Moon T E
Arizona Cancer Center, Tucson 85724.
Prev Med. 1989 Sep;18(5):721-31. doi: 10.1016/0091-7435(89)90043-1.
Principles and methods to guide interpretation require a different emphasis for cancer trials. Assumptions used to design a trial must be validated and modified during the trial to avoid limitations. To maximize information from such trials, recruitment strategies for commonly free-living subjects, measurements of safety and compliance, and ascertainment with pathologic review of endpoints must be obtained. Consideration of multiple endpoints may provide a better interpretation of cancer prevention for skin, colon, and transient occurrences illustrated by cervical dysplasia or biochemical precursors. A careful definition of the limitations of preventive trials is required. These include the actual size of the intervention groups, completeness and duration of follow-up, and comparison between trial participants and a defined source population. To obtain a valid interpretation with adequate precision of intervention effectiveness, time to endpoints should be evaluated using statistical multivariate methods such as Cox proportional hazard or relative risk models. These permit adjustment for important confounding and risk modifiers such as compliance, dietary intake, and drift in control group. The magnitude of the intervention efficacy and the generalizability of results of the trial will be negatively impacted if the intervention has a delayed (latent) effect. Such delay in intervention effect requires added considerations with possible extension of trial duration. Use of confidence limits for intervention effectiveness provides added insight and improved interpretation of prevention trials. The final component of a cancer prevention trial, as with any study, is to interpret and report its results. Providing a valid interpretation with adequate precision to hypotheses of a cancer prevention trial requires added emphasis on the accuracy of the assumptions made to design the trial and the duration of the trial. Design assumptions regarding compliance to the prescribed interventions, time until the experimental intervention achieves full effect, and the frequency of endpoints directly impact on the number of endpoints observed. Terminating a cancer prevention trial before adequate information is obtained, thus severely flawing its interpretation, requires ongoing awareness. Interpretation of a cancer prevention trial should include several added steps: first, investigators to critically review the actual manner in which the trial was conducted; second, carry out an appropriate analysis of the data; and third, review the results and note exceptions or limitations in the data. The results of the trial should be contrasted with previous studies. Implications of the results to future trials should be considered. Finally, these interpretations should be documented in a written report and made available to the scientific community.
指导癌症试验解读的原则和方法需要有不同的侧重点。用于设计试验的假设必须在试验过程中得到验证和修正，以避免局限性。为了从这类试验中获取最大信息，必须制定针对通常自由生活的受试者的招募策略、进行安全性和依从性测量，并通过对终点的病理检查来确定结果。考虑多个终点可能会为皮肤癌、结肠癌以及以宫颈发育异常或生化前体为例的短暂性病变的癌症预防提供更好的解读。需要仔细界定预防性试验的局限性。这些局限性包括干预组的实际规模、随访的完整性和持续时间，以及试验参与者与特定源人群之间的比较。为了以足够的精度对干预效果进行有效解读，应使用Cox比例风险模型或相对风险模型等统计多变量方法来评估达到终点的时间。这些方法允许对重要的混杂因素和风险修正因素进行调整，如依从性、饮食摄入和对照组的变化趋势。如果干预具有延迟（潜在）效应，那么干预效果的大小和试验结果的可推广性将受到负面影响。这种干预效果的延迟需要额外考虑，可能需要延长试验持续时间。使用干预效果的置信区间能够为预防试验提供更多见解并改进解读。与任何研究一样，癌症预防试验的最后一个环节是解读和报告其结果。要对癌症预防试验的假设进行具有足够精度的有效解读，就需要更加注重设计试验时所做假设的准确性以及试验的持续时间。关于对规定干预措施的依从性、实验干预达到完全效果所需的时间以及终点发生频率的设计假设，会直接影响所观察到的终点数量。在未获得足够信息之前就终止癌症预防试验，从而严重影响其解读，这一点需要持续关注。癌症预防试验的解读应包括几个额外步骤：首先，研究人员要严格审查试验实际开展的方式；其次，对数据进行适当分析；第三，审查结果并注意数据中的异常或局限性。试验结果应与先前的研究进行对比。应考虑结果对未来试验的影响。最后，这些解读应记录在书面报告中，并提供给科学界。
