Liver transplantation for hepatocellular carcinoma

INTRODUCTION — Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in the setting of chronic liver disease and cirrhosis. (See "Epidemiology and risk factors for hepatocellular carcinoma".)

The only potentially curative treatment options are resection and liver transplantation. Among patients who are not candidates for liver resection, some who have cirrhosis and HCC are candidates for potentially curative liver transplantation. Unfortunately, even though they might have liver isolated disease, the majority of patients are not eligible for either resection or transplantation because of tumor extent, underlying liver dysfunction, and lack of donor organs. This has led to the development of many other liver-directed treatments and combinations for treatment of HCC including local tumor ablation and various methods of hepatic artery embolization. (See "Surgical resection of hepatocellular carcinoma" and "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates who are eligible for local ablation" and "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation".)

Treatment algorithms for HCC — There are several therapeutic options for treatment of localized HCC. A general approach to treatment is shown in the figure (algorithm 1). An alternative treatment algorithm has been proposed by the Barcelona Clinic, which was updated in 2022 (figure 1) [1].

However, attempts to generate algorithmic approaches to the treatment of HCC are difficult since new treatments and indications for various treatments are evolving rapidly. Furthermore, therapeutic approaches tend to vary based upon the available expertise. These issues and a general approach to treatment of HCC are discussed in detail elsewhere. (See "Overview of treatment approaches for hepatocellular carcinoma".)

EVOLUTION OF TRANSPLANTATION FOR HCC — Liver transplantation for treatment of HCC is attractive because resection of the malignant tumor can be achieved while also replacing the cirrhotic liver that remains at risk for the development of new lesions. However, early experience with transplantation for patients with unresectable local HCC was disappointing. Unacceptable 90-day mortality rates, tumor recurrence in up to 80 percent of patients, and long-term survival rates that were well below that of patients transplanted for non-malignant disease all reflected the advanced nature of the disease [2,3].

A change in the philosophy of transplantation for HCC evolved with the finding that small, incidentally found HCC in explanted livers did not adversely affect survival of patients undergoing liver transplantation for other conditions when compared with patients whose livers did not contain a malignancy [4]. Furthermore, an increasing number of retrospective studies suggested that liver transplantation was as effective and possibly more effective than alternative therapies in carefully selected subgroups of patients.

Liver transplantation for HCC will be discussed here. Partial hepatectomy and nonsurgical options for liver-isolated disease (ie, cryoablation, percutaneous ethanol injection, radiofrequency ablation [microwave], and transarterial chemoembolization), as well as the clinical manifestations and diagnosis of HCC, are reviewed separately (see appropriate topic reviews). An overview of treatment approaches for HCC is also presented elsewhere. (See "Overview of treatment approaches for hepatocellular carcinoma".)

INDICATIONS FOR TRANSPLANTATION — For patients with localized HCC who are not candidates for resection, orthotopic liver transplantation is an appropriate strategy for patients with a single lesion ≤5 cm, up to three separate lesions, none larger than 3 cm, no evidence of gross vascular invasion, and no regional nodal or extrahepatic distant metastases. When these criteria are strictly applied, five-year survival rates 75 percent or higher can be achieved. Overall survival in carefully selected patients undergoing orthotopic liver transplantation (OLT) for HCC is similar to or only slightly worse than the survival of patients undergoing OLT for non-malignant causes. Although randomized trials have not been carried out, uncontrolled series suggest that survival following OLT is as good or better than it is after alternative treatments for HCC in carefully selected patients.

The landmark study of Mazzaferro in 1996 established deceased donor liver transplantation as a viable option for the treatment of HCC [5]. They showed that when transplantation was restricted to patients with early HCC (defined as single lesion ≤5 cm, up to three separate lesions, none larger than 3 cm, no evidence of gross vascular invasion, and no regional nodal or distant metastases), a four-year survival rate of 75 percent could be achieved. These outcomes are similar to expected survival rates for patients undergoing transplantation for cirrhosis without HCC. These criteria have become known as the Milan criteria and have been widely applied around the world in the selection of patients with HCC for liver transplantation [5].

Considerable interest has arisen in expansion of these transplant criteria in highly specialized centers, although such expanded criteria remain purely investigational at present. This subject is discussed in detail below. (See 'Patients who meet expanded transplant criteria' below.)

Extrahepatic staging in patients being considered for transplantation should include computed tomography (CT) of the chest and CT or magnetic resonance imaging (MRI) of the abdomen and pelvis [6]. Bone scan was previously required, but this was changed in December 2012. (See 'Requirements for listing and management while on the wait list' below.)

Survival compared with transplantation for other reasons — Overall survival in carefully selected patients undergoing OLT for HCC is similar to or only slightly worse than survival of patients undergoing OLT for non-malignant causes [7-11].

Analysis of data from the United Network for Organ Sharing (UNOS) provides the most important comparative information about the outcomes in patients undergoing OLT for HCC as compared with non-malignant disease. The most recent report from UNOS focused on 34,324 liver transplants performed between 1987 and 2001, 985 of which were done for HCC [10]. When three different time periods were compared (1987 to 1991, 1992 to 1995, and 1996 to 2001) the five-year survival rates for patients undergoing OLT for HCC increased significantly (25 versus 47 and 61 percent, respectively) despite longer average waiting periods in more recent years (37 versus 103 and 215 days, respectively). By contrast, the five-year survival rate for control patients who underwent OLT for non-malignant reasons was 71 percent and did not change over the study period. These data suggest that the better results with OLT for HCC are more likely attributable to improved patient selection rather than better technique and post-transplant care [12,13].

Prognostic factors for post-transplant survival were evaluated in another report from an international tumor registry that included 790 patients with HCC who were followed for an average of 30 months after OLT [9]. Among the variables that adversely affected overall and/or recurrence-free survival were histologic grade of differentiation, size >5 cm, involved lymph nodes, bilobar tumor involvement, and vascular invasion. Prognostic factors are discussed in detail below. (See 'Outcomes and prognostic factors' below.)

Survival in comparison to other types of therapy — No large randomized trials have directly compared OLT with other forms of therapy for early HCC. Retrospective studies that included adjustment for disease severity suggest that survival following OLT is as good or better than after alternative treatments in carefully selected patients. For patients with anatomically resectable HCC and adequate hepatic reserve, resection remains the standard with which alternative treatment methods must be compared.

Observational series suggest that long-term results after transplantation are at least as good and may be superior to those of resection in some groups [4,14-16]:

●A series from Pittsburgh included 181 patients with HCC, of whom 105 underwent OLT while 76 were resected [4]. During 37 to 53 months of follow-up, no significant differences in survival emerged between the OLT and resection groups when patients without cirrhosis were considered. However, when HCC was associated with cirrhosis, survival rates after OLT were significantly better than those after resection.

●Similar conclusions were drawn in a series of 102 patients with HCC, 50 of whom underwent transplantation and 52 potentially curative liver resection [3]. Overall, three-year survival and recurrence rates were similar in both groups. However, OLT was associated with significantly better outcomes among cirrhotic patients (three-year survival rate 48 versus 23 percent) and those with tumors <3 cm (76 versus 33 percent).

●Comparable results were noted in a report comparing outcomes from liver resection and OLT in 120 cirrhotic patients with HCC [15]. The patient groups were comparable with respect to underlying disease, age, and tumor size, although as expected, resected patients were more often Child class A and B cirrhotics. Despite the apparent advantage for resection candidates, the rate of survival without recurrence significantly favored the transplanted group (46 versus 27 percent) even among patients with one or two small (<3 cm) tumors (three-year recurrence-free survival 83 versus 18 percent, respectively).

●A survival benefit for transplantation was also suggested in a study of 533 (predominantly cirrhotic) patients with HCC who had been treated with OLT, resection, transarterial chemoembolization (TACE), percutaneous ethanol injection (PEI), or no treatment [14]. Analysis was stratified according to the number of lesions, stage of disease, serum alpha-fetoprotein levels, Child-Pugh class (table 1), and viral versus alcoholic cirrhosis. A survival benefit was observed in patients undergoing OLT as compared with other treatments: three- and five-year survivals were 72 and 68 percent for OLT, as compared with 64 and 44 percent for resection, 54 and 36 percent for PEI, and 32 and 22 percent for TACE. The benefit of transplantation was mainly evident in patients with monofocal HCC <5 cm.

An important caveat is that the results of transplantation cited above include only patients who actually received a transplant. Not included are patients with HCC who were listed for transplant but ultimately did not receive a liver transplant because their tumor progressed and exceeded transplant eligibility criteria before the transplant could be performed. Accordingly, intent-to-treat analyses of liver transplantation for HCC consistently demonstrate lower survival rates.

Ultimately, despite the demonstrated benefit of transplantation, particularly in cirrhotic patients with small tumors, the group of patients with HCC who are candidates for OLT and who actually receive a graft is very small. Worldwide, the majority of patients with early stage HCC (often detected in the setting of formal surveillance programs) are treated in the Far East and Asian countries, where OLT is not a wide-spread option because of religious beliefs, lack of living-donor transplant programs, and its prohibitive cost. Without screening (ie, in most of the West), few patients who have cirrhosis and early stage HCC are identified as candidates for OLT.

ALLOCATION OF DONOR ORGANS — Shortage of donor livers has necessitated the development of allocation schema, whereby priority for donor organs is given to the most severely ill patients. In the United States, allocation of deceased donor livers for patients ages 12 years and older is based on the Model for End-stage Liver Disease (MELD) score, a statistical model based upon predicted survival in patients with cirrhosis. A higher point score is assigned to patients who are estimated to have a worse short-term prognosis based upon parameters such as serum bilirubin, serum creatinine, serum sodium, international normalized ratio (INR), serum albumin, and sex (calculator 1 and calculator 2). (See "Model for End-stage Liver Disease (MELD)".)

The use of the pediatric end-stage liver disease (PELD) score for organ allocation in patients younger than age 12 is discussed separately. (See "Acute liver failure in children: Management, complications, and outcomes", section on 'Organ allocation in acute liver failure'.)

For patients with HCC, the traditional MELD criteria are of limited usefulness because the criteria were not developed to predict the risk of death among patients with chronic liver disease who also have HCC. Compared with patients suffering from cholestatic liver disease or viral hepatitis without HCC, many of these patients have minimal liver dysfunction until late in the course of the disease process. Furthermore, in some parts of the United States, the waiting period for orthotopic liver transplantation (OLT) can be as long as 24 months. For patients with HCC, prolonged waiting often results in tumor growth (which may result in disqualification from OLT) as well as progression of the underlying liver disease.

Because of this, a supplemental system for prioritization was developed by the Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) that would provide these patients access to an allograft before their HCC progresses beyond the Milan criteria. Notably, in 2016, the OPTN adopted a downstaging protocol for patients with HCC tumor burden beyond the Milan criteria. Patients meeting criteria for the OPTN downstaging protocol (as outlined in the OPTN policies document [17]) may be eligible for standard MELD HCC exception points and given priority if HCC tumor burden can be downstaged to, and maintained within, Milan criteria with an alpha-fetoprotein (AFP) level <1000 ng/mL using locoregional therapies. (See 'United States' below and 'Patients who meet expanded transplant criteria' below.)

Requirements for listing and management while on the wait list

United States — In the United States, in an attempt to ensure that preoperative assessment is as accurate as possible, UNOS provides a set of specific requirements for giving additional wait list priority for patients with HCC for OLT [17].

The patient must undergo a thorough assessment to evaluate the number and size of tumors, and to rule out extrahepatic spread and/or macrovascular involvement (ie, tumor thrombus in the portal or hepatic vein). This can be accomplished by computed tomography (CT), or magnetic resonance imaging (MRI) plus a staging chest CT scan. In addition, patients must not be eligible for resection, and there must be an indication as to whether the patient has undergone locoregional ("bridging") therapy. (See 'Bridging therapy' below.)

A mandatory six-month waiting period was enacted by OPTN/UNOS in 2015 prior to granting HCC exception points; this policy change has been associated with a decrease in waitlist mortality/dropout, increased transplant probability, fewer regional disparities in transplant opportunity, and no difference in one-year patient and graft survival [18].

There are MELD score exception points for individuals with HCC that attempt to create a more balanced situation regarding the access and priority to transplantation between candidates with HCC exception points and those without HCC with allocation priority based on their MELD points [17]. To be eligible for, and apply to, the National Liver Review Board (NLRB) for MELD exception points the HCC must be stage T2 cancer (table 2) with a serum level of AFP that is ≤1000 ng/mL [17]. Although patients with smaller or larger tumors or higher AFP levels may be listed, only those with American Liver Tumor Study Group stage II HCC (a single HCC between 2 and 5 cm; or two to three lesions, none greater than 3 cm) and an AFP ≤1000 ng/mL who are potential OLT candidates are assigned a higher priority MELD score. Of note, these MELD criteria are applicable to patients with HCC in the setting of cirrhosis. A candidate for an approved exception for HCC is then eligible for automatic approval of an extension, with each approved extension being valid for 90 days.

Prelisting biopsy is not mandatory. However, patients must have imaging findings that are consistent with HCC. Prior to December 2012, the OPTN allocation policy included the following vague language ("candidate must have…a vascular blush corresponding to the area of suspicion on radiographic studies"). As of December 2012, there are more specific imaging criteria for HCC diagnosis and classification, as well as minimal technical specifications for dynamic contrast-enhanced CT and MRI of the liver that must be met [17,19]. Nodules found on imaging of cirrhotic livers must be classified according to the OPTN classification as shown in the table (table 3). OPTN class 5 nodules correspond to an imaging diagnosis of HCC; class 5B and 5T nodules are eligible for automatic prioritization for OLT with exception points [17,20,21]. (See 'Allocation of donor organs' above.)

A single OPTN class 5A nodule corresponds to T1 stage HCC and does not qualify for MELD exception points. However, combinations of 2 or 3 class 5A nodules that meet stage T2 criteria are eligible for automatic priority. Continued documentation of the tumor is required every three months by CT or MRI to ensure continued eligibility for OLT; repeat chest CT is not required to maintain HCC priority scores.

Following implementation of the initial OPTN allocation policy for HCC in 2002, early assessment suggested that waiting times for patients with HCC to receive a deceased donor organ decreased significantly, and that the number of patients dropping out from the waiting list because of disease progression also decreased [22]. Despite this, the similar post-transplant survival rates for patients with HCC in the pre-MELD and post-MELD eras suggest the need for ongoing modifications to the system. Living donor liver transplantation (LDLT) has also been proposed as a partial solution to this problem. (See 'Living donor transplantation' below.)

The MELD exception score — The exception score for HCC is based upon the Median MELD at Transplant (MMAT), which is calculated by using the median of the MELD scores at the time of transplant of all recipients at least 12 years old who were transplanted at hospitals within 250 miles of the candidate's listing hospital within the last year; these values are recalculated twice yearly based on updated cohort information [17].

For individuals at least 18 years old, the following scores are assigned:

●At initial and first extension (90 days after listing) – Score = 6, or the calculated MELD score, whichever is higher (calculator 1 and calculator 2). (See 'MELD 3.0' below and "Model for End-stage Liver Disease (MELD)".)

●Exception points are added after the patient has been wait listed for at least six months, with the maximum exception points for waitlisted patients with HCC being limited to the median MELD score at the region of the donor hospital, minus 3 points (MMAT-3).

●Each approved MELD exception extension is valid for an additional 90 days beginning from the day that the previous exception or extension expired.

●Patients with a postresection recurrence who are eligible for transplantation are immediately assigned an exception score of MMAT-3 without the six-month waiting period.

Of note, there is no longer a fixed MELD score for a given HCC patient, and this policy also reflects a change from prior policy when the highest possible MELD score for a patient with HCC was 34; as of May 2019, it is now no more than 3 points below the MMAT (MMAT-3); this change has led to reduced disparities in access to liver transplantation across UNOS wait regions, especially for patients without HCC [23].

MELD 3.0 — A revised score (MELD 3.0) (calculator 1 and calculator 2) was implemented by the OPTN after extensive evaluation of the predictive ability of the MELD/MELD-Na scores [24]. The MELD 3.0 score is also available online.

The MELD 3.0 includes variables from the prior MELD/MELD-Na models, adds other clinically relevant variables (female sex, serum albumin), and lowers the ceiling for serum creatinine from 4 to 3mg/dL. The rationale for the MELD 3.0 score is to address a sex disparity (as historically, females have consistently had lower liver transplant rates), to reduce the weight given to creatinine in MELD-Na (which is argued to be excessive), and to introduce interaction terms. Further details on MELD 3.0 in patients under evaluation for liver transplantation are discussed separately. (See "Model for End-stage Liver Disease (MELD)", section on 'MELD 3.0'.)

For patients with HCC who are evaluated using MELD 3.0, exception points are allocated so they can be transplanted in a timely manner without overprioritizing them over patients without HCC. There is a six-month delay from listing to receive HCC exception points, with the first HCC exception score being equal to the median MELD at transplant within the donor service area minus three points (MMAT-3), with an increase every 90 days [25]. This is similar to the exception point allocation system used with the previous MELD scores. (See 'The MELD exception score' above.)

While this system may lead to a decreased probability of liver transplantation, it does not adversely affect waitlist dropout [26]. In turn, reduced waitlist dropout may support the main goal of reducing disparities in access to liver transplantation between patients with and without HCC. Further studies are necessary to evaluate and validate the effect of these policies among different populations and disease conditions, especially if they are to serve an international role [27].

Expanded transplant criteria — Notably, patients with HCC tumor burden outside of standard Milan criteria do not receive standard MELD HCC exception points. Patients with vascular invasion (ie, macroinvasion into branches of the portal vein, hepatic veins, or hepatic artery), or with involvement of porta hepatis lymph nodes or other lymph nodes, or who have any metastatic disease outside the liver also do not receive standard MELD HCC exception points. These patients with macrovascular or nodal invasion or metastatic disease are generally not suitable liver transplant candidates due to the extent of tumor burden and high risk for recurrence of HCC after transplant, which is associated with a poor outcome.

However, in December 2016, OPTN adopted a downstaging protocol for patients with HCC tumor burden beyond the Milan criteria (UNOS-DS). Patients meeting criteria for the OPTN downstaging protocol may be eligible for standard MELD HCC exception points and given priority if HCC tumor burden can be downstaged to, and maintained within, Milan criteria with an AFP level <1000 ng/mL using locoregional therapies. Candidates are eligible for a standardized MELD or Pediatric End-stage Liver Disease (PELD) exception if, before completing locoregional therapy, they have lesions that meet one of the following criteria [28]:

•One lesion greater than 5 cm and less than or equal to 8 cm

•Two or three lesions that meet all of the following:

-At least one lesion >3 cm

-Each lesion ≤5 cm, and

-A total diameter of all lesions ≤8 cm

•Four or five lesions each <3 cm, and a total diameter of all lesions ≤8 cm

In addition, their residual disease must meet the criteria for a T2 lesion (table 2).

These patients are not automatically granted MELD exception points but must be referred to the National Liver Review Board for consideration [17]. Exception extension will be automatically approved every 90 days unless one of the following occurs:

•The lesions progress beyond T2 criteria

•AFP level was ≤1000 ng/mL on the initial request but subsequently rises above 1000 ng/mL

•AFP level was initially 1,000 ng/mL, falls below 500 ng/mL after treatment but before the initial request, and then rises to ≥500 ng/mL

•Tumors have been resected since the previous request

Despite this change in policy, not all centers choose to follow these guidelines and consider that these expanded criteria remain investigational. Transplantation outcomes among patients who meet the UNOS-DS criteria and undergo successful downstaging to standard Milan criteria are discussed below. (See 'Patients who meet expanded transplant criteria' below.)

●Patients with AFP >1000 ng/mL – Patients who have T2 lesions but with an AFP level greater than 1000 ng/mL may be treated initially with locoregional therapy. If the candidate's AFP level falls to <500 ng/mL after treatment, the candidate is eligible for a standardized MELD or PELD exception as long as the AFP level remains <500 ng/mL. Candidates with an AFP level ≥500 ng/mL following locoregional therapy must be referred to the NLRB for consideration of a MELD exception.

Outside of the United States — Guidelines vary outside of the United States. The Transplantation Society of Australia and New Zealand has moved to using expanded criteria for liver transplantation for HCC [29]. However, they have moved to using the expanded University of California, San Francisco (UCSF) criteria for transplant, defined as a single tumor up to 6.5 cm, or three tumors with a total tumor diameter of up to 8 cm [29]. (See 'Patients who meet expanded transplant criteria' below.)

A 2010 International Consensus Conference on liver transplantation for HCC concluded that the Milan criteria remain the benchmark for the selection of patients with HCC for transplantation, but that patients could be considered for liver transplantation outside of the Milan criteria if the dynamics of the local waiting list allow it without undue prejudice to other recipients with a better prognosis [6]. Recommendations for liver transplantation in HCC, including assessment of candidates, criteria for listing, management of patients on the transplant waiting list, and post-transplant management, are available from this Conference and are outlined in the table (table 4).

Clinical practice guidelines for liver transplantation in HCC are also available from the European Association for the Study of the Liver (EASL) (table 5) [30].

Bridging therapy — Despite the lack of data from controlled clinical trials, we suggest bridging therapy for patients with HCC who are awaiting a donor liver and who have an estimated waiting time of at least six months. We generally perform immediate radiofrequency ablation (RFA), preferably when the tumor is 3 cm in size or less. Laparoscopic-assisted RFA has the advantage of improved staging, as it can identify those patients who have otherwise occult extrahepatic disease.

Others prefer chemoembolization or radioembolization, particularly if there are two or three lesions, as long as liver function is sufficiently preserved. The role of hepatic resection prior to transplantation remains uncertain, and this approach requires validation in larger studies using intent-to-treat analysis before it is adopted widely in clinical care.

The role of locoregional therapy prior to transplantation for patients whose disease meets Milan criteria and who are expected to have a short time on the wait list is uncertain. However, the mandatory six-month waiting period enacted by OPTN/UNOS in 2015 prior to granting HCC exception points has increased the use of such therapies [31]. The role of locoregional therapy for tumor downstaging among individuals with HCC who do not meet the Milan criteria for OLT is addressed below. (See 'Downstaging through neoadjuvant locoregional therapy' below.)

These recommendations are consistent with those of a 2010 International Consensus Conference on liver transplantation for HCC, which concluded that locoregional "bridging" therapy may be appropriate for patients with UNOS T2 (table 2) HCC and a likely waiting time of longer than six months [6]. The EASL/European Organisation for Research and Treatment of Cancer (EORTC) Clinical Practice Guideline also recommends consideration for neoadjuvant locoregional therapies if the waiting list exceeds six months [32]. Updated guidelines from the American Association for the Study of Liver Disease (AASLD) suggest some form of bridging therapy for patients listed for liver transplantation within T2 (Milan) (table 2) criteria to decrease disease progression and subsequent dropout from the waiting list, without regard to the estimated waiting list time [33]. The AASLD does not recommend one form of liver-directed therapy over another for the purposes of bridging to liver transplantation. Observation with follow-up imaging is suggested over any bridging treatment for patients with cirrhosis awaiting liver transplantation who develop a T1 HCC (table 2).

The limited availability of donor organs has provided the impetus to investigate treatment (eg, percutaneous ethanol injection [PEI], RFA, transarterial chemoembolization [TACE], stereotactic radiotherapy, radioembolization, resection) for early stage HCC in cirrhotic patients to prevent tumor progression, acting as a "bridge" until a suitable donor organ becomes available. The rationale for such therapy is clear, as the rate of "dropout" due to tumor progression while awaiting a donor organ is reported to be approximately 10 to 20 percent [34-37]. The time spent waiting for a donor organ varies throughout the country [38], and thus the durability of the response to a bridging therapy that is required to prevent delisting varies. However, there may also be oncologic benefits to such therapy beyond the bridge to transplant in wait-listed patients [39]. In many (but not all [40]) uncontrolled studies, patients who have a major local tumor response (pathologic complete response or ≥60 percent tumor necrosis [41-43] after locoregional therapies such as TACE or RFA) have a better outcome after transplant. However, the benefits of bridging therapy in patients who have a short time on the waiting list remain uncertain [31].

Combinations of nonresective extirpative therapies may be equally efficacious. As an example, radiofrequency and microwave ablation in combination with transarterial chemoembolization induce equivalent histopathologic coagulation necrosis in HCC patients bridged to liver transplantation [44]. (See 'PEI, RFA, and microwave ablation' below.)

Studies comparing the dropout rates of treated and untreated patients have been difficult to interpret due to heterogeneous populations and different criteria for treatment [37,45,46], and no randomized controlled trials are available. This leaves some uncertainty as to whether any of these maneuvers actually improves outcome. Nevertheless, many centers are pursuing the strategy of TACE, initial resection, or local ablation with PEI, RFA, or stereotactic radiotherapy as a bridging therapy for patients who are on the transplant waiting list.

Chemoembolization — Experience with TACE has been derived mostly from case series and retrospective reports [47-58]. Although the results are somewhat inconsistent, substantial clinical benefit has been observed in some reports without a detrimental impact on post-transplantation survival [49,52-54,59]. One of the most favorable studies, for example, focused on 48 patients with one lesion smaller than 5 cm or three lesions smaller than 3 cm [52]. Following treatment, no patient was withdrawn from the transplant list because of tumor progression. Furthermore, five-year survival rates after OLT were as high as 93 percent, despite a mean waiting time of 178 days.

By contrast, the benefit of TACE has been questioned in other reports [50,55-57]. A 2006 systematic review concluded that there was insufficient good quality evidence to demonstrate that TACE either improved post-transplantation survival, altered post-transplantation complication rates, or impacted on-list drop out.

TACE has also been used to downstage patients with initially more advanced HCC to where they qualify for orthotopic liver transplantation under the Milan criteria [60-64]. Results are quite variable, probably in part due to differences in entry criteria [65]. Rates of successful downstaging are lower in studies with more liberal eligibility criteria. As an example, in one study, only 24 percent of patients were successfully downstaged from stage T3/4 tumors to within Milan criteria using TACE [60], while a success rate of 90 percent is reported by others [63]. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation", section on 'Bridging therapy'.)

While such patients will not automatically receive a higher priority MELD score (because they did not initially meet the Milan criteria), centers can apply to the National Liver Review Board of the OPTN for exception points [17]. (See 'Requirements for listing and management while on the wait list' above and 'Downstaging through neoadjuvant locoregional therapy' below.)

Radioembolization — Although there are less data than with TACE, radioembolization using yttrium-90-labeled microspheres has been shown to limit disease progression, which may allow patients more time to wait for a donor organ [66]. Radioembolization has also been used successfully to downstage patients to within Milan criteria. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation", section on 'Bridging therapy'.)

Stereotactic radiotherapy — Stereotactic body radiotherapy (SBRT) enables the delivery of high doses of radiation therapy to tumors in a few treatment sessions while minimizing the exposure of surrounding normal tissues to radiation. SBRT provides a noninvasive treatment alternative for malignant liver lesions (including HCC) when established curative treatment modalities cannot be applied. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation", section on 'Stereotactic body radiation therapy'.)

Experience with SBRT as a bridge to transplantation is limited, but encouraging [67-69]. There is currently an ongoing international clinical trial. comparing TACE using drug-eluting beads (TACE-DEB) with SBRT prior to transplantation, evaluating differences in toxicity, outcome, and histologic changes in the explant specimens

Initial resection — Initial tumor resection for selected patients with small tumors and adequate liver function, followed by close surveillance and subsequent (secondary) OLT, has been investigated at several centers. The rationale for such an approach is that liver resection, which can be performed without delay, is associated with a high recurrence rate; OLT, which has a better long-term survival [70], is not easily available because grafts are scarce. A third possibility is to offer liver resection first and "salvage" transplantation for tumor recurrence or deteriorating liver function.

The feasibility of this strategy was shown in a prospective series of 473 patients with Child-Pugh class A cirrhosis (table 1) who underwent resection of a solitary HCC ≤5 cm or two to three tumors, all ≤3 cm [71]. With 48-month median follow-up, 67 patients recurred, and 53 (79 percent) were considered eligible for salvage OLT.

In a second retrospective analysis of patients undergoing primary OLT compared with initial resection followed by OLT for positive margins, recurrent disease, or deterioration of hepatic function, there was no difference between the two groups in terms of the difficulty of the operation, postoperative course, or overall or disease-free survival [72].

These and other data suggest that for patients with relatively preserved liver function, initial tumor resection is a reasonable strategy since it allows the majority to retain the option of salvage OLT if they subsequently fail resection or if liver function deteriorates [73-79]. There appears to be no increased morbidity or impaired long-term survival following a subsequent OLT.

On the other hand, high salvage rates have not been obtained by most liver transplant programs [80-82], and not everyone agrees with this approach, particularly given the high variability in waiting times for OLT. Reported rates of "transplantable recurrence" range widely from 25 to 80 percent [81,83,84]. As an example, an observational series from Paris sought to assess the strategy of primary tumor resection followed by salvage OLT for HCC arising in the setting of cirrhosis [81]. Compared with primary transplantation, secondary OLT after initial resection was associated with a higher operative mortality, an increased risk of recurrence, and a worse five-year overall and disease-free survival. Moreover, only one-fourth of the patients with recurrent HCC were transplantable. Thus, these results suggest that initial resection diminishes transplantability and reduces the chance of long-term survival in cirrhotics with HCC. Another important point is that, in contrast to bridging strategies such as RFA or TACE, patients do not get exception points after resection until the tumor recurs.

PEI, RFA, and microwave ablation — Percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), and microwave ablation have also been studied as a "bridge" to transplantation in patients with HCC [54,56,85-87]:

●The safety of pretransplant PEI was shown in a study of 34 patients with HCC who were wait-listed for OLT [85]. Although pain and self-limited fever were frequent, clinically significant complications were uncommon, and there was no evidence of tumor seeding of the needle tract or procedure-related mortality.

●Another study included 40 patients who had undergone percutaneous PEI, RFA, or both prior to OLT [86]. RFA provided a higher rate of complete necrosis in the explants than did PEI, particularly if the nodules were smaller than 3 cm. There were no cases of tumor recurrence at the abdominal wall in patients treated by either approach.

●This finding was reinforced by a larger study of 52 patients who underwent RFA as a bridging strategy prior to OLT [87]. After an average of 13 months on the waiting list, only 3 of 52 patients (5.8 percent) had dropped out due to tumor progression. Forty-one patients went on to transplantation, and the one- and three-year survival rates were 85 and 76 percent respectively. No patient developed a recurrence of their HCC.

●Microwave ablation has also been successfully applied as a bridging maneuver prior to transplantation, although less data are available than with RFA or PEI [44,88].

Thermal ablation can be accomplished percutaneously or laparoscopically. Laparoscopic-assisted thermal ablation has the advantage of improving staging by demonstrating small extrahepatic foci of disease not visible on axial imaging due to resolution issues, and it may allow safer procedures close to the diaphragm and visceral structures.

Unfortunately, the optimism suggested by these results is not shared universally. A retrospective review from the University of Pennsylvania evaluating the utility of pretransplant therapy (RFA or TACE) in the current MELD era compared 31 treated patients with 33 untreated controls [56]. Only approximately one-half of patients who had persistently viable tumor in the explant were identified by a post-treatment MRI. Although the untreated patients waited longer for a donor organ (119 versus 54 days), after 36 months of follow-up, there were no significant differences between the treated and untreated groups in terms of overall survival (84 versus 91 percent), disease-free survival (74 versus 85 percent), cancer recurrence (23 versus 12 percent), or mortality from cancer recurrence (57 versus 25 percent). The authors concluded that there was no evidence of improved outcomes from neoadjuvant bridging therapy.

Because of the retrospective nature of this series, it is possible that there were baseline differences between the groups that could have obscured any benefit from bridging therapy. RFA and PEI are discussed in more detail elsewhere. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates who are eligible for local ablation", section on 'Percutaneous ethanol or acetic acid injection'.)

OUTCOMES AND PROGNOSTIC FACTORS

Tumor-related variables — Several tumor-related variables have been associated with prognosis following orthotopic liver transplantation (OLT) for HCC [4,5,7,15,77,89-101]. Important prognostic factors in one or more studies include tumor number, size, and location (especially bilobar distribution), stage of disease according to the American Liver Tumor Study Group modification of the Tumor, Node, Metastasis (TNM) staging criteria (table 2), histologic grade of differentiation [89], the presence of macrovascular and microvascular invasion [102], absolute level of serum alpha-fetoprotein (AFP) [102-105], and extrahepatic spread. The most consistent association is with tumor size.

Investigators at University of California, San Francisco (UCSF) developed a prognostic scoring system (Risk Estimation of Tumor Recurrence After Transplant [RETREAT]) using data from 721 patients who met Milan criteria (single lesion ≤5 cm; up to three separate lesions, none larger than 3 cm; no evidence of gross vascular invasion; and no regional nodal or distant metastases) and were transplanted for HCC between 2002 and 2012 at three academic transplant centers; the model was validated in a separate cohort of 341 patients also meeting Milan criteria who were transplanted at a fourth academic center over the same time period [102]. (See 'Indications for transplantation' above.)

Three variables were independently associated with disease recurrence (microvascular invasion, serum AFP level at the time of transplantation, and the sum of the largest viable tumor diameter for all viable tumors on explant and the number of viable tumors on explant), and they were used to construct a scoring system to predict one- and five-year recurrence risk. The RETREAT score was created using these three variables, with scores ranging from 0 to 5 or higher, which were highly predictive of HCC recurrence. RETREAT was able to stratify five-year post-liver transplantation recurrence risk, ranging from less than 3 percent with a score of 0 to greater than 75 percent with a score of 5 or higher [102]. Although promising, this model requires independent validation.

Considering the strength and consistency of these associations, optimal candidates for OLT appear to be those with the characteristics that form the Milan criteria:

●A single tumor 5 cm or less in diameter or up to three lesions, all less than 3 cm

●No macrovascular involvement

●No identifiable extrahepatic spread to surrounding lymph nodes, lungs, abdominal organs, or bone

When these criteria are strictly applied, excellent overall three- to four-year actuarial survival rates are achieved (approximately 75 to 85 percent), and approximately 83 to 92 percent of patients are recurrence free [65,92,106].

An important caveat is that these excellent results were achieved in an era with prompt availability of donor organs. The shortage of donors has imposed a delay before transplantation, and during this time, the tumor can progress and render the patients no longer a suitable candidate for transplantation. Most of these results have been based upon analysis of patients who actually received a transplant and did not include all patients with HCC who were eligible for transplant but were not transplanted because their tumor progressed beyond transplant eligibility criteria before a donor organ became available. Thus, achievement of such promising results is contingent upon a short waiting time between diagnosis and actual performance of the transplant. The role of "bridging therapy" for patients who are expected to have a waiting time that exceeds six months is discussed above. (See 'Allocation of donor organs' above and 'Bridging therapy' above.)

Another tool (the Model of Recurrence After Liver Transplantation [MoRAL] score) was initially developed using AFP, the neutrophil to lymphocyte ratio (NLR), and tumor size and was found to be prognostic for survival after liver transplantation in a validation series, mainly in individuals receiving cadaveric liver grafts [107,108].

A subsequent modification based upon serum levels of protein induced by vitamin K absence-II (PIVKA-II, des-gamma carboxyprothrombin) and AFP was introduced by a different group to predict tumor recurrence after living donor liver transplantation for HCC, both within and beyond the Milan criteria [109]. The MoRAL score was defined as 11 times the square root of PIVKA-II (in milli-Anson Units [mAU]/mL) plus 2 times the square root of the serum AFP (in ng/mL). Most laboratories in the United States measure des-gamma carboxyprothrombin in ng/mL; the conversion is 1 ng = 52.6 mAU of purified des-gamma carboxyprothrombin. In both groups, a low MoRAL score (≤314.8) was associated with significantly longer recurrence-free and overall survivals. The MoRAL score appeared to outperform the RETREAT score in both cohorts.

Underlying liver disease — The etiology of the underlying liver disease may prove to be a selection criterion for OLT. Patients with chronic hepatitis C virus (HCV) infection require OLT for HCC more often than do those with HCC and chronic hepatitis B virus (HBV) infection. Patients with HCC in the setting of HBV are more likely to be candidates for resection based upon liver function and individual tumor characteristics [110]. Because patients with HCV tend to have more advanced tumors at presentation and worse underlying liver disease, they have higher recurrence rates and shorter survival times after resection or OLT than those with HCC who are HBV-positive or who have alcoholic cirrhosis as the underlying risk factor [110].

The original study by Mazzaferro that set the Milan criteria was essentially limited to patients with HCV. The fact that HCV is an independent predictor of poor survival has led to reconsideration of the possible "restrictive nature" of the Milan criteria for patients without HCV. (See 'Indications for transplantation' above.)

This issue was addressed in a retrospective review of 71 patients transplanted for HCC, who were divided into those with and without HCV, as well as those within and outside Milan criteria [111]. The survival of patients with HCC that were HCV negative but outside Milan criteria was not statistically different from that of patients who were within Milan criteria. This study had the limitations of relatively small sample as well as being retrospective.

The issue of OLT for patients with HCC and HCV is controversial. Some clinicians support the use of OLT for such patients despite the poorer outcome, while others advocate OLT only for HCC patients with chronic HBV infection in conjunction with post-transplant antiviral therapy [112]. Nonetheless, OLT for HCV-positive patients with HCC remains common nationwide. It is very likely that the "landscape" regarding HCV-positive patients will change significantly in the following years, given the use of newer interferon-free regimens, which are successful even in patients with genotype 1 HCV infection [113]. The success of these regimens will affect the outcome of liver transplantation for these patients, as avoiding or better managing HCV recurrence after liver transplantation will significantly increase survival. Issues concerning treatment of HCV and OLT for patients with hepatitis are discussed elsewhere. (See "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults", section on 'Special patient populations' and "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients" and "Hepatitis C virus infection in liver transplant candidates and recipients".)

Degree and type of immunosuppression — Because immunosuppression to reduce the risk of graft rejection is associated with a higher risk of tumor regrowth, efforts have been underway to reduce doses to an effective minimum [114-116]. The success of this approach was suggested in a retrospective review of 70 consecutive patients undergoing OLT for HCC who received cyclosporine (CSA)-based immunosuppression [115]. Serum CSA levels were significantly higher in those who recurred compared with those who remained tumor-free (278 versus 170 ng/mL, respectively). Receiver operator curve analysis identified an optimal serum CSA cutoff value of 190 ng/mL; patients with higher exposure levels had a 33 percent chance of recurrence (7 of 21) compared with none of 49 patients with lower levels.

Every effort should be made to reduce immunosuppressant doses to an effective minimum. (See "Liver transplantation in adults: Initial and maintenance immunosuppression".)

Benefit of sirolimus — An immunosuppressive agent with intriguing prospects in patients transplanted for HCC is sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR inhibitor). Both in vitro and in vivo studies suggest that this agent has antiproliferative properties against HCC, which may be, at least in part, mediated by interference with vascular endothelial growth factor (VEGF) [117-121].

Several retrospective single-institution retrospective cohort and case-control reports suggest a lower risk of post-transplant tumor recurrence in patients with HCC with the use of sirolimus as compared with other types of immunosuppressive agents (such as the calcineurin inhibitors tacrolimus and CSA) [122-126]. However, these reports are limited by small size and uncertainty as to whether the observed benefits were due to a specific antitumor effect or an impact on liver transplant in general.

To address the last issue, investigators analyzed a registry-based series of 2491 adult recipients of OLT for HCC and 12,167 who were transplanted for non-HCC diagnoses [127]. All patients remained on a stable maintenance immunosuppression protocol for at least six months. In multivariate analysis, the use of sirolimus was associated with a post-transplant survival benefit that was specific to patients transplanted for HCC (hazard ratio [HR] for death 0.53, 95% CI 0.31-0.92). By comparison, there was a trend toward lower rates of survival with the use of sirolimus in patients transplanted for other diagnoses.

A meta-analysis of the available evidence, including the registry-based series described above, concluded that compared with a sirolimus-free regimen, the use of a sirolimus-based regimen significantly decreased overall tumor recurrence (odds ratio [OR] 0.30, 95% CI 0.16-0.55) and significantly lowered recurrence-related mortality (OR 0.29, 95% CI 0.12-0.70) [128].

Although these data are encouraging, they are derived entirely from retrospective studies, and the results could be influenced by imbalances in confounding variables. There is a need for more data (in particular, randomized controlled trials) on the long-term success of sirolimus-based immunosuppression and its side effects before it can be concluded that sirolimus is the most appropriate immunosuppressant for patients undergoing OLT for HCC. Such a trial is underway [129]. Our recommendations are consistent with those of the 2010 International Consensus Conference on liver transplantation for HCC, which concluded that no recommendation could be made on the use of mTOR inhibitors solely to reduce the risk of HCC recurrence outside of a clinical trial [6].

Everolimus is a semisynthetic form of sirolimus that is US Food and Drug Administration (FDA)-approved for immunosuppression following OLT in other settings (although not in the first 30 days after transplantation because of an increased risk of hepatic artery thrombosis). While everolimus is likely to have similar effects as sirolimus, it has not been studied adequately in patients with HCC. (See "Liver transplantation in adults: Initial and maintenance immunosuppression", section on 'Use of mechanistic target of rapamycin (mTOR) inhibitors'.)

Adjuvant systemic therapy — Given the concerns about efficacy, as well as the potential for early recurrence of HCV, adjuvant systemic therapy is not recommended for any patient undergoing liver transplantation for HCC, unless in the context of a clinical trial [6]. Our recommendations are in keeping with those of a 2010 International Consensus Conference on liver transplantation for HCC, which concluded that the current evidence does not justify the routine use of adjuvant antitumor therapy after liver transplantation for HCC outside of a controlled clinical trial [6].

In theory, adjuvant therapy may benefit patients undergoing OLT because removal of the native liver requires extensive manipulation and is likely to result in intraoperative dissemination of tumor cells. Furthermore, immunosuppressive therapy following transplant may facilitate tumor growth. When they occur, post-transplant recurrences tend to occur more rapidly after transplant than after resection [90].

Benefit for adjuvant chemotherapy following OLT for HCC has been suggested in some uncontrolled studies [130-133] but not others [134,135]. Furthermore, in two small controlled trials involving a total of 106 patients, chemotherapy (single agent doxorubicin administered prior to, intraoperatively, and postoperatively in both studies) was not associated with a significantly better five-year survival rate (38 versus 40 percent in one study [136] and 70 versus 63 percent in the second [137]).

Furthermore, questions have been raised regarding a detrimental effect of chemotherapy on recurrence of HCV. In a study of 48 patients undergoing OLT for HCC, 21 of whom received chemotherapy, it was observed that HCV recurrence-free survival rates at 3, 6, and 12 months were 29, 14 and 0 percent in the group receiving chemotherapy, as compared with 76, 38 and 25 percent for the no chemotherapy group [138].

On the other hand, promising results have been reported using a radioimmunologic agent (Licartin, a 131-I-radiolabeled murine monoclonal antibody that targets an HCC-specific molecule, HAb18G/CD147) in a small placebo-controlled randomized double-blind study from China [139]. Sixty patients who had positive immunohistochemical expression of HAb18G/CD147 in their pretransplant HCC biopsy were randomly assigned to three monthly doses of Licartin or a placebo injection starting four weeks after OLT. With median 12-month follow-up, the Licartin group had a significant 30 percent reduction in the risk of recurrence (at one year 27 versus 57 percent) and a 21 percent greater survival rate (at one year 83 versus 62 percent). There were no adverse events specifically attributed to the radioimmunologic agent. Longer follow-up and additional experience in a larger number of patients is needed before concluding that Licartin is beneficial after OLT for HCC.

Sorafenib, a multitargeted tyrosine kinase inhibitor targeting angiogenesis, cell survival, and proliferation in HCC, is a standard therapy for advanced stage disease. It is currently being investigated in protocols as both neoadjuvant "bridging" treatment prior to liver transplantation and as adjuvant treatment to delay or prevent recurrence post-transplantation. The use of sorafenib is not without complications as, at least in theory, it can be associated with bleeding, problems with wound healing, and hepatic decompensation. Several other active agents have been identified and, in some cases, approved for treatment of advanced HCC (eg, lenvatinib, regorafenib, nivolumab), but none of these drugs is yet being investigated for neoadjuvant or adjuvant therapy. (See "Systemic treatment for advanced hepatocellular carcinoma", section on 'Sorafenib' and "Systemic treatment for advanced hepatocellular carcinoma", section on 'Checkpoint inhibitor immunotherapy' and "Systemic treatment for advanced hepatocellular carcinoma", section on 'Regorafenib' and "Systemic treatment for advanced hepatocellular carcinoma", section on 'Lenvatinib'.)

Summary

Alternative approaches to prognostication — There is an ongoing effort to identify molecular or histologic indicators of biologic malignant potential in patients with HCC in order to improve prognostic stratification and selection for transplantation [140-144]. As an example, in 1997, a team from the University of Pittsburgh developed a neural network to predict post-transplant recurrence based on a retrospective analysis of 214 patients with HCC [142]. The model, which incorporated variables such as tumor diameter and number, presence or absence of vascular invasion, and gender was able to predict the outcome correctly in 72 patients of a subsequent series of 103 transplant patients. The same team has undertaken genotype analysis of HCC, exploring the hypothesis that a collection of accumulated molecular changes reflect the evolution of the cancer and may be an effective diagnostic and prognostic tool [145]. Others have documented the importance of gene expression in surrounding liver rather than the tumor itself. (See "Staging and prognostic factors in hepatocellular carcinoma", section on 'New prognostic markers and methods under investigation'.)

LIVING DONOR TRANSPLANTATION — Living donor liver transplantation (LDLT) provides the opportunity to avoid the extended waiting period for a deceased donor organ. This can be a significant benefit in patients with HCC since tumor growth during the waiting period can worsen prognosis [34,146]. LDLT can also be considered for select patients beyond UNOS-DS criteria, although most centers will still require downstaging using bridging therapy and an AFP level <1000 ng/mL in order to consider LDLT. At present, approximately 5 percent of all liver transplants performed in the United States are LDLTs.

Several retrospective series report favorable outcomes, although most have only short-term follow-up [147-153]. In one of the series with the longest follow-up, outcomes among 36 patients undergoing LDLT were compared with those of 147 patients undergoing deceased donor liver transplantation (DDLT) for HCC [151]. The dropout rate for patients listed for LDLT was 0 versus 18 percent of those listed for DDLT, and the waiting time to transplant was significantly shorter (2.6 versus 7.9 months). With a median follow-up of 58 months for the LDLT group and 50 months for the DDLT group, the five-year rate of recurrence in both arms was similar (12 versus 14 percent), as was overall survival (73 versus 71 percent).

Whether there is a distinct survival advantage for LDLT over DDLT is unclear, as illustrated by the following studies:

●Better survival in a strategy utilizing LDLT patients was noted in a Markov model using a hypothetical cohort of patients [154]. Survival rates for patients undergoing LDLT versus DDLT were 86 versus 71 percent at one year, and 68 versus 42 percent at five years, respectively [154].

Some of this apparent better outcome could have been due, at least in part, to a shorter average waiting time for transplant (83 versus 414 days in one series comparing 36 patients undergoing LDLT versus 50 transplanted with a cadaveric donor over the same time period at Mount Sinai Hospital in New York [148]).

●However, others have not shown better outcomes for LDLT as compared with those undergoing DDLT, despite a shorter average waiting time for transplant with LDLT (107 versus 404 days with DDLT) [155].

Furthermore, a meta-analysis of seven comparative studies of LDLT and DDLT found no significant differences in survival rates at one, three, and five years [156].

In addition to reducing the likelihood of dropout from the waiting list and shortening the time to transplant, an aggressive LDLT strategy has the potential to provide access to liver transplantation for patients who otherwise would not be eligible for a DDLT because they do not meet United Network for Organ Sharing (UNOS) priority criteria (ie, one solitary tumor ≤5 cm or two to three tumors all ≤3 cm) [148]. (See 'Indications for transplantation' above.)

As persuasive as this argument might appear, this strategy has been criticized for the following reasons:

●The risk to the donor. The ethical issues related to LDLT are still hotly debated. (See "Living donor liver transplantation in adults".)

●The possibility that a previously ineligible transplant candidate could compete subsequently for a deceased donor graft if the living donor liver failed. This patient would now move to the top (UNOS status 1) of the deceased donor list, thereby depriving other patients on the waiting list from receiving an organ. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)

●The expected benefits of LDLT may not always be realized. For example, because LDLT can limit the waiting time for an organ, it should decrease disease progression so that the recurrence rate is lower post-transplant than it would be for recipients who wait for a deceased donor organ.

●At least some data suggest that the recurrence rate may be higher following LDLT [157,158]. As an example, data on 58 LDLTs and 34 DDLTs from the multicenter Adult-to-Adult Living Donor Liver Transplantation Cohort Study noted a higher rate of HCC recurrence after LDLT (29 versus 0 percent), despite a significantly shorter time to transplantation (160 versus 469 days) [158]. Some have postulated that higher recurrence rates after LDLT than after DDLT may reflect the fact that longer wait times for a deceased donor organ permits the dropout of those patients who are destined to have an early recurrence based upon disease biology, and therefore lower recurrence rates following DDLT [159-161].

Other studies of large (although not completely homogeneous) populations suggest that although five-year recurrence rates were similar between the LDLT and DDLT groups, overall survival was significantly better with LDLT [162].

These studies and the issues they raise stress the need for prospective direct analysis of disease recurrence, long-term survival, and dropout rates in comparable patient cohorts with HCC undergoing either DDLT or LDLT. At present, if a suitable and willing donor is identified, LDLT is a reasonable alternative to waiting 6 to 12 months for a deceased donor graft in patients with HCC who are otherwise eligible for OLT [6,32]. Even if post-transplant outcomes are similar with either approach, LDLT might still be expected to improve survival because it eliminates deaths while awaiting OLT.

This recommendation is consistent with guidelines from the 2010 International Consensus Conference on liver transplantation for HCC, which concluded that LDLT is acceptable for HCC patients who have an expected five-year survival similar to comparably staged patients receiving a deceased donor liver, but that LDLT must be restricted to centers of excellence in liver surgery and liver transplantation to minimize donor risk and maximize recipient outcome [6].

PATIENTS WHO MEET EXPANDED TRANSPLANT CRITERIA

Downstaging through neoadjuvant locoregional therapy — In addition to its use as a "bridging therapy" to reduce the number of dropouts from the transplant list because of tumor progression, local downstaging therapies such as transarterial chemoembolization (TACE), selective radioembolization with yttrium-90 labeled microspheres, and/or radiofrequency ablation (RFA) have also been used to downstage patients with initially more advanced HCC (in some cases, meeting expanded transplant criteria such as the UNOS-DS criteria) to where they qualify for priority listing under the Milan criteria. (See 'Expanded transplant criteria' above.)

At least in the United States, while some centers have adopted the practice of downstaging tumors to fit within regional criteria to apply for Model for End-stage Liver Disease (MELD) exception points for higher-priority transplant, clinical practice is variable, and many centers consider this to be investigational therapy. There is no universal or even majority agreement regarding the optimal method for downstaging, selection criteria, and whether or how this should impact on prioritization for a graft. As noted above, patients who require downstaging to meet Milan criteria are not automatic candidates for HCC MELD exception points through the OPTN, although candidates who meet the criteria as outlined by OPTN can apply to the National Liver Review Board to be considered for exception points [17]. (See 'United States' above.)

Benefit — Several centers have published their experience with this approach [60,62-64,163-173]. The largest experience is a retrospective analysis of prospectively collected data on 2645 consecutive adults undergoing transplantation for HCC between January 2001 and December 2015 at one of five high-volume United States centers adhering to the American Association for the Study of Liver Disease (AASLD)/United Network for Organ Sharing (UNOS) guidelines [173]. Patients were categorized based on radiographic tumor burden at diagnosis: within Milan criteria at the time of transplant (n = 2122), disease beyond Milan criteria who were successfully downstaged to within Milan criteria using locoregional therapy (n = 341), and those whose disease could not be downstaged or had progressed beyond Milan criteria but ultimately received a liver transplant (n = 182). The ten-year post-transplant survival and recurrence rates for these three groups were 61.5 and 13.3 percent for those always within Milan criteria, 52.1 and 20.6 percent for those beyond Milan criteria who were successfully downstaged prior to transplantation, and 43.3 and 41.1 percent for those whose disease was not downstaged prior to transplantation. Although retrospective in nature, these data provide support for a long-term benefit from successful downstaging locoregional therapy in patents whose tumors are initially beyond Milan criteria.

A single randomized trial has been undertaken in these patients, comparing transplantation versus other treatment strategies after downstaging therapy [174]. In this open-label multi-institutional phase 2b/III Italian trial, patients aged 18 to 65 with HCC beyond the Milan criteria without macrovascular invasion or extrahepatic spread, and good liver function (Child-Pugh A to B7, (table 1)) underwent tumor downstaging with locoregional, surgical, or systemic therapies, and those with a partial or complete response according to modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria (table 6) after three months were randomly assigned to liver transplantation or nontransplantation treatment strategies. During the three-month waiting period, sorafenib was allowed. The trial was closed early after enrolling only 74 of the planned 390 patients because of a national program to expand the donor pool, which limited interest in participating in a trial in which the control arm was a nontransplantation strategy. At a median follow-up of 71 months, five-year tumor event-free survival was significantly higher in the transplantation group (77 versus 18 percent, hazard ratio [HR] 0.20, 95% CI 0.07-0.57) as was five-year overall survival (78 versus 31 percent, HR 0.32, 95% CI 0.11-0.92). Treatment-related deaths occurred in four patients, two in each group.

The trial was criticized for early stopping, the long time allowed for achieving downstaging (up to 18 months), the flexibility of the definition of successful downstaging (without a well-defined limit in terms of tumor burden), and the lack of information on how many of the patients in the control group had persistent or progressive disease for which locoregional therapies had failed [175].

There are few studies evaluating the factors that predict successful downstaging from locoregional therapies prior to liver transplantation [164,173]. In the large multicenter study described above, independent variables associated with downstaging failure included tumor size >7 cm or more than three tumors at diagnosis and an AFP level prior to transplant ≥20 ng/mL with <50 percent improvement from maximum value [173].

Choice of therapy and assessing response — Most of the data are using TACE or transarterial radioembolization (TARE). A systematic review of 13 studies (950 patients) concluded that the pooled success rate for downstaging was 48 percent (95% CI 39-58 percent), and that there was no significant difference between TACE and TARE [176]. In a separate analysis of 12 studies (320 patients) the post-liver-transplantation recurrence rate was 16 percent (95% CI 11-23 percent). Post-transplant survival could not be reliably estimated due to interstudy heterogeneity in survival data reporting. Others report higher success rates (successful downstaging in 60 percent of cases) using a combined approach of TACE plus either RFA or radioembolization [164].

Criteria for assessing tumor response to downstaging therapy and determining eligibility for liver transplantation have been proposed but not validated [177].

Guidelines from expert groups — Updated guidelines for treatment of HCC from the AASLD suggest that patients beyond the Milan criteria (≥T3 (table 2)) should be considered for liver transplantation after successful downstaging into the Milan criteria [33]. National Comprehensive Cancer Network (NCCN) guidelines state that "some patients beyond the Milan criteria can be considered for transplantation; extended criteria/downstaging protocols are available at selected centers and through UNOS" [178].

As noted above, in 2016, the OPTN changed their policy to allow transplant prioritization for certain patients who were initially beyond the Milan criteria. Candidates are eligible for a standardized MELD or Pediatric End-stage Liver Disease exception if, before completing locoregional therapy, they have lesions that meet one of the following criteria [17] (see 'Requirements for listing and management while on the wait list' above):

●One lesion greater than 5 cm and less than or equal to 8 cm

●Two or three lesions that meet all of the following:

•At least one lesion greater than 3 cm

•Each lesion less than or equal to 5 cm, and

•A total diameter of all lesions less than or equal to 8 cm

●Four or five lesions each less than 3 cm, and a total diameter of all lesions less than or equal to 8 cm

In addition, the alpha-fetoprotein level has to be <1000 ng/mL, and residual disease must meet the criteria for a T2 lesion (table 2).

These patients are not automatically granted MELD exception points but must be referred to the National Liver Review Board for consideration [17]. Despite this change in policy, not all centers choose to follow these revised guidelines and some consider that these expanded transplantation criteria remain investigational.

Outside of the United States, there are conflicting views of professional organizations. A 2010 International Consensus Conference on liver transplantation for HCC concluded that transplantation may be considered after successful downstaging, but it should only be attempted if five-year survival rates can be achieved that are comparable to those of HCC patients who meet the criteria for liver transplantation without requiring downstaging (table 4) [6]. By contrast, a Clinical Practice Guideline from the European Association for the Study of the Liver (EASL)/European Organisation for Research and Treatment of Cancer (EORTC) concluded that downstaging for HCCs exceeding conventional criteria cannot be recommended and should only be pursued in the context of a clinical trial [32].

POST-TRANSPLANTATION SURVEILLANCE — Following liver transplantation for HCC, patients are at risk for disease recurrence. There is no consensus as to the optimal approach for post-treatment surveillance. Guidelines from the National Comprehensive Cancer Network (NCCN) suggest the following after liver transplantation [179]:

●Imaging every three to six months for two years, then annually

●Assay of serum alpha-fetoprotein (AFP), if initially elevated, every three months for two years then every six months

Guidelines for post-transplant management from a 2010 International Consensus Conference include contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) and AFP measurements every 6 to 12 months [6].

Some have suggested that the post-treatment surveillance strategy be tailored according to the individual risk of post-transplantation recurrence [102]. However, in our view, the current data derived from a retrospective analysis are insufficient to make this recommendation, and we await prospective data confirming the prognostic power of the Risk Estimation of Tumor Recurrence After Transplant (RETREAT) and Model of Recurrence After Liver Transplantation (MoRAL) scores and evaluating their application to post-treatment surveillance. (See 'Tumor-related variables' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatocellular carcinoma" and "Society guideline links: Liver transplantation".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Liver cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Indications for liver transplantation

•Orthotopic liver transplantation (OLT) is a viable and potentially curative option for selected patients with hepatocellular carcinoma (HCC). The two options are deceased donor liver transplantation (DDLT) and living donor liver transplantation (LDLT). Outcomes following OLT in carefully selected patients are similar or only slightly worse than those for patients undergoing OLT for non-malignant causes. Moreover, retrospective studies that adjust for disease severity suggest that survival following OLT is as good as or better than with other alternative treatments for HCC in carefully selected patients. (See 'Survival compared with transplantation for other reasons' above and 'Survival in comparison to other types of therapy' above.)

•For patients with localized HCC who are candidates for surgical resection, we recommend resection rather than transplantation (Grade 1A).

Patients who are not candidates for resection and who have a single lesion ≤5 cm; no more than three separate lesions, none larger than 3 cm; no evidence of gross vascular invasion; and no regional nodal or distant metastases should be referred for OLT. When these criteria are strictly applied, five-year survival rates of 75 percent or higher can be achieved. (See 'Indications for transplantation' above.)

●Requirements for listing – In the United States, in an attempt to ensure that preoperative assessment is as accurate as possible, the United Network for Organ Sharing (UNOS) provides a set of specific requirements for listing patients with HCC for OLT:

•Prelisting biopsy is not mandatory. However, in the United States, requirements for listing for liver transplantation from the Organ Procurement and Transplantation Network (OPTN)/UNOS require that patients have imaging findings that are consistent with HCC; only class 5 nodules meet imaging criteria for listing for transplantation (table 3).

•Shortage of donor livers has necessitated the development of allocation schema, which prioritizes donor organs to the most severely ill patients. In the United States, allocation of for both adults and children is based on the Model for End-stage Liver Disease (MELD) score, a statistical model based upon predicted survival in patients with cirrhosis. A higher point score is assigned to patients who are estimated to have a worse short-term prognosis (calculator 1 and calculator 2). (See "Model for End-stage Liver Disease (MELD)".)

For patients with HCC, a supplemental system for prioritization was developed by OPTN/UNOS that would provide these patients access to an allograft before their HCC progresses beyond the Milan criteria. (See 'Allocation of donor organs' above.)

To receive priority MELD exception points, the HCC must be stage T2 cancer (table 2) with a serum alpha-fetoprotein (AFP) level that is ≤1000 ng/mL [17]. Although patients with smaller or larger tumors or higher AFP levels may be listed, only those with American Liver Tumor Study Group T2 HCC (table 2) are potential OLT candidates are assigned an automatic higher priority MELD score. These MELD criteria are only applicable to patients with HCC developing in the setting of cirrhosis.

For individuals at least 18 years old, the following scores are assigned:

-At initial and first extension (90 days after listing) – Score = 6, or the calculated MELD score, whichever is higher (calculator 1 and calculator 2). (See 'The MELD exception score' above and "Model for End-stage Liver Disease (MELD)".)

-Exception points are added after the patient has been wait listed for at least six months, with the maximum exception points for waitlisted patients with HCC being limited to the median MELD score at the region of the donor hospital, minus 3 points (MMAT-3).

-Each approved MELD exception extension is valid for an additional 90 days beginning from the day that the previous exception or extension expired.

-Patients with a postresection recurrence who are eligible for transplantation are immediately assigned an exception score of MMAT-3 without the six-month waiting period.

•Outside of the United States, international consensus guidelines also suggest that biopsy is not necessary in cirrhotic patients with radiographic findings that are typical for HCC, and a lesion >1 cm (table 4) [6]. (See 'Requirements for listing and management while on the wait list' above.)

•Additional requirements for listing and recommendations for management of patients on the transplant waiting list vary country to country. However, while a patient is on the waiting list for liver transplantation, continued documentation of tumor status is required every three months by CT or MRI to ensure continued eligibility for transplantation. (See 'Requirements for listing and management while on the wait list' above.)

●Indications for bridging therapy – For patients who are estimated to have a waiting time of at least six months, we generally suggest immediate RFA or microwave ablation at the time of listing, preferably when the tumor is 3 cm in diameter or less, to reduce tumor size and delay progression (Grade 2C). Others prefer hepatic arterial embolization as long as liver function is sufficiently preserved. The value of pretransplantation hepatic resection remains uncertain, and this approach is best considered in the context of a clinical trial. (See 'Bridging therapy' above.)

●Expanded transplant criteria

•Some patients whose HCC is beyond the Milan criteria (≥T3 (table 2)) can be considered for OLT after successful downstaging into the Milan criteria. Patients meeting these criteria may be eligible for MELD HCC exception points and given priority if HCC tumor burden can be downstaged to, and maintained within, Milan criteria with an AFP level <1000 ng/mL using locoregional therapies. (See 'Downstaging through neoadjuvant locoregional therapy' above.)

•However, granting of MELD exception points in this situation is not automatic, and at least in the United States, patients must be referred to the National Liver Review Board of the OPTN for consideration of MELD exception. Because not all centers choose to follow this policy, many centers consider that these expanded criteria remain investigational. (See 'United States' above and 'Patients who meet expanded transplant criteria' above.)

●Role of living donor transplantation – The role of LDLT in patients with HCC remains controversial. However, if a suitable and willing donor is identified and the patient is otherwise eligible for transplantation, this approach is a reasonable alternative to waiting 6 to 12 months for a deceased donor graft. (See 'Living donor transplantation' above.)

●Post-transplant management

•Immunosuppressive therapy to reduce the risk of graft rejection is associated with a risk of tumor regrowth. As a result, every effort should be made to reduce doses to an effective minimum. The available data are insufficient to conclude that sirolimus is the most appropriate immunosuppressant for patients undergoing OLT for HCC. (See 'Degree and type of immunosuppression' above.)

•Given the concerns about efficacy, as well as the potential for early recurrence of hepatitis C virus infection, we recommend not administering adjuvant antitumor therapy to any patient undergoing liver transplantation for HCC unless in the context of a clinical trial (Grade 1B). (See 'Adjuvant systemic therapy' above.)

•Following transplantation, patients should undergo periodic surveillance with contrast-enhanced CT or MRI plus serial assay of serum AFP levels. (See 'Post-transplantation surveillance' above.)