Revisit of an unanswered question by pooled analysis of eight cohort studies in Japan: Does cigarette smoking and alcohol drinking have interaction for the risk of esophageal cancer?

Cigarette smoking and alcohol drinking are two major risk factors for esophageal cancer. Not all, but several of case-control studies have indicated interaction between the two factors; however, no prospective study has validated this phenomenon to date. Therefore, the interaction between smoking and alcohol drinking is still open-ended question. To answer this, we conducted a pooled analysis using large-scale population-based cohort studies in Japan. Male subjects from eight cohort studies were included. Cigarette smoking and alcohol drinking were both categorized categorically (never/ever), and in the three consumption levels of pack years and ethanol consumption/day. Effects of smoking and drinking in each study were estimated by Cox regression models. The study-specific results were combined through meta-analysis to obtain summary effects of hazard ratios (HRs) and measures of interactions at both additive and multiplicative scales. Population attributable fractions (PAFs) from smoking and drinking were obtained using distributions of exposures and fully adjusted HRs. In 162 826 male subjects, 954 esophageal cancer incidences were identified. HRs of ever smoking, ever drinking, and their combination were 2.92 (1.59-5.36), 2.73 (1.78-4.18), and 8.86 (4.82-16.30), respectively. Interaction between cigarette smoking and alcohol drinking was significantly positive on the additive scale, but not significant on the multiplicative scale. The joint effect of smoking and drinking in three levels of evaluation showed a similar significant super-additive interaction. PAFs from smoking, drinking, and their combination were 55.4%, 61.2%, and 81.4%, respectively. Cigarette smoking and alcohol drinking had a significant positive additive interaction for esophageal cancer risk.