Original Contribution Effect Modification of the Association of Cumulative Exposure and Cancer Risk by Intensity of Exposure and Time Since Exposure Cessation: A Flexible Method Applied to Cigarette Smoking and Lung Cancer in the SYNERGY Study

The indiscriminate use of the cumulative exposure metric (the product of intensity and duration of exposure) might bias reported associations between exposure to hazardous agents and cancer risk. To assess the independent effects of duration and intensity of exposure on cancer risk, we explored effect modification of the association of cumulative exposure and cancer risk by intensity of exposure. We applied a flexible excess odds ratio model that is linear in cumulative exposure but potentially nonlinear in intensity of exposure to 15 case-control studies of cigarette smoking and lung cancer (1985–2009). Ourmodel accommodatedmodificationof the excess odds ratio per pack-year of cigarette smoking by time since smoking cessation among former smokers. We observed negative effect modifi-cation of the association of pack-years of cigarette smoking and lung cancer by intensity of cigarette smoke for personswhosmokedmore than20–30cigarettes per day. Patterns of effectmodificationwere similaracross individual studies and across major lung cancer subtypes. We observed strong negative effect modification by time since smok