Fujiwara, Yu

Abstract Background Immune-related adverse events disrupt immune checkpoint inhibitor 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 randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors reporting peripheral edema incidence. The incidence of edema was calculated according to adverse event, immune checkpoint inhibitor, and treatment patterns. A random-effects meta-analysis pooled odds ratios (ORs) of edema incidence between immune checkpoint inhibitor and non–immune checkpoint inhibitor groups. A systematic review characterizing the interventions for immune-related peripheral edema was also conducted. Results From 58 RCTs (22 590 patients), treatment-related peripheral edema (grade 1-5) occurred in 2.80% (n = 195 of 6969) of patients receiving immune checkpoint inhibitor monotherapy, 4.96% (n = 112 of 2257) of patients receiving immune checkpoint inhibitor with chemotherapy, and 8.73% (n = 205 of 2349) of patients receiving immune checkpoint inhibitor with targeted therapy. Meta-analysis showed immune checkpoint inhibitor monotherapy had lower treatment-related peripheral edema incidence compared with chemotherapy (OR = 0.45, 95% CI = 0.27 to 0.73; P = .001, I2 = 69%) with the lowest relative incidence among programmed cell death protein 1 vs chemotherapy (OR = 0.41, 95% CI = 0.23 to 0.73; P = .003) and immune checkpoint inhibitor vs taxane chemotherapy (OR = 0.32, 95% CI = 0.18 to 0.58; P < .001). A systematic review of treatment outcomes for immune-related peripheral edema among 40 patients (19 studies) revealed 82.5% (n = 33 of 40) of cases received glucocorticoid treatment, and immune checkpoint inhibitors were permanently discontinued in 35% (n = 14 of 40). Conclusions Peripheral edema is a rare but potentially serious adverse event associated with immune checkpoint inhibitors. Immune checkpoint inhibitors likely confer less peripheral edema risk than taxane therapy. To avoid unnecessary treatment interruptions, treatment discontinuation requires careful consideration, particularly when edema develops following immune checkpoint inhibitor combination therapy.