Systemic Glucocorticoid Use and Risk of Site-Specific Cancers: A Methodologic 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 the use of systemic glucocorticoids affects cancer development. However, these studies face significant methodologic 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 nonmelanoma skin cancers, but these findings were inconsistent and likely influenced by inadequate latency consideration. In contrast, evidence was largely null for breast cancer, whereas results were inconsistent for colorectal cancer and melanoma. Our review highlights the need for robust study designs and analytic approaches to generate unbiased estimates of drugs' effect on cancer incidence.