Vaidya Jayant S, Wenz Frederik, Bulsara Max, Tobias Jeffrey S, Joseph David J, Saunders Christobel, Brew-Graves Chris, Potyka Ingrid, Morris Stephen, Vaidya Hrisheekesh J, Williams Norman R, Baum Michael
Division of Surgery and Interventional Science, University College London, London, UK.
Department of Surgery, Whittington Hospital, Royal Free Hospital and University College London Hospital, London, UK.
Health Technol Assess. 2016 Sep;20(73):1-188. doi: 10.3310/hta20730.
Based on our laboratory work and clinical trials we hypothesised that radiotherapy after lumpectomy for breast cancer could be restricted to the tumour bed. In collaboration with the industry we developed a new radiotherapy device and a new surgical operation for delivering single-dose radiation to the tumour bed - the tissues at highest risk of local recurrence. We named it TARGeted Intraoperative radioTherapy (TARGIT). From 1998 we confirmed its feasibility and safety in pilot studies.
To compare TARGIT within a risk-adapted approach with whole-breast external beam radiotherapy (EBRT) over several weeks.
The TARGeted Intraoperative radioTherapy Alone (TARGIT-A) trial was a pragmatic, prospective, international, multicentre, non-inferiority, non-blinded, randomised (1 : 1 ratio) clinical trial. Originally, randomisation occurred initial lumpectomy (prepathology) and, if allocated TARGIT, the patient received it during the lumpectomy. Subsequently, the postpathology stratum was added in which randomisation occurred initial lumpectomy, allowing potentially easier logistics and a more stringent case selection, but which needed a reoperation to reopen the wound to give TARGIT as a delayed procedure. The risk-adapted approach meant that, in the experimental arm, if pre-specified unsuspected adverse factors were found postoperatively after receiving TARGIT, EBRT was recommended. Pragmatically, this reflected how TARGIT would be practised in the real world.
Thirty-three centres in 11 countries.
Women who were aged ≥ 45 years with unifocal invasive ductal carcinoma preferably ≤ 3.5 cm in size.
TARGIT within a risk-adapted approach and whole-breast EBRT.
The primary outcome measure was absolute difference in local recurrence, with a non-inferiority margin of 2.5%. Secondary outcome measures included toxicity and breast cancer-specific and non-breast-cancer mortality.
In total, 3451 patients were recruited between March 2000 and June 2012. The following values are 5-year Kaplan-Meier rates for TARGIT compared with EBRT. There was no statistically significant difference in local recurrence between TARGIT and EBRT. TARGIT was non-inferior to EBRT overall [TARGIT 3.3%, 95% confidence interval (CI) 2.1% to 5.1% vs. EBRT 1.3%, 95% CI 0.7% to 2.5%; = 0.04; P = 0.00000012] and in the prepathology stratum ( = 2298) when TARGIT was given concurrently with lumpectomy (TARGIT 2.1%, 95% CI 1.1% to 4.2% vs. EBRT 1.1%, 95% CI 0.5% to 2.5%; = 0.31; P = 0.0000000013). With delayed TARGIT postpathology ( = 1153), the between-group difference was larger than 2.5% and non-inferiority was not established for this stratum (TARGIT 5.4%, 95% CI 3.0% to 9.7% vs. EBRT 1.7%, 95% CI 0.6% to 4.9%; = 0.069; P = 0.06640]. The local recurrence-free survival was 93.9% (95% CI 90.9% to 95.9%) when TARGIT was given with lumpectomy compared with 92.5% (95% CI 89.7% to 94.6%) for EBRT ( = 0.35). In a planned subgroup analysis, progesterone receptor (PgR) status was found to be the only predictor of outcome: hormone-responsive patients (PgR positive) had similar 5-year local recurrence with TARGIT during lumpectomy (1.4%, 95% CI 0.5% to 3.9%) as with EBRT (1.2%, 95% CI 0.5% to 2.9%; = 0.77). Grade 3 or 4 radiotherapy toxicity was significantly reduced with TARGIT. Overall, breast cancer mortality was much the same between groups (TARGIT 2.6%, 95% CI 1.5% to 4.3% vs. EBRT 1.9%, 95% CI 1.1% to 3.2%; = 0.56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1.4%, 95% CI 0.8% to 2.5% vs. 3.5%, 95% CI 2.3% to 5.2%; = 0.0086), attributable to fewer deaths from cardiovascular causes and other cancers, leading to a trend in reduced overall mortality in the TARGIT arm (3.9%, 95% CI 2.7% to 5.8% vs. 5.3%, 95% CI 3.9% to 7.3%; = 0.099]. Health economic analyses suggest that TARGIT was statistically significantly less costly than EBRT, produced similar quality-adjusted life-years, had a positive incremental net monetary benefit that was borderline statistically significantly different from zero and had a probability of > 90% of being cost-effective. There appears to be little uncertainty in the point estimates, based on deterministic and probabilistic sensitivity analyses. If TARGIT were given instead of EBRT in suitable patients, it might potentially reduce costs to the health-care providers in the UK by £8-9.1 million each year. This does not include environmental, patient and societal costs.
The number of local recurrences is small but the number of events for local recurrence-free survival is not as small (TARGIT 57 vs. EBRT 59); occurrence of so few events (< 3.5%) also implies that both treatments are effective and any difference is unlikely to be large. Not all 3451 patients were followed up for 5 years; however, more than the number of patients required to answer the main trial question ( = 585) were followed up for > 5 years.
For patients with breast cancer (women who are aged ≥ 45 years with hormone-sensitive invasive ductal carcinoma that is up to 3.5 cm in size), TARGIT concurrent with lumpectomy within a risk-adapted approach is as effective as, safer than and less expensive than postoperative EBRT.
The analyses will be repeated with longer follow-up. Although this may not change the primary result, the larger number of events may confirm the effect on overall mortality and allow more detailed subgroup analyses. The TARGeted Intraoperative radioTherapy Boost (TARGIT-B) trial is testing whether or not a tumour bed boost given intraoperatively (TARGIT) boost is superior to a tumour bed boost given as part of postoperative EBRT.
Current Controlled Trials ISRCTN34086741 and ClinicalTrials.gov NCT00983684.
University College London Hospitals (UCLH)/University College London (UCL) Comprehensive Biomedical Research Centre, UCLH Charities, Ninewells Cancer Campaign, National Health and Medical Research Council and German Federal Ministry of Education and Research (BMBF). From September 2009 this project was funded by the NIHR Health Technology Assessment programme and will be published in full in ; Vol. 20, No. 73. See the NIHR Journals Library website for further project information.
基于我们的实验室工作和临床试验，我们假设乳腺癌保乳术后的放疗可局限于肿瘤床。我们与业界合作开发了一种新的放疗设备和一种新的手术操作，用于向肿瘤床——局部复发风险最高的组织——提供单剂量放疗。我们将其命名为靶向术中放疗（TARGIT）。自1998年起，我们在试点研究中证实了其可行性和安全性。
在数周内，将风险适应性方法下的TARGIT与全乳外照射放疗（EBRT）进行比较。
单纯靶向术中放疗（TARGIT-A）试验是一项务实、前瞻性、国际性、多中心、非劣效性、非盲法、随机（1∶1比例）临床试验。最初，随机分组在初次保乳手术（术前病理检查）时进行，如果被分配到TARGIT组，患者在保乳手术期间接受该治疗。随后，增加了术后病理分层，随机分组在初次保乳手术后进行，这可能使后勤安排更简便，病例选择更严格，但需要再次手术重新打开伤口，以便作为延迟程序进行TARGIT治疗。风险适应性方法意味着，在试验组中，如果在接受TARGIT治疗后术后发现预先指定的未被怀疑的不良因素，则建议进行EBRT。实际上，这反映了TARGIT在现实世界中的应用方式。
11个国家的33个中心。
年龄≥45岁、患有单灶浸润性导管癌且肿瘤大小最好≤3.5 cm的女性。
风险适应性方法下的TARGIT和全乳EBRT。
主要结局指标是局部复发的绝对差异，非劣效性界值为2.5%。次要结局指标包括毒性、乳腺癌特异性死亡率和非乳腺癌死亡率。
2000年3月至2012年6月期间共招募了3451例患者。以下是TARGIT与EBRT相比的5年Kaplan-Meier率。TARGIT与EBRT在局部复发方面无统计学显著差异。总体而言，TARGIT不劣于EBRT [TARGIT为3.3%，95%置信区间（CI）为2.1%至5.1%，EBRT为1.3%，95%CI为0.7%至2.5%；z = 0.04；P = 0.00000012]，在术前病理分层（n = 2298）中，当TARGIT与保乳手术同时进行时也是如此（TARGIT为2.1%，95%CI为1.1%至4.2%，EBRT为1.1%，95%CI为0.5%至2.5%；z = 0.31；P = 0.0000000013）。对于术后延迟TARGIT（n = 1153），组间差异大于2.5%，该分层未确立非劣效性（TARGIT为5.4%，95%CI为3.0%至9.7%，EBRT为1.7%，95%CI为0.6%至4.9%；z = 0.069；P = 0.06640）。保乳手术时给予TARGIT的无局部复发生存率为93.9%（95%CI为90.9%至95.9%），而EBRT为92.5%（95%CI为89.7%至94.6%）（z = 0.35）。在一项计划的亚组分析中发现，孕激素受体（PgR）状态是唯一的结局预测因素：激素反应性患者（PgR阳性）在保乳手术时接受TARGIT的5年局部复发率（1.4%，95%CI为0.5%至3.9%）与接受EBRT时相似（1.2%，95%CI为0.5%至2.9%；z = 0.77）。TARGIT使3级或4级放疗毒性显著降低。总体而言，两组间乳腺癌死亡率大致相同（TARGIT为2.6%，95%CI为1.5%至4.3%，EBRT为1.9%，95%CI为1.1%至3.2%；z = 0.56），但TARGIT导致的非乳腺癌死亡显著减少（1.4%，95%CI为0.8%至2.5%，EBRT为3.5%，95%CI为2.3%至5.2%；z = 0.0086），这归因于心血管疾病和其他癌症导致的死亡减少，使得TARGIT组总体死亡率有降低趋势（3.9% , 95%CI为2.7%至5.8%，EBRT为5.3%，95%CI为3.9%至7.3%；z = 0.099）。卫生经济学分析表明，TARGIT在统计学上比EBRT成本显著更低，产生的质量调整生命年相似，具有正向的增量净货币效益，与零有边缘统计学显著差异，且具有>90%的成本效益概率。基于确定性和概率敏感性分析，点估计似乎不确定性很小。如果在合适的患者中用TARGIT替代EBRT，每年可能为英国的医疗服务提供者节省800万至910万英镑的成本。这还不包括环境、患者和社会成本。
局部复发的病例数较少，但无局部复发生存的事件数并非如此少（TARGIT为57例，EBRT为59例）；如此少的事件发生率（<3.5%）也意味着两种治疗方法都有效，且任何差异都不太可能很大。并非所有3451例患者都进行了5年随访；然而，随访超过5年的患者数量超过了回答主要试验问题所需的患者数量（n = 585）。
对于乳腺癌患者（年龄≥45岁、患有激素敏感的浸润性导管癌且肿瘤大小达3.5 cm的女性），在风险适应性方法下，TARGIT与保乳手术同时进行与术后EBRT效果相同、安全性更高且成本更低。
将通过更长时间的随访重复进行分析。尽管这可能不会改变主要结果，但更多的事件数可能会证实对总体死亡率的影响，并允许进行更详细的亚组分析。靶向术中放疗加量（TARGIT-B）试验正在测试术中给予肿瘤床加量（TARGIT加量）是否优于术后EBRT中给予的肿瘤床加量。
当前受控试验ISRCTN34086741和ClinicalTrials.gov NCT00983684。
伦敦大学学院医院（UCLH）/伦敦大学学院（UCL）综合生物医学研究中心、UCLH慈善机构、Ninewells癌症运动、国家卫生和医学研究委员会以及德国联邦教育与研究部（BMBF）。从2009年9月起，该项目由英国国家卫生研究院卫生技术评估计划资助，并将在《》第20卷第73期全文发表。有关该项目的更多信息，请访问英国国家卫生研究院期刊图书馆网站。
