Studying the effects of non-indicated medications on cancer: Etiologic versus action-focused analysis of epidemiologic data

The study of nonindicated medications on cancer outcomes is challenged by potential time-related biases. The literature has strongly advocated for treating the exposure as time-varying and summarizing the outcomes through a dose-response model (an etiologic-focused analysis). An alternative is to refashion the data to resemble a hypothetical randomized trial of drug use (an action-focused analysis). To our knowledge, their relative treatment of time-related bias and aspects of interpretation have not been compared. In this commentary, using the study of metformin use on colorectal cancer risk by Bradley and colleagues (2018) as motivation, we compare the etiologic versus action-focused analysis of epidemiologic data. We examine their treatment of immortal person-time, time-varying confounding, selection bias, and the biological and clinical relevance of their results. In doing so, we aim to establish areas of common ground and points of departure that can guide future observational studies of medications on cancer risk, recurrence, and survival.