Neoadjuvant and adjuvant therapy in uveal melanoma: toward systemic control of a systemic disease

Uveal melanoma (UM) is a biologically distinct melanoma subtype in which excellent local tumor control contrasts sharply with a high risk of delayed metastases. The frequent occurrence of distant relapse months to years after index local therapy suggests systemic dissemination early in the disease course. Inadvertently, many patients harbor minimal residual disease (MRD), comprising microscopic tumor cell populations that persist after primary tumor treatment and are undetectable by conventional imaging techniques. Historically, UM management has focused on local tumor eradication followed by surveillance, however, better understanding of the clinical trajectory of UM coupled with advances in systemic therapeutics have generated increasing interest in perioperative systemic approaches. Neoadjuvant therapy provides the opportunity to downsize the primary tumor, eliminate occult micrometastatic disease, dynamically evaluate disease biology, and inform further therapeutic decision-making. Adjuvant approaches aim to suppress or eradicate MRD following local control in patients at elevated risk of relapse. Although current evidence remains investigational or early-phase, perioperative systemic therapy represents an important research frontier in UM that holds the potential to reshape its therapeutic paradigm. Herein, we comprehensively synthesize the biological rationale, the latest data, and the ongoing clinical trials supporting perioperative systemic therapy, and discuss the emerging role of circulating tumor DNA (ctDNA) in the management of UM.