Therapeutic potential and adverse events of everolimus for treatment of hepatocellular carcinoma – systematic review and meta‐analysis

Abstract

Everolimus is an orally administrated mammalian target of rapamycin (mTOR) inhibitor. Several large-scale randomized controlled trials (RCTs) have demonstrated the survival benefits of everolimus at the dose of 10 mg/day for solid cancers. Furthermore, mTOR-inhibitor-based immunosuppression is associated with survival benefits for patients with hepatocellular carcinoma (HCC) who have received liver transplantation. However, a low rate of tumor reduction and some adverse events have been pointed out. This review summarizes the antitumor effects and adverse events of everolimus and evaluates its possible application in advanced HCC. For the meta-analysis of adverse events, we used the RCTs for solid cancers. The odds ratios of adverse events were calculated using the Peto method. Manypreclinical studies demonstrated that everolimus had antitumor effects such as antiproliferation and antiangiogenesis. However, some differences in the effects were observed among in vivo animal studies for HCC treatment. Meanwhile, clinical studies demonstrated that the response rate of single-agent everolimus was low, though survival benefits could be expected. The meta-analysis revealed the odds ratios (95% confidence interval [CI]) of stomatitis: 5.42 [4.31–6.73], hyperglycemia: 3.22 [2.37–4.39], anemia: 3.34 [2.37–4.67], pneumonitis: 6.02 [3.95–9.16], aspartate aminotransferase levels: 2.22 [1.37–3.62], and serum alanine aminotransferase levels: 2.94 [1.72–5.02], respectively. Everolimus at the dose of 10 mg/day significantly increased the risk of the adverse events. In order to enable its application to the standard conventional therapies of HCC, further studies are required to enhance the antitumor effects and manage the adverse events of everolimus.

Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma

“…Everolimus, as a mTOR inhibitor, may be a promising therapeutic drug for advanced HCC though no consistent findings of its antitumor effects were observed [134]. Belinostat may induce apoptosis and tumor regression in HCC population by inhibiting HDAC [135].…”

Everolimus and Malignancy after Solid Organ Transplantation: A Clinical Update

“…One meta-analysis concluded that patients with nontransplant HCC showed a low but significant survival benefit under everolimus monotherapy [83], although this does not apply after failure of sorafenib therapy appears inadequate in advanced cases [84]. Management of recurrent HCC is one of the most frequent reasons for starting everolimus in maintenance liver transplant patients.…”

Liver Damage, Inflammation, and Enhanced Tumorigenesis after Persistent mTORC1 Inhibition

“…Very recently, a global phase III study showed that everolimus did not extend overall survival compared to placebo in patients with locally advanced or metastatic HCC after progression on or sorafenib intolerance (ClinicalTrials.gov Identifier: NCT01035229) (Health., 2013; Novaritis, 2013). In addition, everolimus use for HCC treatment was found to result in increased incidence of liver injury (Yamanaka et al, 2013; Zhu et al, 2011). …”