Author Affiliations: Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Wang ZY, Geng L and Zheng SS)

 

Corresponding Author: Shu-Sen Zheng, MD, PhD, FACS, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Tel: +86-571-87236570; Fax: +86-571-87236628; Email: shusenzheng@zju.edu.cn)

 

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

doi: 10.1016/S1499-3872(15)60345-9

Published online March 2, 2015.

 

 

Contributors: ZSS proposed the study. WZY wrote the main content of the article. GL provided advice on medical aspects. ZSS is the guarantor.

Funding: This study was supported by grants from the National Natural Science Foundation of China (81373160), and the Science and Technology Department of Zhejiang Province (2009R50038).

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.

 

 

BACKGROUND: Liver transplantation is the optimal treatment for a selected group of patients with moderate to severe cirrhosis and hepatocellular carcinoma (HCC). Despite the strict selection of candidates, post-transplant recurrence often occurs and markedly reduces the long-term survival of patients with HCC. The present review focuses on the current strategies on preventing the recurrence of HCC after liver transplantation.

 

DATA SOURCES: Relevant articles were identified by extensive searching of PubMed using the keywords "hepatocellular carcinoma", "recurrence" and "liver transplantation" between January 1996 and January 2014. Additional papers were searched manually from the references in key articles.

 

RESULTS: The current theories of HCC recurrence after liver transplantation are: (i) the growth of pre-transplant occult metastases; (ii) the engraftment of circulating tumor cells released at the time of transplantation. Pre-transplant treatment aims to control local tumor by radiofrequency ablation, transarterial embolization and transarterial chemoembolization. The main objective during the operation is to prevent tumor cell dissemination. Post-transplant treatment includes systemic anticancer therapy, antiviral therapy, and most recently, immunotherapy. These strategies concentrate on the control of the tumor when the patients are waiting for transplant, to reduce the release of HCC cells during surgical procedures and to clear the occult HCC cells after transplantation.

 

CONCLUSIONS: Much can be done to prevent HCC recurrence after liver transplantation. In future, effort is likely to be directed towards combining multidisciplinary approaches and various treatment modalities.

 

(Hepatobiliary Pancreat Dis Int 2015;14:145-149)

 

KEY WORDS: hepatocellular carcinoma; recurrence; liver transplantation

Liver transplantation (LT) is the only therapeutic option for patients with unresectable hepatocellular carcinoma (HCC). Moreover, LT, with the advantage of eliminating both the primary tumor and the cirrhotic liver, is the optimal treatment for selected patients with resectable HCC.^[1] However, the initial outcomes of LT for HCC were dismal until the Milan criteria proposed by Mazzaferro et al^[2] were adopted in 1996. The 5-year survival rate of patients after LT meeting these criteria is more than 70%.^{[2, 3]} Unfortunately, HCC patients, even those meeting the criteria, are not completely free from tumor recurrence after LT. It is estimated that around 10%-20% of patients experience HCC recurrence.^[4-7] Therefore, the incidence of tumor recurrence and metastasis after LT remains a major problem.

 

The mechanism of HCC recurrence after LT remains unclear. The growth of pre-transplant occult metastases or the engraftment of circulating tumor cells released at the time of transplantation might play an important role.^[8] Based on this hypothesis, the recent study^[8] focused on reducing the release and engraftment of tumor cells. Specific areas of focus included the selection of recipients before transplantation, the reduction of operative release of HCC cells during surgical procedures, and the clearance of occult HCC cells after transplantation. The purpose of this review is to try to draw more attention to these topics.

 

 

The aim of selection criteria is to exclude candidates with a high risk of extrahepatic metastasis. The first accepted conventional indication was the Milan criteria which defined that patient with cirrhosis and a solitary HCC nodule smaller than 5 cm in diameter, or up to three tumors smaller than 3 cm, and without evidence of vascular invasion or extrahepatic manifestations. Patients with HCC within the Milan criteria have excellent outcomes after LT.^[2] Since then, early-stage HCC has become an indication for LT. However, this policy implies that some HCC patients will be excluded from transplantation because their symptoms are slightly more advanced than those allowed by the selection criteria. With many people suggesting that these criteria are too strict, the possibility that LT may be associated with improved survival in some HCC patients who do not meet the Milan criteria has emerged. Critical studies from UCSF, UCLA and Hangzhou demonstrated that the criteria can indeed be expanded.^[9-12] In particular, the Hangzhou criteria underlined the critical importance of tumor biology, including alpha-fetoprotein (AFP) levels and differentiation.^[13] A recent report^[14] showed that recipients who do not meet the Milan criteria but within the Hangzhou criteria achieved better overall survival. The 1- and 5-year overall survival and 1- and 5-year tumor-free survival of recipients within the Hangzhou criteria were 92.3%, 80.8% and 92.3%, 76.1%, respectively.

 

The assessment of HCC microvascular invasion and differentiation by biopsy has been suggested.^{[15] 18}F-FDG PET/CT could provide effective information on the characteristics of tumor to help the selection of candidates for LT and reduce the rate of recurrence.^[16] The use of serum AFP levels as a biomarker has been explored in other studies.^{[17, 18]} Toso et al^[19] suggested that the patients with a total tumor volume of less than 115 cm³ and AFP level of lower than 400 ng/mL had satisfactory post-transplant survivals. Pathology surrogates such as microvascular invasion and microsatellites close to the main tumor nodule remain significantly related to post-transplant outcome.^[20,21] Furthermore, Jonas et al^[22] proposed that a DNA-index is a strong prognostic indicator for HCC recurrence after LT.

 

 

The fact that there is a waiting time before transplantation led to the widespread use of loco-regional therapy for HCC patients before LT. Neo-adjuvant therapy was to slow the progression of HCC and avoid drop-out. The most widely used treatments included radiofrequency ablation (RFA), transarterial embolization (TAE) and transarterial chemoembolization (TACE). RFA causes the ablation of tumor tissue through heat or local ischemic necrosis. Several reports^{[23, 24]} indicated that these techniques may prevent tumor progression and improve long-term outcomes in HCC patients within the Milan criteria.Tsochatzis et al^[25] demonstrated that pre-transplant TAE significantly reduces HCC recurrence after LT in patients within the Milan criteria. Toso et al^[26] found that the degree of tumor necrosis after TACE is linked to prognosis. However, one study^[27] suggested that TACE could increase the circulating HCC cells which caused HCC recurrence; this side effect may counteract the beneficiary effect of TACE.

 

 

HCC is a friable and highly vascular tumor. The potential risk of mobilization of the total liver together with the tumor during the transplantation procedure includes iatrogenic tumor rupture and spillage of cancer cells into the systemic circulation. Thus, the "no-touch" technique for LT should be advocated and surgeons need to be more aware that liver and HCC mobilization could potentially increase the risk of release of HCC cells. We suggest minimizing the handling and avoiding squeezing of the tumor during transplantation. Moon et al^[28] successfully performed a no-touch technique in living donor LT for HCC.

 

Recent studies^{[29, 30]} have shown that hepatic ischemia-reperfusion (I/R) injury contributes to tumor growth and metastasis. Protective strategies to reduce I/R injury should be considered.

 

Although the rate of HCC recurrence is significantly lower after LT than that in non-transplanted HCC patients, approximately 10%-20% patients have HCC recurrence after LT. This fact suggests that tumor recurrence potentially correlates with an immunosuppressed status after LT, in which the patient's immunity is impaired and unable to prevent tumor progression. Many reports^[31-34] have shown that overexposure to immunosuppressants may increase the risk of HCC recurrence after LT. Vivarelli et al^{[31, 32]} demonstrated a direct relationship between the cumulative dosage of cyclosporine administered after LT and HCC recurrence-free survival, and found that exposure to cyclosporine was an independent determinant of recurrence-free survival. A later study^[33] also showed that both tacrolimus and cyclosporine exposure were independent prognosis factors associated with HCC recurrence, together with microvascular invasion and tumor histological grading. Furthermore, Baksh et al^[34] suggested that tacrolimus may increase tumor recurrence by promoting cell cycle progression through an increase in CDK4 kinase activity.

 

The new immunosuppressive agents called "mammalian target of rapamycin" (mTOR) inhibitors, including sirolimus and everolimus, have raised our great interest due to their anticancer effects. Several reports^{[35, 36]} showed that they decrease the vascular endothelial growth factor and therefore, prevent the progression and recurrence of invasive tumors after transplantation. Toso et al^[37] confirmed that sirolimus-based immunosuppression therapy improved survival of HCC patients after LT. Recently, Li et al^[38] reported that FTY720 suppressed liver tumor metastasis after hepatectomy through attenuating hepatic I/R injury and reducing the numbers of circulating endothelial progenitor cells. This suggests that FTY720 may be a promising immunosuppressive agent candidate for treating liver cancer recurrence after LT.

 

 

Despite failure to show any advantage after hepatectomy of HCC, adjuvant anticancer treatment has been used systematically in preventing recurrence after LT. Two different prospective randomized trials^{[39, 40]} showed that systemic doxorubicin administered after LT was not significantly effective in preventing HCC recurrence. Another study with cisplatinum and adriamycin also showed no benefit to LT recipients.^[41]

 

As a multikinase inhibitor with antiangiogenic and antiproliferative activity, sorafenib displayed promising preliminary benefits in treating advanced stage HCC and is considered as standard systemic treatment for HCC patients who are not candidates for other therapies. The assessment of sorafenib after LT was also included in some studies.^[42-44] The data showed that sorafenib in combination with an mTOR inhibitor could be effective in reducing HCC recurrence in patients post-transplant, with an acceptable incidence of adverse events. Licartin (¹³¹I-metuximab injection) also showed promising results in preventing tumor recurrence in advanced HCC patients post-transplant.^[45]

 

Recent studies^{[46, 47]} found that antiviral therapy decreased HCC-related mortality and HCC recurrence after surgery, and improved overall survival in patients with HBV-related HCC. Thus, treatment of HBV should be continued after LT.

 

Chemopreventive strategies aim at decreasing the risk or delaying the onset of HCC. Several prescribed medications seem to be promising as chemopreventive agents against HCC, including statins, antidiabetic agents and aspirin. Dietary agents such as coffee, vitamin E and fish oil might also reduce the risk of HCC.^[48] Acyclic retinoids (vitamin A analogues) and menatetrenone (a vitamin K2 analogue) have been tested as chemopreventive agents after hepatic resection or local ablative therapy for HCC. Shimizu et al^[49] suggested that acyclic retinoids can successfully prevent HCC recurrence and improve patient survival. Ishizuka et al^[50] found that menatetrenone suppressed the recurrence of HCC and improved survival.

 

Since HCC has immunogenic features, immunotherapy potentially enhances the adaptive anticancer immune response in the tumor-bearing subjects and therefore, is a promising therapeutic approach for HCC. Natural killer cells have an efficient anti-tumor activity and have been exploited as anticancer immunotherapy. Studies^{[51, 52]} described that natural killer cells have the anti-tumor effect and can be used as an adoptive immunotherapy approach to prevent tumor recurrence after LT. Direct perfusion of natural killer cells derived from deceased donor liver graft to HCC recipients is now a therapeutic approach for HCC patients after LT.Thus, natural killer cells could be a promising strategy for the future cell-based immunotherapy for HCC after LT.

 

 

LT offers the best chance of a cure for HCC patients with severe cirrhosis or unresectable tumor. Prevention of HCC recurrence remains a key goal in improving the prognosis after LT. The Hangzhou criteria emphasize the need for biological parameters in the definition of modern criteria. The approach of using molecular signatures in prediction in conjunction with clinical information is promising strategy. Furthermore, other adjuvant therapies, including antiviral treatments, chemoprevention and immunotherapy approaches may improve survival rates.

 

 

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