Trial Size for Near-Optimal Choice Between Surveillance and Aggressive Treatment: Reconsidering MSLT-II

A convention in designing randomized clinical trials has been to choose sample sizes that yield specified statistical power when testing hypotheses about treatment response. Manski and Tetenov recently critiqued this convention and proposed enrollment of sufficiently many subjects to enable <i>near-optimal</i> treatment choices. This article develops a refined version of that analysis applicable to trials comparing aggressive treatment of patients with surveillance. The need for a refined analysis arises because the earlier work assumed that there is only a primary health outcome of interest, without secondary outcomes. An important aspect of choice between surveillance and aggressive treatment is that the latter may have side effects. One should then consider how the primary outcome and side effects jointly determine patient welfare. This requires new analysis of sample design. As a case study, we reconsider a trial comparing nodal observation and lymph node dissection when treating patients with cutaneous melanoma. Using a statistical power calculation, the investigators assigned 971 patients to dissection and 968 to observation. We conclude that assigning 244 patients to each option would yield findings that enable suitably near-optimal treatment choice. Thus, a much smaller sample size would have sufficed to inform clinical practice.

随机临床试验（randomized clinical trial）设计的通行惯例是，在检验治疗反应相关假设时，选取能够达到指定统计功效的样本量。Manski与Tetenov近期对这一通行惯例提出了批判，并建议招募足够多的受试者，以实现近最优（near-optimal）的治疗选择。本文对二人提出的分析框架进行了优化改进，使其可应用于对比患者侵袭性治疗与监测随访的临床试验。之所以需要优化分析，是因为此前的研究仅假设存在单一关注的主要健康结局，未考虑次要结局。侵袭性治疗与监测随访的决策有一个关键考量：前者可能产生副作用。此时需综合考虑主要结局与副作用如何共同决定患者福祉。这就需要针对样本量设计开展新的分析。作为案例研究，我们重新审视了一项针对皮肤黑色素瘤患者，对比淋巴结观察与淋巴结清扫术的临床试验。该原试验通过统计功效计算，将971名患者分配至淋巴结清扫组、968名分配至观察组。我们的结论是，每组分配244名患者即可获得足以支撑合理近最优治疗选择的研究结果。由此可见，仅需更小的样本量即可为临床实践提供参考依据。