Sirolimus-based immunosuppression improves outcomes in liver transplantation recipients with hepatocellular carcinoma beyond the Hangzhou criteria

Abstract

Background: The administration of calcineurin inhibitors (CNIs) posttransplant has been implicated as an independent risk factor for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT). The new immunosuppressive agent sirolimus (SRL) acts as a primary immunosuppressant or antitumor agent. In this study we investigated the effect of sirolimus-based immunosuppression compared to CNIs (non-SRL) on the outcomes of LT candidates with HCC.Methods: We retrospectively analyzed 204 HCC patients who underwent LT in our hospital between January 2, 2014 and December 10, 2017. The median of the follow-up duration of patients was 24.5 months.The patients were divided into a sirolimus (SRL) group (76 patients) and a non-sirolimus (non-SRL) group (128 patients). Patients exceeding the LT criteria were analyzed as subgroups. Disease-free survival (DFS) and overall survival (OS) after tumor recurrence were compared using the Kaplan-Meier method. Univariate and multivariate Cox analyses were used to compare OS between the SRL and non-SRL groups.Results: The SRL group achieved better OS compared to the non-SRL group, while there was no significant difference in DFS. Subgroup (Milan criteria-based or Hangzhou criteria-based) analyses revealed that patients exceeding, rather than meeting, the Milan or Hangzhou criteria benefited from SRL (exceeding the Milan criteria: P=0.002; exceeding the Hangzhou criteria: P<0.001). There was no significant difference in OS between the SRL group and the non-SRL group that met the Milan or Hangzhou criteria.Conclusions: SRL can improve survival outcomes in LT patients with HCC exceeding the Hangzhou criteria.

E2F7 promotes mammalian target of rapamycin inhibitor resistance in hepatocellular carcinoma after liver transplantation

“…Using mTOR inhibitors for at least 3 months after LT for HCC independently reduced the death rate by approximately 30%. Our retrospective study also revealed that patients with a higher tumor burden could achieve a greater survival benefit from sirolimus use after LT 11 . However, given the complicated molecular mechanisms underlying cancer progression, drug resistance is hard to avoid upon targeting the mTOR pathway alone 3 .…”

“…9 mTOR inhibitors, sirolimus and everolimus, are widely used as an immunosuppressant after LT. A recent study based on the SiLVER trial (Clini caltr ials.gov: NCT00355862) emphasized the antitumor effect of mTOR inhibitors in patients with HCC after LT. 10 Using mTOR inhibitors for at least 3 months after LT for HCC independently reduced the death rate by approximately 30%. Our retrospective study also revealed that patients with a higher tumor burden could achieve a greater survival benefit from sirolimus use after LT. 11 However, given the complicated molecular mechanisms underlying cancer progression, drug resistance is hard to avoid upon targeting the mTOR pathway alone. 3 It is of great importance to explore the resistance mechanisms to mTOR inhibitors.…”

mTORi‐based immunosuppression reduces HCC recurrence at the expense of increased adverse side effects: A systematic review and meta‐analysis

“…A total of 1080 full‐text articles were identified and assessed for eligibility. Finally, based on the inclusion and exclusion criteria, 38 articles involving 10,607 HCC patients were included in our meta‐analysis 8–45 …”

“…Pooled risk ratios: primary outcome (recurrence rate, overall mortality) A total of 22 studies [8][9][10][11][12][13][14]17,19,23,25,28,29,33,[35][36][37][38][39][40][41] (6548 subjects) reported recurrence rates. Meta-analysis demonstrated a significant improvement in the recurrence rate with mTORi therapy (RR: .78, 95% CI: .68-.89).…”

Trends of rapamycin in survival benefits of liver transplantation for hepatocellular carcinoma

“…RAPA can also have anti-tumor effects by inhibiting tumor cell proliferation and angiogenesis while exerting immunosuppressive effects. RAPA conversion can effectively reduce the risk of post-LT HCC recurrence and prolong the tumor-free survival time of patients during different studies[ 40 , 41 ]. Subsequently, meta-analysis affirmed to varying degrees the survival benefit of RAPA in HCC patients after LT, but these studies have their limitations because of single-center experience[ 11 , 42 , 43 ].…”