Barry Michael J, Andriole Gerald L, Culkin Daniel J, Fox Steven H, Jones Karen M, Carlyle Maureen H, Wilt Timothy J
aGeneral Medicine Division, Massachusetts General Hospital, Boston, MA, USA.
Clin Trials. 2013;10(6):907-14. doi: 10.1177/1740774513498008. Epub 2013 Aug 29.
The Prostate Cancer Intervention Versus Observation Trial (PIVOT) randomized 731 men with localized prostate cancer to radical prostatectomy or observation.
We describe the methods and results for cause-of-death assignments in PIVOT, and compare them to alternative strategies for ascertaining prostate cancer-specific mortality, as well as to the methods and results in the similar Scandinavian Prostate Cancer Group Study 4 (SPCG-4) trial.
Three PIVOT Endpoints Committee members, blinded to randomized treatment assignments, reviewed medical records and death certificates when available to assign a cause of death using a primary and a secondary adjudication question. Initial disagreements were resolved through discussion. The level of initial agreement among committee members was examined, as well as guesses at randomized treatment assignments for a convenience sample of cases. Final cause of death determinations were compared to death certificates.
Complete agreement on cause of death by all three committee members before any discussion was achieved in 200/354 (56%) cases on the primary and 209/354 (59%) cases on the secondary. However, complete agreement on the primary rose to 306/354 (86%) when 'definite' and 'probably' categories were collapsed, as planned a priori. The three committee members' proportions of correct guesses of randomized treatment assignment were 82/121 (68%), 113/148 (76%), and 99/134 (74%). Using the committee's final adjudications as a gold standard, death certificates had suboptimal sensitivities, specificities, or predictive values depending on how they were used to determine cause of death.
There was no separate 'gold standard' by which to judge the accuracy of the final endpoints committee adjudications, and useful death certificates could not be obtained on about a third of PIVOT participants who died.
The low level of initial agreement on cause of death among endpoint committee members and the potential for biased determinations due to partial unblinding to treatment assignment raise methodologic concerns about using prostate cancer mortality as an endpoint in clinical trials like PIVOT.
前列腺癌干预与观察试验（PIVOT）将731例局限性前列腺癌男性患者随机分为接受根治性前列腺切除术组或观察组。
我们描述PIVOT中死因判定的方法和结果，并将其与确定前列腺癌特异性死亡率的替代策略进行比较，同时也与类似的斯堪的纳维亚前列腺癌研究组4（SPCG - 4）试验中的方法和结果进行比较。
三名PIVOT终点委员会成员在对随机治疗分配不知情的情况下，审查病历和死亡证明（如有），使用一个主要判定问题和一个次要判定问题来确定死因。最初的分歧通过讨论解决。检查了委员会成员之间的初始一致程度，以及对方便抽样病例的随机治疗分配的猜测。将最终死因判定结果与死亡证明进行比较。
在主要判定问题上，200/354（56%）的病例在所有三名委员会成员进行任何讨论之前就死因达成了完全一致，在次要判定问题上为209/354（59%）。然而，按照预先计划将“明确”和“可能”类别合并后，主要判定问题上的完全一致率上升到了306/354（86%）。三名委员会成员对随机治疗分配的正确猜测比例分别为82/121（68%）、113/148（76%）和99/134（74%）。以委员会的最终判定结果作为金标准，根据死亡证明用于确定死因的方式不同，其敏感性、特异性或预测值并不理想。
没有单独的“金标准”来判断最终终点委员会判定的准确性，并且在约三分之一死亡的PIVOT参与者中无法获得有用的死亡证明。
终点委员会成员在死因判定上的初始一致程度较低，以及由于对治疗分配部分未设盲而存在偏差判定的可能性，引发了关于在像PIVOT这样的临床试验中使用前列腺癌死亡率作为终点的方法学问题。
