christian Weiss, Inge Fraunholz, Le-Blanc-Onfroy, Gruber, Polkowski, Dedes, Michael Baum, Mohammed Keshtgar, Glen Ulla Ramm, Martin-Leo Hansmann, R Strohmeier: Niewald, Blohmer, McCready, Hoefer, Falzon, Blackman, Chris Brew-Graves, Michael Douek, Mary Universität Frankfurt am Main, Frankfurt, Germany; Kelemen, Petralia, Baum, Joseph. Falzon, Gloria Petralia, Norman R Williams: Henrik Flyger, Eva Balslev, Niels Bentzon, Paul Statistical analysis: Vaidya, Bulsara, Douek, University College London Hospital, London, Geertsen, Helle Holtveg, Claus Kamby, Niels Williams. United Kingdom; Frederik Wenz, Elena Sperk, Mark Kroman, Faisal Mahmood, Fritz Rank, Birgitte Bruun Obtained funding: Vaidya, Wenz, Williams, Baum. Suetterlin, M Bohrer, S Clausen, B Hermann, R Rasmussen, Lone Gry Schäfer, Peter Michael Administrative, technical, or material support: Hildenbrand, Anke Keller, Uta Kraus-Tiefenbacher, Vestlev, Vera Timmermans Wielenga, Eva Wilken: Vaidya, Corica, Wenz, Pigorsch, Douek, B Kuepper, A Marx, F Melchert, D Neumann, F Herlev/Rigs Hospitals, Copenhagen, Denmark; Brew-Graves, Williams, Potyka, Roberts, Brown, Schneider, V Steil, M Trunk, Frank A. Giordano: Wojciech P Polkowski, Malgorzata Jankiewicz, Polkowski, Dedes, Niewald, Blohmer, Hoefer, Baum. Universitätsmedizin Mannheim, Universität Andrzej Kurylcio, Jerzy Mielko, Magdalena Study supervision: Vaidya, Bulsara, Saunders, Heidelberg, Mannheim, Germany; Christobel Skorzewska, Bogumila Cisel, Monika Lewicka, Edyta Flyger, Tobias, Wenz, Williams, Brown, Pazos, Saunders, David J Joseph, Tammy Corica, Elizabeth Matejek, Jaroslaw Romanek, Andrzej Stanislawek, Blohmer, Kelemen, Baum, Joseph. Kernutt, Mandy Taylor, Eva Vosikova, Claire Jadwiga Sierocinska-Sawa, Zofia Siezieniewska, Haworth: Sir Charles Gairdner Hospital, Perth, WA, Rafal Smyk, Andrzej Bedonski: Medical University of Conflict of Interest Disclosures: Dr Vaidya has Australia; Samuele Massarut, Lorenzo Vinante, Lublin, Lublin, Poland; Mohammed Keshtgar, received a research grant from Photoelectron Corp M Arcicasa, E Bidoli, E Cadiani, E Capra, M Oliva, Katharine Pigott, Tim Davidson, Jayant S Vaidya, (1996-1999) and from Carl Zeiss for supporting data T Perin, S Reccanello, M Roncadin, G Sartor, G Debasis Ghosh, Sarah Needleman, Jawad Keshtgar, management at the University of Dundee Tabaro, M Trovo, R Volpe Mario Mileto, Erica Piccoli, Samia Shah, Katia Pasciuti, Neil Dancer, Kashmira (2004-2008) and has subsequently received Antonella Spada: Centro di Riferimento Oncologico, Metha, Benjamin Earner, Stephan Duck, David honoraria. Drs Vaidya, Tobias, Williams, Potyka, Ms Aviano, Italy; DC Brown, Julie Lidsay, M Adams, DJA Woolf: Royal Free Hospital, London, United Brew-Graves, and Mr Roberts receive funding from Adamson, K Armoogum, J Bosch, JA Dewar, S Kingdom; Jayant S Vaidya, Jeffrey S Tobias, Alan Health Technology Assessment Programme, Edwards, J Gardner, A Gunning, M Hawkes, LB Wilson, Glen Blackman, Rashika Rajakumar, Renata National Institute for Health Research (NIHR), Jordan, A Lee, G Little, C Mackay, AJ Munro, J Parry, Rowicka, Veronica Conteh, Su Ramachandra, Lucy Department of Health for some activities related to CA Purdie, MM Reis, V Walker, RAB Wood: Harbin, R Chaudhuri, Ros Crooks, Francesca Peters, the TARGIT trials. Dr Baum was on the scientific Ninewells Hospital, Dundee, United Kingdom; Tom Connors, George Stasinos, Melissa Hickson, advisory board of Carl Zeiss and was paid monthly Michael Alvarado, Laura Esserman, Alfred Au, Alison Jones, Mulyati Mohamed, Tim Crook, consultancy fees briefly before 2010. Dr Wenz has Alison Bevan, Jay Connolly, Cheryl Ewing, Clark Vivienne Maidens, Sylvia Grieve, Elizabeth Tamufor, received a research grant from Carl Zeiss for Fisher, Shelley Hwang, K Lane, Christina Minami, Lucy Mavriano, Lotta Jonsson, Ciara McNulty: supporting radiobiological research. Carl Zeiss Michelle Oboite, Cathy Park, Jean Pouliot, Theadora Whittington Hospital, London, United Kingdom; sponsors some of the travel and accommodation Sakata, Aron Mohan, Brittany Harrison, Albert Thomas L Summer, Mario Contreras, Paul M for meetings of the international steering Chan, Mitchell Hayes: University of California, San DesRosiers, Irene Gordon, Kazumi Chino, Bedatri committee and data monitoring committee and Francisco Medical Center, San Francisco; Wolfgang Sinha, Cindy McDowell, Mike Ringer, Tammy when necessary for conferences where a Eiermann, Steffi Pigorsch, Stephanie E. Combs, Spurlock, Lisa Ramsey: Lafayette Surgical Clinic, presentation about targeted intraoperative Lafayette, Indiana; Richard A Hoefer, Mary Berry, Beyhan Ataseven, C Becker, B Hoegel, P radiotherapy is being made for all authors apart Kneschaurek, A Lackermeier, M Molls, Carsten Michael Miller, Song Kang: Sentara Surgery from Dr Eiermann who declares that he has no Nieder, Markus Oechsner, Barbara Röper, Sabine Specialists, Hampton, Virginia; Erich Solomayer, K conflicts of interest. No other conflicts are Schill, Ralf Wehrmann, Brigitte Werner, Christopher Abel, S Baum, Rainer Allgayer, R M Bohle, Mustafa reported. Wolf: Frauenklinik vom Roten Kreuz, Munich in Deryal, J Fleckenstein, R Grobholz, Jeanett Koehn, Funding/Support: The study was sponsored by cooperation with Technical University of Munich, Anja Martin-Riedheimer, Marcus Niewald, J. Radosa University College London Hospitals (UCLH)/UCL Dept. of RadioOncology, Germany; Dennis R and J.Friedmann, Markus Promnik, Christian Ruebe, Comprehensive Biomedical Research Centre. Holmes, Melvin Astrahan, Carryl Dubois, Jacqueline W Schmidt: Uniklinikum des Saarlandes, Homburg, Funding was provided by UCLH Charities, NIHR Majors, Sylvia Villegas Mendez, Afshin Rashtian, Germany; David McCready, Akbar Beiki-Ardakani, Health Technology Assessment Programme, Ronald Rivera, Howard Silberman, Melvin John Cho, Susan Done, Jamie Escallon, Anthony W Ninewells Cancer Campaign, National Health and Silverstein, Rashida Soni, Oscar E Streeter Jr, Lina Fyles, Wilfred Levin, Alex Vitkin, Marie Vranic: Medical Research Council, and German Federal Wang, Heather Macdonald, Stephen Sener, America Princess Margaret Cancer Centre, Toronto, Ontario, Ministry of Education and Research (FKZ Casillas: University of Southern California, Los Canada; Siobhan Laws, Dick Rainsbury, Claire Birch, 01ZP0508). The infrastructure of the trial Angeles; Gianmaria Fiorentini, Carli Ballola Adele, Lyn Booth, Caroline Cross, Alan Gately, Virginia Hall, operations office in London, United Kingdom, was Rafaella Barca, Mauro Biancalani, Giampaolo Biti, Kevin Harris, Sanjay Raj, Balvinder Shoker, Virginia supported by core funding from Cancer Research Enrico Cellai, Antonella Compagnucci, Claudio Straker, Jennifer Wilson: Royal Hampshire County Campaign (now Cancer Research UK) when the trial Caponi, Vito Maria Fontanarosa, Roberta Ghezzi, Hospital, Winchester, United Kingdom; Christopher was initiated. Alessandro Ghirelli, Gloria Giustarini, Barbara Grilli Rageth, Uwe Gneveckow, Elisabeth Grob, Guenther Role of the Funder/Sponsor: The funding agencies Leonulli, Francesca Littori, Maurizio Pertici, Visna Gruber, Baerbel Papassotiropoulos, Barbara Tausch, had no role in the design and conduct of the study; Petrina, Paola Raffaele, Francesca Righi, Serenella C Tausch, Zsuszanna Varga, Iris Vergin: Brust collection, management, analysis, and Russo, Michele de Simone, Gina Turrisi, Giuditta Zentrum Seefeld, Zurich, Switzerland; Claudia interpretation of the data; preparation, review, or Zipoli: Ospedale San Giuseppe di Empoli, Empoli, Hutzli, Konstantin J Dedes, Yvonne Burgstaller, approval of the manuscript; and decision to submit Italy; Jens-Uwe Blohmer, Petra Feyer, J Gross, G Rosemary Caduff, Daniel Fink, Guntram Kunz, the manuscript for publication. Jautzke, K Luebbert, Michaela Platzer, Joerg Claudia Linsenmeier, Yousef Najafi, Natalie Gabriel, Preussler, D Puppe, Esther Wiedemann: Sankt Cornelia Betschart, Eleftherios Samartzis, Acknowledgment: We thank the individuals from Gertrauden-Krankenhaus, Berlin, Germany; Michael Ana-Maria Schmidt, Tino Streller, Z Varga, each center whose help has been invaluable. In Henderson, David Blakey, Boon Chua, Ram Das, Madeleine Wick, Cornelia Leo, Zsuzsanna Varga, addition, we thank those who no longer work in the Roslyn Drummond, Annette Haworth, Penny Fogg, Leila Kocan: Breast Centre, Universitätspital Zurich, respective departments and those who may not Stephen Fox, Jodi Lynch, Jane O’Brien, Catherine Zurich, Switzerland; Steinar Lundgren, Anne Beate have been named herein (in order of the date of Poliness, Ann-Marie Power, David Speakman, Tina Marthinsen Langeland, Marianne Brekke, Hans E randomization of the first patient): Chris Thorpe, Melanie Walker: Peter MacCallum Cancer Fjosne, Jomar Frengen, Kristen Helset, Jarle Brew-Graves, Ingrid Potyka, Nicholas Roberts, Centre, Melbourne, VIC, Australia; Montserrat Karlsen: St Olav’s University Hospital, Trondheim, Norman Williams, Haroon Miah, Cinzia Baldini, Bina Pazos, Wolfgang Janni, Ulrich Andergassen, C Balka, Norway; James Edney, Aaron Sasson, Debra Shah, Danielle Maas, Charlene Carvalho, Rachael 8/10 JAMA Oncology July 2020 Volume 6, Number 7 (Reprinted) jamaoncology.com Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 07/11/2021 Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast External Beam Radiotherapy for Early Breast Cancer Original Investigation Research Spence, Robert Thompson, William W West, Sumin accuracy of the data analysis. We thank Michael D 11. Herskind C, Wenz F. Radiobiological comparison Zhou: University of Nebraska Medical Center, O’Shea, PhD, Woodward Informatics, Oxfordshire, of hypofractionated accelerated partial-breast Omaha, Nebraska; Michael Douek, Sarah Aldridge, United Kingdom, for database development, Julie irradiation (APBI) and single-dose intraoperative Ashutosh Kothari, Nick Beechey-Newman, Charles Lindsay, BSc, Ninewells Hospital, Dundee, United radiotherapy (IORT) with 50-kV X-rays. Deehan, Ian Fentiman, Hisham Hamed, Sarah Kingdom, for help in data collection, Uma J. Vaidya Strahlenther Onkol. 2010;186(8):444-451. et al. Harris, Hardeep Johal, Sarah Pinder, Arnie for help with the figures, tables, and editing of the doi:10.1007/s00066-010-2147-9 Purushotham, Vernie Ramalingam, Chris Stacey: manuscript, and several contributors who have 12. Vaidya JS, Walton L, Dewar J. Single dose Guy’s and St Thomas’ Hospital, London, United now left the individual centres. 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Mol 2016;387(10015):229-238. doi:10.1016/S0140-6736 women with early-stage breast cancer (the Oncol. 2014;8(3):766-780. doi:10.1016/j.molonc. (15)00471-7 TARGIT-A trial). Health Technol Assess. 2016;20 2014.02.006 (73):1-188. doi:10.3310/hta20730 31. Livi L, Meattini I, Marrazzo L, et al. Accelerated 28. Fabris L, Berton S, Citron F, et al. partial breast irradiation using intensity-modulated Radiotherapy-induced miR-223 prevents relapse of 10/10 JAMA Oncology July 2020 Volume 6, Number 7 (Reprinted) jamaoncology.com Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 07/11/2021 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Oncology Unpaywall

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Abstract

IMPORTANCE Conventional adjuvant radiotherapy for breast cancer given daily for several Supplemental content weeks is onerous and expensive. Some patients may be obliged to choose a mastectomy instead, and some may forgo radiotherapy altogether. We proposed a clinical trial to test whether radiotherapy could be safely limited to the tumor bed. OBJECTIVE To determine whether delayed second-procedure targeted intraoperative radiotherapy (TARGIT-IORT) is noninferior to whole-breast external beam radiotherapy (EBRT) in terms of local control. DESIGN, SETTING, AND PARTICIPANTS In this prospective, randomized (1:1 ratio) noninferiority trial, 1153 patients aged 45 years or older with invasive ductal breast carcinoma smaller than 3.5 cm treated with breast conservation were enrolled from 28 centers in 9 countries. Data were locked in on July 3, 2019. INTERVENTIONS The TARGIT-A trial was started in March 2000; patients were randomized after needle biopsy to receive TARGIT-IORT immediately after lumpectomy under the same anesthetic vs EBRT and results have been shown to be noninferior. A parallel study, described in this article, was initiated in 2004; patients who had their cancer excised were randomly allocated using separate randomization tables to receive EBRT or delayed TARGIT-IORT given as a second procedure by reopening the lumpectomy wound. MAIN OUTCOMES AND MEASURES A noninferiority margin for local recurrence rate of 2.5% at 5 years, and long-term survival outcomes. RESULTS Overall, 581 women (mean [SD] age, 63 [7] years) were randomized to delayed TARGIT-IORT and 572 patients (mean [SD] age, 63 [8] years) were randomized to EBRT. Sixty patients (5%) had tumors larger than 2 cm, or had positive nodes and only 32 (2.7%) were younger than 50 years. Delayed TARGIT-IORT was not noninferior to EBRT. The local recurrence rates at 5-year complete follow-up were: delayed TARGIT-IORT vs EBRT (23/581 [3.96%] vs 6/572 [1.05%], respectively; difference, 2.91%; upper 90% CI, 4.4%). With long-term follow-up (median [IQR], 9.0 [7.5-10.5] years), there was no statistically significant difference in local recurrence-free survival (HR, 0.75; 95% CI, 0.57-1.003; P = .052), mastectomy-free survival (HR, 0.88; 95% CI, 0.65-1.18; P = .38), distant disease-free survival (HR, 1.00; 95% CI, 0.72-1.39; P = .98), or overall survival (HR, 0.96; 95% CI, 0.68-1.35; P = .80). CONCLUSIONS AND RELEVANCE These long-term data show that despite an increase in the Author Affiliations: Author number of local recurrences with delayed TARGIT-IORT, there was no statistically significant affiliations are listed at the end of this article. decrease in mastectomy-free survival, distant disease-free survival, or overall survival. Corresponding Author: Jayant S. TRIAL REGISTRATION ISRCTN34086741, ClinicalTrials.gov Identifier: NCT00983684 Vaidya, MBBS, MS, DNB, PhD, Division of Surgery and Interventional Science, University College London, 43-45 Foley St, London W1W 7JN, JAMA Oncol. 2020;6(7):e200249. doi:10.1001/jamaoncol.2020.0249 United Kingdom (jayantvaidya@ Published online April 2, 2020. Corrected on May 21, 2020. gmail.com). (Reprinted) 1/10 Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 07/11/2021 Research Original Investigation Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast External Beam Radiotherapy for Early Breast Cancer n 2018, there were 2 million new cases of breast cancer di- agnosed worldwide and 626 000 deaths. Most patients are Key Points I suitable for treatment with breast-conserving surgery and Question For early breast cancer, is 5-year local control with adjuvant radiotherapy, rather than total mastectomy. The delayed second-procedure targeted intraoperative radiotherapy TARGIT-A randomized clinical trial (accrual from 2000-2012) (TARGIT-IORT) noninferior to whole-breast postoperative external compared risk-adapted TARGeted intraoperative radio- beam radiotherapy (EBRT), and how do long-term outcomes compare? therapy (TARGIT-IORT) during the initial surgical excision of 2-5 the cancer with conventional whole-breast external beam Findings In this randomized clinical trial including 1153 2,6,7 radiotherapy (EBRT) over several weeks. The results of participants, delayed second-procedure TARGIT-IORT was not this trial demonstrated noninferiority particularly when noninferior to EBRT at 5-year complete follow-up; however, long-term (median 9 years) mastectomy-free survival, distant TARGIT-IORT was delivered at the time of initial excision of disease-free survival, and overall survival were not different. cancer. In 2004, 4 years after accrual began in the main Meaning For early breast cancer, delayed second-procedure TARGIT-A trial, and at the request of potentially high-volume single-dose TARGIT-IORT given by reopening the lumpectomy wound had similar long-term mastectomy-free and overall survival centers, we sought and received additional ethics approval and compared with EBRT despite higher local recurrence. opened a parallel study. This was previously referred to as “postpathology stratum” and recruited 1153 patients using a separate randomization table. Patients were randomized af- ter their initial surgery to have either conventional fraction- ing of delayed TARGIT-IORT in the operation theater. A po- ated whole-breast radiotherapy (n = 572), or to undergo a fur- tential benefit was that the inclusion criteria could be made ther operation to deliver delayed radiotherapy to the wound more selective, choosing the patients with better prognosis (n = 581) by reopening the original incision. This trial was ini- based on the full histopathologic results that would be avail- tiated mainly because of the convenience of easier schedul- able after tumor excision. For example, the knowledge of the Figure 1. Flowchart and CONSORT Diagram Flowchart outlining recruitment to trial of delayed TARGIT-IORT vs EBRT Eligibility: Age ≥45 years Primary tumor already excised Unifocal invasive ductal carcinoma preferably ≤3.5 cm, cN0-N1 (MRI not required) Suitable for breast-conserving surgery 1153 Randomized 581 Randomized to delayed 572 Randomized to conventional radiotherapy TARGIT-IORT delivered as a single dose to the Standard fractionated EBRT over 3-6 weeks tumor bed with intrabeam to the reopened tumor bed as a second procedure B CONSORT diagram EBRT indicates whole-breast external 1153 Patients enrolled and randomized after excision of tumor beam radiotherapy; MRI, magnetic resonance imaging; TARGIT-IORT, targeted intraoperative radiotherapy. A, Flowchart outlining recruitment to 581 Randomized to delayed second-procedure TARGIT-IORT 572 Randomized to EBRT trial of delayed TARGIT-IORT vs EBRT. B, CONSORT diagram of participant 2 Withdrawn from further follow-up 6 Withdrawn from further follow-up randomization. The difference in number 12 Did not receive allocated treatment 18 Did not receive allocated treatment withdrawn was not statistically b b 2 Received EBRT 8 Received TARGIT-IORT and EBRT significant (P = .15). 0 Did not receive TARGIT-IORT or EBRT 3 Did not receive TARGIT-IORT or EBRT As per protocol, 31 of 581 patients 10 Had a mastectomy 7 Had a mastectomy (5.3 %) allocated to delayed TARGIT-IORT received EBRT after 569 Received allocated treatment 554 Received allocated treatment TARGIT-IORT. 538 Received delayed TARGIT-IORT 554 Received EBRT Two of 581 patients (0.3%) 31 Received TARGIT-IORT plus EBRT allocated to delayed TARGIT-IORT received EBRT and 8 of 572 (1.4%) 581 Included in analysis 572 Included in analysis allocated EBRT received TARGIT-IORT as well. 2/10 JAMA Oncology July 2020 Volume 6, Number 7 (Reprinted) jamaoncology.com Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 07/11/2021 Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast External Beam Radiotherapy for Early Breast Cancer Original Investigation Research Table 1. Patient and Tumor Characteristics Table 1. Patient and Tumor Characteristics (continued) a a No. (%) No. (%) Delayed Delayed TARGIT-IORT EBRT TARGIT-IORT EBRT b b Characteristic (n = 581) (n = 572) P value Characteristic (n = 581) (n = 572) P value Age, y Chemotherapy ≤50 30 (5.2) 23 (4.02) Received 26 (4.5) 14 (2.5) 51-60 166 (28.6) 171 (29.9) Did not receive 553 (95.5) 546 (97.5) 61-70 302 (52.0) 284 (49.7) Unknown 2 (0.3) 12 (2.1) >70 83 (14.3) 94 (16.4) Abbreviations: DCIS, ductal carcinoma in situ; EBRT, whole-breast external Pathologic tumor size, mm beam radiotherapy; ER, estrogen receptor; PgR, progesterone receptor; TARGIT-IORT, targeted intraoperative radiotherapy. ≤10 294 (51.0) 290 (51.8) For percentage calculation, the denominator for unknown percentages is the 11-20 249 (43.2) 243 (43.4) total number randomized (581 and 572) and the denominator for each >20 33 (5.7) 27 (4.8) category is the total number of known cases. Unknown 5 (0.9) 12 (2.1) P values are given for differences between TARGIT-IORT and EBRT, calculated using a χ test for known values. Grade 1 305 (56.5) 339 (63.8) 2 204 (37.8) 159 (29.9) microscopically measured tumor size, grade, and nodal sta- 3 31 (5.7) 33 (6.2) tus could be used to select a much lower-risk patient popula- Unknown 41 (7.1) 41 (7.2) tion before randomization. Margin This delayed procedure was performed at a median (IQR) Free 539 (92.9) 520 (92.4) of 37 (29-51) days after the initial excision as a second surgical DCIS only 16 (2.8) 18 (3.2) procedure in the operation theater, rather than immediate in- Invasive 25 (4.3) 25 (4.5) traoperative radiotherapy given during the initial cancer op- Unknown 1 (0.2) 9 (1.6) eration. This article describes the long-term outcomes of this Lymphovascular invasion parallel study. Absent 536 (94.7) 533 (96.6) Present 30 (5.3) 19 (3.4) Unknown 15 (2.6) 20 (3.5) Methods Lymph nodes involved 0 543 (93.6) 537 (95.2) The TARGIT-A trial was a pragmatic, prospective, interna- 1-3 34 (5.9) 26 (4.6) tional, multicenter, open label, randomized, phase 3 trial that >3 3 (0.5) 1 (0.2) compared the policy of risk-adapted TARGIT-IORT vs the con- Unknown 1 (0.2) 8 (1.4) ventional policy of whole-breast EBRT. The trial protocol (https:// ER status njl-admin.nihr.ac.uk/document/download/2006598) and the details of sample size calculations, the process of random Positive 569 (98.3) 550 (97.9) 6,7 allocation, have been previously described. The trial protocol Negative 10 (1.7) 12 (2.1) is available in Supplement 1. The study received ethics approval Unknown 2 (0.3) 10 (1.7) from the joint University College London and University College PgR status London Hospital committees of ethics of human research. Positive 440 (81.8) 423 (82.0) Negative 98 (18.2) 93 (18.0) Participants Unknown 43 (7.4) 56 (9.8) Women were eligible to participate in the delayed TARGIT- ERBB2 status IORT trial if their breast cancer was already excised. They Positive 30 (5.4) 33 (6.0) needed to be aged 45 years or older with unifocal breast can- Negative 526 (94.6) 515 (94.0) cer on examination and conventional imaging. Pragmati- Unknown 25 (4.3) 24 (4.2) cally, we permitted individual centers to prespecify the final Method of presentation postoperative histopathologic criteria that would make pa- Screen detected 420 (73.6) 395 (70.5) tients eligible for randomization and these were prespecified Symptomatic 151 (26.4) 165 (29.5) in the center’s treatment policy document. Because most cen- Unknown 10 (1.7) 12 (2.1) ters specified criteria for eligibility: aged 50 years or older, grade Endocrine therapy 1 or 2 disease, and uninvolved nodes, only 5% of patients in Received 336 (58.0) 334 (59.4) the trial had any adverse prognostic criteria. All patients gave Did not receive 243 (42.0) 228 (40.6) .63 informed written consent and needed to be available for regu- lar follow-up for at least 10 years. Follow-up clinical examina- Unknown 2 (0.3) 10 (1.8) tion was at least every 6 months for the first 5 years and an- (continued) nually thereafter, including a mammogram once per year. jamaoncology.com (Reprinted) JAMA Oncology July 2020 Volume 6, Number 7 3/10 Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 07/11/2021 Research Original Investigation Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast External Beam Radiotherapy for Early Breast Cancer Figure 2. Actual Follow-up and Expected Follow-up for the Trial of Delayed Second-Procedure TARGIT-IORT vs EBRT 40 EBRT/actual EBRT/expected Delayed TARGIT-IORT (actual) Delayed TARGIT-IORT (expected) 0 2 46 8 10 12 Years No. at risk EBRT/actual 572 560 550 526 379 167 63 EBRT/expected 572 563 555 543 406 180 74 EBRT indicates whole-breast external Delayed TARGIT-IORT (actual) 581 570 562 542 402 197 83 beam radiotherapy; TARGIT-IORT, Delayed TARGIT-IORT (expected) 581 574 567 555 417 208 88 targeted intraoperative radiotherapy. Random allocation was in a 1:1 ratio, to receive either single- tions of local recurrence rate at 5-year complete follow up dose delayed TARGIT-IORT or EBRT as per standard sched- should not cross 2.5% in absolute terms. ules over several weeks, with randomization blocks stratified Kaplan-Meier graphs were displayed as recommended by by center. The flow diagram and CONSORT diagram are given Pocock et al, who recommend that the x-axis of these graphs in Figure 1A and B. should be extended until 10% to 20% of patients are at risk of The concept and the delayed TARGIT-IORT technique have an event. The log-rank test was used to compare the differ- 3-5,8-11 been described previously and enabled these patients to ence between survival functions and to obtain P values. have their radiotherapy in 1 sitting, albeit by undergoing a sec- ond procedure, usually under a general anesthetic. Radia- Main Outcomes and Measures tion was given over 20 to 50 minutes delivering 20 Gy to the The cause of death was specified by the center. If the cause was surface of the tumor bed attenuating to 5 to 7 Gy at 1-cm depth. specified as a non–breast cancer event and no distant disease The patients in the conventional arm underwent stan- was recorded, it was defined as a non–breast cancer death. If dard EBRT, which always included fractionated whole-breast the death was recorded by the center to be related to breast radiotherapy for 3 to 6 weeks, with or without an EBRT tu- cancer, or as per convention, if breast cancer was present at mor bed boost, as determined by local criteria prespecified by the time of death, or if the cause of death was recorded as un- the collaborating center. known or uncertain, it was presumed to be a breast cancer death. Statistical Analysis Figure 1B shows the CONSORT diagram, which describes The statistical analysis plan (Supplement 1) was signed off on the treatment received in each of the randomized arms. The by the chair of the independent steering committee and an in- reference date for completeness was May 2, 2018, 8 years af- dependent senior statistician before the unblinded data were ter the first data lock. A patient was considered as having com- sent to the trial statistician for the current analysis. It speci- plete follow-up if they were seen for the specified duration of fied the primary outcome as local recurrence-free survival. This follow-up, had died, or had withdrawn from the trial. As the 13 14 outcome, consistent with the DATECAN and STEEP guide- last patient was randomized in 2012, the statistical analysis plan lines, estimates the chance of a patient being alive without lo- specified that the 5-year follow-up would be considered com- cal recurrence and therefore included local recurrence or death plete if 95% of patients had complete follow-up. It also speci- as events, ie, patients who had died were not censored. The fied that 10-year follow-up would be considered complete if other outcomes included mastectomy-free survival, distant dis- the patient had at least 10 years of follow-up, had been seen ease-free survival, overall survival, breast cancer mortality and within 1 year of the reference date, or had died or withdrawn; non–breast cancer mortality. Statistical analysis was per- the 10-year follow-up would be considered complete if this was formed using established methods, using STATA statistical soft- achieved by 90% of patients. Because there was no specific trial ware (versions 15.0 and 16.0, STATA Corp) for data compila- funding for individual centers, return of follow-up relied on 13-15 tion, validation, and analysis. Data analysis took place individual investigators and their teams’ efforts, enthused by between September 11, 2019 to January 15, 2020. the trial-center team. The trial statistician and the chief inves- In the original protocol, noninferiority was specified as tigator produced reports of completeness of follow up using being achieved if the difference in 5-year local recurrence rate blinded databases on a regular basis. As recommended by the did not cross a stringent margin of 2.5%. However, we have ap- independent steering committee, the database was un- plied an even more rigorous criterion since 2013: that the up- blinded for analysis once the prespecified goals for complete- per 90% CI of the absolute difference in the binomial propor- ness of follow up were achieved. The reference date for analy- 4/10 JAMA Oncology July 2020 Volume 6, Number 7 (Reprinted) jamaoncology.com Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 07/11/2021 Follow-up, % Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast External Beam Radiotherapy for Early Breast Cancer Original Investigation Research Table 2. Twelve-Year Kaplan-Meier Estimates of Outcomes Measures for TARGIT-IORT vs EBRT Delayed TARGIT-IORT (n = 581) EBRT (n = 572) Significance test for the full follow-up Kaplan-Meier estimates Kaplan-Meier estimates Outcomes Events (95% CI) Events (95% CI) HR (95% CI) P value for log rank Local recurrence-free survival Estimate 0.75 (0.57-1.003) .052 5-y 41 92.87 (90.44-94.70) 19 96.63 (94.77-97.84) 10-y 98 80.16 (76.19-83.54) 72 84.36 (80.51-87.51) 12-y 106 75.30 (70.13-79.72) 79 78.38 (72.32-83.27) Invasive local recurrence-free survival Estimate 0.75 (0.56-1.002) .051 5-y 38 93.39 (91.03-95.15) 17 96.99 (95.20-98.12) 10-y 95 80.68 (76.73-84.02) 68 85.15 (81.35-88.23) 12-y 103 75.87 (70.72-80.24) 75 79.23 (73.23-84.04) Mastectomy-free survival Estimate 0.88 (0.65-1.18) .38 5-y 39 93.24 (90.87-95.02) 23 95.93 (93.93-97.27) 10-y 82 83.79 (80.14-86.83) 75 83.82 (79.94-87.01) 12-y 92 77.80 (72.57-82.16) 79 80.44 (75.16-84.71) Distant disease-free survival Estimate 1.00 (0.72-1.39) .98 5-y 26 95.49 (93.44-96.90) 18 96.80 (94.97-97.97) 10-y 62 87.50 (84.13-90.19) 62 86.91 (83.37 89.74) 12-y 71 81.98 (76.91-86.04) 67 82.18 (76.44-86.65) Overall survival Estimate 0.96 (0.68-1.35) .80 5-y 19 96.70 (94.87-97.88) 13 97.69 (96.06-98.65) 10-y 56 88.62 (85.35-91.19) 56 87.77 (84.22-90.56) 12-y 65 83.13 (78.11-87.10) 59 84.72 (79.52-88.70) Breast cancer mortality Estimate 0.81 (0.43-1.52) .50 5-y 9 1.58 (0.82-3.01) 4 0.72 (0.27-1.90) 10-y 20 3.79 (2.45-5.83) 16 3.50 (2.11-5.77) 12-y 21 4.39 (2.77-6.93) 17 4.63 (2.52-8.43) Mortality from other causes Estimate 1.02 (0.68-1.55) .89 5-y 10 1.75 (0.95-3.23) 9 1.60 (0.84-3.06) 10-y 36 7.90 (5.69-10.90) 40 9.05 (6.62-12.31) 12-y 44 13.05 (9.35-18.05) 42 11.17 (7.78-15.88) Abbreviations: EBRT, whole-breast external beam radiotherapy; HR, hazard ratio; TARGIT-IORT, targeted intraoperative radiotherapy. Each of these survival measures include death as an event. sis was 3 July 2019, so that all events up until 2 July 2019 were included for analysis. The chief investigator/corresponding au- Results thor and the trial statistician (J.S.V. and Ma.B.) had access to all data sent by the trial center for analysis; all authors were Overall, 581 women were randomized to delayed TARGIT- responsible for the decision to submit the article. Since the last IORT and 572 to EBRT. The patient and tumor characteristics analysis, the trial oversight has been provided by an indepen- are given in Table 1 and were well matched between the ran- dent steering committee, appointed by the Health Technol- domization arms. Most patients were estrogen receptor posi- ogy Assessment program of the National Institute of Health Re- tive (1119 [98%]), ERBB2 negative (1041 [94%]); 670 patients search, Department of Health, United Kingdom. (58%) received endocrine therapy, and 40 (3.5%) received che- jamaoncology.com (Reprinted) JAMA Oncology July 2020 Volume 6, Number 7 5/10 Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 07/11/2021 Research Original Investigation Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast External Beam Radiotherapy for Early Breast Cancer Figure 3. Twelve-Year Kaplan-Meier Curves Comparing Delayed Second-Procedure TARGIT-IORT vs EBRT A B Local recurrence-free survival Distant disease-free survival 100 100 EBRT EBRT 80 80 Delayed TARGIT-IORT Delayed TARGIT-IORT 60 60 40 40 20 20 HR, 0.75 (95% CI, 0.57-1.003); log-rank P = .052 HR, 1.00 (95% CI, 0.72-1.39); log-rank P = .98 0 0 0 2 46 8 10 12 0 2 46 8 10 12 Years Years No. at risk No. at risk Delayed TARGIT-IORT 581 567 544 513 378 178 78 Delayed TARGIT-IORT 581 565 557 538 399 193 81 EBRT 572 559 547 520 370 161 57 EBRT 572 559 546 519 374 165 61 C D Mastectomy-free survival Overall survival 100 100 EBRT EBRT 80 80 Delayed TARGIT-IORT Delayed TARGIT-IORT 60 60 40 40 20 20 HR, 0.88 (95% CI, 0.65-1.18); log-rank P = .38 HR, 0.96 (95% CI, 0.68-1.35); log-rank P = .78 0 0 0 2 46 8 10 12 0 2 46 8 10 12 Years Years No. at risk No. at risk Delayed TARGIT-IORT 581 563 545 521 387 186 78 Delayed TARGIT-IORT 581 570 562 542 402 197 83 EBRT 572 557 543 517 367 159 57 EBRT 572 560 550 526 379 167 63 EBRT indicates whole-breast external beam radiotherapy; TARGIT-IORT, 95% confidence intervals. The orange lines represent EBRT with light orange targeted intraoperative radiotherapy. In each of these Kaplan-Meier graphs, the shading indicating the 95% confidence intervals. blue lines represent delayed TARGIT-IORT with light blue shading indicating the motherapy. The completeness of follow-up is demonstrated conserving surgery occurs predominantly in the index 17,18 in Figure 2. quadrant, despite the fact that more than 60% of patients At 5-year complete follow-up, the local recurrence rates suitable for breast conserving surgery are known to have mi- 17-19 were TARGIT-IORT, 23 (including 3 DCIS) of 581 (3.96%) vs croscopic foci of the disease outside the index quadrant. EBRT, 6 (including 2 DCIS) of 572 (1.05%), giving a difference The delayed TARGIT-IORT approach was proposed mainly of 2.9% with its upper 90% CI of 4.4, which crossed the non- for logistical reasons. It allowed better planning of operation inferiority margin of 2.5%. theaters as well as theoretically stricter selection of patients Kaplan-Meier estimates and log-rank P values for de- with low-risk disease based on final histopathologic analysis layed TARGIT-IORT vs EBRT are given in Table 2 and Figure 3. results. It also allowed using TARGIT-IORT in patients com- The median follow-up was 9 years and the differences be- ing to a cancer center after having had their cancer excised in tween delayed TARGIT-IORT and EBRT were not statistically a smaller or remote hospital. Concordant with the results of significant for local recurrence-free survival, invasive local re- our 2013 analysis, with mature follow-up (5 years complete fol- currence-free survival, mastectomy-free survival, distant dis- low-up with a median of 9 years) delayed TARGIT-IORT was ease-free survival, breast cancer mortality, non–breast can- found not to be noninferior to EBRT in terms of local control, cer mortality, and overall survival. No patients had uncontrolled with the upper 90% confidence limit of the 2.9% absolute dif- local recurrence at the time of death. ference in the 5-year local recurrence rate being 4.4%, which is above our stringent 2.5% noninferiority margin. This noninferiority margin of 2.5% was decided after con- siderable thought, and is much more stringent than the 7% Discussion margin set in the in the ELIOT trial, the only other trial to our The TARGIT-A trial was originally conceived because of the knowledge of intraoperative radiotherapy. We believe that clinicopathologic observation that local recurrence after breast- it is important to consider how much the absolute differ- 6/10 JAMA Oncology July 2020 Volume 6, Number 7 (Reprinted) jamaoncology.com Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 07/11/2021 Survival, % Survival, % Survival, % Survival, % Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast External Beam Radiotherapy for Early Breast Cancer Original Investigation Research ences seen in the trial matter to the patient. When consider- had already occurred and fibrosis was setting in by the time ing treatments for patients with early breast cancer, local re- the delayed TARGIT-IORT was delivered (median, 37 days currence has been given great importance because of the later). A limitation of the study was that we did not antici- perceived risk of consequent mastectomy, the danger of dis- pate a change in surgical practice in later years, such that tant disease, and the potentially lower survival. The long- the tumor bed was approximated after tumor excision term data show that there was no impairment of mastectomy- rather than leaving a cavity. The resultant scarring could free survival, distant disease-free survival, or overall survival, have made it difficult to accurately locate the primary up to 12 years from randomization (Figure 3). Moreover, qual- tumor bed. Given the rapid attenuation of dose, with dis- ity of life studies have shown that despite having a second pro- tance from the applicator surface, adequate dose may not cedure, the quality of life and patient-reported outcomes, such have reached the original tumor bed. Finally, one can also as cosmesis, breast-related quality of life, and breast pain, have speculate that the additional surgical trauma owing to the 21,22 been demonstrated to be superior with TARGIT-IORT, and necessary second procedure in every case of delayed TARGIT-IORT could stimulate residual cancer cells. Not- this approach is preferred by patients even in the face of a hy- 23,24 pothetically higher local recurrence risk. These findings withstanding these theoretical reasons, the final judgments may mitigate some of the patient concerns, and results of must be based on the long-term outcomes data. further patient preference research would help these discussions. Conclusions Limitations The reasons for higher local recurrence with delayed Partial breast irradiation was heralded as a new standard at second-procedure TARGIT-IORT may be multifactorial. the time of the first publication of the TARGIT-A trial and sev- First, the propensity of tumor recurrence in the index quad- eral other supporting clinical trials have since been pub- rant could be owing to a tumor promoting effect of the lished: including the ELIOT trial, interstitial 25-27 30 31,32 microenvironment of the surgical wound, a risk that has wire-brachytherapy, and partial breast EBRT. Based on been shown to be beneficially manipulated by TARGIT-IORT the randomized evidence of immediate TARGIT-IORT, which 25,27,28 6,7,33 to the fresh tumor bed, but perhaps not when has been shown to be an effective alternative to EBRT, it TARGIT-IORT is given as a delayed second procedure. Sec- is clear that the preferred timing of using TARGIT-IORT is im- ond, the surgical procedure of lumpectomy has changed. mediately—during the initial surgical excision of breast can- Early on in the trial, the tissues around the tumor bed were cer. However, when immediate TARGIT-IORT has not been pos- often not approximated after lumpectomy, and the tumor sible, the long-term data presented in this article may help bed remained easily identifiable as a fluid-filled cavity at inform discussions by clinicians and patients who wish to avoid the time of the second procedure, although some healing a prolonged postoperative course of EBRT. ARTICLE INFORMATION University, Germany (Wenz, Sperk); Red Cross Blanc-Onfroy); Brust Zentrum Seefeld, Zurich, Hospital, Department of Gynecology and Zurich, Switzerland (Gruber); Department of Accepted for Publication: January 16, 2020. Obstetrics, Technical University of Munich, Munich, Surgical Oncology, Medical University of Lublin, Open Access: This is an open access article Germany (Pigorsch, Eiermann); Department of Lublin, Poland (Polkowski); Breast Center, distributed under the terms of the CC-BY License. Surgery, University of California, San Francisco Universitätsspital Zürich, Zurich, Switzerland © 2020 Vaidya JS et al. JAMA Oncology. (Alvarado); Nuffield Department of Surgical (Dedes); Saarland University Medical Center, Published Online: April 2, 2020. Sciences, University of Oxford, Oxford, United Homberg, Germany (Niewald); Sankt doi:10.1001/jamaoncol.2020.0249 Kingdom (Douek); Patient Advocate and Writer, Gertrauden-Krankenhaus, and The Charité – London, United Kingdom (Bernstein); Department Universitätsmedizin Berlin, Berlin, Germany Correction: This article was corrected on May 21, of Surgery, Ninewells Hospital, Dundee, United (Blohmer); Princess Margaret Cancer Centre 2020, to change the liscensing type to open access Kingdom (Brown); Department of Surgery, Royal Toronto, Toronto, Ontario, Canada (McCready); CC-BY type and to correct an error in Figure 1B. Hampshire County Hospital, Winchester, United Sentara Surgery Specialists, Hampton, Virginia Author Affiliations: Division of Surgery and Kingdom (Laws); University Medical Center (Hoefer); Ashikari Breast Center, New York Medical Interventional Science, University College London, Mannheim, Department of Gynecology and College, New York, New York (Kelemen); London, United Kingdom (Vaidya, Bulsara, Obstetrics, Medical Faculty Mannheim, Heidelberg Department of Surgery, University College London Brew-Graves, Williams, Potyka, Roberts, Baum); University, Germany (Sütterlin); Department of Hospitals, London, United Kingdom (Petralia); Department of Biostatistics, University of Notre Oncology, St Olav’s University Hospital, Trondheim, Department of Pathology, University College Dame, Fremantle, West Australia, Australia Norway (Lundgren); Department of Clinical and London Hospitals, London, (Bulsara); University of Western Australia School of Molecular Medicine, Norwegian University of United Kingdom (Falzon). Surgery, West Australia, Australia (Saunders); Science and Technology (NTNU), Trondheim, Author Contributions: Professors Vaidya and Department of Breast Surgery, University of Norway (Lundgren); Helen Rey Breast Cancer Bulsara had full access to all of the data in the study Copenhagen, Copenhagen, Denmark (Flyger); Foundation, John Wayne Cancer Institute, and take responsibility for the integrity of the data Department of Clinical Oncology, University College University of Southern California, Los Angeles and the accuracy of the data analysis. London Hospitals, London, United Kingdom (Holmes); Department of Radiation Oncology, Study concept and design: Vaidya, Saunders, Tobias, (Tobias); Department of Radiation Oncology, Sir Centro di Riferimento Oncologico di Aviano (CRO) Corica, Wenz, Douek, Eiermann, Blohmer, Charles Gairdner Hospital, Perth, West Australia, IRCCS, Aviano, Italy (Vinante); Instituto Oncologico Baum, Joseph. Australia (Corica, Joseph); Department of Surgery, Veneto, Padoa, Italy (Bozza); University Hospital, Acquisition, analysis, or interpretation of data: Centro di Riferimento Oncologico di Aviano (CRO) Department of Radiation Oncology, Ludwig All authors. IRCCS, Aviano, Italy (Massarut); University Medical Maximilians Universitat, Munich, Germany (Pazos); Drafting of the manuscript: Vaidya, Bulsara, Center Mannheim, Department of Radiation Oncologue radiothérapeute, Institut de Saunders, Tobias, Douek, Roberts, Holmes, Oncology, Medical Faculty Mannheim, Heidelberg Cancérologie de l’Ouest, Nantes, France (Le jamaoncology.com (Reprinted) JAMA Oncology July 2020 Volume 6, Number 7 7/10 Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 07/11/2021 Research Original Investigation Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast External Beam Radiotherapy for Early Breast Cancer Baum, Joseph. Sarpong, Jack Grierson, Neil McCartan, Charlie Darius Dian, Sylvia Dondl, Klaus Friese, Julia Critical revision of the manuscript for important Mizon, Mortez Ali, Cindy Li, Alex Shirley, Joanna Jueckstock, Thomas Kirchner, Klaus Krimmel, Doris intellectual content: Vaidya, Saunders, Flyger, Hadley, Fatima Akbar, Muhammad Hammed, Daryl Mayr, Susanne Reinhard, Dr Schaffer, Christian Tobias, Corica, Massarut, Wenz, Pigorsch, Alvarado, Hagan, Olive Murphy, Tina Lennon, Joan Houghton; Schindlbeck, Harald Sommer, Justus Well: Ludwig Douek, Eiermann, Brew-Graves, Williams, Potyka, Surgical Interventional Trials Unit, Division of Maximilians Universität, Munich, Germany; M Roberts, Bernstein, Brown, Sperk, Laws, Sutterlin, Surgery and Interventional Science, University Kaufmann, H Boettcher, J Moog, Achim Rody, Claus Lundgren, Holmes, Vinante, Bozza, Pazos, College London. Jayant S Vaidya, Jeffrey S Tobias, Rödel, S Schopohl, Christian Weiss, Inge Fraunholz, Le-Blanc-Onfroy, Gruber, Polkowski, Dedes, Michael Baum, Mohammed Keshtgar, Glen Ulla Ramm, Martin-Leo Hansmann, R Strohmeier: Niewald, Blohmer, McCready, Hoefer, Falzon, Blackman, Chris Brew-Graves, Michael Douek, Mary Universität Frankfurt am Main, Frankfurt, Germany; Kelemen, Petralia, Baum, Joseph. Falzon, Gloria Petralia, Norman R Williams: Henrik Flyger, Eva Balslev, Niels Bentzon, Paul Statistical analysis: Vaidya, Bulsara, Douek, University College London Hospital, London, Geertsen, Helle Holtveg, Claus Kamby, Niels Williams. United Kingdom; Frederik Wenz, Elena Sperk, Mark Kroman, Faisal Mahmood, Fritz Rank, Birgitte Bruun Obtained funding: Vaidya, Wenz, Williams, Baum. Suetterlin, M Bohrer, S Clausen, B Hermann, R Rasmussen, Lone Gry Schäfer, Peter Michael Administrative, technical, or material support: Hildenbrand, Anke Keller, Uta Kraus-Tiefenbacher, Vestlev, Vera Timmermans Wielenga, Eva Wilken: Vaidya, Corica, Wenz, Pigorsch, Douek, B Kuepper, A Marx, F Melchert, D Neumann, F Herlev/Rigs Hospitals, Copenhagen, Denmark; Brew-Graves, Williams, Potyka, Roberts, Brown, Schneider, V Steil, M Trunk, Frank A. Giordano: Wojciech P Polkowski, Malgorzata Jankiewicz, Polkowski, Dedes, Niewald, Blohmer, Hoefer, Baum. Universitätsmedizin Mannheim, Universität Andrzej Kurylcio, Jerzy Mielko, Magdalena Study supervision: Vaidya, Bulsara, Saunders, Heidelberg, Mannheim, Germany; Christobel Skorzewska, Bogumila Cisel, Monika Lewicka, Edyta Flyger, Tobias, Wenz, Williams, Brown, Pazos, Saunders, David J Joseph, Tammy Corica, Elizabeth Matejek, Jaroslaw Romanek, Andrzej Stanislawek, Blohmer, Kelemen, Baum, Joseph. Kernutt, Mandy Taylor, Eva Vosikova, Claire Jadwiga Sierocinska-Sawa, Zofia Siezieniewska, Haworth: Sir Charles Gairdner Hospital, Perth, WA, Rafal Smyk, Andrzej Bedonski: Medical University of Conflict of Interest Disclosures: Dr Vaidya has Australia; Samuele Massarut, Lorenzo Vinante, Lublin, Lublin, Poland; Mohammed Keshtgar, received a research grant from Photoelectron Corp M Arcicasa, E Bidoli, E Cadiani, E Capra, M Oliva, Katharine Pigott, Tim Davidson, Jayant S Vaidya, (1996-1999) and from Carl Zeiss for supporting data T Perin, S Reccanello, M Roncadin, G Sartor, G Debasis Ghosh, Sarah Needleman, Jawad Keshtgar, management at the University of Dundee Tabaro, M Trovo, R Volpe Mario Mileto, Erica Piccoli, Samia Shah, Katia Pasciuti, Neil Dancer, Kashmira (2004-2008) and has subsequently received Antonella Spada: Centro di Riferimento Oncologico, Metha, Benjamin Earner, Stephan Duck, David honoraria. Drs Vaidya, Tobias, Williams, Potyka, Ms Aviano, Italy; DC Brown, Julie Lidsay, M Adams, DJA Woolf: Royal Free Hospital, London, United Brew-Graves, and Mr Roberts receive funding from Adamson, K Armoogum, J Bosch, JA Dewar, S Kingdom; Jayant S Vaidya, Jeffrey S Tobias, Alan Health Technology Assessment Programme, Edwards, J Gardner, A Gunning, M Hawkes, LB Wilson, Glen Blackman, Rashika Rajakumar, Renata National Institute for Health Research (NIHR), Jordan, A Lee, G Little, C Mackay, AJ Munro, J Parry, Rowicka, Veronica Conteh, Su Ramachandra, Lucy Department of Health for some activities related to CA Purdie, MM Reis, V Walker, RAB Wood: Harbin, R Chaudhuri, Ros Crooks, Francesca Peters, the TARGIT trials. Dr Baum was on the scientific Ninewells Hospital, Dundee, United Kingdom; Tom Connors, George Stasinos, Melissa Hickson, advisory board of Carl Zeiss and was paid monthly Michael Alvarado, Laura Esserman, Alfred Au, Alison Jones, Mulyati Mohamed, Tim Crook, consultancy fees briefly before 2010. Dr Wenz has Alison Bevan, Jay Connolly, Cheryl Ewing, Clark Vivienne Maidens, Sylvia Grieve, Elizabeth Tamufor, received a research grant from Carl Zeiss for Fisher, Shelley Hwang, K Lane, Christina Minami, Lucy Mavriano, Lotta Jonsson, Ciara McNulty: supporting radiobiological research. Carl Zeiss Michelle Oboite, Cathy Park, Jean Pouliot, Theadora Whittington Hospital, London, United Kingdom; sponsors some of the travel and accommodation Sakata, Aron Mohan, Brittany Harrison, Albert Thomas L Summer, Mario Contreras, Paul M for meetings of the international steering Chan, Mitchell Hayes: University of California, San DesRosiers, Irene Gordon, Kazumi Chino, Bedatri committee and data monitoring committee and Francisco Medical Center, San Francisco; Wolfgang Sinha, Cindy McDowell, Mike Ringer, Tammy when necessary for conferences where a Eiermann, Steffi Pigorsch, Stephanie E. Combs, Spurlock, Lisa Ramsey: Lafayette Surgical Clinic, presentation about targeted intraoperative Lafayette, Indiana; Richard A Hoefer, Mary Berry, Beyhan Ataseven, C Becker, B Hoegel, P radiotherapy is being made for all authors apart Kneschaurek, A Lackermeier, M Molls, Carsten Michael Miller, Song Kang: Sentara Surgery from Dr Eiermann who declares that he has no Nieder, Markus Oechsner, Barbara Röper, Sabine Specialists, Hampton, Virginia; Erich Solomayer, K conflicts of interest. No other conflicts are Schill, Ralf Wehrmann, Brigitte Werner, Christopher Abel, S Baum, Rainer Allgayer, R M Bohle, Mustafa reported. Wolf: Frauenklinik vom Roten Kreuz, Munich in Deryal, J Fleckenstein, R Grobholz, Jeanett Koehn, Funding/Support: The study was sponsored by cooperation with Technical University of Munich, Anja Martin-Riedheimer, Marcus Niewald, J. Radosa University College London Hospitals (UCLH)/UCL Dept. of RadioOncology, Germany; Dennis R and J.Friedmann, Markus Promnik, Christian Ruebe, Comprehensive Biomedical Research Centre. Holmes, Melvin Astrahan, Carryl Dubois, Jacqueline W Schmidt: Uniklinikum des Saarlandes, Homburg, Funding was provided by UCLH Charities, NIHR Majors, Sylvia Villegas Mendez, Afshin Rashtian, Germany; David McCready, Akbar Beiki-Ardakani, Health Technology Assessment Programme, Ronald Rivera, Howard Silberman, Melvin John Cho, Susan Done, Jamie Escallon, Anthony W Ninewells Cancer Campaign, National Health and Silverstein, Rashida Soni, Oscar E Streeter Jr, Lina Fyles, Wilfred Levin, Alex Vitkin, Marie Vranic: Medical Research Council, and German Federal Wang, Heather Macdonald, Stephen Sener, America Princess Margaret Cancer Centre, Toronto, Ontario, Ministry of Education and Research (FKZ Casillas: University of Southern California, Los Canada; Siobhan Laws, Dick Rainsbury, Claire Birch, 01ZP0508). The infrastructure of the trial Angeles; Gianmaria Fiorentini, Carli Ballola Adele, Lyn Booth, Caroline Cross, Alan Gately, Virginia Hall, operations office in London, United Kingdom, was Rafaella Barca, Mauro Biancalani, Giampaolo Biti, Kevin Harris, Sanjay Raj, Balvinder Shoker, Virginia supported by core funding from Cancer Research Enrico Cellai, Antonella Compagnucci, Claudio Straker, Jennifer Wilson: Royal Hampshire County Campaign (now Cancer Research UK) when the trial Caponi, Vito Maria Fontanarosa, Roberta Ghezzi, Hospital, Winchester, United Kingdom; Christopher was initiated. Alessandro Ghirelli, Gloria Giustarini, Barbara Grilli Rageth, Uwe Gneveckow, Elisabeth Grob, Guenther Role of the Funder/Sponsor: The funding agencies Leonulli, Francesca Littori, Maurizio Pertici, Visna Gruber, Baerbel Papassotiropoulos, Barbara Tausch, had no role in the design and conduct of the study; Petrina, Paola Raffaele, Francesca Righi, Serenella C Tausch, Zsuszanna Varga, Iris Vergin: Brust collection, management, analysis, and Russo, Michele de Simone, Gina Turrisi, Giuditta Zentrum Seefeld, Zurich, Switzerland; Claudia interpretation of the data; preparation, review, or Zipoli: Ospedale San Giuseppe di Empoli, Empoli, Hutzli, Konstantin J Dedes, Yvonne Burgstaller, approval of the manuscript; and decision to submit Italy; Jens-Uwe Blohmer, Petra Feyer, J Gross, G Rosemary Caduff, Daniel Fink, Guntram Kunz, the manuscript for publication. Jautzke, K Luebbert, Michaela Platzer, Joerg Claudia Linsenmeier, Yousef Najafi, Natalie Gabriel, Preussler, D Puppe, Esther Wiedemann: Sankt Cornelia Betschart, Eleftherios Samartzis, Acknowledgment: We thank the individuals from Gertrauden-Krankenhaus, Berlin, Germany; Michael Ana-Maria Schmidt, Tino Streller, Z Varga, each center whose help has been invaluable. In Henderson, David Blakey, Boon Chua, Ram Das, Madeleine Wick, Cornelia Leo, Zsuzsanna Varga, addition, we thank those who no longer work in the Roslyn Drummond, Annette Haworth, Penny Fogg, Leila Kocan: Breast Centre, Universitätspital Zurich, respective departments and those who may not Stephen Fox, Jodi Lynch, Jane O’Brien, Catherine Zurich, Switzerland; Steinar Lundgren, Anne Beate have been named herein (in order of the date of Poliness, Ann-Marie Power, David Speakman, Tina Marthinsen Langeland, Marianne Brekke, Hans E randomization of the first patient): Chris Thorpe, Melanie Walker: Peter MacCallum Cancer Fjosne, Jomar Frengen, Kristen Helset, Jarle Brew-Graves, Ingrid Potyka, Nicholas Roberts, Centre, Melbourne, VIC, Australia; Montserrat Karlsen: St Olav’s University Hospital, Trondheim, Norman Williams, Haroon Miah, Cinzia Baldini, Bina Pazos, Wolfgang Janni, Ulrich Andergassen, C Balka, Norway; James Edney, Aaron Sasson, Debra Shah, Danielle Maas, Charlene Carvalho, Rachael 8/10 JAMA Oncology July 2020 Volume 6, Number 7 (Reprinted) jamaoncology.com Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 07/11/2021 Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast External Beam Radiotherapy for Early Breast Cancer Original Investigation Research Spence, Robert Thompson, William W West, Sumin accuracy of the data analysis. We thank Michael D 11. Herskind C, Wenz F. Radiobiological comparison Zhou: University of Nebraska Medical Center, O’Shea, PhD, Woodward Informatics, Oxfordshire, of hypofractionated accelerated partial-breast Omaha, Nebraska; Michael Douek, Sarah Aldridge, United Kingdom, for database development, Julie irradiation (APBI) and single-dose intraoperative Ashutosh Kothari, Nick Beechey-Newman, Charles Lindsay, BSc, Ninewells Hospital, Dundee, United radiotherapy (IORT) with 50-kV X-rays. Deehan, Ian Fentiman, Hisham Hamed, Sarah Kingdom, for help in data collection, Uma J. Vaidya Strahlenther Onkol. 2010;186(8):444-451. et al. Harris, Hardeep Johal, Sarah Pinder, Arnie for help with the figures, tables, and editing of the doi:10.1007/s00066-010-2147-9 Purushotham, Vernie Ramalingam, Chris Stacey: manuscript, and several contributors who have 12. Vaidya JS, Walton L, Dewar J. Single dose Guy’s and St Thomas’ Hospital, London, United now left the individual centres. Travel and targeted intraoperative radiotherapy (TARGIT) for Kingdom; Angela Keleher, Eileen Abate, Nicole accommodation for meetings of the international breast cancer can be delivered as a second Cappillino, Laszlo Csury, Edward Farhangi, Anne steering committee and data monitoring procedure under local anaesthetic. World J Surg Kim, Sutini Ngadiman, Dimitrios Papadopoulos, Dan committee were provided by Carl Zeiss. Individual Oncol. 2006;4:2. doi:10.1186/1477-7819-4-2 Pavord, P Hank Schmidt, Camilo Torres, Erika centres were self-financed. We thank all the 13. Tunes da Silva G, Logan BR, Klein JP. Methods Mednick: Vassar Brothers Medical Center, patients who kindly participated in the trial. for equivalence and noninferiority testing. Biol Poughkeepsie, New York; P Kelemen, Andrew Manuscript preparation was helped by the trial Blood Marrow Transplant. 2009;15(1)(suppl):120-127. 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