Hepatotoxicity in patients with solid tumors treated with PD-1/PD-L1 inhibitors alone, PD-1/PD-L1 inhibitors plus chemotherapy, or chemotherapy alone: systematic review and meta-analysis

Abstract

Background This meta-analysis examined the risk of hepatotoxicity in patients with solid tumors who received a PD-1/PD-L1 inhibitor alone, a PD-1/PD-L1 inhibitor plus chemotherapy, or chemotherapy alone. Methods Potentially eligible studies were identified by searches of Embase and PubMed. All included studies were randomized controlled trials (RCTs) that examined patients with solid tumors who received a PD-1/PD-L1 inhibitor and/or chemotherapy. Results We included 20 clinical trials (11,634 patients). Thirteen trials compared PD-1/PD-L1 inhibitor monotherapy with chemotherapy. These two groups had similar risk for elevated markers of hepatotoxicity (based on analysis of all marker grades and high marker grades), although the PD-1/PD-L1 inhibitor group had an elevated relative risk (RR) of elevated aspartate aminotransferase (AST; RR = 2.13, 95% CI = 1.04 to 4.36, P = 0.04) when considering high grades alone; however, this disparity was not significant for comparisons of the pembrolizumab and nivolumab subgroups with the chemotherapy group. Compared with chemotherapy, PD-1/PD-L1 inhibitors increased the risk of all-grade hepatitis (RR = 5.85, 95% CI = 1.85 to 18.46, P < 0.01), and high-grade hepatitis (RR = 5.66, 95% CI = 1.58 to 20.27, P < 0.01). Seven other studies compared PD-1/PD-L1 inhibitor plus chemotherapy with chemotherapy alone. The combined treatment led to a higher risk for all-grade hepatitis (RR = 2.14, 95% CI = 1.29 to 3.55, P < 0.01) and high-grade hepatitis (RR = 5.24, 95%CI = 1.89 to 14.52, P < 0.01), but these groups had similar risk for all-grade and high-grade elevated markers of hepatotoxicity. Conclusions Relative to chemotherapy alone, PD-1/PD-L1 inhibitors with or without chemotherapy increased the risk of all-grade and high-grade hepatitis, but generally did not increase the risk of elevated blood markers of hepatotoxicity.

Toxoplasma gondii-derived antigen modifies tumor microenvironment of Ehrlich solid carcinoma murine model and enhances immunotherapeutic activity of cyclophosphamide

“…These findings match with the previous studies reporting mild elevation of liver transaminases induced by CP standard doses [ 36 ], yet, this does not usually coincide with hepatic histopathological changes, as aforementioned [ 35 ]. Indeed, treatment with CP showed mild central necrotic areas in liver sections that could be probably caused by CP hepatic metabolism [ 15 ].…”

“…However, immune-mediated hepatitis has been reported in patients with solid tumors receiving immunotherapy, while lacking signs of blood hepatotoxicity. This explains our findings of inflammatory hepatic reaction with all adopted treatments that was associated with improvement of hepatic transaminases [ 35 ].…”

Rutin and Hesperidin Alleviate Paclitaxel‐Induced Nephrocardiotoxicity in Wistar Rats via Suppressing the Oxidative Stress and Enhancing the Antioxidant Defense Mechanisms

“…Tese alterations in biochemical parameters strongly correlate with several deleterious renal histological changes and lesions, including degenerative changes and nuclear pyknosis of the lining epithelium of the renal tubules, associated with glomerulonephritis, focal interstitial nephritis, and congestion. Other studies have shown similar histological alterations [55,[61][62][63]. Paclitaxel-induced nephrotoxicity may refect the alteration and degeneration of glomerular composition and decreased glomerular fltration rate in rats [60].…”

Drug-Induced Liver Injury: Highlights and Controversies in the Recent Literature

“…Immune checkpoint inhibitors (ICIs) have been a cornerstone of treatment in a variety of previously difficult-to-treat cancers but are associated with a variety of immune-mediated adverse effects, including hepatotoxicity [97]. Guo et al performed a large literature review of clinical trials that evaluated PD-1/PD-L1 compared to traditional chemotherapy and found that PD-1/PD-L1 treatment was associated with increased risk of all-grade hepatitis (RR = 5.85, p < 0.01), and high-grade hepatitis (RR = 5.66, p < 0.01) [98]. Various groups have reported the incidence and clinical signature of immune-mediated liver injury (ILICI) in the past year [99][100][101][102][103][104][105].…”