Background Determining whether screening with multicancer detection (MCD) tests saves lives requires randomized controlled trials (RCTs). To inform RCT design, we estimated cancer-mortality outcomes from hypothetical MCD RCTs. Methods We used the Hu-Zelen model, previously used to plan the NLST, to estimate mortality reductions, sample-size, and power for 9 cancers for different RCT design parameters and MCD test parameters. Results Our base-case RCT with 5 yearly screens and 100,000 people ages 60-74 in each arm, who also undergo standard-of-care screens, has 87-89% power to detect an 9-10% mortality reduction (NNS = 578-724) over 7-9 years. The majority of prevented deaths were from lung-cancers (base-case (64-66%) and all sensitivity analyses), 8-10% from colorectal-cancer, and 26% from the other 7-cancers, mostly from stomach/ovary/esophagus (due to excellent stage-1 survival) and less from liver/pancreas (poor stage-1 survival) or head/neck-cancer/lymphoma (excellent stage-4 survival). There was limited power for mortality reductions at most individual cancer sites. Base-case findings were sensitive to test sensitivity, stage-shifts, and mean sojourn times in the preclinical state (especially for lung-cancer), but 90% power could be recovered by recruiting a substantially higher risk population. Conclusions Large-scale MCD RCTs would have 89% power to detect a ∼10% cancer-mortality reduction over a relatively short 7-9 year timeframe from trial entry. The estimated NNS for MCD RCTs compares favorably to mammographic screening. Most prevented cancer-deaths in a well-powered MCD RCT would likely be from lung-cancer. Non-lung/CRC cancer sites could be a meaningful proportion of prevented cancer-deaths but power is insufficient to isolate non-lung-cancer mortality reductions.

中文翻译：

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设计随机对照试验，以估计多癌种检测筛查的癌症死亡率降低


背景 确定使用多癌种检测 （MCD） 测试进行筛查是否能挽救生命需要随机对照试验 （RCT）。为了给 RCT 设计提供信息，我们估计了假设 MCD RCT 的癌症死亡率结果。方法 我们使用以前用于规划 NLST 的 胡-Zelen 模型来估计不同 RCT 设计参数和 MCD 测试参数的 9 种癌症的死亡率降低、样本量和功效。结果我们的基准情况 RCT 每年进行 5 次筛查，每组 100,000 名 60-74 岁的人，他们也接受了标准护理筛查，具有 87-89% 的检测能力，可以检测到 7-9 年内死亡率降低 9-10% （NNS = 578-724）。大多数预防的死亡来自肺癌（基本情况 （64-66%） 和所有敏感性分析），8-10% 死于结直肠癌，26% 死于其他 7 种癌症，主要来自胃/卵巢/食道（由于出色的 1 期生存率）和较少来自肝脏/胰腺（较差的 1 期生存率）或头/颈部癌/淋巴瘤（出色的 4 期生存率）。在大多数单个癌症部位，降低死亡率的能力有限。基本情况发现对临床前状态下的测试敏感性、分期转移和平均逗留时间敏感（尤其是肺癌），但可以通过招募风险高得多的人群来恢复 90% 的功效。结论 大规模 MCD RCT 在试验开始后相对较短的 7-9 年时间内具有 89% 的检测能力，可以检测到 ∼10% 的癌症死亡率降低。MCD RCT 的估计 NNS 优于乳腺 X 线摄影筛查。在有力的 MCD RCT 中，大多数预防癌症死亡可能是肺癌。 非肺癌/CRC 癌症部位可能在预防癌症死亡中占有相当大的比例，但不足以隔离非肺癌死亡率的降低。