Incidence and treatment-modifying impact of immune checkpoint inhibitor–associated peripheral edema: a systematic review and meta-analysis

INTRODUCTION: Immune-related adverse events (irAEs) disrupt immune checkpoint inhibitor (ICI) therapy and impact quality of life. Peripheral edema is common among patients with cancer, however, the causality of peripheral edema can be unclear in the context of multidrug regimens. METHODS: PubMed/MEDLINE, Embase, and Web of Science were searched to identify Phase 3 RCTs evaluating ICIs reporting peripheral edema incidence. The incidence of edema was calculated according to AE, ICIs, and treatment patterns. A random-effects meta-analysis pooled odds ratios (ORs) of edema incidence between ICI and non-ICI groups. A systematic review characterizing the interventions for irAE peripheral edema was also conducted. RESULTS: From 58 RCTs (22590 patients), treatment-related (TRAE) peripheral edema (Grade 1 to 5) occurred in 2.80% (n = 195/6969) of patients receiving ICI monotherapy, 4.96% (n = 112/2257) receiving ICI with chemotherapy, and 8.73% (n = 205/2349) receiving ICI with targeted therapy. Meta-analysis showed ICI monotherapy had lower TRAE peripheral edema compared to chemotherapy (OR = 0.45, 95% CI [0.27,0.73], p = 0.001, I 2=69%) with lowest relative incidence among PD-1 vs chemotherapy (OR = 0.41, 95% CI [0.23,0.73], p = 0.003) and ICI vs taxane chemotherapy (OR = 0.32, 95% CI [0.18,0.58], p < 0.001). A systematic review of treatment outcomes for irAE peripheral edema among 40 patients (19 studies) revealed 82.5% (n = 33/40) of cases received glucocorticoid treatment and ICIs were permanently discontinued in 35% (n = 14/40). CONCLUSIONS: Peripheral edema is a rare but potentially serious adverse event associated with ICIs. ICIs likely confer less peripheral edema risk than taxane therapy. To avoid unnecessary treatment interruptions, treatment discontinuation requires careful consideration-particularly when edema develops following ICI combination therapy.