Should we consider gallbladder cancer a new smoking-related cancer? A comprehensive meta-analysis focused on dose-response relationships.

The few studies on the association of smoking with gallbladder cancer risk have given conflicting results. Here, we provide the most accurate and up-to-date quantification of the effect of cigarette smoking on gallbladder cancer risk, and investigate for the first time the dose-response relationships. Using an innovative approach for the identification of publications, we conducted a systematic review and meta-analysis of epidemiological studies published until March 2019 on the association of smoking with gallbladder cancer risk. Pooled relative risks (RRs) for smoking were estimated using random-effects models; one-stage random-effects log-linear models were used for dose-response relationships. Out of 22 eligible articles, 20 (11 case-control and 9 cohort studies) were included in the meta-analysis, for a total of 4,676 gallbladder cancer cases. Compared to never smokers, the pooled RR was 1.33 (95% confidence interval [CI]: 1.17-1.51) for current and 1.07 (95% CI: 0.94-1.23) for former smokers. The risk of gallbladder cancer increased linearly with smoking intensity and duration, the RR being 1.60 (95% CI: 1.21-2.11) for 30 cigarettes/day and 1.25 (95% CI: 1.01-1.56) for 30 years of smoking. There was a nonsignificant linear decrease in gallbladder cancer risk with increasing time since quitting, compared to current smokers. Former smokers reached the risk of those who had never smoked 20 years after quitting. This comprehensive meta-analysis suggests a moderately but significantly higher risk of gallbladder cancer for current but not former smokers. We also provide the first report of a linear increase in gallbladder cancer risk according to smoking intensity and duration.