Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation

Abstract

There is currently no consensus on the most suitable treatment for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation. This open, multicenter, retrospective, uncontrolled cohort study was designed to evaluate the safety and preliminary efficacy of the combined use of a mammalian target of rapamycin (mTOR) inhibitor and sorafenib in this setting. In 31 patients who suffered from HCC recurrence after liver transplantation, the immunosuppressive therapy was changed to mTOR inhibitors, and systemic treatment with sorafenib was initiated. This combination was maintained until symptomatic tumor progression, death, hepatic decompensation, or unacceptable toxicity occurred. Primary treatment efficacy was determined by overall survival and progression-free survival, and secondary efficacy was determined by the overall response rate. Toxicity parameters associated with the use of sorafenib and mTOR inhibitors were also analyzed. The overall response rate according to the Response Evaluation Criteria in Solid Tumors was 3.8% (1/26), and there was sustained stabilization of the disease in 13 additional cases (50.0%). The median overall survival was 19.3 months [95% confidence interval (CI) ¼ 13.4-25.1 months], and the median time to progression was 6.77 months (95% CI ¼ 2.3-11.1 months). Only 2 grade 3/4 cases of hyperglycemia and 1 case of grade 3/4 mucositis were reported, and they were possibly related to mTOR inhibitors. The most common severe adverse event probably related to sorafenib was diarrhea (12.9%). In conclusion, the coadministration of sorafenib and an mTOR inhibitor could be effective despite notable toxicity in patients with post-liver transplant HCC recurrence not suitable for radical therapy. The toxicity and efficacy need to be further evaluated in randomized controlled studies for this combination to be considered a valid option. Liver Transpl 18:45-52, 2012. V C 2011 AASLD.

Management of recurrent hepatocellular carcinoma after liver transplant

“…In experimental models of HCC, the mTOR pathway was aberrantly activated in up to half of the cases. Although the currently available data came from retrospective studies and are premature, there is the hope that mTOR-based immunosuppressive therapy after LT will one day come into use [48] . The use of sorafenib, an inhibitor of multiple tyrosine kinases (including c-Raf and b-Raf), has been approved as a first-line treatment for advanced HCC [49] .…”

Oxaliplatin Plus S1 for Treating Sorafenib-Refractory Recurrent Hepatocellular Carcinoma after Liver Transplantation

“…The case is especial for SORA and EVL-resistance HCC. Although SORA and EVL are generally recommended sequentially or co-instantaneously, there is still lack of optimal treatment modality [2][3][4]6]. No alternative drug or treatment had shown an obvious survival benefit in HCC with SORA or EVLresistant after transplant [11].…”

“…Compared to various therapeutic approaches used before recurrence, including local treatment, hepatic resection and chemotherapy, no standard posttransplant adjuvant chemotherapy has been established. Sorafinib (SORA) and everolimus (EVL) have already been investigated for application in recurrence HCC after LT [3][4][5][6] based on roles of B-Raf and mammalian target of rapamycin (mTOR)/protein kinase B (AKT) pathways in the pathogenesis of HCC [7,8]. Targeted next generation sequencing (NGS) of tumor samples can provide molecular abnormalities of different pathways for prediction of treatment outcomes.…”

The Role of Liver Transplantation in the Treatment of Hepatocellular Carcinoma – a Single Center Experience from Budapest

“…Introduction of mTOR-inhibitors to the immunosuppressive therapy protocols guided to lower tumour incidence among transplant patients in general [16]. Coadministration of sorafenib and an mTOR in- hibitor could be eff ective in patients with posttransplant HCC recurrence not suitable for radical therapy, but the toxicity and effi cacy need to be further evaluated [17]. In our department we are trying to fi nd mTOR activity in the HCC, normal and cirrhotic liver biopsies to evaluate the potential effi cacy of our immunosuppressive strategy.…”