Systemic glucocorticoid use and risk of site-specific cancers: a methodological systematic review of observational studies.

Systemic glucocorticoids, widely prescribed for inflammatory and autoimmune diseases, have long been suspected of increasing cancer risk through immunosuppressive and metabolic effects. Randomized trials are often unethical and difficult to conduct, leaving observational studies the best option to determine whether use of systemic glucocorticoids impacts cancer development. However, these studies face significant methodological issues that may compromise the validity of their findings. We systematically reviewed observational studies published up to May 1, 2025 (PubMed, Embase, Web of Science, and the Cochrane Library). We included 38 cohort and case-control studies assessing systemic glucocorticoid use and site-specific cancer risks. All included prevalent users, 34% had time-window bias, 50% lacked appropriate lag-time, and 74% were not restricted to specific patient populations based on glucocorticoid indications. Some studies reported positive associations for non-Hodgkin lymphoma. Similarly, some positive estimates were reported for lung and non-melanoma skin cancers, but these findings were inconsistent and likely influenced by inadequate latency consideration. In contrast, evidence was largely null for breast cancer, while results were inconsistent for colorectal cancer and melanoma. Our review highlights the need for robust study designs and analytical approaches to generate unbiased estimates of drugs' effect on cancer incidence.