Author Affiliations: Department of Surgery (Bodzin AS and Busuttil RW); Department of Medicine, Division of Hematology/Oncology (Finn RS), UCLA, Los Angeles, California, USA

Corresponding Author: Ronald W Busuttil, MD, PhD, Distinguished Professor and Executive Chairman, The William P. Longmire, Jr. Chair in Surgery, David Geffen School of Medicine at UCLA, Department of Surgery, Chief, Division of Liver and Pancreas Transplantation, Director, The Dumont-UCLA Transplant and Liver Cancer Centers, Director, The Pfleger Liver Institute, 757 Westwood Plaza, Suite 8236, USA (Email: Rbusuttil@mednet.ucla.edu)

 

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60371-X

Published online May 21, 2015.

 

 

Contributors: BRW proposed the study design and concept, and aided in drafting manuscript. BAS and FRS performed acquisition of data and aided in drafting manuscript. All authors critically reviewed the manuscript. BRW is the guarantor.

Funding: None.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

In this issue, Lin et al^[1] presented a well-written meta-analysis regarding the use of adjuvant chemotherapy in orthotopic liver transplant (OLT) recipients with hepatocellular carcinoma (HCC). They highlighted the need for further investigation about the post-OLT management of HCC. The treatment of advanced HCC remains a difficult challenge as there is limited response to chemotherapeutics even after resection and limited literature is available to support the use of chemotherapy after OLT for HCC. This study delves into the importance of preventing HCC recurrence and prolonging survival after transplantation. The conclusions claim that chemotherapy may be useful in increasing survival and prolonging disease-free survival; however the findings that it does not prevent recurrence remain troublesome. Perhaps one of the greatest limitations is that cytotoxic agents have never been shown to improve survival in advanced disease and therefore it is difficult to see a role in the early/adjuvant setting.

 

Although this study examines the use of both older and newer agents, and single vs combination regimens, the only current recommended and accepted systemic therapy for HCC is the multi-kinase inhibitor sorafenib. The use of sorafenib in HCC as monotherapy for advanced HCC was established in the SHARP trial. This randomized double-blind, placebo controlled trial examined 602 HCC patients and demonstrated a median time to radiologic progression of 5.5 months in the sorafenib arm vs 2.8 months in the placebo. The median survival demonstrated an advantage in the sorafenib arm as compared to the placebo at 10.7 and 7.9 months, respectively (P<0.001).^[2] Though the improvement was modest, these were hallmark results as they represented for the first time that this systemic agent had been proven to extend survival in advanced disease. Given its activity in advanced HCC, a rationale question was whether it could delay or prevent recurrence after curative treatment. This question was addressed in the STORM study. The STORM trial was randomized, double-blind, placebo-controlled trial looking at sorafenib post resection or ablation to prevent recurrence of HCC. Unfortunately this study showed no difference in recurrence-free survival, time to recurrence, or overall survival between the two groups. In addition drop out rates were higher in the treatment group. These are concerning results for the prospects of sorafenib's efficacy in the adjuvant setting.^[3]

 

Sorafenib therapy in the setting OLT for HCC has been evaluated in small studies as mentioned in this paper with some evidence that show potential overall survival benefit and perhaps some decreased recurrence but there also appears to be increased toxicity in this setting.^[4] Unfortunately, these data are based on small sample sizes and retrospective reviews. Fortunately, further work is ongoing in the clinical trial titled Sorafenib Tosylate Following a Liver Transplant in Treating Patients with Liver Cancer which is a phase II randomized placebo-controlled blinded trial examining high risk OLT recipients with HCC, including those patients with microvascular or macrovascular invasion; tumor outside the Milan criteria; poor tumor differentiation; and patients with elevated alpha-fetoprotein >500 ng/mL or protein induced by vitamin K (PIVKA) >400 ng/mL. This study is ongoing and aims to further establish a protocol for this patient population in order to prevent HCC recurrence and extend recurrence-free survival.^[5]

 

Lastly, there has been enthusiasm regarding the use of mTOR inhibitors such as sirolimus and everolimus to prevent HCC recurrence. Sirolimus as part of the immunosuppressive regimen has been evaluated retrospectively concerning HCC and OLT and has shown some improvement of patient survival. There are promising results including recurrence-free survival, but unfortunately the evidence is mixed.^{[6, 7]} There has also been interest in the use of everolimus in dealing with HCC. The EVOLVE-1 study looked at everolimus or placebo after progression on sorafenib in advanced HCC; however no survival benefit was seen.^[8] Despite this study, the use of everolimus after OLT has shown potentially favorable results. A single-center study found that the application of everolimus is associated with both increased overall survival and decreased recurrence rate of HCC.^[9] In addition, the data from the analysis of an H2304 randomized controlled trial using everolimus plus a reduced tacrolimus based regimen in contrast to a tacrolimus alone regimen, recently presented at the World Transplant Congress, demonstrated the decrease of HCC recurrence in the everolimus group; however further analysis is ongoing.^[10] The use of mTOR inhibitors continues to be looked at in the Silver Trial which will hopefully shed some light on the benefit of their use after OLT.

 

Adjuvant therapy after OLT for HCC remains a difficult topic amongst the transplant community, however newer anti-cancer agents as well as immunosuppressive therapies are being evaluated in ongoing trials that aim to establish their role in this setting. Given the overwhelming improvement in results after OLT for HCC with the use of strict selection criteria, we hope to have continued improvement leading to excellent long-term results with these newer therapies.

 

 

1 Lin HS, Wan RH, Gao LH, Li JF, Shan RF, Shi J. The role of adjuvant chemotherapy after liver transplantation for hepatocellular carcinoma: a systematic review and meta-analysis. Hepatobiliary Pancreat Dis Int 2015;14:236-245. PMID: 26063023 

2 Rimassa L, Santoro A. Sorafenib therapy in advanced hepatocellular carcinoma: the SHARP trial. Expert Rev Anticancer Ther 2009;9:739-745. PMID: 19496710

3 Bruix J, Takayama T, Mazzaferro V, Chau G, Yang J, Kudo M, et al. STORM: A phase III randomized, double-blind, placebo-controlled trial of adjuvant sorafenib after resection or ablation to prevent recurrence of hepatocellular carcinoma (HCC). J Clin Oncol 2014; suppl 5: abstr 4006.

4 Saab S, McTigue M, Finn RS, Busuttil RW. Sorafenib as adjuvant therapy for high-risk hepatocellular carcinoma in liver transplant recipients: feasibility and efficacy. Exp Clin Transplant 2010;8:307-313. PMID: 21143097

5 ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier. Sorafenib tosylate following a liver transplant in treating patients with liver cancer. Available from: https://clinicaltrialsgov/show/NCT01624285. 2015.

6 Klintmalm GB, Nashan B. The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence. J Transplant 2014;2014:845438. PMID: 24719752

7 Zimmerman MA, Trotter JF, Wachs M, Bak T, Campsen J, Skibba A, et al. Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Liver Transpl 2008;14:633-638. PMID: 18324656

8 Zhu AX, Kudo M, Assenat E, Cattan S, Kang Y, Lim HY, et al. EVOLVE-1: Phase 3 study of everolimus for advanced HDD that progressed during or after sorafenib. J Clin Oncol 2014; suppl 3: abstr 172.

9 Ferreiro AO, Vazquez-Millán MA, López FS, Gutiérrez MG, Diaz SP, Patiño MJ. Everolimus-based immunosuppression in patients with hepatocellular carcinoma at high risk of recurrence after liver transplantation: a case series. Transplant Proc 2014;46:3496-3501.

10 Junge G, Saliba F, De Simone P, Fischer L, Dong G, Speziale A, et al. Everolimus impact on hepatocellular carcinoma recurrence after liver transplantation - 12, 24, and 36 months data from 719 liver transplant recipients. H2304 Study Group, Basel, Switzerland. International Congress of ILTS, ELITA, LICAGE. 2014. (Abstract A376.)