Biologics, small molecules, and extraintestinal malignancies in inflammatory bowel disease: practical questions and evidence-based answers.

Malignancy in inflammatory bowel disease (IBD) is a clinical challenge, encompassing cancer risk with biologics and small molecules and the management of patients with previous malignancy. This review addresses questions on malignancy risk and treatment decisions in IBD, with emphasis on advanced therapies. A bibliographic search identified studies evaluating cancer risk in patients with IBD treated with these agents. The evidence is reassuring. Anti-TNF monotherapy does not appear to increase malignancy risk, although uncertainty persists for lymphoma and melanoma, particularly with concomitant thiopurines, which account for the clearest excess lymphoma risk. Vedolizumab and ustekinumab show favorable safety profiles, and early data for selective anti-IL-23 agents are encouraging. In patients with a history of cancer, available data do not indicate a clear increase in new or recurrent malignancy with anti-TNF agents, vedolizumab, or ustekinumab, although the evidence is largely observational. Evidence for JAK inhibitors and S1P receptor modulators remains limited, supporting a cautious approach, particularly in older or high-risk patients and in those with prior malignancy. In active or recent cancer, decisions should be individualized and multidisciplinary, integrating IBD severity, cancer characteristics, prognosis, prior anticancer therapy, and time since diagnosis. Temporary treatment withdrawal during cancer therapy is often appropriate, although earlier biologic reintroduction may be feasible in selected cases. Cancer treatment should not be compromised because of IBD, as chemotherapy and radiotherapy are feasible, whereas immune checkpoint inhibitors may trigger IBD flares. However, evidence remains constrained by confounding, heterogeneous populations, and limited long-term follow-up, underscoring the need for prospective safety studies.