Noncancer-Related Mortality in Randomized Clinical Trials: A Meta-Analysis

Cancer screening is a critical tool in cancer control, reducing cancer-specific mortality. However, it also has potential harms, including overdiagnosis and overtreatment. Measuring the effect of screening based on all-cause mortality is insensitive to both benefits and harms and requires substantially large sample sizes. Understanding the impact of screening on noncancer-related (off-target) mortality is essential for evaluating its overall benefit.

To assess the association between cancer screening and off-target mortality by comparing mortality rates between screened and unscreened populations based on randomized clinical trials (RCTs).

The analysis examined all RCTs included in a previously published (August 28, 2023) meta-analysis of cancer screening trials that included the end point of all-cause mortality in addition to targeted cancer mortality.

All RCTs included in the previous meta-analysis were included. The latest search in that meta analysis was conducted on October 12, 2022, with no language or publication date restrictions.

The study followed relevant portions of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. Two authors independently extracted data, and a third author verified those data. Off-target mortality was analyzed using rate ratios (RRs) and 95% CIs via a fixed-effects model. Heterogeneity was assessed using the I2 statistic.

The primary outcome was off-target mortality, defined as deaths with a cause that was not the targeted cancer.

A total of 17 RCTs (8 of colorectal, 3 prostate, 3 lung, 2 breast, and 1 multiple cancers) including 1 305 924 participants with 18 508 192 person-years of follow-up were included. Screening did not significantly increase off-target mortality (RR, 1.00; 95% CI, 1.00-1.01); the overall increase in off-target mortality was 0.2% (95% CI, -0.5% to 0.9%). There was no evidence of heterogeneity between trials (I2 = 0.00%; Cochran Q = 14.96, df = 18; P = .66). The trial-specific RRs ranged from 0.89 (95% CI, 0.69-1.15) to 1.09 (95% CI, 0.98-1.22), with all 95% CIs including 1. Targeted cancer deaths accounted for 2.6% to 33.1% of all deaths, depending on the cancer type.

These findings show that randomization to cancer screening was not associated with more than a very small increase in noncancer-related mortality, with the 95% CI excluding an increase of greater than 1%. The findings emphasize the importance of evaluating targeted and off-target mortality separately rather than relying solely on all-cause mortality.