Sorafenib delays recurrence and metastasis after liver transplantation in a rat model of hepatocellular carcinoma with high expression of phosphorylated extracellular signal-regulated kinase

Abstract

Liver transplantation (LT) is one of the curative treatments for hepatocellular carcinoma (HCC). However, cancer recurrence and metastasis after LT are common in some HCC patients with high-risk factors (even in those within the Milan criteria). It remains unclear whether adjuvant therapy with sorafenib inhibits HCC recurrence and metastasis after LT. Therefore, we performed orthotopic LT in an August Irish Copenhagen (ACI) rat model of HCC. Because LT involves immune rejection and tolerance and it is unknown whether sorafenib influences the immune response, we also investigated the effects of sorafenib on immune balance. In this study, we established an allogeneic rat LT model in which liver grafts were taken from Lewis rats and transplanted into ACI rats with orthotopic HCC, and they were administered cyclosporine A to prevent acute allograft rejection. From day 7 after LT, sorafenib was administrated at 30 mg/kg/day for 3 weeks. Our results showed that the serum levels of vascular endothelial growth factor and hepatocyte growth factor significantly increased after LT, and the T helper 1 (T h 1)/T helper 2 (T h 2) immune balance was shifted toward a T h 2 response after immunosuppressant administration. In comparison with controls, the rats in the sorafenib group showed significantly inhibited extracellular signal-regulated kinase phosphorylation and improved progression-free survival and overall survival. The tumor proliferation rate and angiogenesis in posttransplant recurrent tumor tissues decreased in the sorafenib group, and the tumor apoptosis rate increased. There was no significant difference in the T h 1/T h 2 immune balance between the sorafenib and control groups. In conclusion, adjuvant therapy with sorafenib is highly effective at inhibiting cancer recurrence and metastasis without influencing the Additional Supporting Information may be found in the online version of this article.

Strategies to improve outcome of patients with hepatocellular carcinoma receiving a liver transplantation

“…Sorafenib have shown to delay HCC recurrence and metastasis after LT in a rat model [137] . In a prospective not randomized pilot study, 7 patients with HCC above Milan criteria were treated with sorafenib after LT, and compared with 12 matched historical controls in whom sorafenib had not been used [138] .…”

Novel strategy of sirolimus plus thymalfasin and huaier granule on tumor recurrence of hepatocellular carcinoma beyond the UCSF criteria following liver transplantation: A single center experience

“…However, patients who undergo LT have a high risk of tumor recurrence due to long-term use of FK506; whereby subsequent administration of immunosuppressive drugs may accelerate the risk of mortality (1–3,25). Although current treatments for post-LT recurrence in patients with advanced HCC has limited efficacy (2,5,8–11), the recent ‘SiLIVER’ study demonstrated that SRL may act as an efficacious immunosuppressive drug and an antineoplastic agent for LT patients, with favorable clinical safety and efficacy comparable to that of FK506 (13).…”

“…Liver transplantation (LT) is currently the most viable and effective treatment option for patients with hepatocellular carcinoma (HCC) except for surgical resection, thus it may be used for patients where resection is not an option (1). Although the implementation of the Milan and University of California at San Francisco (UCSF) criteria has improved post-LT survival rates, patients who do not fit the UCSF criteria currently undergo LT worldwide (2,3).…”

“…Furthermore, no consensus on the most suitable prophylaxis and treatment for recurrent HCC following LT is currently available. Although sorafenib has demonstrated efficacy for tumor recurrence (1,2,8,9), the results are unsatisfactory, with a challenging adverse event profile (10,11). Sorafenib also exhibits less favorable results in Asian patients compared with European patients (9,10).…”

Recipient C6 rs9200 genotype is associated with hepatocellular carcinoma recurrence after orthotopic liver transplantation in a Han Chinese population

“…Currently, tumor size, number, histological grade of differentiation, microvascular and macrovascular invasion, alpha-fetoprotein and ischemia time are well-known predictors of HCC recurrence after OLT. [5][6][7][8][9][10] Recently, adjuvant therapy with sorafenib 11 and obesity 12 was shown to be related to post-transplantation recurrence.…”