Associated Links Among Smoking, Chronic Obstructive Pulmonary Disease, and Small Cell Lung Cancer: A Pooled Analysis in the International Lung Cancer Consortium

• Cumulative smoking of the first 50 pack-years is associated with a sharper increase in SCLC risk.
• Smoking behaviors have a higher risk on SCLC among COPD subjects, and COPD patients have a 1.86-fold higher risk of SCLC.
• Risks of smoking behaviors on SCLC are partially mediated through COPD.A strong association between smoking and SCLC is noted whereas the dose–response relationships are less clear. We demonstrate that cumulative smoking of the first 50 pack-years is associated with a sharper increase in SCLC risk. Moreover, although the relationship between smoking and COPD or COPD and SCLC is well-established, no study has investigated the causal pathway among smoking, COPD, and SCLC. Here we reveal the risks of smoking behaviors on SCLC which are partially mediated (up to 7.6%) through COPD. The findings warrant further experimental study to elucidate the mechanisms in this causal pathway.

BackgroundThe high relapse and mortality rate of small-cell lung cancer (SCLC) fuels the need for epidemiologic study to aid in its prevention.MethodsWe included 24 studies from the ILCCO collaboration. Random-effects panel logistic regression and cubic spline regression were used to estimate the effects of smoking behaviors on SCLC risk and explore their non-linearity. Further, we explored whether the risk of smoking on SCLC was mediated through COPD.FindingsSignificant dose–response relationships of SCLC risk were observed for all quantitative smoking variables. Smoking pack-years were associated with a sharper increase of SCLC risk for pack-years ranged 0 to approximately 50. The former smokers with longer cessation showed a 43%quit_for_5–9 years to 89%quit_for_≥ 20 years declined SCLC risk vs. subjects who had quit smoking < 5 years. Compared with non-COPD subjects, smoking behaviors showed a significantly higher effect on SCLC risk among COPD subjects, and further, COPD patients showed a 1.86-fold higher risk of SCLC. Furthermore, smoking behaviors on SCLC risk were significantly mediated through COPD which accounted for 0.70% to 7.55% of total effects.InterpretationThis is the largest pooling study that provides improved understanding of smoking on SCLC, and further demonstrates a causal pathway through COPD that warrants further experimental study.