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 = .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 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

重要性 连续数周每天对乳腺癌进行常规辅助放疗既繁重又昂贵。有些患者可能不得不选择乳房切除术，而有些患者可能会完全放弃放射治疗。我们提出了一项临床试验，以测试放射治疗是否可以安全地限制在肿瘤床内。

目的 确定延迟二期手术靶向术中放疗（TARGIT-IORT）在局部控制方面是否不劣于全乳外照射放疗（EBRT）。

设计、设置和参与者 在这项前瞻性、随机（1:1 比率）非劣效性试验中，来自 9 个国家的 28 个中心的 1153 名年龄在 45 岁或以上且接受保乳治疗的直径小于 3.5 cm 的浸润性导管乳腺癌患者入组。数据于 2019 年 7 月 3 日锁定。

干预 TARGIT-A 试验于 2000 年 3 月开始；患者在穿刺活检后被随机分配接受 TARGIT-IORT 在肿瘤切除术后立即接受相同的麻醉与 EBRT 相比，结果已被证明是非劣效的。本文描述的一项平行研究始于 2004 年；切除癌症的患者使用单独的随机表随机分配接受 EBRT 或延迟 TARGIT-IORT 作为第二次手术，通过重新打开肿块切除术伤口。

主要结果和措施 5 年时局部复发率为 2.5% 和长期生存结果的非劣效性界值。

结果 总体而言，581 名女性（平均 [SD] 年龄，63 [7] 岁）被随机分配至延迟 TARGIT-IORT，572 名患者（平均 [SD] 年龄，63 [8] 岁）被随机分配至 EBRT。60 名患者 (5%) 的肿瘤大于 2 cm，或淋巴结阳性，只有 32 名 (2.7%) 的患者年龄小于 50 岁。延迟 TARGIT-IORT 并不劣于 EBRT。5 年完整随访时的局部复发率为：延迟 TARGIT-IORT 与 EBRT（分别为 23/581 [3.96%] vs 6/572 [1.05%]；差异，2.91%；上 90% CI，4.4 %）。长期随访（中位 [IQR]，9.0 [7.5-10.5] 年），局部无复发生存期无统计学差异（HR，0.75；95% CI，0.57-1.003；P  = . 052），无乳房切除术生存率（HR，0.88；95% CI，0.65-1.18；P = .38)、远处无病生存期 (HR, 1.00; 95% CI, 0.72-1.39; P  = .98) 或总生存期 (HR, 0.96; 95% CI, 0.68-1.35; P  = .80) .

结论和相关性 这些长期数据表明，尽管延迟 TARGIT-IORT 的局部复发数量有所增加，但无乳房切除术生存率、无远处无病生存率或总生存率没有统计学意义的下降。

试验注册 ISRCTN34086741，ClinicalTrials.gov 标识符：NCT00983684