Liver transplantation for HCC: its role

Liver transplantation (LT) is the only treatment that offers a chance of cure for hepatocellular carcinoma (HCC) and the underlying liver cirrhosis simultaneously, but the availability of liver grafts and the aggressiveness of tumor recurrence are critical limiting factors of LT for patients with HCC. In most Asian countries, the serious shortage of deceased donors and the strong demand for LT has lead to the development of living-donor LT (LDLT) as a practical alternative replacing deceased-donor LT (DDLT). Grafts in Western countries are issued from DDLT and graft allocations are under the responsibilities of state agencies which apply strict rules based on the MELD (model for end-stage liver disease) score. Considering that HCC recurrence is the most common cause of post-transplant patient death, recipient candidates should be prudently selected through objectively established criteria. Points in addition to the MELD score can be allotted to patients with HCC providing that the HCC remains within the Milan criteria. The increasing number of LT candidates with HCC results in increasing waiting periods, which necessitate the consideration of pretransplant treatment of HCC, including partial liver resection. Both specific Western units and some Asian major LDLT centers have challenged the Milan criteria. The eligibility criteria of both DDLT and LDLT for HCC are likely to be expanded more than before, but this still requires further qualified risk–benefit analyses. The development of new effective treatment modalities before LT and for HCC recurrence might expand the selection criteria further without incurring an increased recurrence rate.     

Outcomes of loco-regional therapy for down-staging of hepatocellular carcinoma prior to liver transplantation

BACKGROUND: The number of loco-regional therapies (LRTs) for hepatocellular carcinoma (HCC) has increased dramatically during the past decade. Many patients with HCC who were beyond the Milan criteria were allowed to receive a liver transplantation (LT) once the HCC was successfully down-staged. This retrospective study aimed to analyze the outcomes of LRTs prior to LT in patients with HCC beyond the Milan criteria. METHODS: We analyzed 56 patients treated from June 2006 to March 2010: 22 met the Milan crit...     

Current opinion on the role of resection and liver transplantation for hepatocellular cancer

Hepatocellular carcinoma (HCC) represents one of the most common cancers worldwide with rising incidence in developed countries. The best treatment options with curative intent for patients with HCC are liver resection or transplantation, although the role of hepatic ablative therapies has also been recognized. Surgical resection has emerged as the primary treatment in carefully selected patients of HCC. With the advances in surgical and radiological techniques, the perioperative mortality has been reduced to less than 5 % depending on the extent of resection and hepatic reserve. The role of liver transplantation (LT) as the mainstay of treatment for the majority of patients with HCC has evolved in the last few decades. Historically, the Milan criteria have been considered the gold standard for selecting patients; more expanded selection criteria to include those with more advanced tumors have been implemented in recent years. Living donor liver transplantation (LDLT) has emerged as a way to expand the donor pool and has influenced the role of transplantation for HCC, especially in communities with little access to cadaveric transplantation. Salvage transplantation is an alternative option as it allows a window for the biologically less favorable lesions to declare tumor behavior. Salvage transplantation also decreases the burden on transplant resources. Sirolimus, a novel immunosuppressant drug with anti-tumor effect, may have a role in limiting the severity of recurrent disease after transplantation for HCC, and play an important role in the future management of transplant recipients. This article examines the literature on current status of management of HCC.     

Current challenges in liver transplantation for hepatocellular carcinoma

Liver transplantation (LT) is the best option of cure for hepatocellular carcinoma (HCC). Notwithstanding several alternatives, Milan Criteria remain the cornerstone for patient selection. Currently, expanded criteria patients are unsuitable for LT without taking downstaging approaches and response to therapies into consideration. Relative weight of HCC as indication to LT is increasing and that generates competition with MELD-described non-cancer indications. Allocation policies should be adjusted accordingly, considering principles of urgency and utility in the management of the waiting list and including transplant benefit to craft equitable criteria to deal with the limited resource of donated grafts. Maximization of cost-effectiveness of LT in HCC can be also pursued through changes in immunosuppression policies and multimodal management of post-transplant recurrences. This review is focused on those constantly mutating challenges that have to be faced by anyone dealing with the management of HCC in the context of liver transplantation.     

Bridging and downstaging treatments for hepatocellular carcinoma in patients on the waiting list for liver transplantation

Several therapeutic procedures have been proposed as bridging treatments for patients with hepatocellular carcinoma(HCC)awaiting liver transplantation(LT).The most used treatments include transarterial chemoembolization and radiofrequency ablation.Surgical resection has also been successfully used as a bridging procedure,and LT should be considered a rescue treatment in patients with previous HCC resection who experience tumor recurrence or post-treatment severe decompensation of liver function.The aims of bridging treatments include decreasing the waiting list dropout rate before transplantation,reducing HCC recurrence after transplantation,and improving post-transplant overall survival.To date,no data from prospective randomized studies are available;however,for HCC patients listed for LT within the Milan criteria,prolonging the waiting time over 6-12 mo is a risk factor for tumor spread.Bridging treatments are useful in containing tumor progression and decreasing dropout.Furthermore,the response to pre-LT treatments may represent a surrogate marker of tumor biological aggressiveness and could therefore be evaluated to prioritize HCC candidates for LT.Lastly,although a definitive conclusion can not be reached,the experiences reported to date suggest a positive impact of these treatments on both tumor recurrence and post-transplant patient survival.Advanced HCC may be downstaged to achieve and maintain the current conventional criteria for inclusion in the waiting list for LT.Recent studies have demonstrated that successfully downstaged patients can achieve a 5-year survival rate comparable to that of patients meeting the conventional criteria without requiring downstaging.     

Neo-adjuvant therapy for hepatocellular carcinoma before liver transplantation: Where do we stand?

Liver transplantation(LT)for hepatocellular carcinoma(HCC)within Milan criteria is a widely accepted optimal therapy.Neo-adjuvant therapy before transplantation has been used as a bridging therapy to prevent dropout during the waiting period and as a down-staging method for the patient with intermediate HCC to qualify for liver transplantation.Transarterial chemoembolization and radiofrequency ablation are the most commonly used method for locoregional therapy.The data associated with newer modalities including drugeluting beads,radioembolization with Y90,stereotactic radiation therapy and sorafenib will be discussed as a tool for converting advanced HCC to LT candidates.The concept"ablate and wait"has gained the popularity where mandated observation period after neoadjuvant therapy allows for tumor biology to become apparent,thus has been recommended after downstaging.The role of neo-adjuvant therapy with conjunction of"ablate and wait"in living donor liver transplantation for intermediate stage HCC is also discussed in the paper.     

Patient and tumour biology predict survival beyond the Milan criteria in liver transplantation for hepatocellular carcinoma

Background

Patients with hepatocellular carcinoma (HCC) beyond the Milan criteria are not considered for liver transplantation (LT) in many centres; however, LT may be the only treatment able to achieve long-term survival in patients with unresectable HCC. The aim of this study was to assess the role of recipient age and tumour biology expressed by the DNA index in the selection of HCC patients for LT.

Patients

Clinicopathological data of 364 patients with HCC who underwent LT between 1989 and 2010 were evaluated. Overall survival (OS) was analysed by patient age, tumour burden based on Milan criteria and the DNA index.

Results

After a median follow-up time of 78 months, the median survival was 100 months. Factors associated with OS on univariate analysis included Milan criteria, patient age, hepatitis C infection, alpha-fetoprotein (AFP) level, the DNA index, number of HCC, diameter of HCC, bilobar HCC, microvascular tumour invasion and tumour grading. On multivariate analysis, HCC beyond Milan criteria and the DNA index >1.5 independently predicted a worse OS. When stratifying patients by both age and Milan criteria, patients ≤60 years with HCC beyond Milan criteria had an OS comparable to that of patients >60 years within Milan criteria (10-year OS: 33% versus 37%, P = 0.08). Patients ≤60 years with HCC beyond Milan criteria but a favourable DNA index ≤1.5 achieved excellent long-term outcomes, comparable with those of patients within Milan criteria.

Conclusions

Patients ≤60 years may undergo LT for HCC with favourable outcomes independently of their tumour burden. Additional assessment of tumour biology, e.g. using the DNA index, especially in this subgroup of patients can support the selection of LT candidates who may derive the most long-term survival benefit, even if Milan criteria are not fulfilled.     

Biological markers of hepatocellular carcinoma for use as selection criteria in liver transplantation

The Milan criteria (MC) have been widely accepted as an effective way of selecting patients with early‐stage hepatocellular carcinoma (HCC) for curative liver transplantation (LT). However, since a substantial subset of HCC patients exists that is beyond the MC but with the potential for good outcomes after LT, several institutions have recently proposed new extended criteria. To explore optimal criteria that can reasonably predict the risk of recurrence, it is considered that new markers of biological behavior are needed in addition to morphological tumor size and number. Several promising candidates for such biological markers have been reported, including serum tumor markers such as alpha‐fetoprotein and des‐gamma‐carboxy prothrombin, inflammatory markers such as C‐reactive protein and neutrophil‐to‐lymphocyte ratio, response to pre‐transplant treatments for bridging therapy or down‐staging, and fluorine‐18‐fluorodeoxyglucose positron emission tomography. However, the role of these biological markers in patient selection criteria for LT has yet to be clarified. This review article aims to summarize the results of recent reported studies and to display perspectives for the establishment of optimal criteria that incorporate such biological markers.     

Selection of patients with hepatocellular carcinoma for liver transplantation: Past and future

The aim of liver transplantation(LT) for hepatocellular carcinoma(HCC) is to ensure a rate of disease-free survival similar to that of patients transplanted due to benign disease. Therefore, we are forced to adopt strict criteria when selecting candidates for LT and prioritizing patients on the waiting list(WL), to have clarified indications for bridging therapy for groups at risk for progression or recurrence, and to establish certain limits for downstaging therapies. Although the Milan criteria(MC) remain the standard and most employed criteria for indication of HCC patients for LT by far, in the coming years, criteria will be consolidated that take into account not only data regarding the size/volume and number of tumors but also their biology. This criteria will mainly include the alpha fetoprotein(AFP) values and, in view of their wide variability, any of the published logarithmic models for the selection of candidates for LT. Bridging therapy is necessary for HCC patients on the WL who meet the MC and have the possibility of experiencing a delay for LT greater than 6 mo or any of the known risk factors for recurrence. It is difficult to define single AFP values that would indicate bridging therapy(200, 300 or 400 ng/m L); therefore, it is preferable to rely on the criteria of a French AFP model score 2. Other single indications for bridging therapy include a tumor diameter greater than 3 cm, more than one tumor, and having an AFP slope greater than 15 ng/m L per month or 50 ng/m L for three months during strict monitoring while on the WL. When considering the inclusion of patients on the WL who do not meet the MC, it is mandatory to determine their eligibility for downstaging therapy prior to inclusion. The upper limit for this therapy could be one lesion up to 8 cm, 2-3 lesions with a total tumor diameter up to 8 cm, or a total tumor volume of 115 cm~3. Lastly, liver allocation and the prioritization of patients with HCC onthe WL should take into account the recently described HCC model for end-stage liver disease, which considers hepatic function, HCC size and the number and the log of AFP values. This formula has been calibrated with the survival data of non-HCC patients and produces a dynamic and more accurate assessment model.     

Serum biomarkers and risk of hepatocellular carcinoma recurrence after liver transplantation

Liver transplantation(LT) is the only potentially curative treatment for selected patients with cirrhosis and hepatocellular carcinoma(HCC) who are not candidates for resection. When the Milan criteria are strictly applied, 75% to85%of 3-to 4-year actuarial survival rates are achieved, but up to 20% of the patients experience HCC recurrence after transplantation. The Milan criteria are based on the preoperative tumor macromorphology, tumor size and number on computed tomography or magnetic resonance imaging that neither correlate well with posttransplant histological study of the liver explant nor accurately predict HCC recurrence after LT, since they do not include objective measures of tumor biology. Preoperative biological markers, including alpha-fetoprotein, desgamma-carboxiprothrombin or neutrophil-to-lymphocyte ratio and platelet-tolymphocyte ratio, can predict the risk for HCC recurrence after transplantation.These biomarkers have been proposed as surrogate markers of tumor differentiation and vascular invasion, with varied risk magnitudes depending on the defined cutoffs. Different studies have shown that the combination of one or several biomarkers integrated into prognostic models predict the risk of HCC recurrence after LT more accurately than Milan criteria alone. In this review, we focus on the potential utility of these serum biological markers to improve the performance of Milan criteria to identify patients at high risk of tumoral Published online: January 27, 2019 recurrence after LT.Liver transplantation(LT) is the only potentially curative treatment for selected patients with cirrhosis and hepatocellular carcinoma(HCC) who are not candidates for resection. When the Milan criteria are strictly applied, 75% to85%of 3-to 4-year actuarial survival rates are achieved, but up to 20% of the patients experience HCC recurrence after transplantation. The Milan criteria are based on the preoperative tumor macromorphology, tumor size and number on computed tomography or magnetic resonance imaging that neither correlate well with posttransplant histological study of the liver explant nor accurately predict HCC recurrence after LT, since they do not include objective measures of tumor biology. Preoperative biological markers, including alpha-fetoprotein, desgamma-carboxiprothrombin or neutrophil-to-lymphocyte ratio and platelet-tolymphocyte ratio, can predict the risk for HCC recurrence after transplantation.These biomarkers have been proposed as surrogate markers of tumor differentiation and vascular invasion, with varied risk magnitudes depending on the defined cutoffs. Different studies have shown that the combination of one or several biomarkers integrated into prognostic models predict the risk of HCC recurrence after LT more accurately than Milan criteria alone. In this review, we focus on the potential utility of these serum biological markers to improve the performance of Milan criteria to identify patients at high risk of tumoral recurrence after LT.     

Hepatocellular carcinoma beyond Milan criteria: Management and transplant selection criteria

Liver transplantation(LT) for hepatocellular carcinoma(HCC) has been established as a standard treatment in selected patients for the last two and a half decades. After initially dismal outcomes, the Milan criteria(MC)(single HCC ≤ 5 cm or up to 3 HCCs ≤ 3 cm) have been adopted worldwide to select HCC patients for LT, however cumulative experience has shown that MC can be too strict. This has led to the development of numerous expanded criteria worldwide. Morphometric expansions on MC as well as various criteria which incorporate biomarkers as surrogates of tumor biology have been described. HCC that presents beyond MC initially can be downstaged with locoregional therapy(LRT). Post-LRT monitoring aims to identify candidates with favorable tumor behavior. Similarly, tumor marker levels as response to LRT has been utilized as surrogate of tumor biology. Molecular signatures of HCC have also been correlated to outcomes; these have yet to be incorporated into HCC-LT selection criteria formally. The ongoing discrepancy between organ demand and supply makes patient selection the most challenging element of organ allocation. Further validation of extended HCCLT criteria models and pre-LT treatment strategies are required.     

Milan criteria are useful predictors for favorable outcomes in hepatocellular carcinoma patients undergoing liver transplantation after transarterial chemoembolization

INTRODUCTION Hepatocellular carcinoma (HCC) is a major global health problem involving more than 500 000 new cases a year. Several treatment modalities, such as liver transplantation (LT), surgical resection, radiofrequency ablation (RFA), and percutaneou…     

Current controversies surrounding liver transplantation for hepatocellular carcinoma

Liver transplantation (LT) for hepatocellular carcinoma (HCC) has progressed rapidly over the last decade from a futile therapy to the first choice therapy for suitable patients. Excellent outcomes of LT for HCC can be largely attributed to the use of the Milan Criteria, which have restricted LT to patients with early stage tumors. These criteria may be conservative, and it is likely that a subset of patients with tumors beyond these criteria can have acceptable outcomes. However, there is currently insufficient data to accept more liberal criteria as a standard of care, and a higher quality evidence base must be achieved to prevent poor utilization of valuable donor liver resources. In the future, it is probable that more sophisticated selection criteria will emerge incorporating aspects of tumor biology beyond tumor size and number. Dropout from the waiting list due to tumor progression remains a clinical challenge particularly in regions with prolonged waiting times. Priority allocation using HCC MELD points is a practical and transparent solution that has successfully reduced waitlist dropout for HCC patients. Further refinements of the HCC MELD point system are required to ensure equity of access to LT for non‐HCC patients and prioritization of HCC patients with the highest risk of dropout. Improving the evidence base for pre‐LT locoregional therapy to prevent waitlist dropout is an urgent and difficult challenge for the LT community. In the interim transplant clinicians must restrict the use of these therapies to those patients who are most likely to benefit from them.     

Hepatocellular Carcinoma and Liver Transplantation: State of the Art

Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in chronic liver disease and cirrhosis. The incidence of HCC is growing worldwide.With respect to any other available treatment for liver cancer, liver transplantation (LT) has the highest potential to cure. LT allows for removal at once of both the tumor (“seed”) and the damaged-hepatic tissue (“soil”) where cancerogenesis and chronic liver disorders have progressed together. The Milan criteria (MC) have been applied worldwide to select patients with HCC for LT, yielding a 4-year survival rate of 75%. These criteria represent the benchmark for patient selection and are the basis for comparison with any other suggested criteria.However, MC are often considered to be too restrictive, and recent data show that between 25% and 50% of patients with HCC are currently transplanted beyond conventional indications. Consequently, any unrestricted expansion of selection criteria will increase the need for donor organs, lengthen waiting periods, increase drop-out rates, and impair outcomes on intention-to-treat analysis. Management of HCC recurrence after LT is challenging. There are a few reports available regarding the safety and efficacy of sorafenib for HCC recurrence after LT, but the data are heterogeneous. A multi-center prospective randomized controlled trial comparing placebo with sorafenib is advised. Alternatively, a meta-analysis of patient survival with sorafenib for HCC recurrence after LT could be helpful to characterize the therapeutic benefit and safety of sorafenib.Here, we review the use of LT for HCC, with particular emphasis on the selection criteria for transplantation in patients with HCC and management of HCC recurrence after LT.     

Liver transplantation as a management of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a poor prognosis if untreated. It is ranked the third among the causes of cancer-related death. There are multiple etiologic factors that can lead to HCC. Screening for early HCC is challenging due to the lack of well specific biomarkers. However, early diagnosis through successful screening is very important to provide cure rate. Liver transplantation (LT) did not gain wide acceptance until the mid-1980s, after the effective immunosuppression with cyclosporine became available. Orthotopic LT is the best therapeutic option for early, unresectable HCC. It is limited by both, graft shortage and the need for appropriate patient selection. It provides both, the removal of tumor and the remaining cirrhotic liver. In Milan, a prospective cohort study defined restrictive selection criteria known as Milan criteria (MC) that led to superior survival for transplant patients in comparison with any other previous experience with transplantation or other options for HCC. When transplantation occurs within the established MC, the outcomes are similar to those for nonmalignant liver disease after transplantation. The shortage of organs from deceased donors has led to the problems of long waiting times and dropouts. This has led to the adoption of extended criteria by many centers. Several measures have been taken to solve these problems including prioritization of patients with HCC, use of pretransplant adjuvant treatment, and living donor LT.     

Liver transplantation for HCC: validation of prognostic power of the RETREAT score for recurrence in a UK cohort

BackgroundThe Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score as a prognostic index for recurrence has been reported previously and has not been validated outside the USA. Our study has validated the score in a single center UK cohort of patients being transplanted for HCC.MethodsLT for HCC between 2008 and 2018 at our center were analyzed. Recurrence-free survival (RFS) was compared by the RETREAT score and validated using Net Reclassification Improvement (NRI) by comparing it to Milan criteria.Results346 adult HCC patients were transplanted of whom 313 were included. 28 (8.9%) had a recurrence. Summation of largest diameter and total number of viable tumors (HR = 1.19, p < 0.001), micro-/macro-vascular invasion (HR = 3.74, p = 0.002) and AFP>20 ng/ml (HR = 3.03, p = 0.005) were associated with recurrence on multivariate analysis. RFS decreased with increasing RETREAT score (log-rank p = 0.016). RETREAT performed better than Milan with significant NRI at 1- and 2-years post-transplant (0.43 (p = 0.004) and 0.38 (p = 0.03) respectively).ConclusionLT outcomes using the revised UK criteria are equivalent to Milan criteria. Further, RETREAT score was validated as a prognostic index for the first time in a UK cohort and may assist risk stratification, selection for adjuvant therapies and guide surveillance.     

Prognostic implication of early posttransplant hypercholesterolemia in liver transplantation for patients with hepatocellular carcinoma

Background: Hyperlipidemia is a common complication after liver transplantation(LT) and develops mostly in the early posttransplant period. Recently, some studies have reported a positive correlation between hyperlipidemia and favorable prognosis in patients with hepatocellular carcinoma(HCC) undergoing hepatectomy. This study aimed to evaluate the possibility of predicting prognosis in HCC patients receiving LT by early posttransplant dyslipidemia. Methods: From January 2015 to December 2017, a...     

Liver transplantation for hepatocellular carcinoma: current topics in France

Background

Excellent survival obtained with liver transplantation (LT) for limited hepatocellular carcinoma (HCC) in patients with chronic liver disease is still challenged by the increasing discrepancy between candidates and grafts available. We review the current strategy of LT for HCC in our country highlighting the tendency: (1) to expand recipient selection beyond the Milan criteria, (2) to use systematic pre-LT treatments with a greater number of resections and (3) new rules for graft attribution.

Results

Although the vast majority of cirrhotic patients with HCC are transplanted within the Milan criteria; the number of candidates is continually rising, while the number of grafts available is stable with a disappearance of adult LDLTs. Moreover, the new rules for organ allocations, mainly based on the MELD score, minimize the accessibility to liver grafts for patients with HCC and compensated liver disease. For these reasons, in France we have observed an increase in waiting time for HCC patients, leading to the extensive use of pre-LT treatments in order to limit the list dropouts. Many studies have been performed on transarterial chemo-embolization (TACE) and supraselective TACE. Moreover, the use of liver resection (LR) as a bridge therapy, showing that initial resection does not impair short- and long-term survival, led French surgeons to develop the concept of LR as a way to select patients who might benefit from LT and to use it, in selected cases, as a primary therapy, considering LT as salvage treatment in case of recurrence.

Conclusions

The number of HCC candidates who cannot benefit from a LT is increasing worldwide. The French answer to this situation involves pre-LT treatments, particularly partial LR, based mainly on the excellent Japanese results in this field. Moreover, the country of « égalité » is actually modifying the rules of graft attribution in order to reduce the inequality between the HCC patients with poor and good liver function.     

The evolution of liver transplantation for hepatocellular carcinoma (past, present, and future)

Over the past quarter-century, liver transplantation (LT) has been established as a durable therapy for all forms of end-stage liver disease. LT appears ideally suited for hepatocellular carcinoma (HCC), as it involves complete oncologic resection and correction of the underlying liver dysfunction. Since LT based on the Milan criteria has been shown to provide good diseasefree survival, LT is considered the optimal treatment for small HCC, especially in patients with underlying chronic liver disease. However, because there is a severe shortage of organ donors, not all patients in need can be offered LT. Transplant listing criteria must simultaneously determine the greatest number of suitable candidates for LT while rejecting the smallest number of those who could benefit from LT. The amended model for end-stage liver disease allocation policy has had a positive effect on liver transplant candidates with HCC, and their number has been increasing significantly over the past several years. To minimize dropout from the waiting list, the treatment of HCC with procedures such as chemoembolization, radiofrequency ablation, or ethanol injection in patients awaiting LT have become widespread. It is currently accepted that liver resection is the best option for the treatment of small HCC when liver function is well preserved, and that LT is preferred when liver function is severely impaired (Child-Pugh class B or C). However, the question arises as to what is the best option for Child-Pugh class A patients with early HCC eligible for both resection and LT, especially in Western countries. HCC is a major indication for living donor liver transplantation (LDLT), because the risk of dropout while waiting is negligible. Extension of the Milan criteria in the setting of LDLT may offer more patients a potentially curative treatment without reducing the donor pool of organs for patients on the waiting list with nonmalignant liver disease. However, imprudent expansion of the selection criteria may result in more patients with HCC being cured at the expense of a higher incidence of recurrence.