The incidence and therapeutic regimen altering effects of immune checkpoint inhibitor–associated peripheral edema: A systematic review and meta-analysis.

Abstract

e14601 Background: Immune checkpoint inhibitors (ICIs) provide a long-term survival benefit across multiple cancer types, however immune-related adverse events (irAEs) occasionally disrupt treatments and impact quality of life. Peripheral edema from ICIs can occur due to increased peripheral vascular permeability. Thus, we aimed to evaluate the incidence and outcomes of ICI-related peripheral edema. Methods: MEDLINE, Embase, and Web of Science were searched to identify phase 3 randomized controlled trials (RCTs) reporting peripheral edema events in patients treated with ICIs. Incidence rates of peripheral edema were analyzed based on treatment patterns (monotherapy/combination therapy) and ICI subtypes (PD-1/PD-L1/CTLA-4). A random effect model meta-analysis was utilized to calculate pooled odds ratios of edema incidence between treatment groups. Finally, a systematic review was conducted to summarize treatment outcomes of peripheral edema associated with ICIs. Results: Overall, 58 RCTs comprising 22,590 patients were identified for the incidence analysis. Peripheral edema as treatment-related adverse events (TRAE) (Grade 1-5) occurred in 2.80% of patients receiving ICI monotherapy (n = 195/6969; PD-1 inhibitors: 2.22% [n = 104/4694], PD-L1: 3.73% [n = 58/1557], CTLA-4: 4.60% [n = 33/718]), 4.96% (n = 112/2257) of patients receiving ICI with chemotherapy, and 8.73% (n = 205/2349) of patients receiving ICI with molecular-targeted therapy. Grade 3-5 TRAE peripheral edema occurred in 0.19% (n = 13/6969) of patients treated with ICI monotherapy. 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). Subgroup analysis based on ICI subtypes showed high heterogeneity in subgroups (p , I 2 = 87.1%), but PD-1 inhibitors were associated with lower incidence than chemotherapy (OR = 0.41, 95% CI [0.23, 0.73], ). Subgroup analysis of chemotherapy regimens revealed that taxane chemotherapy was associated with a higher incidence of TRAE peripheral edema than ICI monotherapy (OR = 0.32, 95% CI [0.18, 0.58], p = < 0.001), but the edema incidence was comparable between ICI monotherapy and non-taxane chemotherapy (OR = 1.05, 95% CI [0.53, 2.08], p = 0.13). A systematic review of irAE peripheral edema treatment outcomes identified 19 studies comprising 40 patients. In total, 82.5% (n = 33/40) of cases received glucocorticoid treatment, with 55.0% (n = 22/40) requiring a high dose (≥ 1 mg/kg/day) of prednisone. ICI was discontinued in 77.5% of patients (n = 31/40) due to peripheral edema with permanent discontinuation in 35% (n = 14/40). Conclusions: Peripheral edema is an occasional but clinically significant side effect of ICI therapy. Management of irAE edema can result in permanent ICI discontinuation, which has implications for cancer treatment outcomes.