2010 International consensus conference on liver transplantation for hepatocellular carcinoma: Texts of experts

Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide and the third most common cause of cancer-related deaths; the number of new cases per year is approaching 750,000. The magnitude of the incidence of HCC has discouraged any attempts to apply liver transplantation (LT) as the prevailing curative therapy for HCC worldwide because of the limited sources of donated organs (deceased and living donors) and the poor access to sophisticated health care systems in some geographical areas. If these limitations continue to prevail throughout the world, any attempt to significantly reduce HCC-related mortality rates through the application of LT will be delusional. International experiences have confirmed, however, the potential of LT to definitively cure HCC because it presents a unique opportunity to remove both the tumor (HCC is associated with 695,000 deaths per year) and the underlying cirrhosis. Despite its limited access, LT has become the standard of care for patients with small HCCs and the main driving force for alternative strategies offered to patients with intermediate HCCs. In 1996, a prospective cohort study defined restrictive selection criteria that led to superior survival for transplant patients in comparison with any other previous experience with transplantation or other options for HCC. Since then, these selection criteria have become universally known as the Milan criteria (MC) in recognition of their origin. Ever since their adoption in clinical practice, the MC have helped doctors to single out early-stage HCC as a prognostic category of cancer presentation that is amenable to curative treatments. After their implementation, the favorable posttransplant outcomes that were observed in cohort series were so convincing that the MC immediately became the standard of care for early HCC, and further validation by randomized controlled trials (RCTs) was prevented. After the passage of approximately a decade, researchers began to challenge the MC with other proposals designed to capture those patients not meeting the MC who could achieve similar posttransplant survival rates through the expansion of the accepted tumor limits for transplant eligibility. None of these expanded criteria have become the new reference standard for selecting LT candidates with HCC; any broadening of the selection criteria for transplantation is inevitably hampered by severe

How should patients with hepatocellular carcinoma recurrence after liver transplantation be treated?

Norman Kneteman, Tito Livraghi, David Madoff, Eduardo de Santibanez, and Michael Kew Division of Transplantation, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada; Department of Interventional Radiology, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; Division of Interventional Radiology, New York-Presbyterian/Weill Cornell Medical Center, New York, NY; General Surgery and Liver Transplant Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; and Department of Medicine, Groote Schuur Hospital, Cape Town, South Africa

Liver Transplantation for Hepatocellular Carcinoma: Impact of the MELD Allocation System and Predictors of Survival

Hepatocellular carcinoma (HCC) is a major health problem, being the fifth most common cancer worldwide. The incidence of HCC is increasing in Europe and the United States, and it is currently the leading cause of death among patients with cirrhosis. The advent of surveillance programs has led to a change in the stage of tumors detected. In more than half of the cases, these tumors will be suitable for potentially curative treatments, such as resection, transplantation, and percutaneous ablation.

Michael R. Lucey, Norah Terrault, Lolu Ojo, J. Eileen Hay, James Neuberger, Emily Blumberg, and Lewis W. Teperman Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI; Gastroenterology Division, Department of Medicine, University of California San Francisco, San Francisco, CA; Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, MI; Mayo Clinic, Rochester, MN; Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom; Division of Infectious Diseases, University of Pennsylvania School of Medicine, Philadelphia, PA; and Department of Surgery, NYU Transplant Associates, New York, NY

Watch a video presentation of this article Watch the interview with the author As recently as 5 years ago, any discussion regarding the optimal liver transplantation (LT) criteria for hepatocellular carcinoma (HCC) would have revolved primarily around tumor size and number. However, the previous debate surrounding the Milan criteria versus expanded criteria has largely subsided for several reasons. Not only have worldwide organ shortages led to concern that expanded criteria may cause undue prejudice for those patients with even slightly better post-LT prognosis, they have also led to longer LT wait times, which in turn has led to increased use of local-regional therapy (LRT) as a bridge to LT. To this end, the optimal LT criteria for HCC must not only account for tumor size and number, but additional markers of tumor biology including alpha-fetoprotein (AFP) and novel biomarkers, response to LRT, and 18F-labeled fluoro-2-deoxyglucose positron emission tomography (18F-FDG-PET) imaging. When outlining the optimal LT criteria for patients with HCC, it is imperative to account for transplant survival benefit, defined as a patient’s post-LT life expectancy minus their wait-list life expectancy. Although most HCC selection criteria have focused on the former (ensuring acceptable post-LT life expectancy), the latter is just as important in that patients with a long wait-list life expectancy will derive less benefit from LT. Berry and Ioannou1 found that patients with HCC derive a significantly lower 5-year survival benefit from LT than patients without HCC. Importantly, however, the goal for LT for patients with (and without) HCC is survival well beyond 5 years, whereas wait-list removal because of tumor progression is accompanied by poor long-term survival. When approaching wait-list survival to design the optimal LT criteria, both tumor and liver-related factors should be considered. Using the European HCC and LT (EurHeCaLT) project, Lai et al.2 studied more than 2100 patients and found that Model for End-Stage Liver Disease (MELD) score less than 13, tumor burden within Milan criteria, and complete response to LRT were all factors that decreased the survival benefit of LT. These results are similar to a previous analysis from our center3 that showed that patients with a single, small 2- to 3-cm tumor and low AFP level less than 20 ng/mL who had a complete response to LRT (20% of cohort) have a very low risk of wait-list dropout, and thus likely derive minimal short-term benefit from LT. Finally, an analysis of the United Network of Organ Sharing (UNOS) database4 found that a combination of tumor (single lesion 2-3 cm and AFP < 20 ng/mL) and liver-related characteristics (Child A cirrhosis and MELD–sodium [MELD-Na] < 15) identifies a subgroup with a low wait-list dropout risk. Taken together, patients with compensated liver disease and relatively minimal tumor burden who have a low AFP level and complete response to LRT have a long wait-list life expectancy, and thus optimal LT criteria should reduce (or eliminate) priority for these patients. Nearly all of the proposed pre-LT selection criteria models have incorporated one or more serum makers in addition to various tumor size and number cutoffs. AFP has received the most attention, with a plethora of data suggesting that an elevated AFP level significantly worsens post-LT outcome. A recent multicenter study5 and analysis of the UNOS database6 have shown that post-LT outcome worsens beginning at an AFP cutoff of 16 to 20 ng/mL. On the other end of the spectrum, various cutoffs have been used for exclusion from LT including a more than 400 ng/mL cutoff7 and a 1000 ng/mL cutoff in the United States.8 However, the optimal LT criteria would go one step further to take into account AFP response to LRT (Table 1). In the UNOS database, for patients with an AFP ever greater than 1000 ng/mL, reduction of AFP at LT to less than 100 ng/mL after LRT results in a 5-year survival rate of 88% compared with 67% in those whose AFP level at LT reduced to 101 to 499 ng/mL and only 49% if AFP remained greater than 1000 ng/mL at the time of LT.9 Similarly, Halazun et al.10 showed that AFP responders to LRT (e.g., AFP 200-1000 ng/mL that decreased to <200 ng/mL with LRT) had significantly better post-LT outcome than AFP nonresponders. Rising AFP slope of more than 7.5 to 15 ng/mL/month despite LRT also predicts poor post-LT outcome.11, 12 Additional serum marker cutoffs associated with inferior post-LT outcome include AFP-L3 greater than 35%, des-γ carboxyprothrombin (DCP) greater than 400 mAU/mL (or 7.5 ng/mL), and neutrophil-to-lymphocyte ratio (NLR) greater than 513-15 (Table 1), although these findings require confirmation. Although post-LT outcome for the majority of patients within Milan criteria (excluding those with a very high AFP) are quite good, one relatively recent advance has been to better identify those patients beyond Milan criteria who will have acceptable post-LT survival. One common strategy in such patients is tumor down-staging, especially in the United States, where currently patients must be within Milan criteria to receive MELD exception. Although tumor progression after LRT typically portends a poor post-LT prognosis,2, 12 complete or partial response to down-staging treatments functions as a criterion to select those with good tumor biology, and thus likely acceptable post-LT outcome. Single-center and multicenter studies from UNOS Region 516, 17 have shown excellent post-LT outcome after successful down-staging in carefully selected patients exceeding the Milan criteria with post-LT outcomes comparable with those always within Milan. This down-staging protocol (Table 2) has recently become national policy in the United States. However, in patients with HCC exceeding these criteria (“all-comers”) who undergo attempted down-staging (Table 2), both wait-list outcome and intention-to-treat survival are poor. Sinha et al.18 found an 80% probability of dropout within 3 years of HCC diagnosis for those presenting within “all-comers” criteria, along with a 5-year intention-to-treat survival rate of only 20%, suggesting that an upper limit in tumor burden probably exists beyond which successful LT after tumor down-staging becomes an unrealistic goal. AND A patient with acute hepatic decompensation after LRT is not eligible for LT unless criteria for successful down-staging and minimal observation period are met. Another potential selection criterion for patients beyond Milan criteria, especially in LT centers with either short LT wait times or prior to live donor liver transplant (LDLT), is to use 18F-FDG-PET scans, an excellent predictor of worse tumor differentiation and microvascular invasion. FDG-negative patients beyond Milan criteria have satisfactory post-LT outcome,19, 20 whereas those with a tumor-to-nontumor ratio (TNR) greater than 2 tend to do poorly19 (Table 1). Worldwide, time from HCC diagnosis to LT varies quite significantly by center and primarily depends on deceased donor organ supply versus demand, as well as how commonly LDLT is performed. In the United States, a mandatory delay of 6 months before granting MELD exception was introduced in 2015 primarily to balance access to LT for patients with and without HCC, but it may improve candidate selection as well. A minimal observation period is required to assess tumor behavior (e.g., radiographic and AFP response to LRT) to avoid transplanting aggressive tumors21 (Fig. 1). Analyses of the UNOS database have found that a short waiting time of less than 4 to 6 months is associated with worse post-LT outcome.22 Long wait times, in contrast, could lead to more aggressive tumor biology and unnecessary wait-list dropout. A recent multicenter study found that the optimal time from HCC diagnosis to deceased donor LT to minimize wait-list dropout and post-LT recurrence was 6 to 18 months (Table 1), because those who received LT outside this “sweet spot” had a 60% increased risk for recurrence within 5 years of LT (16% versus 10%).23 Given the desire to increase access to LT for as many patients with HCC as possible, along with the multitude of data suggesting that many patients beyond Milan criteria have acceptable post-LT outcome, a number of pre-LT selection models have been proposed (Table 3). One interesting aspect regarding these criteria is that centers with longer wait times use down-staging/response to LRT by necessity, whereas centers that primarily perform LDLT and have short wait times tend to have fairly liberal tumor burden criteria but rely heavily on biomarkers and/or negative 18F-FDG-PET scan. For example, the National Cancer Center Korea criteria include total tumor diameter less than 10 cm and negative PET scan, and in LDLT recipients meeting these criteria, overall survival rate at 5 years post-LT was 84% compared with only 60% in those exceeding these criteria.20 In addition, the Kyoto criteria include those with fewer than 10 tumors, largest tumor size less than 5 cm, and DCP level less than 400 mAU/mL with 5-year post-LDLT survival rate of 82% compared with 42% in those not meeting these criteria.15 5-Year recurrence-free survival: Tumor #: 0.68 Size: 0.64 DCP: 0.71 To maximize survival benefit, the LT community should consider reducing (or eliminating) priority for the 10% to 20% of patients with HCC with very long wait-list life expectancy (e.g., Child-Pugh A, low MELD and AFP, and single tumor up to 3 cm with complete response to LRT). On the other end of the tumor burden spectrum, some determination of tumor biology should be obtained in patients presenting beyond Milan criteria (in addition to AFP). Reasonable approaches include LRT for tumor down-staging, measuring novel biomarkers such as AFP-L3 and DCP, and PET scan. Results from the various proposed pre-LT models (Table 3) that include such criteria have suggested that acceptable post-LT outcome can be achieved in selected patients with HCC beyond Milan criteria. Although it is impossible to compare all of these selection models, the optimal LT criteria should be center specific, taking into account the availability of donor organs and what post-LT outcome is considered acceptable. Centers performing primarily LDLT may be willing to accept lower 5-year post-LT survival rates by using less restrictive criteria than centers with significant organ shortages, where post-LT outcome for patients with or without HCC should be similar.

Hepatitis B and C viruses yield carcinogenic effects and cause hepatocellular carcinoma (HCC), which is becoming one of the most challenging health problems in many countries.1-3 Although new promising strategies for liver resection have been developed recently,4 liver transplantation remains the only cure for HCC in many cases, particularly because of the severe underlying liver disease and presence of portal hypertension.5 Additionally, HCC is often multifocal, and thus total hepatectomy followed by orthotopic liver transplantation (OLT) remains the best rational approach. Two obstacles hamper the "unrestricted" therapy of HCC with transplantation. First, the necessary immunosuppression may lead to a rapid and aggressive tumor recurrence in patients with an advanced disease. Second, the chronic imbalance between the increasing number of candidates for liver transplantation and the limited organ supply has made it necessary to limit OLT to patients with a good prognosis. Over many years, most centers and national policymakers of organ allocation have applied the restrictive selection criteria reported in 1996 by Mazzaferro et al.,6 who demonstrated a 4-year survival rate of 75%. Mazzaferro et al. defined in their study the so-called "Milan criteria," which limit OLT to patients presenting with a single HCC less than 5 cm in diameter or 2 to 3 lesions less than 3 cm in diameter (Table 1). HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; OLT, orthotopic liver transplantation; PIVKA-II, prothrombin induced by vitamin K absence II; UCLA, University of California at Los Angeles; UCSF, University of California at San Francisco. In recent years, several groups from different countries have challenged these restrictive criteria. A group from the University of California at San Francisco (UCSF) retrospectively analyzed 2000 patients presenting with a single tumor less than 6.5 cm in diameter or 2 lesions less than 4.5 cm in diameter with a total tumor diameter less than 8 cm.7 They reported an astonishing 5-year patient survival of 75%. The same group published in 2007 the results of a prospective validation study of 168 patients who met the UCSF criteria on pretransplant imaging.8 The results confirmed their initial observation; for example, the 38 patients who exceeded the Milan criteria but met the UCSF criteria had a 5-year recurrence-free probability of 93.6%. The group from The University of California, Los Angeles, CA, reviewed their 22-year experience with 467 patients with HCC who underwent an OLT.9 In this large series, patients meeting the Milan criteria had 5-year survival comparable to that of patients respecting the UCSF criteria, whereas those presenting tumors beyond UCSF criteria had significantly lower 5-year survival. A plea for expanded criteria came also from the International Registry of Hepatic Tumors in Liver Transplantation, from which data from 1206 transplant recipients with HCC were available.10 In this report, patients with 2 to 4 tumors less than 5 cm or single lesions less than 6 cm had recurrence-free survival equivalent to that of patients presenting with HCC within the Milan criteria. Even less restrictive criteria were applied by the group from Kyoto, who reported the results of living donor liver transplantation (LDLT) in 125 patients with HCC.11 These authors defined new criteria based on a multivariate analysis of risk factors for posttransplant recurrence, including a wide range of preoperative tumor variables. They found that patients with up to 10 tumors less than 5 cm in diameter and with less than 400 mAU/mL prothrombin induced by vitamin K absence II (a new tumor marker for HCC),12 as documented in 78 patients, enjoyed an 86.7% 5-year survival, whereas those exceeding these criteria had a 5-year survival of only 34.4%. Another group from Japan reported a series of 60 patients who underwent LDLT for HCC, in which the number of tumors did not correlate with the prognosis, but only patients with a tumor diameter of more than 5 cm had significantly poorer prognosis.13 A third Japanese group from Tokyo applied the so called "5-5 rule" by limiting adult living liver transplantation to patients with up to 5 nodules with a maximum diameter of 5 cm.14 The recurrence-free 3-year survival of patients who fulfilled the criteria was 94% versus 50% of those patients exceeding the 5-5 rule. The Berlin group reported on a small series of 21 recipients of LDLT for HCC, in which solitary HCCs were accepted, regardless of their diameter, unless vascular invasion was identified.15 In this study, the diameter for single HCC was not limited, and multiple HCC tumors were considered acceptable up to a diameter of 6 cm for the largest nodule and a total diameter of 15 cm. The overall 3-year survival of patients in this study not meeting the Milan criteria (n = 13) or the UCSF criteria (n = 8) was 62% and 53%, respectively. Most of the recent studies looking at OLT for HCC reported on excellent results in many patients exceeding the Milan criteria.8-12 Of note, the Berlin group accepted a lower long-term survival rate (53%, as discussed previously) by further exceeding the Milan and UCSF criteria to tumors with diameters more than 10 cm. This more aggressive approach raises the question of what survival rate is acceptable for LDLT16-18 or, in other words, whether expanded criteria associated with poorer outcome are acceptable in patients receiving a living donor graft.18, 19 Thus, accumulating evidence from at least 7 important studies published in 20078-11, 13-15 indicates that the Milan criteria are becoming outdated. The question, however, is which criteria should be the new gold standard. Sung-Gyu Lee and colleagues20 from the Asan Medical Center, Seoul, Korea, provide challenging data in this issue of Liver Transplantation. On the basis of a retrospective analysis of 221 LDLT recipients with HCC, they submit that minimal criteria for OLT can be dramatically widened (≤6 nodules with the largest tumor size ≤ 5 cm and absence of gross vascular invasion). One hundred eighty-six of the 221 patients were within these criteria, enjoying an actuarial 76.3% 5-year survival. In contrast, those patients beyond the so-called Asan criteria had only an 18.9% 5-year survival. The posttransplant tumor recurrence rates of the 22 patients beyond the Milan criteria, but within the Asan criteria, after 1, 3, and 5 years were 0%, 9.1%, and 9.1%, respectively. The same figures regarding patient survival were 100%, 88.9%, and 80%. The strength of this article is the largest reported series of LDLTs performed in patients with HCC at a single center. The authors of this high-volume center demonstrate a low perioperative 3-month mortality of only 6.8%. By the enlargement of the Milan criteria, 22 (10%) of the patients with HCC could benefit from a long-term survival comparable to that of patients transplanted within the Milan criteria. Because these excellent results are acceptable for both living donors and deceased donors, this article on LDLT does not touch the ethically critical question of whether criteria for living donation may be looser than those used for deceased donors.21 This retrospective analysis from Lee et al.20 has, however, some important shortcomings. A potential flaw lies in the study design. The authors identified their new criteria through a multivariate analysis of a variety of risk factors for recurrence of HCC. In an attempt to validate their new criteria, they used the very same patient population, which resulted, not surprisingly, in good prognostic and discriminatory power. This approach is questionable, as any newly defined criteria should be validated in a different patient population and at best with a prospective protocol, as recently performed for the UCSF criteria.8 Next, because of the epidemiology of liver disease in Korea, 93.2% of the patients suffered from post–hepatitis B cirrhosis; this might represent an important factor related to the good outcome observed in patients transplanted with the enlarged criteria.22 In Western countries and North America, hepatitis C virus infection is the leading cause for end-stage liver disease and HCC. A recent study by a group from Rochester, NY, has shown that hepatitis C is a significant predictor of tumor recurrence and impaired survival after OLT in patients with HCC.23 The authors of this study concluded that there may be a benefit in an expansion of the Milan criteria for HCC in the non–hepatitis C population. This conclusion seems supported by the results of Lee et al. Although the group of Lee in Korea and other groups from Japan have challenged the Milan criteria, accepting a much higher number of nodules (up to 10!),11, 13, 14 a number of groups from the United States and Europe have mainly focused on enhanced criteria regarding the tumor diameter (more than 5 cm).8-10, 15 In conclusion, the current article by Lee et al.20 in this issue of Liver Transplantation is well in line with several other recent reports, which also propose enlarged criteria beyond the Milan criteria for OLT in patients with HCC. Because healthcare provider and national rules for listing patients with HCC still rely on the Milan criteria, it seems imperative to redefine the criteria on the basis of these many recent reports. An international consensus conference is urgently needed.

Potential conflict of interest: Nothing to report. See Article on Page 369 For patients with hepatocellular carcinoma (HCC) exceeding the Milan criteria, survival after liver transplantation (LT) incrementally decreases with increasing tumor size and number.1 The allocation system for deceased donors in the United States is largely restricted to HCC within Milan criteria and does not accommodate to even modest expansion of tumor size.2 Wait‐list dropout rates remain substantial even for HCC within Milan criteria in long wait‐time regions.3 Living donor liver transplantation (LDLT) has been performed for patients with HCC beyond Milan criteria adhering to the principle that the risk to the donor is justified by the expectation of an acceptable outcome for the recipient (double equipoise).4 However, the boundaries of tumor size and number to be considered for LDLT have varied widely among centers without a consensus based on reproducible data.5 Furthermore, the minimal acceptable survival threshold after LDLT has not been well defined. In this issue of Liver Transplantation, Llovet et al. from the Barcelona Clinic Liver Cancer (BCLC) group report their longterm results up to 10 years following LDLT for HCC beyond Milan criteria in a prospectively applied protocol.6 The study cohort met the proposed BCLC extended criteria (1 tumor > 5 cm but ≤ 7 cm, 2‐3 tumors at least 1 tumor > 3 cm but ≤ 5 cm, or 4‐5 tumors ≤ 3 cm) and other protocol eligibility requirements including Eastern Cooperative Oncology Group performance status 0 and Child‐Pugh class A/B. Out of 22 patients enrolled between 2001 and 2014, 5 were successfully downstaged with local‐regional therapy (LRT) from beyond BCLC extended criteria to within Milan criteria. A total of 12 of the 22 patients received LRT, in whom 10 were downstaged to within Milan criteria prior to LDLT. This study was therefore composed of a heterogeneous group of patients who underwent LDLT either with extended criteria or after tumor downstaging—2 different approaches that should be considered separately. Explant tumor stage exceeded BCLC extended criteria in 50% (understaged) and within Milan criteria in 18% (downstaged). Poorly differentiated tumor grade and microvascular invasion were observed in 23% and 46%, respectively. Despite the frequency of unfavorable histopathologic characteristics, 5‐ and 10‐year survival rates after LDLT were excellent at 80% and 67%, respectively. The cumulative probability of HCC recurrence was 24% and 44% at 5 and 10 years, respectively. In all but 1 case, HCC recurrence occurred beyond 4 years after LDLT. The reason for the surprising predominance of late HCC recurrence is unknown. All 7 (32%) patients with HCC recurrence had recurrent hepatitis C after LDLT, including 5 with graft cirrhosis. Some of these cases might therefore represent de novo HCC development in a graft with advanced fibrosis rather than recurrent tumor. An intriguing question raised in the BCLC study is whether downstaging is preferable to expansion of criteria in LDLT. The proposed BCLC extended criteria are very similar to the University of California, San Francisco downstaging criteria, which also include an upper limit in the total tumor diameter (1 tumor > 5 cm but ≤ 8 cm, 2‐3 tumors at least 1 tumor > 3 cm but ≤ 5 cm with total tumor diameter ≤8 cm, or 4‐5 tumors ≤ 3 cm and total tumor diameter ≤8 cm).7 The 10 patients in the BCLC study who achieved downstaging to within Milan criteria by preoperative radiographic assessment had a significantly better 5‐ and 10‐year survival of 90% when compared with that in the other 12 patients who did not receive LRT or did not achieve downstaging (70% and 52%, respectively). These observations thus provide further support of downstaging as a selection tool,7 but the small sample size precludes drawing firm conclusions. When compared with the proposed BCLC extended criteria, more liberal upper limits in tumor size and number for LDLT have been advocated by other groups predominantly from Asia.5 Some of these proposed criteria have incorporated additional assessments of tumor aggressiveness (histology or biomarkers) beyond tumor size and number in candidate selection. Alpha‐fetoprotein (AFP) is a well‐established biomarker for discriminating prognosis after LT for HCC.1 An AFP > 1000 ng/mL is associated with particularly poor post‐LT outcomes and has been implemented as an exclusion criterion in the priority system of organ allocation in the United States (unless AFP decreases to <500 ng/mL with LRT).9 None of the patients in the BCLC study had AFP > 1000 ng/mL and only 1 had an AFP > 100 ng/mL before LDLT. The extended Toronto criteria10 pose no restrictions in tumor size and number but require biopsy of the largest tumor to exclude poorly differentiated tumor grade. With this approach, the 5‐year post‐LT survival of 69% was similar to that for HCC within Milan criteria.10 The National Cancer Center Korea criteria include total tumor diameter <10 cm and negative [18F]fludeoxyglucose positron emission tomography. In LDLT recipients meeting these criteria preoperatively, the 5‐year survival was 84% versus 54% in those exceeding these criteria.11 Des‐gamma‐carboxyprothrombin (DCP) has been incorporated into the Kyoto criteria. Those with <10 tumors, largest tumor <5 cm, and DCP of <400 mAU/mL had a 5‐year survival of 88% after LDLT, versus only 42% in those exceeding these criteria.12 Although these liberal criteria have produced surprisingly good 5‐year survival after LDLT, they require independent validation. In summary, the results of this pilot study by the BCLC group6 highlight a cautious approach to expanding HCC indications for LDLT, with 5‐ and 10‐year survival rates comparable to that in patients receiving a cadaveric graft. The small number of patients represents a major limitation, and the results therefore require confirmation in a larger cohort. This study also suggests superior outcome with downstaging to Milan that may prove to be the preferred approach over expanded criteria for LDLT. A large, prospective multicenter study applying uniform expanded criteria with and without downstaging and incorporating biomarkers of tumor aggressiveness in candidate selection will take us 1 step closer to developing a consensus approach to LDLT for HCC.

Hepatocellular carcinoma (HCC) has been a major reason for liver transplantation (LT). Globally, LT for HCC is performed on the basis of the Milan criteria, and if performed within those criteria, then the outcome is not different from that of LT performed for other primary diseases. On the other hand, the scope of the Milan criteria covers only early-stage HCC, and many HCC patients do not meet the criteria even at the time of diagnosis. Therefore, over the last decade, efforts have been made to perform LT for patients whose clinical characteristics lie outside the Milan criteria. In Japan, more than 99% of LTs are living donor LTs (LDLTs) and more than 15% of LTs are performed in patients with HCC. The 1- and 3-year actual survival rates of LDLT for HCC in Japan are 82 and 79%, respectively. Efforts to extend the Milan criteria have also been made in Japan. To improve the outcome of LT for HCC, pre- and postoperative management of hepatitis B and hepatitis C, and immunosuppressant specific for this type of LT are still crucial issues. In this review, we provide an overview of current outcome, efforts to extend the Milan criteria, control of viral hepatitis, and immunosuppression for LT in patients with HCC.

Comparison of hepatitis B prophylactic outcomes in living donor liver transplantation recipients who meet the Milan or UCSF criteria

The Milan criteria are still considered the gold standard for patient selection criteria for liver transplantation in patients with hepatocellular carcinoma. However, those criteria may be too strict and thus exclude a significant number of patients who could benefit from liver transplantation. Based on this notion, many expanded selection criteria have been suggested. In Asian countries, where there is a serious shortage of deceased donor organs, living donor liver transplantation accounts for the majority of all liver transplant cases. Because living donor liver transplantation is not controlled by the public allocation system, the indications for living donor liver transplantation can be expanded. In Korea, living donor liver transplantation depends entirely on the discretion of the transplant team and the donor. Hence, Korean transplant centers have had a reasonable amount of experience with liver transplantation for advanced hepatocellular carcinoma. Experiences in Korea show that serum alpha-fetoprotein level, des-gamma-carboxy prothrombin level and positron emission tomography are very useful biomarkers in predicting tumor recurrence after transplantation. Tumors that show favorable levels of these biomarkers might not recur after transplantation despite being morphologically advanced. In addition, combination therapy with mammalian target of rapamycin inhibitors and sorafenib may improve survival even after tumor recurrence. Therefore, in Korea, living donor liver transplantation is considered even for cases of far advanced hepatocellular carcinoma if a recipient has no other effective treatment options and a well-informed donor wishes to willingly participate.

Improvement in Survival Associated With Adult-to-Adult Living Donor Liver Transplantation

We read with great interest the recent article by Yoshizumi et al. (1), which evaluated the risk factors that increased mortality after living-donor liver transplantation. Their study found that male recipients of transplants from female donors (FM), those having pretransplantation diabetes mellitus (DM), and having a model for end-stage liver disease score of 20 or more were independent risk factors that predicted poor survival for LDLT recipients. Nevertheless, close inspection of the study revealed some methodological issues that are worth mentioning and clarifying. First, Yoshizumi et al. (1) reported 335 cases of living-donor liver transplantation (LDLT), which included 180 cases of benign end-stage liver diseases and 155 cases of hepatocellular carcinoma (HCC). HCC accounts for nearly half of the cohort patients, and HCC recurrence is the main cause of death in the study (14/80). However, none of the risk factors that increased mortality after LDLT in the study, to our knowledge, is related to HCC recurrence. Tumor recurrence is the main cause of death after liver transplantation for HCC, as demonstrated by previous studies (2, 3). Not surprisingly, some factors associated with biologic aggressiveness, such as tumor number, tumor differentiation grade, presence of a peritumoral capsule, and microscopic vascular invasion, were independent predictors of survival (4–7). In other words, tumor biology determines outcome after liver transplantation for HCC, whereas for benign end-stage liver diseases, the factors that predicted survival were model for end-stage liver disease scores and Child-Pugh category (8–10). Recently, Li et al. (11) reported that preoperative renal dysfunction, intraoperative red blood cell transfusions of greater than 5 U, and female-to-male gender match were independent risk factors that predicted poor survival for LDLT recipients with benign end-stage liver diseases. Therefore, it is not very proper to analyze the factors that predicted poor survival of LDLT recipients, which were mixed by benign end-stage liver diseases and HCC. The authors should separately analyze the factors that predicted survival of LDLT for HCC and benign end-stage liver diseases. Second, the authors reported that the 1-year, 3-year, and 5-year survival rates after LDLT for HCC were 91.7%, 80%, and 69%, whereas rates for benign end-stage liver diseases were 80.5%, 74.7%, and 73.0% (in Table 2 of Yoshizumi et al. (1)). Patients in the HCC group showed higher 1-year, 3-year, 5-year survival rates compared with patients in the benign end-stage liver diseases group, although this difference was not statistically significant (P=0.077). Did the authors consider that the long-term survival rates of LDLT for HCC were equal to LDLT for benign liver diseases? What criteria were used to screen HCC patients for LDLT in the authors’ institute? Milan criteria, University of California San Francisco criteria, or other criteria? Third, the distribution of the HCC was markedly skewed among the four groups (in Table 1 of Yoshizumi et al. (1)), and the FM group owned the highest proportion of HCC in the four groups (P<0.001). Although the HCC was not identified as a risk factor that predicted poor survival in the study, a subgroup analysis in the FM group should be performed according to the HCC to exclude the effect of HCC on survival. Moreover, the pretransplantation DM is another risk factor that predicted poor survival after LDLT. Similarly, the distribution of the pretransplantation DM was markedly skewed among the four groups (in Table 1 of Yoshizumi et al. (1)). The female donor to female recipient group owned the lowest proportion of pretransplantation DM (0%), whereas the FM group owned a significantly higher proportion of pretransplantation DM (20.33%) (P=0.001). In contrast, the FM group showed significantly worse patient survival rates compared with the female donor to female recipient group (P<0.01). In order to exclude the effect of pretransplantation DM on survival in the FM group, a subgroup analysis should be performed according to the pretransplantation DM. The authors can perform a subgroup analysis in the FM group according to the graft weight-standard liver weight ratio. Why did the authors not perform a subgroup analysis in the FM group according to the pretransplantation DM?

Hepatocellular carcinoma (HCC) is the second most common cause of male cancer death in Korea, where the major etiology, chronic hepatitis B virus infection, is endemic. With a high incidence of unresectable HCCs and a low cadaveric organ donation rate, the number of adult living-donor liver transplantations (LDLTs) has increased rapidly, by tenfold, over the past 10 years, as an alternative to deceased-donor liver transplantation (DDLT) in Asia, including Korea. Currently, HCC accounts for more than 40% of the indications for adult LDLT as the associated decompensation cirrhosis or unresectable HCC with 2.8% perioperative mortality at our institute. In determining eligibility for LDLT, the Milan criteria, which have a major aim of reducing the wastage of cadaveric liver grafts, still remain the gold standard. Our published results with 168 adult LDLTs show no difference from the results with DDLT for HCC that meets the Milan criteria. However, since a substantial proportion of adult LDLT patients not fulfilling the Milan criteria have been found to survive for longer than expected, and because a live donor organ is a private gift, most LDLT programs in Korea accept HCC patients beyond the Milan criteria, and the reported 3-year survival rates for such patients are approximately 63%. Our new proposal for expanded criteria (Asan criteria; tumor diameter <or=5 cm, number of lesions <or=6, no gross vascular invasion) in LDLT has focused on extending the number limits but keeping the maximum tumor size at 5 cm, because even modest expansion of tumor size limits beyond the Milan criteria adversely affected survival. The overall 5-year patient survival rates were 76.3 and only 18.9% within and beyond the Asan criteria, respectively; these criteria broaden the indications for patient selection and can more accurately identify patients who will benefit from LDLT than the conventional Milan criteria and the University of California at San Francisco criteria. In Asia, where the option for DDLT is minimal or negligible, LDLT with the modest expanded selection criteria will continue to provide a chance of long-term survival for some patients with advanced HCC.