Reply to: Comments to “Should we consider gallbladder cancer a new smoking‐related cancer? A comprehensive meta‐analysis focused on dose‐response relationships”

Dear Editor, We read with great interest the letter wrote by McGee and Koshiol as a reply to our paper on the association between cigarette smoking and the risk of gallbladder cancer recently published in the International Journal of Cancer. In this letter, the authors commented the findings of our meta-analysis, comparing them with the results of their pooled analysis of 26 prospective studies within the Biliary Tract Cancers Pooling Project, which analyzed the association between smoking and gallbladder cancer risk. McGee and Koshiol identified three main key points to be considered when evaluating the current evidence on the association between cigarette smoking and gallbladder cancer: First, gallbladder cancers should be analyzed separately from other cancers of the biliary tract. We completely agree with McGee and Koshiol that it is important to consider gallbladder cancer separately from other biliary tract cancers (including intrahepatic and extrahepatic bile ducts and ampulla of Vater), given the heterogeneity of the associations by anatomic site in the biliary tract. Although it is true that in our meta-analysis at least five out of eight cohort studies reported relative risk for current vs never smokers for biliary tract cancers and gallbladder cancers combined, we did our best to consider only studies that included estimates for gallbladder cancer, without reducing drastically the number of studies to be included in our meta-analysis. In fact, we excluded articles reporting estimates of risk exclusively for extrahepatic bile duct or ampulla of Vater cancers. We, therefore, agree with the suggestion by McGee and Koshiol to consider gallbladder cancer only in future reviews, with the hope that further original studies will be published following this suggestion. Second, the relationship between cigarette smoking and gallbladder cancer risk could be modified by geographical factors. In our meta-analysis, we found a higher risk of gallbladder cancer due to cigarette smoking in Asia and North America, than in Europe and Oceania but we acknowledged that most of evidence came from Asia. In the discussion of our manuscript, we mentioned the possible modification role of geographic area on this association, reporting that in Asia there is a higher frequency of gallstones, a known risk factor for gallbladder cancer. Also, as commented by McGee and Koshiol in their letter, pancreaticobiliary maljunction and congenital choledochal cysts are more prevalent in Asians than in Europeans. Thus, the effect of smoking on gallbladder cancer risk could be amplified in those populations. We, therefore, understand the importance of the pooled analysis conducted within the Biliary Tract Cancers Pooling Project, since it includes studies mainly conducted in North America or Europe, filling the knowledge gap on the association between smoking and gallbladder cancer risk in these geographic areas. Third, elements of the analytic approach and study design should be weighed when evaluating the strength of the current evidence. We recognize the importance of pooled analyses in general, and in particular of the Biliary Tract Cancers Pooling Project, since they can provide estimates adjusted for relevant confounders. In fact, this is not possible in meta-analyses, since the pooled estimates rely on the results of published articles. In our meta-analysis, we observed that practically all studies provided estimates adjusted for sex and age, but only a few case-control studies and no cohort studies accounted for the presence of gallstones. This, of course, is a main inherent limitation of our meta-analysis. For this reason, the pooled analysis by McGee et al is an important study that adds further relevant information on the effect of smoking on gallbladder cancer risk. We thank McGee and Koshiol for the reply to our metaanalysis and for having highlighted three important aspects to be considered in future studies. We hope that additional studies, together with evidence from our meta-analysis and their pooled analysis, will allow to further clarify the role of smoking on the risk of gallbladder cancer.