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.

Introduction

Liver cancer is the second most common cause of death from cancer worldwide, estimated to be responsible for nearly 746,000 deaths in 2012 (9.1% of the total). The prognosis for liver cancer is very poor, with an overall ratio of mortality to incidence of 0.95, and the geographical patterns in incidence and mortality are similar (see Table 1).1

Table 1

Liver cancer. Estimated incidence, mortality, and 5-year prevalence worldwide in 2012

Estimated numbers (thousands)	Men			Women			Both sexes
	Cases	Deaths	5-yr prev	Cases	Deaths	5-yr prev	Cases	Deaths	5-yr prev
World	554	521	453	228	224	180	782	746	633
More developed regions	92	80	112	42	43	51	134	123	164
Less developed regions	462	441	341	186	182	129	648	622	469
USA	23	17	21	8	7	7	30	24	27
China	293	282	220	101	101	71	395	383	291
India	17	17	8	10	10	5	27	27	13
European Union	36	32	33	16	17	14	52	48	47

Source: Globoscan 2012

HCC represents more than 90% of primary liver cancers and is a major global health problem. The incidence of HCC increases progressively with advancing age in all populations, reaching a peak at 70 years.2 HCC has a strong male preponderance, with a male to female ratio estimated to be 2.4.1 The pattern of HCC occurrence has a clear geographical distribution.1,3 In 2012, 83% of the estimated 782,000 new cancer cases worldwide occurred in less developed regions.1 The incidence of HCC is growing worldwide.

A variety of important risk factors for the development of HCC have been identified. These include chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, alcohol intake, hereditary hemochromatosis, aflatoxin exposure, and cirrhosis of almost any cause. However, HCC can also occur in patients without known risk factors. Approximately 90% of HCC are associated with a known underlying risk factor (see Table 2). Cirrhosis may be caused by chronic viral hepatitis, alcohol, inherited metabolic diseases such as hemochromatosis or alpha-1-antitrypsin deficiency or Wilson's disease, non-alcoholic fatty liver disease, autoimmune hepatitis, and Budd-Chiari syndrome. All etiologic forms of cirrhosis may be complicated by tumor formation, but the risk is higher in patients with hepatitis infection. Overall, one-third of cirrhotic patients will develop HCC during their lifetime.3–7 Rarely, HCC can develop in the absence of cirrhosis.

Table 2

Geographical distribution of main risk factors for HCC worldwide

Geographic area	AAIR M/F	Risk factors HCV (%)	HBV (%)	Alcohol (%)	Others (%)
Europe	6.7/2.3	60–70	10–15	20	10
Southern	10.5/3.3
Northern	4.1/1.8
North America	6.8/2.3	50–60	20	20	10(NASH)
Asia and Africa		20	70	10	10(Aflatoxin)
Asia	21.6/8.2
China	23/9.6
Japan	20.5/7.8	70	10–20	10	10
Africa	1.6/5.3
World	16/6	31	54	15

AAIR, Age-adjusted incidence rate; HBV, Hepatitis B virus; HCV, Hepatitis C virus.

Updated from Llovet et. al. according to IARC

Overall, the incidence of HCC is increasing not only in the general population of patients with cirrhosis, but also in some subgroups of patients, like those with human immunodeficiency virus (HIV) infection or thalassemia. In fact, significant improvement in outcomes due to iron chelating drugs in thalassaemic patients and to highly active anti-retroviral therapy (HAART) in HIV patients has recently revealed HCC as a main complication of the underlying hepatic disease.8–13

Liver transplantation (LT) is an established treatment for HCC.14,15 If donor graft supply was unlimited, every cirrhotic patient with HCC would be offered LT as the optimal treatment for their disease. Relative to any other available treatment for liver cancer, LT has the highest potential to cure4,6 because of its ability to remove at once both the seeded-HCC and the damaged-hepatic tissue where cancerogenesis and chronic liver disorders have together progressed.16

The criteria for determining whether a HCC patient is eligible, upfront, for LT are very heterogeneous and relatively ill-defined. Another controversy is how to manage HCC recurrence after LT because there is little evidence available regarding improvement of survival with any treatment after LT.

Here, we present a state-of-the-art review on LT for HCC. In particular, this review concentrates on two topics, respectively, selection criteria for LT in patients with HCC and management of HCC recurrence after LT.

Selection criteria for liver transplantation in patients with hepatocellular carcinoma: Milan criteria or expanded criteria?

The number of LTs for HCC has increased worldwide; and currently in Europe, about 27% of all LT patients have HCC.18 More specifically, in some Mediterranean areas of France, Italy, and Spain, LT for HCC represents more than 40% of transplants. Over the last decade in Western countries, HCC has had the highest growth increment of all indications for LT.17,18 This trend is even more pronounced in Eastern countries, where HCC, in some instances, has equalized or even overtaken cirrhosis as the leading indication for LT.19

The broad selection criteria applied two decades ago led to poor results in terms of recurrence (32–54% at 5 years) and survival (5-year survival <40%), but allowed for the identification of the best candidates for this procedure.6,20,21 Since the initial results of LT for HCC were negative, likely because LT was initially reserved for advanced HCC not suitable for resection, the reliability of the procedure was questioned. In 1996, the publication of a pivotal prospective study on 48 patients transplanted for HCC under predefined criteria (single HCC ≤5 cm or 3 HCC ≤3 cm each), the so called “Milan criteria” (MC), showed a 4 year survival of 75%.22 Successively, some pioneering groups selecting “optimal candidates” reported 70% 5-year survival with a recurrence rate below 15%.23–26 Due to these data, LT is now considered to be the first-line treatment for patients with single HCC ≤5 cm or 3 HCC ≤3 cm each (see Table 3).4–6 All publication to date use the strict guidelines set by the MC when considering LT for treatment of HCC.4–6 A meta-analysis has confirmed the strong association of MC with a survival advantage (HR 1.7) and with a low risk of selecting an aggressive biologic behavior with respect to patients exceeding them. In fact, G3 tumors and microvascular invasion are less frequent when MC are met, with a HR of 4.8 and 2.5, respectively.27

Table 3

Recommendations on liver transplantation for hepatocellular carcinoma based on the level of evidence and the strength of the data (classification of evidence adapted from National Cancer Institute) and the strength of recommendations following previously reported systems (GRADE systems), according to EASL-EORTC clinical practice guidelines on the management of HCC6

	Levels of evidence*	Grade of recommendation°
LT Milano IN	2A	1A
LDLT	2A	2B
LT extended	2B	2B
Down-staging	2D	2C

Adapted from National Cancer Institute

GRADE system

LT, Liver transplantation; LDLT, Living donor liver transplantation.

According to European (ELTR) and American (OPTN) registries, the overall 5-year survival of patients transplanted within the MC (65–78%) is similar to non-HCC indications (65–87%).27–29 As a consequence of their success, the MC have been integrated in the BCLC staging system30,31 and in the United Network for Organ Sharing (UNOS) pre-transplant staging for organ allocation in the US,32 and remain the benchmark for any other prognostic criteria proposed for expanding the indication for LT in cirrhotic patients with HCC.33

The need to obtain the optimal benefit from the limited number of organs that are available has prompted the maintenance of strict selection criteria so as to list only those patients with early HCC who have the highest likelihood of survival after transplant. However, this means that some patients with slightly more advanced HCC in whom transplant would offer an acceptable, but not excellent outcome, are excluded from the procedure.34–36

Nevertheless, MC are often considered to be too restrictive and a plethora of “expanded criteria” have been suggested. In summary, in order to establish a new policy allowing for expansion of criteria for transplantation, it is essential to develop robust data for the specific category of patients included in the proposed expansion. Novel criteria might have a major impact on all transplant programs and the data needed to support any change should be impeccable. In addition, the impact of the expansion on non-HCC patients waiting for LT should be taken into account.3

None of these expanded criteria have been prospectively and independently validated. The partial exceptions are the University of San Francisco (UCSF) criteria (single tumor ≤6.5 cm or multiple HCC ≤3 nodules ≤4.5 cm, with the total tumor diameter ≤8 cm). Notably, there is a significant overlap between patients meeting the Milan and the UCSF criteria, resulting in a modest expansion of the exact number of HCC patients eligible for LT (estimated to be 5–10%).37 In fact, UCSF criteria on explant identified retrospectively a cohort of patients whose survival was not significantly different from those of patients transplanted for HCC inside the MC.38 The same results have been demonstrated by other retrospective experiences from other centers using UCSF criteria. Moreover, a recent prospective study showed a 5 year survival not significantly different in patients transplanted for HCC inside Milan and UCSF criteria.39

Today, expansion to UCSF criteria has already been challenged from the pathological point of view by the up-to-seven criteria (i.e. those HCC having the number 7 as the sum of the size of the largest tumor and the number of tumors).36 In a multicenter retrospective study on over 1,700 explants, the authors demonstrated that HCC inside the “up-to-seven” criteria at explant and without microvascular invasion had a 5 year survival not significantly different from those inside the MC, while survival was significantly worst in cases of HCC inside the “up-to-seven” criteria and with microvascular invasion.36 This pathology-based proposal has been recently validated in an independent series,40 but the findings must be further validated with prospective studies and is not suitable clinical practice.

The major concerns about the expansion proposals are the lack of specific data on overall survival and drop-out rate on the waiting list for the patients outside the current criteria but fulfilling the expanded criteria. Other recent studies challenging the Milan criteria have proposed different algorithms to optimize patient selection. Nonetheless, 5-year outcome prediction could vary from 70% to 40% depending on the presence of microvascular invasion. Thus, preoperative markers of vascular invasion would be required prior to adopting these criteria.6

Presently, it is likely that a modest expansion of the number of potential candidates may be considered for validated criteria (such as the up-to-seven criteria that largely include the UCSF criteria), which demonstrate comparable survival for patients outside the MC (see Table 3).6,16 As repeatedly noted in scientific and regulatory contexts, 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 (ITT) analyses.

In the present context, the term “down-staging” defines the reduction of the intra-hepatic HCC burden to meet acceptable criteria for LT,41 “acceptable” criteria being driven by good expected survival after LT.42 This equates to a 5-year survival comparable to that of HCC patients who meet transplant criteria without requiring down-staging.33 Namely, the principle of down-staging is to select a more favorable tumor biology, as determined by response to treatment in the perspective of positive post-LT outcome.41 From the seminal experience of the UCSF group, most of the published reports have used the MC as the endpoint for down-staging. In doing so, for a minimal observation period of 3 months (suggested to confirm a sustained response to treatment), a comparable or only slightly reduced survival than that achieved with HCC meeting MC before LT has been reported.41

According to recommendations, either MC or a modest expansion can be targeted in elective LT for HCC, while for down-staging only conversions to conventional MC are acceptable.33 Trans-arterial chemoembolization (TACE) is the single treatment modality most often applied to HCC down-staging, followed by radiofrequency ablation (RFA), radioembolization, and surgical resection.43–48 In the large majority of centers, the choice of treatment – either alone or in combination – is made within multidisciplinary transplant-tumor boards.49 Although a treatment strategy based on the individual components of patients/tumors is largely justified, it raises concerns of selection bias when a comparison among treatment strategies is attempted. The same applies to the criteria of exclusion from down-staging procedures, which remain largely undescribed.16

Considering the current data, down-staging of patients beyond MC cannot be adopted as a tool to refine patient selection and further research is required (see Table 3).6 This research should be based on the principle that 5-year survival outcomes of patients undergoing transplantation after successful down-staging should be similar to those of patients transplanted following MC. The EASL-EORTC panel considers, though, that a special policy should be adopted for patients already on the waiting list for LT with tumors progressing beyond MC and liver only disease. In this special circumstance, it is recommended to place the candidate on hold until down-staging by local ablation or chemoembolization is achieved and maintained for at least 3 months.6

In summary, guidelines still indicate LT only to HCC inside MC.4–6 However, as published experiences show, many centers perform LT outside the MC, using criteria that are different from center to center. Recent data show that even in large areas, between 25% and 50% of patients with HCC are currently transplanted beyond conventional indications.33,36,38,39,50–54 As a results, any unrestricted expansion of selection criteria will increase the need for donor organs, resulting in lengthened waiting periods, increased drop-out rates, and impaired outcomes in ITT analyses. Extreme deviations from efficiency and equity endpoints should be avoided in criteria expansion.

Whatever the criteria adopted, a significant problem of HCC candidates for LT is drop-out, patients who do not reach the goal of LT because of progression of HCC or causes unrelated to HCC. Many studies have investigated the risks for drop-out, despite its difficulty to define, and these factors include tumor multinodularity, neoadjuvant treatment failures, and elevated AFP or MELD. From an opposing point of view, given the organ shortage, some patients with single HCC <2 cm may benefit from alternative treatments and should avoid LT unless recurrence occurs, highlighting the possibility of salvage transplantation in the low risk population.

Living donor liver transplantation (LDLT), where the right hepatic lobe of a healthy donor is used, has emerged as an alternative to deceased LT.55–56 In 2000, there was great enthusiasm for LDLT, and it was estimated that it would represent a significant proportion of the patients transplanted with HCC.57 Unfortunately, the associated risks of death (estimated in 0.3%) and life-threatening complications (2%) for the healthy donor have diminished the interest of the transplant community.58,59,60 Due to the complexity of the procedure, LDLT must be restricted to centers of excellence in hepatic surgery and transplantation.

Outcome results with LDLT compared with deceased LT have been controversial. Although some studies suggested that LDLT was associated with higher risk of recurrence, these data have not been confirmed.61,62 Cost–effectiveness studies suggested that LDLT can be offered to patients with HCC if the waiting list exceeds 7 months,63 a policy adopted by the panel of EASL-EORTC.6

Hepatocellular carcinoma recurrence after liver transplantation: the need of treatment despite no evidence of survival benefit

Management of HCC recurrence after LT is complex and challenging. Despite the metastatic nature of such a recurrence, treatments resemble those used for HCC in cirrhosis, although there is no evidence that such treatments could improve survival of patients with HCC recurrence after LT.

Approachable localized HCC recurrence should undergo surgery, with indication resembling those of HCC in cirrhosis. Recurrences not suitable for surgery should be treated with RFTA or TACE. However, both surgery and other treatments are empirical, as no evidence of survival benefit exists.

Sorafenib is the treatment of choice for advanced HCC, since survival in sorafenib patients with underlying liver cirrhosis is longer than placebo control.64,65 Theoretically, such a systemic therapy could be the best approach for HCC recurrence after LT. However, different observational studies of patients treated with sorafenib for HCC recurrence after LT have reported contradictory results regarding safety and efficacy. In fact, while some authors emphasize the effectiveness and safety of sorafenib, pushing for the general acceptance of the treatment for HCC recurrence after LT, others had safety concerns.66–84 In particular, one group reported grade 3–4 adverse events in 92% of 13 patients, resulting in sorafenib discontinuation in 77%.72 Another study of 11 consecutive patients described a high rate of intolerance or side-effects, causing drug discontinuation in 36%.70 Moreover, some patients in another study died because of massive gastrointestinal bleeding, possibly due to an interaction between everolimus and sorafenib that could facilitate gastrointestinal bleeding.69,75,85 In fact, a concern for the concomitant use of sorafenib and HAARTs in HIV has also been reported.86

Taken all together, the experiences on treatment with sorafenib for HCC recurrence after LT are too heterogeneous to draw a definite conclusion and further studies are needed. It is advisable that the effort of a multi-center prospective randomized controlled sorafenib versus placebo trial should be made to address this controversial topic. Alternatively, a meta-analysis of survival of patients treated with sorafenib for HCC recurrence after LT could help to identify possible solutions.

Conclusions

LT has the highest potential cure rate for HCC relative to other options, but the proportion of individuals with HCC on the waiting list for transplant is growing. The MC are the benchmark for patient selection and the basis for comparison with any other suggested criteria. Expansion of criteria is not a widely recommended strategy, since there is a lack of relevant evidence. Any expansion should avoid the saturation of the listing system and poor long-term outcomes after LT. Any unrestricted expansion of selection criteria will increase the need for donor organs, resulting in lengthened waiting periods, increased drop-out rates, and impaired outcomes in ITT analyses. Extreme deviations from efficiency and equity endpoints should be avoided in criteria expansion. “Down-staging” is the reduction of the intra-hepatic HCC burden to meet acceptable criteria for LT. The principle of the strategy is to select individuals whose tumors have a more favorable biology, as determined by treatment response in the perspective of positive post-LT outcome. However, treatment may not necessarily change the outcome of LT. Overall, down-staging is weakly recommended as a LT selection tool, unless it is applied in prospective studies with survival and disease-progression endpoints.