Supplementary Material for: Association Between Smoking Cessation and the Risk of Cholangiocarcinoma and Ampulla of Vater Cancer: A Nationwide Cohort Study

Introduction: The association between smoking cessation and intrahepatic and extrahepatic cholangiocarcinoma (iCCA and eCCA) risk is unclear. Furthermore, the association in individuals with preexisting risk factors is unknown. We aimed to investigate the association between smoking status (especially smoking cessation) and CCA risk according to individuals’ glycemic status. Methods: In this nationwide cohort study, 9,520,629 adults without cancer who underwent national health screening by the Korean National Health Insurance Service in 2009 were followed up through 2018. The hazard ratios (HRs) and 95% confidence intervals (CIs) for CCA were estimated after adjusting for potential confounders. Results: During the 78.3 person-years of follow-up, 16,236 individuals were newly diagnosed with CCA. Quitters had a significantly lower risk of iCCA and eCCA compared to current smokers in all glycemic status groups (all P<0.01). The HRs (95% CIs) for iCCA in current smokers and quitters were 1.33 (1.24–1.43) vs. 0.98 (0.90–1.06) in individuals with normoglycemia, 1.49 (1.37–1.63) vs. 1.17 (1.06–1.28) in individuals with prediabetes, and 2.15 (1.96–2.37) vs. 1.58 (1.42–1.75) in individuals with diabetes, compared to never-smokers with normoglycemia. Current smokers with diabetes or prediabetes had a synergistically increased risk of iCCA (all P<0.01). However, quitters with diabetes and prediabetes had an iCCA risk comparable to that of never-smokers. Analysis of eCCA yielded similar results. Smoking was not independently associated with the risk of the ampulla of Vater cancer. However, smoking combined with diabetes or prediabetes was associated with an increased risk of the ampulla of Vater cancer (all P<0.05). Discussion/Conclusion: Smoking cessation was associated with a reduced risk of CCA, despite the synergistically increased risk in current smokers with diabetes and prediabetes. Our findings suggest a crucial opportunity to reduce the risk of CCA. More individualized and intensive cancer prevention education is needed against CCA.

引言：戒烟与肝内胆管癌（intrahepatic cholangiocarcinoma, iCCA）、肝外胆管癌（extrahepatic cholangiocarcinoma, eCCA）发病风险的关联尚不明确，且合并既往危险因素人群中的此类关联亦尚未可知。本研究旨在依据受试者的血糖状态，探究吸烟状态（尤其是戒烟行为）与胆管癌（cholangiocarcinoma, CCA）发病风险的关联。
方法：本项全国性队列研究纳入2009年接受韩国国民健康保险公团（Korean National Health Insurance Service）全国健康筛查的9520629名无癌症病史的成年人，随访至2018年。研究在校正潜在混杂因素后，估算了胆管癌发病风险的风险比（hazard ratio, HR）及95%置信区间（confidence interval, CI）。
结果：在总计78.3人年的随访期间，共16236名受试者新发胆管癌。在所有血糖状态亚组中，戒烟者的肝内胆管癌与肝外胆管癌发病风险均显著低于当前吸烟者（所有P<0.01）。以血糖正常且从不吸烟者为参照，血糖正常人群中当前吸烟者与戒烟者的肝内胆管癌风险比（95%置信区间）分别为1.33（1.24~1.43）与0.98（0.90~1.06）；糖尿病前期人群中分别为1.49（1.37~1.63）与1.17（1.06~1.28）；糖尿病人群中分别为2.15（1.96~2.37）与1.58（1.42~1.75）。合并糖尿病或糖尿病前期的当前吸烟者，其肝内胆管癌发病风险呈协同升高（所有P<0.01）；而合并糖尿病或糖尿病前期的戒烟者，其肝内胆管癌发病风险与从不吸烟者相当。针对肝外胆管癌的分析得到了相似结果。吸烟本身与壶腹癌（ampulla of Vater cancer）的发病风险无独立关联，但合并糖尿病或糖尿病前期的吸烟人群，其壶腹癌发病风险显著升高（所有P<0.05）。
讨论/结论：尽管合并糖尿病或糖尿病前期的当前吸烟者肝内胆管癌风险呈协同升高，但戒烟与胆管癌发病风险降低显著相关。本研究结果提示，降低胆管癌发病风险存在重要可行路径，需针对胆管癌开展更具个体化特征的强化癌症预防教育。