Prospective randomized comparison of digital breast tomosynthesis plus synthesized images versus standard full-field digital mammography (TOSYMA)

随机对照TOSYMA研究检验了以下假设：与标准数字2D乳腺X射线摄影相比，数字乳腺断层合成摄影（DBT）和合成2D乳腺X射线摄影的组合导致浸润性乳腺癌筛查检出率的临床相关性增加。然而，DBT导致的癌症检出率预期增加也可能是由于过度诊断。因此，评估DBT的使用是否不仅能提高癌症检测率，还能降低间隔期癌症的发生率，这一点很重要。为了平衡DBT在提高癌症检测率方面的潜在获益与过度诊断的可能性，研究方案中定义了两个主要终点：浸润性乳腺癌的检出率和浸润性间隔癌24个月的累积发病率。将应用分层检验程序来解释多重性，在分层排序假设序列的第一位评价检出率，在第二位评价间隔癌症发生率。假设的预定义顺序对应于医学背景下的自然层次结构：只有在癌症检测增加的情况下，才提出间隔癌症率降低的问题。根据预定义的假设顺序和计划阶段研究的主要目的，初始样本量计算仅基于第一个主要终点（检出率）。然而，随着对间隔期癌症的研究以评估断层合成摄影引起的潜在过度诊断的影响越来越受到国家和国际关注，似乎最重要的是获得合理的统计功效以评价两个主要终点。这需要将最初计算的80 000至120 000名妇女的样本量增加，修订后的样本量计算同时考虑了检出率和间隔期癌症发生率。在不了解当前招募TOSYMA研究数据的情况下进行，即所有计划假设均基于不属于正在进行的研究的外部数据。关于第一个主要终点的假设-最初的计算所依据的-已经根据同时可获得的数据进行了更新和修订。预期的样本量增加为评估两个主要假设提供了独特的可能性，并可能有助于提供目前普遍缺乏的对断层合成乳腺癌检测有效性的见解。增加样本量比设计一个新的验证性试验来评估间隔期癌症发病率要有效得多。

The randomised controlled TOSYMA study examines the hypothesis that the combination of Digital Breast Tomosynthesis (DBT) and synthesised 2D mammograms leads to a clinically relevant increase in the screening detection rate of invasive breast cancer compared to the standard, digital 2D mammography.However, the expected increase in cancer detection caused by DBT could also be due to overdiagnosis. For this reason, it is important to assess whether the use of DBT not only increases cancer detection but also reduces the occurrence of interval cancers.To balance the potential benefit of DBT in terms of raised cancer detection against the potential for overdiagnosis, two primary endpoints have been defined in the study protocol: the detection rate of invasive breast cancers and the cumulative 24-month incidence of invasive interval cancers. A hierarchical test procedure will be applied to account for multiplicity, evaluating the detection rate in the first and the interval cancer rate in the second place of the sequence of hierarchically ordered hypotheses. The pre-defined order of hypotheses corresponds to the natural hierarchy in the medical context: the issue of a reduction in the interval cancer rate is only raised in the case of increased cancer detection. According to the pre-defined order of hypotheses and the primary objective of the study in the planning phase, the initial sample size calculation was based solely on the first primary endpoint (detection rate). However, as the investigation of interval cancers to assess the impact of potential overdiagnosis caused by tomosynthesis has gained increasing national and international attention, it seems most important to achieve a reasonable statistical power for the evaluation of both primary endpoints. This requires an increase of the initially calculated sample size of 80,000 to 120,000 women.The revised sample size calculation takes into account both, the detection rate and the interval cancer rate. It was carried out without knowledge of the data from the currently recruiting TOSYMA study, i.e. all planning assumptions are based on external data that do not belong to ongoing study. The assumptions regarding the first primary endpoint - on which the initial calculation was based - have been updated and revised in accordance with data that became accessible in the meantime. The multiple significance level of 5% is still maintained.The intended sample size increase offers the unique potential to evaluate both primary hypotheses and may help to provide currently universally lacking insights into the effectiveness of breast cancer detection with tomosynthesis. A sample size increase is much more efficient than designing a new confirmatory trial for the assessment of interval cancer rates.