Yeh Justin, Gupta Shruti, Patel Sunny J, Kota Vamsi, Guddati Achuta K
Medical College of Georgia, Augusta University, Augusta, GA 30909, USA.
Division of Hematology/Oncology, Georgia Cancer Center, Augusta University, Augusta, GA 30909, USA.
Ecancermedicalscience. 2020 Nov 13;14:1142. doi: 10.3332/ecancer.2020.1142. eCollection 2020.
The incorporation of crossover in randomised controlled trials is accepted as an ethical obligation, especially in cancer clinical trials. The more common type of crossover is crossover allowance, which allows patients assigned to one arm to switch to another arm if there is an established benefit in the crossover arm. In contrast, crossover-designed studies involve switching patients from all arms to a different arm as part of the study design. Crossover allowance may have advantages in patient recruitment and incorporating crossover after initial positive results fulfil ethical requirements. However, crossover can also contribute to confounding major endpoints of studies, such as overall survival or the second progression-free survival interval. For this reason, it is important to investigate and identify potential trends of crossover in clinical trials testing novel therapies.
Data about cancer clinical trials were extracted from clinicaltrials.gov. The search query was limited to completed phase III studies in adult populations. Location was limited to the USA. Date range extended from 1990 to 2019. Search query included the terms: cancer; completed- recruitment status; age: 18-65+ years; sex: all; location: USA; and study phase: phase 3. Studies were then excluded if they were not randomised controlled trials (RCTs) with the primary purpose of treatment and if they did not test cancer-related interventions.
A total of 744 clinical trials were identified. There were 459 RCTs aimed at treatment, and of those, 35 utilised crossover. The start dates of these crossover trials ranged from 1997 to 2012. Thirty studies utilised crossover allowance. Prostate, breast and gastrointestinal stromal tumour cancers were the most represented cancer types in crossover studies. Among the 30 studies, the median proportion of patients who crossed over relative to the original arm assignment ranged from 2% to 88%, with a median of 57.5%.
The proportion of identified clinical trials with crossover compared to those without is extremely small. Crossover in clinical trials studying cancer treatment does not appear to be a widespread practice. Even though statistical approaches to mitigate confounding exist, crossover can still skew accurate reporting of the impact of experimental therapies on overall survival.
在随机对照试验中纳入交叉设计被视为一项道德义务，尤其是在癌症临床试验中。更常见的交叉类型是交叉允许，即如果交叉组已证实有获益，允许分配到一组的患者转至另一组。相比之下，交叉设计研究是将所有组的患者转至不同组作为研究设计的一部分。交叉允许在患者招募以及在初始阳性结果满足伦理要求后纳入交叉设计方面可能具有优势。然而，交叉也可能导致研究的主要终点出现混杂，如总生存期或第二次无进展生存期。因此，在测试新疗法的临床试验中研究和识别交叉的潜在趋势很重要。
从clinicaltrials.gov提取癌症临床试验数据。检索查询限于已完成的针对成年人群的III期研究。地点限于美国。日期范围从1990年至2019年。检索查询包括以下术语：癌症；已完成的招募状态；年龄：18 - 65岁及以上；性别：所有；地点：美国；研究阶段：3期。如果研究不是以治疗为主要目的的随机对照试验（RCT），或者未测试癌症相关干预措施，则将其排除。
共识别出744项临床试验。有459项旨在治疗的RCT，其中35项采用了交叉设计。这些交叉试验的开始日期从1997年到2012年。30项研究采用了交叉允许。前列腺癌、乳腺癌和胃肠道间质瘤是交叉研究中最具代表性的癌症类型。在这30项研究中，相对于原始分组交叉的患者的中位比例在2%至88%之间，中位数为57.5%。
已识别的有交叉设计的临床试验与无交叉设计的临床试验相比，比例极小。研究癌症治疗的临床试验中的交叉设计似乎并非普遍做法。尽管存在减轻混杂的统计方法，但交叉设计仍可能歪曲实验疗法对总生存期影响的准确报告。
