对于早期乳腺癌保乳手术患者，传统的术后辅助放疗需要每天进行，并且连续长达数周，既费时又费钱。一些患者可能不得不选择乳房切除术，而一些患者可能完全放弃放疗。2000～2012年，TARGIT-A研究对保乳术中即刻靶向放疗与术后全乳放疗进行了比较，前者效果毫不逊色。不过，如果保乳术后最终病理结果发现肿瘤风险较高，可能仍然需要进行术后全乳放疗。于是，2004年TARGIT-A启动了一项附加研究，对保乳术后低风险患者的延迟术中靶向放疗与术后全乳放疗进行了比较。
2020年4月2日，《美国医学会杂志》肿瘤学分册在线发表英国伦敦大学学院、牛津大学、奈恩韦尔斯医院、皇家汉普郡医院、澳大利亚圣母大学、西澳大学、查尔斯·盖尔德纳爵士医院、丹麦哥本哈根大学、意大利阿维亚诺肿瘤中心、帕多瓦大学威尼托肿瘤研究所、德国海德堡大学、慕尼黑理工大学、慕尼黑大学、萨尔大学洪堡医疗中心、柏林大学医学院夏里特医院、旧金山加利福尼亚大学、南加利福尼亚大学、森塔拉外科医疗中心、纽约医学院、挪威科技大学、圣奥拉夫医院、法国西部癌症研究所、瑞士塞弗尔德乳腺中心、苏黎世大学医院、波兰卢布林医科大学、加拿大多伦多大学玛格丽特公主癌症中心的TARGIT-A并行研究报告，比较了延迟术中靶向放疗与术后全乳放疗对肿瘤局部复发和患者生存结局的长期影响。
NCT00983684: A Randomised Controlled Trial to Compare Targeted Intra-operative Radiotherapy With Conventional Post-operative Radiotherapy After Conservative Breast Surgery for Women With Early Stage Breast Cancer (TARGIT)
该国际多中心前瞻非劣效随机对照临床研究自2004年起从9个国家28个临床研究中心入组年龄至少45岁且肿瘤小于3.5厘米的低风险乳腺导管浸润癌保乳术后患者1153例，按1∶1的比例分为延迟术中靶向放疗组和术后全乳放疗组。延迟术中靶向放疗组于首次乳房肿块切除术后中位37天（四分位29～51天）重新打开乳房肿块切除伤口进行靶向放疗，在20～50分钟内对肿瘤切除部位（瘤床）表面给予20戈瑞、1厘米深处给予5～7戈瑞。预设非劣效临界值为5年局部复发率相差2.5%，并对长期生存结局进行比较。数据截至2019年7月3日，2019年9月11日～2020年1月15日对数据进行分析。
结果，延迟术中靶向放疗组581例平均年龄63±7岁，术后全乳放疗组572例平均年龄63±8岁。其中60例患者（5%）肿瘤大于2厘米或淋巴结阳性，32例（2.7%）年龄小于50岁。
完成5年随访时，延迟术中靶向放疗组与术后全乳放疗组相比，局部复发率为3.96%比1.05%，相差2.91%（90%置信区间上限：4.4%）。
完成中位9.0年（四分位7.5～10.5）长期随访时，延迟术中靶向放疗组与术后全乳放疗组相比：
局部无复发生存率相近（风险比：0.75，95%置信区间：0.57～1.003，P=0.052）
乳房未切除生存率相近（风险比：0.88，95%置信区间：0.65～1.18，P=0.38）
无远处病变生存率相近（风险比：1.00，95%置信区间：0.72～1.39，P=0.98）
总生存率相近（风险比：0.96，95%置信区间：0.68～1.35，P=0.80）
因此，该研究长期数据结果表明，延迟术中靶向放疗与术后全乳放疗相比，虽然5年局部复发率较高，但是长期局部无复发生存率、乳房未切除生存率、无远处病变生存率、总生存率相近。
JAMA Oncol. 2020 Apr 2. [Epub ahead of print]
Effect of Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast Radiotherapy on Local Recurrence and Survival: Long-term Results From the TARGIT-A Randomized Clinical Trial in Early Breast Cancer.
Jayant S. Vaidya; Max Bulsara; Christobel Saunders; Henrik Flyger; Jeffrey S. Tobias; Tammy Corica; Samuele Massarut; Frederik Wenz; Steffi Pigorsch; Michael Alvarado; Michael Douek; Wolfgang Eiermann; Chris Brew-Graves; Norman Williams; Ingrid Potyka; Nicholas Roberts; Marcelle Bernstein; Douglas Brown; Elena Sperk; Siobhan Laws; Marc Sütterlin; Steinar Lundgren; Dennis Holmes; Lorenzo Vinante; Fernando Bozza; Montserrat Pazos; Magali Le Blanc-Onfroy; Günther Gruber; Wojciech Polkowski; Konstantin J. Dedes; Marcus Niewald; Jens Blohmer; David McCready; Richard Hoefer; Pond Kelemen; Gloria Petralia; Mary Falzon; Michael Baum; David Joseph.
University College London, London, United Kingdom; University College London Hospitals, London, United Kingdom; University of Oxford, Oxford, United Kingdom; Patient Advocate and Writer, London, United Kingdom; Ninewells Hospital, Dundee, United Kingdom; Royal Hampshire County Hospital, Winchester, United Kingdom; University of Notre Dame, Fremantle, West Australia, Australia; University of Western Australia School of Surgery, West Australia, Australia; Sir Charles Gairdner Hospital, Perth, West Australia, Australia; University of Copenhagen, Copenhagen, Denmark; Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy; Instituto Oncologico Veneto, Padoa, Italy; Heidelberg University, Germany; Technical University of Munich, Munich, Germany; Ludwig Maximilians Universitat, Munich, Germany; Saarland University Medical Center, Homberg, Germany; The Charité - Universitatsmedizin Berlin, Berlin, Germany; University of California, San Francisco; University of Southern California, Los Angeles; Sentara Surgery Specialists, Hampton, Virginia; New York Medical College, New York, New York; St Olav's University Hospital, Trondheim, Norway; Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Institut de Cancérologie de l'Ouest, Nantes, France; Brust Zentrum Seefeld, Zurich, Zurich, Switzerland; Universitatsspital Zürich, Zurich, Switzerland; Medical University of Lublin, Lublin, Poland; Princess Margaret Cancer Centre Toronto, Toronto, Ontario, Canada.
This secondary analysis of the TARGIT-A randomized clinical trial compares the effect of delayed second-procedure targeted intraoperative radiotherapy (TARGIT-IORT) with whole-breast external beam radiotherapy (ERBT) on local recurrence at 5 years and long-term survival outcomes among women with early breast cancer.
QUESTION: For early breast cancer, is 5-year local control with delayed second-procedure targeted intraoperative radiotherapy (TARGIT-IORT) noninferior to whole-breast postoperative external beam radiotherapy (EBRT), and how do long-term outcomes compare?
FINDINGS: In this randomized clinical trial including 1153 participants, delayed second-procedure TARGIT-IORT was not noninferior to EBRT at 5-year complete follow-up; however, long-term (median 9 years) mastectomy-free survival, distant disease-free survival, and overall survival were not different.
MEANING: For early breast cancer, delayed second-procedure single-dose TARGIT-IORT given by reopening the lumpectomy wound had similar long-term mastectomy-free and overall survival compared with EBRT despite higher local recurrence.
IMPORTANCE: Conventional adjuvant radiotherapy for breast cancer given daily for several 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=0.052), mastectomy-free survival (HR, 0.88; 95% CI, 0.65-1.18; P=0.38), distant disease-free survival (HR, 1.00; 95% CI, 0.72-1.39; P=0.98), or overall survival (HR, 0.96; 95% CI, 0.68-1.35; P=0.80).
CONCLUSIONS AND RELEVANCE: These long-term data show that despite an increase in the number of local recurrences with delayed TARGIT-IORT, there was no statistically significant decrease in mastectomy-free survival, distant disease-free survival, or overall survival.
TRIAL REGISTRATION: ISRCTN34086741, ClinicalTrials.gov Identifier: NCT00983684
DOI: 10.1001/jamaoncol.2020.0249
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