文章：

替代终点在癌症研究中的前景与危险

The promise and peril of surrogate end points in cancer research

原文发布日期：2002-01-01

DOI: 10.1038/nrc702

类型: Review Article

开放获取: 否

要点：

1. Intervention studies or prospective observational epidemiological investigations that use incident cancer as an end point are large, lengthy and costly. Similarly, therapeutic trials based on time to recurrence or mortality can require large numbers of patients and a long follow-up.
2. Therefore, studies with surrogate end points — biomarkers of preclinical carcinogenesis — are attractive because they are potentially smaller, shorter and considerably less costly than their counterparts with cancer end points.
3. Studies based on surrogate end points, however, are inherently less reliable than studies with the 'true' end point (for example, incident cancer, cancer recurrence or mortality). It is important to know when the use of surrogate end points is appropriate and when it is not.
4. A key issue is whether the test of an association between an exposure (or treatment) and a surrogate end point will reliably indicate whether there is an association between the exposure (treatment) and cancer. Three statistical conditions are needed to establish this: first, the surrogate end point is associated with cancer; second, the exposure (treatment) is associated with the surrogate end point; and third, the surrogate end point 'mediates' the association between exposure (treatment) and cancer. Causal pathway diagrams are useful in understanding these conditions.
5. A second important issue is whether the magnitude of the association between exposure (treatment) and the surrogate end point predicts the magnitude of the association between exposure (treatment) and cancer. A promising approach to this problem relies on the meta-analysis of a series of studies in which exposure (treatment), surrogate end points and cancer are measured concurrently.
6. Even a strong surrogate end point, such as colorectal adenomatous polyps, might not yield definitive results for colorectal cancer.
7. Nevertheless, there are settings, such as preliminary evaluations of potential therapeutic agents or exploratory investigations of aetiological factors, in which data based on surrogate end points could pave the way for subsequent definitive studies.

要点翻译：

1. 以新发癌症为终点的干预性研究或前瞻性观察流行病学调查规模庞大、耗时长久且成本高昂。同样，基于复发时间或死亡率的治疗试验也需要大量患者和长期随访。
2. 因此，采用替代终点（临床前致癌过程的生物标志物）的研究更具吸引力，因为它们可能比以癌症为终点的研究规模更小、周期更短且成本显著降低。
3. 然而，基于替代终点的研究本质上不如使用"真实"终点（如新发癌症、癌症复发或死亡率）的研究可靠。关键在于明确何时适合使用替代终点，何时不适合。
4. 核心问题在于：对暴露（或治疗）与替代终点之间关联的检验能否可靠地指示暴露（治疗）与癌症之间存在关联。这需要满足三个统计学条件：第一，替代终点与癌症存在关联；第二，暴露（治疗）与替代终点存在关联；第三，替代终点"中介"了暴露（治疗）与癌症之间的关联。因果路径图有助于理解这些条件。
5. 第二个重要问题是：暴露（治疗）与替代终点之间的关联强度是否能预测暴露（治疗）与癌症之间的关联强度。解决这一问题的有效方法依赖于对系列研究的荟萃分析，这些研究需同步测量暴露（治疗）、替代终点和癌症指标。
6. 即使是结直肠腺瘤性息肉这类强效替代终点，也可能无法为结直肠癌提供确定性结论。
7. 尽管如此，在潜在治疗剂的初步评估或病因探索性研究等场景中，基于替代终点的数据可为后续确定性研究奠定基础。

英文摘要：

Both experimental and observational studies of cancer need to have an end point. Traditionally, in aetiological and prevention studies, that end point has been the incidence of cancer itself, whereas in therapeutic trials, the end point is usually time to cancer recurrence or death. But cancer takes a long time to develop in an individual and is rare in the population. Therefore, aetiological studies and prevention trials must be large and lengthy to be meaningful. Similarly, many therapeutic trials require a long follow-up of large numbers of patients. Surrogate end points — markers of preclinical cancer or of imminent recurrence — are therefore an attractive alternative. But how can we be sure that a study with a surrogate outcome gives us the right answer about the true end point?

摘要翻译： 

癌症实验与观察性研究都必须设定一个终点。传统上，病因学与预防研究以癌症本身的发病率为终点，而治疗试验的终点通常是癌症复发或死亡的时间。然而，癌症在个体体内发展缓慢，在人群中又属罕见，因此病因学研究和预防试验必须规模大、时间长才有意义；同样，许多治疗试验也需要对大量患者进行长期随访。于是，替代终点——即临床前癌症或即将复发的标志物——便成为颇具吸引力的替代方案。但如何才能确信一项采用替代结局的研究能就真正的终点给出正确答案？

原文链接：

The promise and peril of surrogate end points in cancer research