Visceral adiposity and systemic inflammation in the obesity paradox in patients with unresectable or metastatic melanoma undergoing immune checkpoint inhibitor therapy: a retrospective cohort study

BACKGROUND: The obesity paradox is a topic of increasing interest in oncology and epidemiology research. Although this phenomenon has been observed in melanoma patients receiving immune checkpoint inhibitors, little is known about its mechanism. We aim to investigate the prognostic value of obesity and its association with adiposity and systemic inflammation. METHODS: This retrospective study evaluates the data of patients who received pembrolizumab or nivolumab for unresectable or metastatic melanoma between June 2015 and April 2021. The skeletal muscle index (SMI) and visceral fat index (VFI) (cm(2)/m(2)) were calculated by dividing the cross-sectional areas of skeletal muscle and visceral fat by height squared. The systemic immune-inflammation index (SII) was defined as the total peripheral platelet count×neutrophil/lymphocyte ratio. Cox proportional hazard regression analysis was conducted to determine the association with overall survival. RESULTS: We analyzed 266 patients with a median age of 60 years (IQR 51–69 years; 135 men and 131 women). The protective effect of obesity was independent of covariates (HR 0.60; 95% CI 0.37 to 0.99; p=0.048), but disappeared after adjusting for VFI (HR 0.76; 95% CI 0.41 to 1.40; p=0.380) or SII (HR 0.71; 95% CI 0.42 to 1.18; p=0.186). An increase of 10 cm(2)/m(2) in VFI was associated with longer overall survival after adjusting for covariates (HR 0.88; 95% CI 0.79 to 0.99; p=0.029). The prognostic value of VFI remained and predicted favorable overall survival after additional adjustment for SMI (HR 0.86; 95% CI 0.76 to 0.98; p=0.025), but disappeared with adjustment for SII (HR 0.92; 95% CI 0.82 to 1.03; p=0.142). An increase of 100×10(9)/L in SII was associated with poor overall survival when adjusted for covariates (HR 1.08; 95% CI 1.05 to 1.11; p<0.001) or when additionally adjusted for VFI (HR 1.07; 95% CI 1.04 to 1.10; p<0.001). CONCLUSIONS: Visceral adiposity and systemic inflammation are significant prognostic factors in patients with unresectable or metastatic melanoma receiving immune checkpoint inhibitors. The prognostic impact of visceral adiposity is dependent on systemic inflammation status.