Lack of benefits of mammalian target of rapamycin inhibitor in patients transplanted for hepatocellular carcinoma: Is this the end of the story?

Recurrent hepatocellular carcinoma (HCC) after liver transplantation (LT) generally carries a dismal prognosis, with fewer than 10% amenable to resection and a median survival of only a year from diagnosis. Despite adherence to the Milan criteria, HCC still recurs in 10%-15% after LT. It has been postulated that calcineurin inhibitors (CNIs) may amplify HCC recurrence risk. Immunosuppression based on mammalian target of rapamycin (mTOR) inhibitors, sirolimus, and everolimus, for HCC has been proposed in recent years. Everolimus is a derivative of sirolimus with improved bioavailability. The mTOR inhibitors have long been suggested to have antineoplastic properties because mTOR regulates cell growth, proliferation, metabolism, and aging, with the mTOR pathway frequently up-regulated in HCC. Initial reports had suggested that sirolimus use is associated with a reduced risk of HCC recurrence after LT. A systematic review by Cholongitas et al. has demonstrated a significantly decreased rate of HCC recurrence with a mTOR inhibitor when compared to standard CNI-based immunosuppression (8% versus 14%), despite a higher proportion with HCC beyond Milan criteria and microvascular invasion in the mTOR inhibitor group. A major criticism of this analysis is the inclusion of mostly retrospective single-center observational studies that are limited by having a small sample size. There are also safety concerns about the use of sirolimus after LT, particularly a high incidence of hepatic artery thrombosis leading to a “Black Box” warning. Many centers have adopted sirolimus-based immunosuppression for HCC patients after LT, even if there are still uncertainties regarding the drug’s safety and efficacy. In this issue of Liver Transplantation, Yanik et al. further explore the impact of mTOR inhibitors using the Scientific Registry of Transplant Recipients (SRTR) in the United States from 2002 to 2012. The authors compared the outcomes of 234 HCC patients who received sirolimus within the first 3 months after LT with 3702 HCC patients never treated with sirolimus. They linked the SRTR database with national pharmacy claims, and those with discrepant sirolimus information between these 2 systems and those who died or experienced HCC recurrence within 3 months of LT were excluded. Sirolimus-treated patients were more likely to have HCC outside of the Milan criteria (11% versus 5%), but alpha-fetoprotein (AFP) levels were similar between the 2 groups. No significant differences between the 2 groups in all-cause mortality, cancer-specific mortality, and HCC recurrence were observed. In the subgroup within Milan criteria, cancer-specific mortality and HCC recurrence rates were nonsignificantly lower among sirolimus users. For LT recipients age 55 years, sirolimus use was associated with a significantly higher all-cause mortality. The older subgroup (>55 years) Abbreviations: AFP, alpha-fetoprotein; CNI, calcineurin inhibitor; HCC, hepatocellular carcinoma; LT, liver transplantation; mTOR, mammalian target of rapamycin; RETREAT, Risk Estimation of Tumor Recurrence After Transplant; SiLVER, Sirolimus in Liver Transplant Recipients with HCC; SRTR, Scientific Registry of Transplant Recipients.