Liver transplantation and hepatocellular carcinoma 2023: a narrative review of management and outcomes

Introduction

Background

Hepatocellular carcinoma (HCC) is the sixth most frequent tumor in the United States (US) and the fourth leading cause of death (1). HCC occurs mostly in the setting of chronic liver disease and cirrhosis, and its incidence is growing (1). Liver transplantation (LT) can be an effective treatment option for eligible patients with HCC, providing excellent post-transplant outcomes with a low risk of HCC recurrence, especially when strict criteria for patient selection and post-transplant management are followed (2).

Rationale and knowledge gap

Selection models have moved beyond simple radiographic tumor burden and now incorporate indices of tumor biology (3). As models continue to evolve, additional aspects of tumor biology, such as response to locoregional therapy (LRT), may be incorporated as the field strives to expand access to LT to those will benefit most from it (4). The demand has led to the expansion of LT for HCC beyond the Milan Criteria (MC), using down-staging (5). While the UNOS-DS (United Network for Organ Sharing-down-staging) criteria expands the indications for transplant for HCC beyond the traditional MC, there is interest in the outcomes of patients with tumor burden beyond UNOS-DS criteria (5). The upper tumor limits are yet to be determined.

Objective

The present literature review focuses on recent epidemiological trends, selection criteria, organ allocation, bridge therapies and post-transplant recurrence. We present this article in accordance with the Narrative Review reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-23-341/rc).

Methods

Information was gathered predominantly using PubMed search tools to identify studies relating to “carcinoma, hepatocellular”, “liver neoplasms”, “survival rate/trends”, “liver transplantation”, “United States”, “treatment outcome”. Reference lists of articles were reviewed, and relevant findings were included. Government regulated organ procurement and transplant registry websites were separately reviewed, and standardized reported data was collected and aggregated. See Methodology Table below for further information (Table 1).

Recent epidemiological trends

The underlying liver disease states that lead to LT have dramatically evolved over the last few decades (1). As the opioid epidemic spread across the country, the total number and proportion of patients requiring LT for hepatitis C virus (HCV) rose accordingly (6). The introduction of direct acting antiviral treatments (DAAs) to cure HCV in 2013 provided hope for many and was a pivotal moment in the fields of infectious diseases and transplant hepatology (7). As a result, the number of patients listed for LT due to HCV has continued to decline, but cases of metabolic-associated steatohepatitis (MASH, formerly non-alcoholic steatohepatitis) and alcohol-associated liver disease (ALD) have risen steadily and in 2015 surpassed HCV as the leading indications for LT (6). Disparities within this rise have emerged, most notably that by 2019, 47.7% of men without HCC listed for LT had ALD, compared to 29.4% of women. Women were more commonly listed for MASH, although ALD was still prevalent. The last decade has shown a growing body of research published on early LT for patients with acute alcohol-associated hepatitis (AH) (6,8,9).

In addition to underlying primary liver diseases, many patients listed for LT have concomitant HCC. The landscape of LT for HCC has paralleled the changes in patients transplanted for primary liver diseases. Between 2014 and 2019 there was a 22% decline in the proportion of patients listed for LT for HCV related HCC and a 14.5% increase in the proportion of patients listed for LT for MASH related HCC (6). By 2019 MASH was the most common etiology of HCC in women listed for LT (45.3%), while HCV was declining but was still the most common precipitant in men (37.8% vs. 31% for MASH). Racial disparities were apparent, with HCV representing a much higher burden of HCC related LT listings in Black patients compared to White and Hispanic patients, potentially indicating higher barriers to HCV treatment amongst Black patients. Among Asian patients, hepatitis B virus (HBV) was the most common etiology of HCC related LT listings, found in 47.5% of those listed for LT with HCC in 2019.

The field of LT was transformed, once again, by the COVID-19 pandemic in 2020. There was an initial decline in the total number of transplants as resources were focused on control of the pandemic. What emerged after, however, was a striking increase in the number of transplant listings for ALD, and specifically AH (6). Between November 2020 and May 2021 the percent of LTs for ALD nationwide increased steadily, and skewed towards a younger and sicker patient population as compared to the years immediately prior (6). The number of LT performed for HCC declined during that time.

Allocation of organs

The first successful LT was performed in 1967, but the National Organ Transplant Act of 1984 represents the start of the current era of transplantation (10). It established the UNOS and the registry to monitor transplant data and outcomes (11,12). UNOS allocation of LT currently considers multiple factors including disease severity, waitlist time, blood type, and distance from donor hospital. Allocation policies have evolved to decrease bias and improve post-transplant outcomes.

Initially waitlist time and whether the recipient was hospitalized determined priority, but to better emphasize illness severity the Child-Turcot-Pugh class system was implemented (12,13). In 2002 UNOS began utilizing Model for End stage Liver Disease (MELD) and in 2016 transitioned to the MELD-Na score, which incorporates serum sodium. In 2023 the MELD model was adjusted again, now accounting for sex and albumin, to decrease gender-based disparities in LT against women (12,13).

Currently in the US those patients with UNOS T1 (one tumor up to 2 cm) or UNOS T2 (one tumor up to 5 cm or three tumors up to 3 cm) are eligible to receive MELD exception points after a mandatory wait time of six months (Median Meld at Transplant minus 3-MMaT minus 3) (12). The guidelines for what makes a patient with HCC eligible for exception points, and more broadly a viable transplant candidate, have changed over time. The 1996 publication of the MC found that patients with small, unresectable HCC who underwent LT with either one tumor under 5 cm in diameter or no more than three tumors under 3 cm in diameter had a four-year 83% recurrence-free survival rate (2). This became the standard for determining which patients with HCC would have acceptable survival outcomes post-LT until further research on tumor biology and treatment responsiveness emerged.

Researchers found that patients outside of the MC but with a low alpha-fetoprotein (AFP) value had better survival outcomes post-LT than patients within the MC but with elevated AFP levels (14). An AFP level >1,000 ng/mL was found to have such poor outcomes associated with it that it became an exclusion criterion for receiving UNOS exception points, and ranges of AFP levels are now incorporated into post LT prognostication models (14).

Beginning in 2001 with the less restrictive University of California San Francisco (UCSF) criteria, increasing ranges of tumor size combinations were shown to be safe for LT (15). Studies have since demonstrated that larger, treatment responsive tumors that were able to be downstaged from UCSF criteria to Milan, or from beyond UCSF to within, have good survival outcomes post LT (4,5,14,15). By transplanting patients whose tumors are responsive to treatment, UNOS is better able to select a population that will do well post-LT. UNOS now combines downstaging data with AFP changes to provide exception points to the best possible candidates (12).

There are a variety of paths to final transplantation. Deceased donor transplants can come from donors after cardiac or after brain death. Transplanting HCV positive organs into HCV negative recipients has grown in popularity and the human immunodeficiency virus (HIV) Organ Policy Equity Act (HOPE Act), which passed in 2013 and was implemented in 2015, allowed for the transplantation of HIV positive organs into HIV positive recipients (16,17). Lastly, living donor transplant is becoming more common, despite a small decrease in 2020 likely due to the COVID-19 pandemic. Unfortunately, 18% of patients on the wait list for transplant in 2020 were removed from the list after becoming too sick for transplant or dying (16,17). This exemplifies the persistent fragility of this population, and the need for advance care planning and palliative care (PC) involvement regardless of transplant candidacy and even while goals are still life prolonging.

Selection criteria, risk scores, and living donor liver transplant (LDLT)

For over two decades the MC have guided patient selection for LT with low rates of recurrence and acceptable post-transplant survival (2). Despite this, many have argued that the MC are overly restrictive and lack markers of tumor biology. In 2001, Yao et al. proposed the University of California San Francisco criteria (single tumor ≤6.5 cm or up to 3 tumors ≤4.5 cm with total tumor diameter ≤8 cm) and demonstrated that expanding tumor burden beyond MC did not lead to worse outcomes with a 5-year survival of 75% (3).

Various expanded selection criteria based on differing tumor numbers and sizes have since been reported (see Table 2) (2,3,18-22). One such criteria named the “up-to-7”, proposed by Mazzaferro, limits total tumor size and number to 7. In a study of >1,000 patients with HCC exceeding MC on explant pathology, those patients meeting the up-to-7 criteria had equivalent 5-year survival compared to those with MC. As the number of reported expanded selection criteria continued to increase, the so-called “Metroticket model” by Mazzaferro and colleagues suggested that increasing tumor burden beyond MC translated into worse outcomes (21). While expanding criteria beyond MC has allowed more patients with HCC access to LT, there is a limit to what radiographic and pathologic criteria alone can safely achieve. Newer selection models incorporating markers of tumor biology are increasingly used to better select patients for transplant.

The best understood marker of HCC is AFP, which is highly associated with pathologic characteristics and decreased survival in patients with HCC (23). Various upper AFP limits have been suggested above which patients should be excluded from transplant, with AFP >1,000 ng/mL having been shown in multiple studies to be one of the strongest predictors of poor outcomes (24). In addition to the absolute AFP, there is evidence that the dynamic change of AFP, such as a rapidly increasing AFP pre-transplant, is a poor prognostic indicator in HCC patients undergoing transplant (22). Given this, it is no surprise that combining both radiographic tumor burden with AFP has been crucial in developing selection criteria for patients beyond traditional MC.

In 2012, the French AFP model was reported incorporating AFP, as it independently predicted tumor recurrence and correlated with vascular invasion (19). The model combined tumor size (up to 3, 3–6, and >6 cm), number of masses, and AFP. It demonstrated a better ability to predict HCC recurrence than MC alone, and showed acceptable outcomes in certain patients beyond MC but with an AFP ≤100 ng/mL. Mazzaferro et al. created the Metroticket 2.0 model in 2018, incorporating AFP into the original up-to-7 criteria (21). This second Metroticket model demonstrated that as AFP increased, lower tumor burden is needed to achieve excellent outcomes (i.e., up-to-7 if AFP <200 ng/mL, up-to-5 if AFP 200–400 ng/mL, and up-to-4 if AFP 400–1,000 ng/mL). More recently, the New York/California (NYCA) score was developed using the dynamic AFP response between the maximum and final pretransplant AFP, as this response was shown to predict outcomes (4). The AFP response was combined with tumor number and size to create the NYCA score which outperformed the MC and French AFP models in predicting HCC recurrence. This model was recently validated and the authors concluded that incorporating AFP response into selection criteria allows for safe expansion beyond MC, offering LT to patients who might be otherwise be denied LT (22). Selection models have moved beyond simple radiographic tumor burden and now incorporate indices of tumor biology. As models continue to evolve, additional aspects of tumor biology, such as response to LRT, may be incorporated as the field strives to expand access to LT to those will benefit most from it.

For patients with HCC, LDLT is an attractive alternative to waiting for a suitable deceased donor liver transplant (DDLT). While the initial study comparing outcomes of LDLT to DDLT for HCC showed higher HCC recurrence in the LDLT group, more recent studies have demonstrated similar post-transplant outcomes (25,26). Several recent analyses have shown the clear benefit of LDLT for HCC including a superior 5-year intention-to-treat survival of 68% for LDLT vs. 57% for DDLT, as well as significant reduction in the dropout risk, indicating it should be utilized more often (27,28). Transplantation for advanced HCC beyond MC is more suitable for LDLT, as opposed to DDLT, where the scarcity of organs requires allocation to those with optimal expected survival. A recent study from India described an experience with LDLT for HCC in patients who had undergone downstaging of portal vein tumor thrombosis, which otherwise carries a dismal prognosis (29). In total, 25 patients with portal vein tumor thrombosis were successfully downstaged after treatment with stereotactic body radiation and transarterial chemo- or radio-embolization (TACE or TARE). The 5-year overall and recurrence-free survival was 57% and 51%, respectively, comparable to survival in patients undergoing LDLT without portal vein thrombosis. This report highlights the evolving role that LDLT plays in the treatment of HCC.

Bridge therapy, response and waiting time

Management of patient with HCC on the waiting list aims to avoid disease progression. There is a lack of randomized controlled trials (RCTs) recommending neo-adjuvant therapies to reduce drop out risk due to tumor progression. An international consensus conference in 2012 reported no benefit for bridge therapy in patients with UNOS T1 tumors, but it might be appropriate for UNOS T2 lesions if their transplant wait time was expected to be six months or longer (30). However, the optimal bridge therapy has yet to be reported and is guided by multi-disciplinary tumor boards with most patients receiving one LRT prior to transplant. Many options exist including trans-arterial chemoembolization, trans-arterial radioembolization also known as y90, thermal ablation, resection, systemic therapy, radiation, and immunotherapy (31-41). Bridge therapy is being utilized significantly more in the modern era. Kwong et al. recently reported an analysis of over 20,000 liver transplant candidates with HCC exception points and found the proportion of patients receiving at least one LRT increased to 92% in the year 2018 compared to 42% in 2003 (42). In that study, TACE was still the most utilized therapy (50% in 2018) while thermal ablation accounted for 22%. Furthermore, y90 increased significantly over the time period, comprising 19% of LRT in 2018 compared to less than five percent in 2013 (42).

A phase 2 trial from Salem et al. found that in patients with HCC Barcelona Clinic Liver Cancer (BCLC) Stage A or B, treatment with radioembolization y90 significantly prolongs time to progression compared to TACE (26 vs. 6.8 months; P=0.002) (33). Of the patients listed for LT, those receiving y90 had a transplant rate of 87% vs. 70% for TACE. This trial proposed that y90 may reduce waitlist drop out, and thus has changed practice for this institution (Northwestern) (34). Furthermore, Kim et al. recently reported on the RASER trial which was a single center study evaluating the efficacy of y90 in 29 patients with early-stage HCC <3 cm not amenable to ablation (43). The trial found a complete tumor response in 83% of patients and a partial response of 17% by mRECIST criteria. The authors concluded that y90 was successful and well tolerated with a low complication rate in patients with early-stage HCC when ablation was not favorable based on tumor location. The LEGACY study by Salem et al. studied 162 patients with solitary HCC <8 cm to assess selective radioembolization with y90 to the tumor bearing hepatic segment termed “radiation segmentectomy” rather than traditional lobar y90 infusion (44). Radioembolization was performed in 21% of patients prior to LT with a median follow up 30 months. For the entire cohort, the objective response rate was 88% with 66% of patients exhibiting duration of response >6 months and a three-year overall survival of 93% in patients undergoing LT. Complete pathological necrosis was achieved when the dose exceeded 400 Gy arguing that this should be the “threshold” dose.

In the recent 2022 update of the BCLC Treatment algorithm for LT candidates with wait time of greater than six months; ablation, TACE or y90 can all be used for bridging (45). In addition, the new version stratifies with the goal of getting more patients to transplant including small multifocal HCC and subgroup of BCLC B patients who were successfully downstaged to within MC. For BCLC-0 and A patients who are not LT candidates, ablation is the preferred approach (45). Bridge therapies also are tailored to the specific number of tumors, location of the tumor and their relationship to major vascular and biliary structures. Practice patterns are driven by tumor characteristics as previously mentioned but also are influenced by institutional practice.

With respect to wait time, the optimal time from HCC diagnosis to transplant has yet to be elucidated. Time to transplant is a double-edged sword as rapid movement to transplant may result in transplanting aggressive tumors that have not yet had their biology tested and thus are susceptible to increased recurrence. Whereas prolonged wait time is associated with dropout from the LT wait list, reported up to 20% in the literature at one year. Halazun et al. analyzed 6,160 HCC patients from the UNOS database undergoing LT and found that patients transplanted in regions with short wait times (median 1.6 months) was an independent predictor of poor overall survival (HR 1.55, P<0.0001) (46). Mehta et al. analyzed 911 patients undergoing LT from three centers in the US with short, medium, long wait times with the goal of finding a “sweet-spot” (47). In their study, wait list dropout was 18% at 11.3 months, and they found that patients with very short wait times (<6 months) or very long (>18 months) were associated with an increased risk of HCC recurrence (HR 1.60, P=0.043) (47). As we move forward to find the optimal wait time, the literature must harmonize and come to a consensus as to whether HCC diagnosis is the first time point or is it the time of listing at a transplant center. Inevitably there is a time lapse as to when patients are diagnosed and then referred and then listed at a transplant center.

Response to bridge therapy can be variable and criteria used to evaluate response to treatment are of upmost importance. Regardless of the LRT chosen, data show that complete pathologic response (cPR) and degree of tumor necrosis on explant review is associated with reduced recurrence and improved survival (48). In an analysis from the US Multicenter HCC Transplant Consortium, DiNorcia et al. found that of 3,439 patients undergoing LT, 23% had cPR and these patients had significantly lower 1 and 5-year incidence of HCC recurrence (1.3% and 5.2%) and improved 1 and 5-year survival rates (92% and 75%) compared to those patients who did not achieve cPR (48). Interestingly, short wait time patients and those receiving more than three LRT were less likely to achieve cPR.

The first criteria to evaluate response to treatment was the response evaluation criteria in solid tumors (RECIST) where a complete response was the disappearance of all target lesions (49). The RECIST criteria was then “modified” to mRECIST where a complete response is the disappearance of any intra-tumoral arterial enhancement (50). Uniform agreement on which criteria to evaluate tumor response is important to provide homogeneity in the literature. The European Association for the Study of the Liver (EASL) criteria has also been used which takes into account tumor necrosis and has a similar concept as mRECIST with respect to tumor viability and uptake of contrast by the tumor on arterial phase CT or MRI (51).

Downstaging vs. all-comers

The percentage of LT performed for HCC continues to rise resulting in an increased number of HCC patients on the waiting list (52). This demand has led to the expansion of LT for HCC beyond the MC, using down-staging. Tumor down-staging utilizes LRT to treat HCC with initial tumor burden exceeding MC to within acceptable LT criteria. Radiographic response to LRT is a marker of favorable tumor biology while tumor progression implies aggressive tumor biology and higher post-LT HCC recurrence (53). Down-staging aims to select a subset of patients with response to LRT who will do well following LT. Down-staging has been proven to be an effective bridge to LT. In 2015, the UCSF group published their single-center experience using a down-staging protocol and found that those successfully down-staged to within MC had outcomes similar to those always within MC with a 5-year post-LT survival of 78% (54). In 2017, UNOS and the Organ Procurement and Transplantation Network (OPTN) formally adopted the UCSF/Region 5 down-staging protocol (UNOS-DS). Patients meeting these criteria who are successfully down-staged to within MC receive automatic exception points after a 6-month waiting period (55). These criteria were validated in a large multicenter study as well as UNOS database study again showing similar outcomes for patients down-staged to within MC as compared to those always within MC (56). More recently, the first and only multicenter prospective study on tumor-downstaging based on the UNOS-DS protocol from the MERITS-LT consortium, comprising of seven centers from four UNOS regions, demonstrated a >80% probability of successful down-staging with a 2-year HCC recurrence of 7.9% (57). The Italian XXL trial was the first RCT of down-staging in which patients with HCC beyond MC were randomized to either LT or further LRT with systemic therapy. The trial’s LT group had superior tumor-free and overall survival compared to the control group (5-year survival 77% vs. 31%), concluding that downstaging-tumor response could contribute to expanding HCC transplant criteria (58).

While the UNOS-DS criteria expands the indications for transplant for HCC beyond the traditional MC, there is interest in the outcomes of patients with tumor burden beyond UNOS-DS criteria. Patients with tumor burden beyond MC who respond to LRT may have superior survival after LT in comparison to other available treatments. The all-comers down-staging (AC-DS) protocol goes beyond the UNOS-DS criteria with no upfront limit on initial tumor burden. The UCSF group’s all-comers experience reported 80% probability of dropout at 3- and 5-year intention-to-treat survival of only 21% (59). Two recent UNOS database studies similarly demonstrated poor outcomes associated with all-comers—including inferior 3-year post-LT survival and high dropout rates after successful DS (57,60). Taken together, these data suggest there is likely a tumor burden limit beyond which down-staging is unlikely to be successful and that all-comers should be carefully selected for transplant.

Similar to patients with significant tumor burden, those with macrovascular invasion of the hepatic or portal veins have limited treatment options and are excluded from both the UNOS-DS and AC-DS protocols. However, LRT can be used to achieve a radiological regression of vascular invasion potentially allowing for a safe window for transplant, similar to the principles of down-staging. Assalino et al. conducted a multicenter study of HCC patients transplanted after a complete radiologic regression and reported acceptable 5-year survival of 60%. Recurrence rates were 27% however, a subset of patients with pretransplant AFP <10 ng/mL had favorable post-transplant recurrence of 11% (61). Soin et al. reported acceptable survival rates in patients with PVTT with LDLT after successful down-staging with a 5-year survival of 57% (29).

Recurrence: predictors, prevention, and therapy

Despite the implementation of strict criteria, HCC recurrence post LT remains up to 20%, occurring mostly within 2–3 years post LT (5). In a large multicenter study, the median time to recurrence was 17 months and the rates of recurrence were 5.1% at 1 year, 14.3% at 5 years, and 16.4% at 10 years (5). The probability of HCC recurrence was 11.3% at 5 years after LT and 13.3% at 10 years after LT for the MC group (at diagnosis), 19.1% at 5 years and 20.6% at 10 years for the downstaged group (at LT), and 38.9% at 5 years and 41.4% at 10 years for the patients who failed downstaging 14. PreLT predictors of recurrence were tumor burden (beyond MC at diagnosis), number of LRT >2, and AFP >20 ng/mL at transplantation (5).

Early recurrence, defined as <2 years is associated with a significantly worse prognosis (5). Liver-only recurrence occurs in 15–40%; extrahepatic disease is likely due to growth of occult metastases. Various risk factors have been described leading to pre- and post-LT scoring systems. Table 3 summarizes scoring systems including tumor burden and serum biomarkers (2-4,18,19,21,62-71). Serum biomarkers, both static or dynamic such as AFP, neutrophil/Lymphocyte ratio NLR, AFP L3% and s-gamma-carboxyprothrombin have been identified. Disease burden may not necessarily be associated with tumor biology. Numerous studies have shown that AFP responders to LRT consistently had superior post LT outcomes (48). The most important characteristics on explant pathology were micro- and macrovascular invasion, satellite lesions and tumor differentiation.

Given the LT recurrence risk, post LT surveillance offers early identification and treatment and the ability to offer potential curative therapies (70). A surveillance strategy should include cross section imaging of the abdomen such as contrast enhanced computer tomography (CT) or magnetic resonance imaging (MRI) and non-contrast CT for the lungs. Other sites of metastases, such as bones or brain, should be investigated if clinical suspicion is high. AFP seems to be the only biomarker proved to be efficient to monitor during surveillance and usually is measured every 6 months. To date, there are no standardized surveillance protocols. A minimal surveillance of at least 3 years has been proposed with no difference in RFS between patients undergoing 3 vs. 6 months interval follow up scans (70). The UCSF team proposed a surveillance strategy based on RETREAT score (including microvascular invasion, serum AFP at LT, and diameter of the largest nodule plus the total number of nodules on the explant liver) (70). The scoring ranges from no surveillance for patients with a RETREAT score of 0 (based on 3% 5-year rate of recurrence), surveillance every 6 months for 2 years for patients with a RETREAT score of 1–3, surveillance every 6 months for 5 years for patients with a RETREAT score of 4, and surveillance every 3–4 months for 2 years followed by every 6 months for years 2–5 for patients with a RETREAT score of 5 or more. Additional biomarkers such as AFP-L3% and DCP must be validated for monitoring for post LT recurrence.

The influence of immunosuppression on HCC recurrence after LT has been a topic of debate. Some studies suggest that immunosuppression may increase the risk of HCC recurrence by promoting tumor growth and inhibiting the immune system’s ability to detect and eliminate cancer cells. Calcineurin inhibitor (CNI) exposure is associated with an increased risk of recurrence and is dose dependent (72). Mammalian target of rapamycin (mTOR) is upregulated in several mutations found in HCC, and when found is considered as a marker of aggressive cancer. MTOR inhibitors (mTORi) have anti-angiogenic and anti-proliferative effects in such cases (73). In several retrospective studies and meta-analyses, mTORi showed a reduction in recurrence and increased survivability, 13.8% vs. 8.0%, P<0.001 (74). In an RCT, mTORi were compared to non mTORi immunosuppression; the authors demonstrated a slight advantage in recurrence free survival in the first 3–5 years that disappeared with time. The International Liver Transplantation Society, in its Transplant Oncology Consensus Conference recommended levels of lower than 10 ng/mL for tacrolimus and lower than 300 ng/mL for cyclosporine.

The advent of DAA therapy has raised concerns about the possible adverse effects of DAA on the recurrence and aggressiveness of HCC, but these concerns have proven unfounded. A large retrospective multi-institutional study including nearly 800 patients showed similar overall (HR 0.9) and early HCC recurrence (HR 0.96) in patients receiving DAA and in those who did not (7). A follow-up study in the same cohort reported a significant reduction in risk of death (HR 0.54) in patients treated with DAA (75).

Management of patients with recurrent HCC after LT draws some parallels to management of primary LT, with a clear benefit of treatment modalities with curative intent (5). Therapeutic options post LT differ with the location and extent of recurrence and so does survivability. In a series of 106 patients treated for recurrence of HCC after LT the highest survival rate at 3 years was achieved in the surgery alone group (60%), followed by the group with combined surgical and non-surgical treatment (37%), and non-surgical treatment (11%) (76). In a large retrospective study, recipients who underwent surgical treatment for their recurrence achieved a median survival of 31.6 months (5). A subgroup of patients with isolated and favorable tumor biology would benefit from resection. Patients receiving surgical treatment for recurrence had generally favorable recurrent tumor characteristics. Resections performed were mostly for solitary [70 (69.3%)] and extrahepatic [90 (89.1%)] tumors, with an AFP <200 ng/mL [71 (73.2%)] at the time of recurrence (5).

In a large study of 661 patients resected for HCC. Fifty-six (16%) of patients with recurrent HCC were listed for LT and 63% ultimately transplanted with 23% drop out due to tumor progression (77). Salvage LT (SLT) is another proposed curative therapy for patients with HCC recurrence post liver resection (rate 70% at 5 years) (78). The long-term oncologic outcomes remain unclear. An intention to treat analysis of 110 patients demonstrated a 5-year ITT OS of 69% and disease-free survival of 60%. The SLT strategy was successful in 56% of patients. It seems that the outcomes of salvage transplantation for recurrent HCC after hepatic resection are, at least, comparable to the results of primary transplantation for HCC even when examined on an intention-to-treat basis.

For patients with unresectable recurrent HCC after LT, LRT has been considered as a potential treatment modality—however, there is scant published data. Systemic therapy has a limited use in recurrence of HCC after LT. Sorafenib, a multi-kinase inhibitor showed a median survival of 10.6 months compared with 2.2 months for supportive care (79). Regorafenib, another multi-kinase inhibitor, is used as a second line treatment and provides median survival of 13.1 vs. 5.5 months (80). All of the patients in that trial (n=25) suffered from at least one adverse event. Metronomic capecitabine has the same safety profile as sorafenib and compared to best supportive care showed increased median OS of 22 vs. 7 months, P<0.01 (79).

The use of immunotherapy for the treatment of HCC recurrence is a topic of ongoing research. While immunotherapy has shown promising results in the treatment of advanced HCC, in the setting of LT, it may interfere with immune tolerance against the transplanted liver. In review of the literature, reported graft rejection rates range from 25–54%, with relatively rapid development of graft rejection in patients who did develop it (81). Further research is needed to determine the optimal timing, dosing, and patient selection for immunotherapy in the post-transplant setting.

Future directions

An evolving area of interest is molecular testing in HCC. Genomic assays of HCC have demonstrated several key signaling pathways and signatures associated with HCC progression and survival (82). Such markers will most likely be incorporated into future prognostic scoring system.

A new diagnostic tool known as “liquid biopsy” has emerged over the past few years (83). Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) are cornerstones of liquid biopsy (83).

In view of certain limitations of traditional imaging and reporting methods, radiomics has emerged as a burgeoning technology that could transform potential pathological and physiological information from routine-acquired images into high-dimensional quantitative and mineable imaging data (84). It has already been demonstrating great potential in the diagnosis, classification and staging, clinical decision assistance, and prognosis and survival predictions of HCC (84).

Immunotherapy has revolutionized the treatment of advanced HCC over the past few years (85). Improved outcomes have been demonstrated in the use of neoadjuvant therapy from early phase trials in various solid tumor types. Several phase 2 trials have shown excellent pathologic response in a resection cohort (86). Early experience with immunotherapy in the pre-LT setting has been discouraged due to scattered reports of severe rejection and graft loss (87). Encouraging data based on case reports and case series have been recently published demonstrating acceptable risk with excellent pathologic response (41). Further investigation is needed to evaluate patient selection, minimal washout and observation period between the last drug dose and transplantation.

HCC diagnosis occurs at advanced stages in nearly two thirds where treatment is ineffective or often delayed. Dropout rates on the wait list due to tumor progression are up to 30%. In addition, quality of life (QoL) is impaired due to symptoms from high tumor burden and psychological distress (88). A recent pilot RCT at an academic center demonstrated that outpatient PC interventions within routine HCC care is feasible and potentially improve QoL and symptoms (89). PC is underutilized for HCC patients and frequently delayed due to inadequate resources, lack of education for non-PC providers and inadequate modeling for integration of PC within liver clinics. A larger study must be explored to understand the benefit of early incorporation of PC in patients undergoing LT with HCC.

Strengths and limitations

This review represents a comprehensive compilation and evaluation of relevant literature and governing body guidelines, as interpreted by experts in the fields of transplant hepatology and surgery. We have included the history of the topic, when relevant, to provide readers with insight into the evolution of transplantation. Despite this, we are unable to fully capture the nuanced decisions that go into individualized patient treatment plans. We also deferred a detailed description of UNOS organ allocation algorithms which are beyond the scope of this review.

Conclusions

LT is the optimal treatment for patients with early-stage HCC. The landscape of LT for HCC has paralleled the changes in patients transplanted for primary liver diseases. The increasing demand for LT for HCC has led to continued efforts to expand LT indications for HCC. Down-staging to within MC provides acceptable long-term survival and UNOS-DS criteria are now accepted national policy. Centers need to be highly selective when pursuing LT for these patients. Implementation of various risk models based on pre- and post-LT risk factors have enabled the classification of patients into low and high-risk groups. The role of immunosuppressive regimens using mTORi in the prevention of recurrence after LT remains controversial. Efforts are needed to identify consistent prognostic biomarkers before and after LT. Improved imaging techniques are needed to define response ahead of pathologic assessments and oncologic outcomes. The use of pre-LT immunotherapy, although encouraging, needs to be further explored.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by Guest Editors (Sukeshi Patel Arora and Sherri Rauenzahn Cervantez) for the series “Comprehensive Care for Patients with Hepatocellular Carcinoma: Insights from the 2022 San Antonio Liver Cancer Symposium” published in Annals of Palliative Medicine. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-23-341/rc

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-23-341/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form. (available at https://apm.amegroups.com/article/view/10.21037/apm-23-341/coif). The series “Comprehensive Care for Patients with Hepatocellular Carcinoma: Insights from the 2022 San Antonio Liver Cancer Symposium” was commissioned by the editorial office without any funding or sponsorship. P.T. received consultation and honorarium from AstraZeneca and Boston Scientific. D.Z. has been awarded a 2023 ACG Medical Resident Clinical Research Award from the American College of Gastroenterology to study palliative, supportive, and end of life care for people with liver disease. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Llovet JM, Zucman-Rossi J, Pikarsky E, et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2016;2:16018. [Crossref] [PubMed]
2. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-9. [Crossref] [PubMed]
3. Yao FY, Fidelman N. Reassessing the boundaries of liver transplantation for hepatocellular carcinoma: Where do we stand with tumor down-staging? Hepatology 2016;63:1014-25. [Crossref] [PubMed]
4. Halazun KJ, Tabrizian P, Najjar M, et al. Is it Time to Abandon the Milan Criteria?: Results of a Bicoastal US Collaboration to Redefine Hepatocellular Carcinoma Liver Transplantation Selection Policies. Ann Surg 2018;268:690-9. [Crossref] [PubMed]
5. Tabrizian P, Holzner ML, Mehta N, et al. Ten-Year Outcomes of Liver Transplant and Downstaging for Hepatocellular Carcinoma. JAMA Surg 2022;157:779-88. [Crossref] [PubMed]
6. Puigvehí M, Hashim D, Haber PK, et al. Liver transplant for hepatocellular carcinoma in the United States: Evolving trends over the last three decades. Am J Transplant 2020;20:220-30. [Crossref] [PubMed]
7. Singal AG, Rich NE, Mehta N, et al. Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection Is Associated With Increased Survival in Patients With a History of Hepatocellular Carcinoma. Gastroenterology 2019;157:1253-1263.e2. [Crossref] [PubMed]
8. Anderson MS, Valbuena VSM, Brown CS, et al. Association of COVID-19 With New Waiting List Registrations and Liver Transplantation for Alcoholic Hepatitis in the United States. JAMA Netw Open 2021;4:e2131132. [Crossref] [PubMed]
9. Kuo YF, Kwo P, Wong RJ, et al. Impact of COVID-19 on Liver Transplant Activity in the USA: Variation by Etiology and Cirrhosis Complications. J Clin Transl Hepatol 2023;11:130-5. [PubMed]
10. Birmingham K. Thomas Starzl. Nat Med 2003;9:10. [Crossref] [PubMed]
11. Available online: https://optn.transplant.hrsa.gov/about/history-nota
12. Heimbach JK. Evolution of Liver Transplant Selection Criteria and U.S. Allocation Policy for Patients with Hepatocellular Carcinoma. Semin Liver Dis 2020;40:358-64. [Crossref] [PubMed]
13. Wiesner RH, McDiarmid SV, Kamath PS, et al. MELD and PELD: application of survival models to liver allocation. Liver Transpl 2001;7:567-80. [Crossref] [PubMed]
14. Mehta N, Dodge JL, Roberts JP, et al. Alpha-Fetoprotein Decrease from > 1,000 to < 500 ng/mL in Patients with Hepatocellular Carcinoma Leads to Improved Posttransplant Outcomes. Hepatology 2019;69:1193-205. [Crossref] [PubMed]
15. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394-403. [Crossref] [PubMed]
16. Available online: https://optn.transplant.hrsa.gov/professionals/by-topic/hope-act/.
17. Available online: https://srtr.transplant.hrsa.gov/annual_reports/2020/Liver.aspx#LI_dist_adult_waiting_diag_b64.
18. Mazzaferro V, Llovet JM, Miceli R, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009;10:35-43. [Crossref] [PubMed]
19. Duvoux C, Roudot-Thoraval F, Decaens T, et al. Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria. Gastroenterology 2012;143:986-94.e3; quiz e14-5. [Crossref] [PubMed]
20. Lai Q, Nicolini D, Inostroza Nunez M, et al. A Novel Prognostic Index in Patients With Hepatocellular Cancer Waiting for Liver Transplantation: Time-Radiological-response-Alpha-fetoprotein-INflammation (TRAIN) Score. Ann Surg 2016;264:787-96. [Crossref] [PubMed]
21. Mazzaferro V, Sposito C, Zhou J, et al. Metroticket 2.0 Model for Analysis of Competing Risks of Death After Liver Transplantation for Hepatocellular Carcinoma. Gastroenterology 2018;154:128-39. [Crossref] [PubMed]
22. Halazun KJ, Rosenblatt RE, Mehta N, et al. Dynamic α-Fetoprotein Response and Outcomes After Liver Transplant for Hepatocellular Carcinoma. JAMA Surg 2021;156:559-67. [Crossref] [PubMed]
23. Onaca N, Davis GL, Jennings LW, et al. Improved results of transplantation for hepatocellular carcinoma: a report from the International Registry of Hepatic Tumors in Liver Transplantation. Liver Transpl 2009;15:574-80. [Crossref] [PubMed]
24. Hameed B, Mehta N, Sapisochin G, et al. Alpha-fetoprotein level > 1000 ng/mL as an exclusion criterion for liver transplantation in patients with hepatocellular carcinoma meeting the Milan criteria. Liver Transpl 2014;20:945-51. [Crossref] [PubMed]
25. Kulik LM, Fisher RA, Rodrigo DR, et al. Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort. Am J Transplant 2012;12:2997-3007. [Crossref] [PubMed]
26. Limkemann AJP, Abreu P, Sapisochin G. How far can we go with hepatocellular carcinoma in living donor liver transplantation? Curr Opin Organ Transplant 2019;24:644-50. [Crossref] [PubMed]
27. Lai Q, Sapisochin G, Gorgen A, et al. Evaluation of the Intention-to-Treat Benefit of Living Donation in Patients With Hepatocellular Carcinoma Awaiting a Liver Transplant. JAMA Surg 2021;156:e213112. [Crossref] [PubMed]
28. Goldaracena N, Gorgen A, Doyle A, et al. Live donor liver transplantation for patients with hepatocellular carcinoma offers increased survival vs. deceased donation. J Hepatol 2019;70:666-73. [Crossref] [PubMed]
29. Soin AS, Bhangui P, Kataria T, et al. Experience With LDLT in Patients With Hepatocellular Carcinoma and Portal Vein Tumor Thrombosis Postdownstaging. Transplantation 2020;104:2334-45. [Crossref] [PubMed]
30. Clavien PA, Lesurtel M, Bossuyt PM, et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 2012;13:e11-22. [Crossref] [PubMed]
31. Llovet JM, Real MI, Montaña X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002;359:1734-9. [Crossref] [PubMed]
32. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 2003;37:429-42. [Crossref] [PubMed]
33. Salem R, Gordon AC, Mouli S, et al. Y90 Radioembolization Significantly Prolongs Time to Progression Compared With Chemoembolization in Patients With Hepatocellular Carcinoma. Gastroenterology 2016;151:1155-1163.e2. [Crossref] [PubMed]
34. Salem R, Gabr A, Riaz A, et al. Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience. Hepatology 2018;68:1429-40. [Crossref] [PubMed]
35. Lu DS, Yu NC, Raman SS, et al. Percutaneous radiofrequency ablation of hepatocellular carcinoma as a bridge to liver transplantation. Hepatology 2005;41:1130-7. [Crossref] [PubMed]
36. Poon RT, Fan ST, Lo CM, et al. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg 2002;235:373-82. [Crossref] [PubMed]
37. Belghiti J, Cortes A, Abdalla EK, et al. Resection prior to liver transplantation for hepatocellular carcinoma. Ann Surg 2003;238:885-92; discussion 892-3. [Crossref] [PubMed]
38. Vitale A, Volk ML, Pastorelli D, et al. Use of sorafenib in patients with hepatocellular carcinoma before liver transplantation: a cost-benefit analysis while awaiting data on sorafenib safety. Hepatology 2010;51:165-73. [Crossref] [PubMed]
39. Chow PHW, Gandhi MAsia-Paciifc Hepatocellular Carcinoma Trials Group. Phase III multi-centre open-label randomized controlled trial of selective internal radiation therapy (SIRT) versus sorafenib in locally advanced hepatocellular carcinoma: The SIRveNIB study. J Clin Oncol 2017;35:400. [Crossref]
40. Wong TC, Lee VH, Law AL, et al. Prospective Study of Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma on Waitlist for Liver Transplant. Hepatology 2021;74:2580-94. [Crossref] [PubMed]
41. Tabrizian P, Florman SS, Schwartz ME. PD-1 inhibitor as bridge therapy to liver transplantation? Am J Transplant 2021;21:1979-80. [Crossref] [PubMed]
42. Kwong AJ, Ghaziani TT, Yao F, et al. National Trends and Waitlist Outcomes of Locoregional Therapy Among Liver Transplant Candidates With Hepatocellular Carcinoma in the United States. Clin Gastroenterol Hepatol 2022;20:1142-1150.e4. [Crossref] [PubMed]
43. Kim E, Sher A, Abboud G, et al. Radiation segmentectomy for curative intent of unresectable very early to early stage hepatocellular carcinoma (RASER): a single-centre, single-arm study. Lancet Gastroenterol Hepatol 2022;7:843-50. [Crossref] [PubMed]
44. Salem R, Johnson GE, Kim E, et al. Yttrium-90 Radioembolization for the Treatment of Solitary, Unresectable HCC: The LEGACY Study. Hepatology 2021;74:2342-52. [Crossref] [PubMed]
45. Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol 2022;76:681-93. [Crossref] [PubMed]
46. Halazun KJ, Patzer RE, Rana AA, et al. Standing the test of time: outcomes of a decade of prioritizing patients with hepatocellular carcinoma, results of the UNOS natural geographic experiment. Hepatology 2014;60:1957-62. [Crossref] [PubMed]
47. Mehta N, Heimbach J, Lee D, et al. Wait Time of Less Than 6 and Greater Than 18 Months Predicts Hepatocellular Carcinoma Recurrence After Liver Transplantation: Proposing a Wait Time "Sweet Spot". Transplantation 2017;101:2071-8. [Crossref] [PubMed]
48. DiNorcia J, Florman SS, Haydel B, et al. Pathologic Response to Pretransplant Locoregional Therapy is Predictive of Patient Outcome After Liver Transplantation for Hepatocellular Carcinoma: Analysis From the US Multicenter HCC Transplant Consortium. Ann Surg 2020;271:616-24. [Crossref] [PubMed]
49. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205-16. [Crossref] [PubMed]
50. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010;30:52-60. [Crossref] [PubMed]
51. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001;35:421-30. [Crossref] [PubMed]
52. Mehta N, Dodge JL, Hirose R, et al. Increasing Liver Transplantation Wait-List Dropout for Hepatocellular Carcinoma With Widening Geographical Disparities: Implications for Organ Allocation. Liver Transpl 2018;24:1346-56. [Crossref] [PubMed]
53. Mehta N, Dodge JL, Goel A, et al. Identification of liver transplant candidates with hepatocellular carcinoma and a very low dropout risk: implications for the current organ allocation policy. Liver Transpl 2013;19:1343-53. [Crossref] [PubMed]
54. Yao FY, Mehta N, Flemming J, et al. Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumors within Milan criteria. Hepatology 2015;61:1968-77. [Crossref] [PubMed]
55. Organ Procurement and Transplantation Network. Changes to HCC Criteria for Auto Approval. Changes to HCC Criteria for Auto Approval. Available online: https://optn.transplant.hrsa.gov/media/1922/liver_hcc_criteria_for_auto_approval_20160815.pdf (2017).
56. Mehta N, Dodge JL, Grab JD, et al. National Experience on Down-Staging of Hepatocellular Carcinoma Before Liver Transplant: Influence of Tumor Burden, Alpha-Fetoprotein, and Wait Time. Hepatology 2020;71:943-54. [Crossref] [PubMed]
57. Mehta N, Frenette C, Tabrizian P, et al. Downstaging Outcomes for Hepatocellular Carcinoma: Results From the Multicenter Evaluation of Reduction in Tumor Size before Liver Transplantation (MERITS-LT) Consortium. Gastroenterology 2021;161:1502-12. [Crossref] [PubMed]
58. Mazzaferro V, Citterio D, Bhoori S, et al. Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial. Lancet Oncol 2020;21:947-56. [Crossref] [PubMed]
59. Sinha J, Mehta N, Dodge JL, et al. Are There Upper Limits in Tumor Burden for Down-Staging of Hepatocellular Carcinoma to Liver Transplant? Analysis of the All-Comers Protocol. Hepatology 2019;70:1185-96. [Crossref] [PubMed]
60. Huang AC, Dodge JL, Yao FY, et al. National Experience on Waitlist Outcomes for Down-Staging of Hepatocellular Carcinoma: High Dropout Rate in All-Comers. Clin Gastroenterol Hepatol 2023;21:1581-9. [Crossref] [PubMed]
61. Assalino M, Terraz S, Grat M, et al. Liver transplantation for hepatocellular carcinoma after successful treatment of macrovascular invasion - a multi-center retrospective cohort study. Transpl Int 2020;33:567-75. [Crossref] [PubMed]
62. Sugawara Y, Tamura S, Makuuchi M. Living donor liver transplantation for hepatocellular carcinoma: Tokyo University series. Dig Dis 2007;25:310-2. [Crossref] [PubMed]
63. Lee SG, Hwang S, Moon DB, et al. Expanded indication criteria of living donor liver transplantation for hepatocellular carcinoma at one large-volume center. Liver Transpl 2008;14:935-45. [Crossref] [PubMed]
64. Lee JH, Cho Y, Kim HY, et al. Serum Tumor Markers Provide Refined Prognostication in Selecting Liver Transplantation Candidate for Hepatocellular Carcinoma Patients Beyond the Milan Criteria. Ann Surg 2016;263:842-50. [Crossref] [PubMed]
65. Halazun KJ, Najjar M, Abdelmessih RM, et al. Recurrence After Liver Transplantation for Hepatocellular Carcinoma: A New MORAL to the Story. Ann Surg 2017;265:557-64. [Crossref] [PubMed]
66. Taketomi A, Sanefuji K, Soejima Y, et al. Impact of des-gamma-carboxy prothrombin and tumor size on the recurrence of hepatocellular carcinoma after living donor liver transplantation. Transplantation 2009;87:531-7. [Crossref] [PubMed]
67. Takada Y, Uemoto S. Liver transplantation for hepatocellular carcinoma: the Kyoto experience. J Hepatobiliary Pancreat Sci 2010;17:527-32. [Crossref] [PubMed]
68. Kim JM, Kwon CH, Joh JW, et al. Expanded criteria for liver transplantation in patients with hepatocellular carcinoma. Transplant Proc 2014;46:726-9. [Crossref] [PubMed]
69. Shimamura T, Akamatsu N, Fujiyoshi M, et al. Expanded living-donor liver transplantation criteria for patients with hepatocellular carcinoma based on the Japanese nationwide survey: the 5-5-500 rule - a retrospective study. Transpl Int 2019;32:356-68. [Crossref] [PubMed]
70. Mehta N, Heimbach J, Harnois DM, et al. Validation of a Risk Estimation of Tumor Recurrence After Transplant (RETREAT) Score for Hepatocellular Carcinoma Recurrence After Liver Transplant. JAMA Oncol 2017;3:493-500. [Crossref] [PubMed]
71. Sapisochin G, Goldaracena N, Laurence JM, et al. The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: A prospective validation study. Hepatology 2016;64:2077-88. [Crossref] [PubMed]
72. Rodríguez-Perálvarez M, Tsochatzis E, Naveas MC, et al. Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma. J Hepatol 2013;59:1193-9. [Crossref] [PubMed]
73. Matter MS, Decaens T, Andersen JB, et al. Targeting the mTOR pathway in hepatocellular carcinoma: current state and future trends. J Hepatol 2014;60:855-65. [Crossref] [PubMed]
74. Geissler EK, Schnitzbauer AA, Zülke C, et al. Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial. Transplantation 2016;100:116-25. [Crossref] [PubMed]
75. Singal AG, Rich NE, Mehta N, et al. Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study. Gastroenterology 2019;156:1683-1692.e1. [Crossref] [PubMed]
76. Bodzin AS, Lunsford KE, Markovic D, et al. Predicting Mortality in Patients Developing Recurrent Hepatocellular Carcinoma After Liver Transplantation: Impact of Treatment Modality and Recurrence Characteristics. Ann Surg 2017;266:118-25. [Crossref] [PubMed]
77. Tabrizian P, Jibara G, Shrager B, et al. Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis. Ann Surg 2015;261:947-55. [Crossref] [PubMed]
78. de Haas RJ, Lim C, Bhangui P, et al. Curative salvage liver transplantation in patients with cirrhosis and hepatocellular carcinoma: An intention-to-treat analysis. Hepatology 2018;67:204-15. [Crossref] [PubMed]
79. Ravaioli M, Cucchetti A, Pinna AD, et al. The role of metronomic capecitabine for treatment of recurrent hepatocellular carcinoma after liver transplantation. Sci Rep 2017;7:11305. [Crossref] [PubMed]
80. Iavarone M, Invernizzi F, Czauderna C, et al. Preliminary experience on safety of regorafenib after sorafenib failure in recurrent hepatocellular carcinoma after liver transplantation. Am J Transplant 2019;19:3176-84. [Crossref] [PubMed]
81. Gassmann D, Weiler S, Mertens JC, et al. Liver Allograft Failure After Nivolumab Treatment-A Case Report With Systematic Literature Research. Transplant Direct 2018;4:e376. [Crossref] [PubMed]
82. Beaufrère A, Caruso S, Calderaro J, et al. Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsies. J Hepatol 2022;76:343-52. [Crossref] [PubMed]
83. von Felden J, Garcia-Lezana T, Schulze K, et al. Liquid biopsy in the clinical management of hepatocellular carcinoma. Gut 2020;69:2025-34. [Crossref] [PubMed]
84. Hectors SJ, Lewis S, Besa C, et al. MRI radiomics features predict immuno-oncological characteristics of hepatocellular carcinoma. Eur Radiol 2020;30:3759-69. [Crossref] [PubMed]
85. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 2020;382:1894-905. [Crossref] [PubMed]
86. Marron TU, Schwartz M, Corbett V, et al. Neoadjuvant Immunotherapy for Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022;9:571-81. [Crossref] [PubMed]
87. Nordness MF, Hamel S, Godfrey CM, et al. Fatal hepatic necrosis after nivolumab as a bridge to liver transplant for HCC: Are checkpoint inhibitors safe for the pretransplant patient? Am J Transplant 2020;20:879-83. [Crossref] [PubMed]
88. Webster K, Cella D, Yost K. The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System: properties, applications, and interpretation. Health Qual Life Outcomes 2003;1:79. [Crossref] [PubMed]
89. Verma M, Kalman R, Horrow J, et al. Feasibility of a Palliative Care Intervention within Routine Care of Hepatocellular Carcinoma: A Pilot Randomized Controlled Trial. J Palliat Med 2023;26:334-41. [Crossref] [PubMed]