Noncancer-Related Mortality in RCTs With Targeted Screening

In a meta-analysis reported in JAMA Network Open, Lei et al found a small nonsignificant increase in off-target mortality from noncancer causes or cancers that were not the target of screening in randomized controlled trials (RCTs) with screened and unscreened populations.

As stated by the investigators, “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.”

Study Details   

The analysis included 17 randomized RCTs encompassing 1,305,924 participants with 18,508,192 person-years of follow-up; the trials included 8 in colorectal, 3 in prostate, 3 in lung, 2 in breast, and 1 in multiple cancers. The analysis investigated the association between cancer screening and off-target mortality by comparing mortality rates between screened and unscreened populations in the RCTs.

Key Findings

Screening was not associated with increased risk of off-target mortality (rate ratio = 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%). No evidence of heterogeneity was observed between trials (I² = 0.00%; Cochran Q = 14.96, df = 18; P = .66).

The trial-specific rate ratios ranged from 0.89 (95% CI = 0.69–1.15; lung cancer trial) to 1.09 (95% CI = 0.98–1.22; lung cancer trial), with 95% CIs including 1 in all trials. Targeted cancer deaths accounted for 2.6% to 33.1% of all deaths, depending on trial and cancer type.

The investigators concluded: “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.”

Jiayao Lei, PhD, of Karolinska Institutet, Solna, Sweden, and Peter Sasieni, PhD, of Centre for Cancer Screening, Prevention and Early Diagnosis, Wolfson Institute of Population Health, Queen Mary University of London, London, United Kingdom, are the corresponding authors for the JAMA Network Open article.

Disclosure: The study was supported by the Swedish Research Council, Swedish Cancer Society, European Union’s Horizon 2020 Research and Innovation Programme, and Cancer Research UK. For full disclosures of all study authors, visit jamanetwork.com.