Hepatologists' Perception of the Recipient Registration Criteria for Deceased Donor Liver Transplantation: A Survey in Hokuriku, Japan

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

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.

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

Liver transplantation is the optimal radical therapy for patients with cirrhosis and hepatocellular carcinoma (HCC). The Milan criteria are widely applied for deceased donor liver transplantation (DDLT) in the western countries. Living donor liver transplantation (LDLT), however, prevails in Asian countries due to the extreme shortage of deceased donor organs. In contrast to DDLT, the feasibility of LDLT is not restricted by the national allocation system, and therefore the indications for LDLT in patients with HCC depend on institutional policies that consider both the operative risk to the donor and the survival benefit for the recipient. The results of a nationwide survey as well as the experiences of individual centers demonstrate similar outcomes for patients whose tumors fall within the Milan criteria and those whose tumors extend beyond the Milan criteria.

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.

The aim of this work is to study the different factors that affect the outcome of living donor liver transplantation for patients with hepatocellular carcinoma (HCC). Between April 2003 to November 2014, 62 patients with liver cirrhosis and HCC underwent living donor liver transplantation (LDLT) in the National Liver Institute, Menoufia University, Egypt. The preoperative, operative, and postoperative data were analyzed. After studying the pathology of explanted liver; 44 (71%) patients were within the Milan criteria, and 18 (29%) patients were beyond Milan; 13 (21.7%) of patients beyond the Milan criteria were also beyond the University of California San Francisco criteria (UCSF) criteria. Preoperative ablative therapy for HCC was done in 22 patients (35.5%), four patients had complete ablation with no residual tumor tissues. Microvascular invasion was present in ten patients (16%) in histopathological study. Seven (11.3%) patients had recurrent HCC post transplantation. The 1, 3, 5years total survival was 88.7, 77.9, 67.2%, respectively, while the tumor-free survival was 87.3, 82.5, 77.6%, respectively. Expansion of selection criteria beyond Milan and UCSF had no increased risk effect on recurrence of HCC but had less survival rate than patients within the Milan criteria. Microvascular invasion was an independent risk factor for tumor recurrence.

Predictors of outcome of living donor liver transplantation for hepatocellular carcinoma

Predictors of Outcome of Living Donor Liver Transplantation for Hepatocellular Carcinoma

Predicting Hepatocellular Carcinoma Recurrence Beyond Milan Criteria After Liver Resection for Solitary Hepatocellular Carcinoma

Echinococcus granulosus: A novel parenchymal sparing surgical treatment

Programmed death protein 1 (PD-1) pathway is one of the most critical mechanisms in tumor biology of hepatocellular carcinoma (HCC). The study aimed to assess the prognostic influence of pretransplant serum soluble PD-1 (sPD-1) in patients undergoing liver transplantation for treatment of HCC.Data from 229 patients with HCC who underwent living donor liver transplantation between January 2010 and December 2015 were retrospectively evaluated. Stored serum samples were used to measure sPD-1 concentrations.Overall survival (OS) and disease-free survival (DFS) rates were 94.3% and 74.5% at 1 year; 78.2% and 59.2% at 3 years; and 75.4% and 55.5% at 5 years, respectively. Prognostic analysis using pretransplant serum sPD-1 with a cut-off of 93.6 μg/mL (median value of the study cohort) did not have significant prognostic influence on OS (P = .69) and DFS (P = .26). Prognostic analysis using sPD-1 with a cut-off of 300 μg/mL showed similar OS (P = .46) and marginally lower DFS (P = .070). Combination of Milan criteria and sPD-1 with a cutoff of 300 μg/mL showed similar outcomes of OS and DFS in patients within and beyond Milan criteria. Multivariate analysis revealed that only Milan criteria was an independent prognostic for OS and DFS, but pretransplant sPD1 with a cut-off of 300 μg/mL did not become a prognostic factor.The results of this study demonstrate that pretransplant serum sPD-1 did not show significant influences on post-transplant outcomes in patients with HCC. Further large-scale, multicenter studies are necessary to clarify the role of serum sPD-1 in liver transplantation recipients.

Programmed death protein 1 (PD-1) pathway is one of the most critical mechanisms in tumor biology of hepatocellular carcinoma (HCC). The study aimed to assess the prognostic influence of pretransplant serum soluble PD-1 (sPD-1) in patients undergoing liver transplantation for treatment of HCC. Data from 229 patients with HCC who underwent living donor liver transplantation between January 2010 and December 2015 were retrospectively evaluated. Stored serum samples were used to measure sPD-1 concentrations. Overall survival (OS) and disease-free survival (DFS) rates were 94.3% and 74.5% at 1 year; 78.2% and 59.2% at 3 years; and 75.4% and 55.5% at 5 years, respectively. Prognostic analysis using pretransplant serum sPD-1 with a cutoff of 93.6 µg/mL (median value of the study cohort) did not have significant prognostic influence on OS (p = 0.69) and DFS (p = 0.26). Prognostic analysis using sPD-1 with a cutoff of 300 µg/mL showed similar OS (p = 0.46) and marginally lower DFS (p = 0.070). Combination of Milan criteria and sPD-1 with a cutoff of 300 µg/mL showed similar outcomes of OS and DFS in patients within and beyond Milan criteria. Multivariate analysis revealed that only Milan criteria was an independent prognostic for OS and DFS, but pretransplant sPD1 with a cutoff of 300 µg/mL did not become a prognostic factor. The results of this study demonstrate that pretransplant serum sPD-1 did not show significant influences on post-transplant outcomes in patients with HCC. Further large-scale, multicenter studies are necessary to clarify the role of serum sPD-1 in liver transplantation recipients.

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

Comparison of the survival and tolerability of radioembolization in elderly vs. younger patients with unresectable

An international conference of transplant physicians, surgeons, and allied health professionals was held in Vancouver, Canada, on September 15 and 16, 2005 to address the care of the live lung, liver, pancreas, and intestine organ donor. The Vancouver Forum was convened under the auspices of the Ethics Committee of The Transplantation Society. Forum participants included over 100 leaders in organ transplantation, representing many countries from around the world, including participants from the following continents: Africa, Asia, Australia, Europe, North and South America. The objective of the Vancouver Forum was to develop an international standard of care for the live lung, liver, pancreas and intestinal organ donor. This Vancouver Forum followed a conference convened in Amsterdam on the care of the live kidney donor (1, 2). There were four organ specific work groups at the Vancouver Forum: lung, liver, pancreas and intestine. Each organ work group addressed the following topics in concert and reported their findings in a plenary presentation to all participants: