{"doi":"10.1002/ijc.32998","title":"Comments on “Should we consider gallbladder cancer a new smoking‐related cancer? A comprehensive meta‐analysis focused on dose‐response relationships”","abstract":"Cigarette smoking is an established risk factor for many cancers. However, as described in the latest monograph from the International Agency for Research on Cancer, the epidemiologic evidence for a causal role of cigarette smoking in the etiology of gallbladder cancer remains insufficient.1 Given the unsuitability of a randomized control trial to answer this question, we must rely on observational evidence. We therefore read with great interest the recent meta-analysis of cigarette smoking and gallbladder cancer risk by Lugo et al.2 This meta-analysis included case-control and cohort studies that provided risk or mortality estimates for either gallbladder cancer alone or biliary tract cancers and gallbladder cancer combined. Lugo et al found that cigarette smoking was positively associated with gallbladder cancer, with a pooled risk for current vs. never smoking across two case-control and eight cohort studies of 1.33 (95% CI: 1.17-1.51). Increasing levels of smoking duration and intensity were also positively associated with gallbladder cancer risk. In addition, the authors analyzed time since smoking cessation, which was linearly associated with lower risk of gallbladder malignancies. Interestingly, in our recent pooled analysis of individual-level participant data from 26 prospective studies, there was less evidence for an effect of cigarette smoking on gallbladder cancer incidence.3 The overall hazard ratio for gallbladder cancer and current vs. never smoking was 1.18 (95% CI 0.98-1.43), suggestive of a potential modest effect of cigarette smoking on gallbladder cancer incidence. However, the effect estimate was smaller in magnitude than in the analysis by Lugo et al, findings were not consistent across all smoking measures, and there was less convincing evidence of a dose-response effect (eg, all P-trend for smoking duration, intensity and pack-years ≥0.34). While it remains to be determined if cigarette smoking has a causal role in the etiology of gallbladder cancer, we would like to discuss three key points that may be important in evaluating the current body of evidence. #1. Given evidence for etiologic heterogeneity, gallbladder cancers should be analyzed separately from other cancers of the biliary tract. In our recent pooled analysis, there was substantial heterogeneity of associations by anatomic site in the biliary tract. This heterogeneity was particularly strong when comparing gallbladder cancers to other cancers of the biliary tract (ie, cancers of the intrahepatic and extrahepatic bile ducts and ampulla of Vater, all P-heterogeneity <.001).3 In the meta-analysis conducted by Lugo et al, at least five out of eight cohort studies in the current vs never smoking analysis assessed biliary tract cancers and gallbladder cancers combined,4-8 which may in part explain the larger effect estimates since we observed stronger smoking associations with other biliary tract cancers.3 In addition, the remaining three cohort studies either analyzed gallbladder cancer mortality, not incidence, or did not provide strong evidence of an association with gallbladder cancer incidence. Many prior analyses have combined gallbladder cancers with other cancers that occur within the biliary tract, which may result in misleading estimates given mounting evidence for etiologic heterogeneity across anatomic sites. Thus, we recommend that future studies analyze gallbladder cancers separately from other biliary tract cancers. #2. The relationship between cigarette smoking and gallbladder cancer risk could be modified by geographical factors. In the analysis by Lugo et al, there was evidence of effect modification by geography. In particular, higher pooled relative risks (RR) for the effect of ever vs never cigarette smoking on gallbladder cancer risk were observed in Asia (RR: 1.43) and North America (RR: 1.52), while the relative risks in Europe (RR: 1.16) and Oceania (RR: 1.00) were modest or null.2 It is plausible that the effect of cigar","journal":"International Journal of Cancer","year":2020,"id":118108,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9608,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":291448,"name":"Jill Koshiol","orcid":"0000-0002-3832-6204","position":1,"is_corresponding":false},{"id":370676,"name":"Emma E. McGee","orcid":"0000-0002-7456-6408","position":0,"is_corresponding":true}],"reference_count":9,"raw_metadata":null,"created_at":"2026-07-18T23:13:58.531532Z","pmid":"32275767","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}