Toward Optimizing the Indications for Orthotopic Liver Transplantation in Hepatocellular Carcinoma

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1 LIVER TRANSPLANTATION 17:S6-S13, 2011 SUPPLEMENT Toward Optimizing the Indications for Orthotopic Liver Transplantation in Hepatocellular Carcinoma Didier Samuel, 1,2,3 Massimo Colombo, 4 Hachem El-Serag, 5,6 Rodolphe Sobesky, 1,2,3 and Nigel Heaton 7 1 Centre Hepato-Biliaire, AP-HP Hopital Paul Brousse, Villejuif, France; 2 Unite 785, Inserm, Villejuif, France; 3 UMR-S785, Univ Paris-Sud, Villejuif, France; 4 First Division of Gastroenterology, Foundation of the Scientific Institute for Research, Hospitalization, and Health Care, Mangiagalli and Regina Elena Hospital, Milan, Italy; 5 Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX; 6 Baylor College of Medicine, Houston, TX; and 7 Institute of Liver Studies, King s College Hospital, London, United Kingdom Key Points 1. Liver transplantation is currently an effective therapy for patients with HCC who meet the Milan criteria. 2. The proportion of patients on waiting lists for liver transplantation who have HCC has increased substantially in recent years. HCC is currently one of the major indications for liver transplantation; it is the indication for approximately one-third of liver transplants. 3. If the Milan criteria are not met, the survival rates after liver transplantation for HCC tend to decrease, mainly because of the catastrophic consequences of HCC recurrence. 4. A few studies have supported liver transplantation when the Milan criteria are exceeded, but extensions beyond the Milan criteria remain controversial. Even if an individual patient with HCC who does not meet the Milan criteria might benefit from liver transplantation, the limited number of currently available donor organs limits the indications for liver transplantation to those patients with HCC who have the greatest likelihood of survival after the procedure. 5. To patients with early-stage HCC, surgical resection can be offered if the hepatocellular function is well maintained and severe portal hypertension is not present. 6. To enable patients with HCC to have access to liver transplantation that is similar to the access for other patients without HCC in the MELD allocation system, additional points based on the number and size of HCC lesions are assigned to patients on the waiting list. However, this system requires further refinement to ensure that it is as fair as possible. 7. Liver transplantation for HCC should be restricted to those patients who are expected to have the same posttransplant survival as that of patients with nonneoplastic end-stage chronic liver disease. 8. On the basis of these considerations, a 5-year survival rate of 50% after liver transplantation for HCC seems too low. Liver Transpl 17(10 Suppl 2): S6-S13, VC 2011 AASLD. Received February 10, 2011; accepted July 18, Treatment algorithms for hepatocellular carcinoma (HCC) have evolved into a multidisciplinary therapeutic approach that includes both palliative and curative options. Liver transplantation for HCC has become increasingly common; in Europe, HCC currently accounts for approximately 25% of all indications for liver transplantation. As improvements in treating complications of cirrhosis, controlling the replication of hepatitis B virus (HBV) with nucleos(t)ide analogues, and retarding the replication of hepatitis C virus (HCV) have occurred, the risk of dying from Abbreviations: AFP, alpha-fetoprotein; AP-HP, Assistance Publique-Hôpitaux de Paris; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; Inserm, Institut National pour la Santé et la Recherche Médicale, French National Institute for Health and Medical Research; MELD, Model for End-Stage Liver Disease. Potential conflict of interest: Nothing to report. Address reprint requests to Prof. Didier Samuel, M.D., Ph.D., Centre Hepato-Biliaire, Hopital Paul Brousse, Assistance Publique-Hôpitaux de Paris, 12 Avenue Paul Vaillant Couturier, Villejuif, France. Telephone: þ ; FAX: þ ; didier. samuel@pbr.aphp.fr DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases S6 Liver Transplantation, Vol 17, No 10, Suppl 2 (October), 2011: pp S6-S13

2 LIVER TRANSPLANTATION, Vol. 17, No. 10, 2011 SAMUEL ET AL. S7 decompensated cirrhosis has decreased. In contrast, at least partially because of the increasing survival of patients with cirrhosis in general, HCC has gradually emerged as the most common complication of cirrhosis. Within the past 3 years, the proportion of patients with HCC on waiting lists for liver transplantation has increased dramatically; this proportion has reached more than 30% in France (Agency of Biomedicine), 26% across Europe (European Liver Transplant Registry), and 34% in the United States. 1 Currently, HCC is one of the major indications for liver transplantation worldwide. RATIONALE FOR ADVOCATING LIVER TRANSPLANTATION FOR HCC HCC is the most common primary tumor of the liver; it accounts for 90% of all primary cancers that arise in the liver. 2-4 Cirrhosis is present in approximately 90% of HCC cases. The incidence of HCC has increased substantially in several parts of the world because chronic HCV and HBV infections have become more common. 3,5-7 In the absence of treatment, HCC is associated with a poor prognosis; the 5- year overall survival rate is less than 10%. 8 In the past, HCC was almost always diagnosed at a late stage when patients had become symptomatic and showed evidence of appreciable hepatocellular decompensation. At this late stage, the chance of any treatment significantly improving survival is small. In addition, a high morbidity rate was associated with specific therapies such as surgical resection and systemic chemotherapy. During the past 20 years, major efforts have been made to identify patients at risk of developing HCC, and screening programs for detecting HCC have been introduced. 9,10 Currently, approximately half of patients with HCC who receive care at referral centers and a considerably smaller proportion of patients in community practices are diagnosed at an early stage before cancer-related symptoms have developed. When it is feasible, the partial resection of a cirrhotic liver with HCC is associated with survival rates varying from 35% to 62% at 3 years and from 17% to 50% at 5 years; the rates depend on the stage of the disease. 11,12 The risk of tumor recurrence is high; it may exceed 70% 5 years after the procedure The application of this surgery or therapies designed to ablate tumors is frequently limited by impaired hepatocellular function, severe portal hypertension, or multiple tumor nodules. Hepatic resection tends to be applicable only to solitary liver nodules less than 5 cm in diameter in patients with cirrhosis that is classified as Child-Pugh class A and is associated with mild portal hypertension. Liver transplantation has the advantage of removing both the primary tumor and the underlying cirrhotic liver; the procedure also increases the possibility of determining the etiology of the tumor. HISTORY OF LIVER TRANSPLANTATION FOR HCC The early experience with liver transplantation frequently included patients with HCC because of the lack of alternative treatments and the associated poor life expectancy. After an initial period of enthusiasm during the 1980s, the high recurrence rates and the low 5-year survival rates when liver transplantation was undertaken for large and multinodular HCCs led to liver transplantation being contraindicated for patients with large tumors. 17,18 In 1991, Iwatsuki et al. 19 reported more satisfactory survival rates for patients with small HCCs who underwent liver transplantation. In addition, excellent outcomes after liver transplantation (similar to those for patients with nonmalignant diseases) were reported for patients with small HCCs that had been detected fortuitously during surgery. 20 These tumors either were solitary or comprised just a few nodules less than 5 cm in diameter. At that time, these results of liver transplantation for HCC provided a rationale for the development of criteria for selecting patients with HCC who were better candidates for liver transplantation. 21 In 1993, Bismuth et al. 22 reported that patients with fewer than 3 tumor nodules (each < 3 cm in diameter) were suitable candidates for liver transplantation because their disease-free survival rate after the procedure was superior to the rate after liver resection. Consequently, the performance of liver transplantation for patients with small HCCs became established after the 1996 publication of a study by Mazzaferro et al. 23 They reported excellent outcomes after liver transplantation for patients with a solitary HCC nodule less than 5 cm in diameter or with up to 3 HCC nodules that were each less than 3 cm in diameter; these features were designated the Milan criteria. The 5- year survival rate of patients with HCC selected according to the Milan criteria currently exceeds 70%. 23 Early-stage HCC has become an accepted conventional indication for liver transplantation. SHOULD LIVER TRANSPLANTATION BE RESTRICTED TO A SUBGROUP OF PATIENTS WITH HCC? Because of the paucity of donor organs, efforts have been made to optimize the effectiveness of liver transplantation through the application of strict criteria for selecting patients who have the greatest likelihood of prolonged survival after surgery. However, this policy implies that some patients with HCC slightly more advanced than those allowed by the current strict selection criteria will be excluded, even though liver transplantation for these patients might be associated with acceptable (if not excellent) long-term outcomes. 24,25 The main findings of a 2005 French consensus conference on indications for liver transplantation were as follows: For some patients who undergo liver transplantation for what is considered to be early-stage

3 S8 SAMUEL ET AL. LIVER TRANSPLANTATION, October 2011 HCC, a pathological examination of the explanted liver reveals no HCC. In the United States, this lack of evidence in explanted livers occurs for 14% of patients with a diagnosis of HCC before liver transplantation Excellent 5-year survival rates can currently be achieved after liver resection in patients with a solitary HCC (<3 cm in diameter) and Child- Pugh class A cirrhosis. 3. Patients with HCC who meet the extended University of California San Francisco criteria for liver transplantation, which were established by Yao et al. 24 (1 nodule < 6.5 cm in diameter or multiple nodules, with the largest < 4.5 cm in diameter and the sum of all diameters < 8 cm), have a recurrence-free survival rate after liver transplantation that is close to that achieved with the Milan criteria 4. The concept that liver transplantation may be associated with improved survival in patients with HCC who do not meet the strict Milan criteria has emerged. Consequently, the question has arisen whether (and to what extent) indications for liver transplantation in patients with HCC should be extended. Although data supporting an extension of the selection criteria are limited, an apparent opportunity for extending these criteria has arisen. 27 However, because of the shortage of donor organs, hepatologists are obliged to maintain strict selection criteria for liver transplantation. In particular, patients with HCC who do not meet the Milan criteria have limited access to liver transplantation, and alternative therapeutic approaches for these patients should be considered. In recent years, the perioperative mortality rate associated with liver surgery by experienced surgical teams has been reduced to less than 5%. 12,28 These improved outcomes have resulted from advances in surgery, radiology, and perioperative care and the application of strict criteria for patient selection. Despite a lack of comparative studies, it is possible to recommend hepatic resection for patients with a single HCC lesion if (1) the liver is noncirrhotic or (2) the liver is cirrhotic but hepatocellular function is well maintained, the serum bilirubin level is normal, and the hepatic venous pressure gradient is low. After hepatic resection, the main issue is whether HCC recurs and the opportunity for liver transplantation is lost. Treatment for recurrent disease has not been adequately investigated. However, it has been suggested that patients with recurrent disease may still be candidates for salvage liver transplantation; according to retrospective analyses of patients with recurrent disease, it appears that the majority might benefit from this therapeutic option. 29,30 Because the most accurate predictors of recurrent HCC due to disseminated disease can be identified from pathological findings, some authors have proposed that patients with a high risk of recurrence (those with vascular invasion by the tumor and satellite lesions) should be considered for liver transplantation immediately after hepatic resection. 31 Another determinant of survival and quality of life after liver transplantation is the nature of the underlying liver disease. The recurrence of an HCV infection, which is almost universal in patients with viremia due to HCV who undergo liver transplantation, is consistently associated with shorter survival versus that of comparable patients with diseases of other etiologies. 1,32 In contrast, major advances in the management of HBV infections have led to an appreciably improved prognosis for patients undergoing liver transplantation for HBV-induced chronic liver disease. In addition, control of the underlying liver disease may be a reason for not recommending liver transplantation for patients with small HCCs and well-maintained hepatocellular function because effective alternative therapeutic options are available. Indeed, if the underlying disease can be controlled satisfactorily and the hepatocellular function is well maintained, treatments other than liver transplantation may be optional for patients with small HCCs. This approach is driven by the need to develop a therapeutic strategy that includes alternatives to the use of the limited supply of donor livers but maintains good 5-year survival rates for HCC. In addition to the tumor burden, other important factors that are not specific to HCC should be considered before patients with HCC are selected for liver transplantation. The outcomes after liver transplantation often depend on the selection criteria, which include the etiology of the underlying liver disease and the age of the patient. No specific recommendations concerning age cutoffs apply to HCC or noncancerous conditions. Discussions of the merits of liver transplantation should be conducted on a case-bycase basis. However, the lack of donor organs is the principal factor limiting any extension of the indications for liver transplantation. The shortage of donor organs has led to the introduction of liver transplantation using allografts from living donors. This development has raised the question of whether the therapeutic goals for patients with access to both living and cadaveric donors should be the same. One possible answer to this question was proposed by Bhangui et al., 33 who compared the prognosis of recipients of grafts from living donors (n ¼ 36) with that of recipients of cadaveric grafts (n ¼ 147). Using an intention-to-treat analysis, they found that the recurrence and survival rates in the 2 patient groups were comparable. Living donor liver transplantation is associated with shorter waiting times and, therefore, fewer wait-list deaths; consequently, it is an attractive alternative for patients with HCC who meet validated selection criteria. Because the outcomes of living donor liver transplantation for patients with HCC who do not fulfill the Milan criteria have not been adequately assessed, caution is warranted before living donor liver transplantation is adopted for patients who do not meet validated criteria for selection.

4 LIVER TRANSPLANTATION, Vol. 17, No. 10, 2011 SAMUEL ET AL. S9 WHAT IS THE GOAL: A BENEFIT FOR INDIVIDUAL PATIENTS OR SURVIVAL FOR PATIENTS WITH HCC AFTER LIVER TRANSPLANTATION SIMILAR TO THAT FOR PATIENTS WITHOUT HCC? Long-term survival is the most important outcome when the benefit of any treatment for cancer is being assessed. In the past, a 5-year survival threshold of 50% for patients with liberal selection criteria was considered to be the benchmark generally accepted by hepatologists in the field of liver transplantation. Survival after liver transplantation for HCC is closely linked to the limits of the Milan criteria; for patients with HCC outside these limits, the survival rates tend to decrease, mainly because of the consequences of disease recurrence. Even if a particular patient in this subgroup might benefit from liver transplantation, the overall 5-year survival rate of 50% for the entire subgroup is not acceptable in the current era of donor organ shortages. 34,35 Several groups have proposed extensions of the Milan criteria for liver transplantation, but most studies that are cited in support of these proposals have been retrospective and have been based on analyses of explanted livers (ie, information not available before surgery). 24,35-39 Recently, Mazzaferro et al. 25 made an interesting contribution to this controversy in their retrospective review of pathology after liver transplantation for HCC in 1556 patients; 1112 of these patients had tumors that did not fulfill the Milan criteria. In a subgroup of 283 patients not meeting the Milan criteria whose tumors were within the up-to-7 criteria (ie, HCCs with a maximum score of 7, with the score being the sum of the size of the largest tumor and the total number of tumors) and were not characterized by microvascular invasion, the overall 5-year survival rate was 71.2%. Despite the inherent methodological concerns associated with retrospective pathological assessments of the tumor burden, this study provides further support for liver transplantation for patients with HCC lesions not meeting the Milan criteria because the limits for the extension of the Milan criteria were chosen to achieve a survival rate similar to that for patients with HCC meeting the Milan criteria. In addition, a 70% threshold for the 5- year survival rate was chosen, and this is similar to the rate expected for patients undergoing liver transplantation for other, noncancerous conditions. Finally, the 50% survival threshold, which may be considered ethically acceptable, seems to be arbitrary and could perhaps be applicable if there were no shortage of donor organs. To determine an appropriate threshold, the available models for selecting patients for liver transplantation may be adjusted so that the allocation of allografts for different liver diseases becomes more equitable. It may be appropriate to compare data on the survival of patients with and without HCC after liver transplantation with respect to the Model for End-Stage Liver Disease (MELD) score. It may then be possible to determine a minimum survival threshold after liver transplantation for patients with HCC that will not be detrimental to those without HCC. When accepted selection criteria are used, the results of liver transplantation for HCC are generally acceptable. To determine the impact of MELD scores on liver transplantation for HCC, a review of the registry of the United Network for Organ Sharing was undertaken, and the reviewers found 4-year survival rates of 72.7% for patients with exceptions to the MELD criteria, 78% for patients without HCC, and 67.8% for patients with HCC but without exceptions to the MELD criteria. 40 These analyses have provided an assessment of the first 5 years of the application of the MELD-based allocation system for liver transplantation in patients with HCC and have provided an opportunity for optimizing future indications for liver transplantation in these patients. Although the survival rates are significantly lower for patients with HCC, they appear to be relatively satisfactory and are likely to be acceptable to both physicians and patients. In this study, when the allocation system included exceptions to the MELD-based scoring system, the survival rate after liver transplantation for patients with HCC who met validated criteria approached the survival rate of patients without HCC. To optimize the allocation of donated organs, Volk et al. 41 focused on the lowest acceptable survival rate after liver transplantation for which the use of donor organs of standard quality could be justified. They examined how liver transplantation for patients with HCC not meeting the Milan criteria might affect the survival of patients on a waiting list during the preoperative and postoperative periods; they found that if liver transplantation were performed for patients not meeting the Milan criteria, there would be a significant adverse impact on other patients on the waiting list. Their study suggested that for a national policy, a 5-year survival rate of 61% after liver transplantation would be required for any extension to the Milan criteria to compensate for the adverse effects on other patients. 41 Although this study is the only one to have clearly addressed this particular issue, it has several limitations. It did not evaluate the use of donor organs of marginal quality, and it assumed that long-term survival after liver transplantation does not vary as a function of the preoperative MELD score. There is a lack of studies addressing these issues in the literature. In addition, the extrapolation of these findings to routine clinical practice is limited by our inability to accurately predict survival after liver transplantation for individual patients with HCC who do not meet the Milan criteria. However, in the current environment, a threshold 5-year survival rate of 50% may seem low because of the current shortages of donor organs. Finally, to what extent can the life expectancy of the entire cohort of patients after liver transplantation be reduced and still remain acceptable, and how might an increase in the proportion of HCC patients who receive liver transplants affect the mortality of

5 S10 SAMUEL ET AL. LIVER TRANSPLANTATION, October 2011 patients without HCC on the waiting list? These questions raise ethical issues that require consideration, assessment, and resolution. Therefore, even though liver transplantation for patients with HCC who do not meet the Milan criteria may be associated with benefits in individual cases, the adoption of an extension of the conventional selection criteria remains controversial, particularly in an era of donor organ shortages. As long as these shortages persist, acceptable survival thresholds for HCC patients after liver transplantation will have to be as close as possible to those applicable to patients with liver disease in the absence of HCC. PRIORITIZING EQUITABLE POLICIES FOR LIVER TRANSPLANTATION IN PATIENTS WITH HCC AND PATIENTS WITHOUT HCC The United Network for Organ Sharing has developed a system that prioritizes liver transplantation for patients who have the highest risk of wait-list mortality. The MELD score has been selected as the most clinically appropriate tool for accurately predicting mortality in patients with chronic liver disease. 42 However, the MELD score does not accurately predict survival in some patients, such as those with HCC. To enable patients with HCC to undergo liver transplantation at a rate similar to that for patients without HCC, additional points based on the number and size of the HCC nodules are assigned to patients with HCC on the waiting list; the intention is to match the risk of death for those with similar MELD scores but no HCC. 42,43 With this new allocation system, Ioannou et al. 40 showed that patients with HCC exceptions had a survival rate after liver transplantation that was similar to the survival rate of patients without HCC. The survival rate of patients with HCC who did not receive MELD exceptions was significantly worse after liver transplantation than the survival rate of patients without HCC. However, this system of patient selection requires further refinement to ensure that it is as fair as possible. In the United States, the application of MELD exceptions to the selection of patients with HCC has been associated with an increase in the number of liver transplants performed for HCC. 44 Changes in the allocation of points have been proposed, and a 3-month waiting time for the detection of patients with rapidly progressing tumors may be adopted so that patients with aggressive tumors are not accepted for liver transplantation. 27,40 Despite the application of MELD exceptions, the survival rate of patients with HCC after liver transplantation is still not as good as the survival rate of patients without HCC who have similar MELD scores. 40 The development of equitable policies has been hampered by a lack of robust predictors for identifying patients at a high risk of disease progression and patients at a high risk of dropout. In patients with aggressive tumors, there is a high risk of progression while they are on the waiting list; if priority points are incorporated into their selection scores, their longterm results after liver transplantation will be less than optimal because of the increased rate of recurrence associated with aggressive tumors. Dropout from the waiting list is an indirect measure of access rates for liver transplantation. An evaluation of the risk of dropout for patients with and without HCC was reported by Washburn et al., 45 who studied patients listed for liver transplantation between 2005 and The probability of dropout was estimated with a competing risk analysis and a Cox model for the time to dropout. Overall, the patients without HCC had a higher dropout rate than the patients with HCC. A multivariate analysis of risks showed that the MELD score and the serum alpha-fetoprotein (AFP) level were the most influential predictors of dropout among the patients with HCC. On the basis of the lower dropout rates, the authors suggested that patients with HCC are more likely to benefit from the current allocation scheme, partly because the application of a static exception score does not incorporate the underlying MELD score. A composite score that incorporates the MELD score, the AFP level, and the tumor size might further improve the prioritization of patients with HCC for liver transplantation; the usefulness of such a score needs to be confirmed. Liver transplantation has been shown to be efficacious for patients with HCC who meet the Milan criteria. Although the MELD scoring system has been successful in the allocation of deceased donor livers, the selection of patients with HCC on the basis of MELD exception scores currently requires refinement. The most recent data suggest that patients with HCC should continue to benefit from enhanced access to liver transplantation in comparison with patients without HCC. The development of a continuous HCC score that is similar to the MELD score may be a more consistent and impartial tool for ensuring that access to deceased donor livers is equivalent for candidates with HCC and candidates without HCC. To further improve the prioritization of patients, prognostic markers such as those currently applied to examinations of explants should be made available for the stratification of patients before liver transplantation. Clinical, biochemical, and molecular data may be made available in the future to assist with decisions related to liver transplantation for patients diagnosed with HCC. WHAT GLOBAL IMPROVEMENTS CAN BE ANTICIPATED? Together with advances in the overall care of patients who undergo liver transplantation and in the prevention of the recurrence of the original disease, improvements that are specific to patients with HCC are awaited; these may include the determination of prognostic markers before liver transplantation.

6 LIVER TRANSPLANTATION, Vol. 17, No. 10, 2011 SAMUEL ET AL. S11 First, several studies have renewed interest in the AFP level before liver transplantation as a predictor of dropout from the waiting list and the postoperative recurrence of tumors. 40,45,46 In one study, a threshold AFP level of 455 ng/ml was found to be a useful predictor of poor survival after liver transplantation along with the MELD score. 40 Similarly, Washburn et al. 45 showed that AFP levels correlated with the risk of dropout; this risk increased from 7.4% with AFP levels < 500 ng/ml to 24.9% with AFP levels > 1000 ng/ml after patients were placed on the waiting list for liver transplantation. Although no clear cutoff for AFP levels has been defined, Vibert et al. 46 found that in patients with cirrhosis and HCC whose AFP levels increased by more than 15 lg/l per month, liver transplantation was associated with a low overall 5- year survival rate of 54% (a rate that is debatable with the shortage of donor organs). These findings suggest that a progressive increase in serum AFP levels may be a surrogate marker of aggressive HCC and may be a useful observation for the selection of patients for liver transplantation. Second, studies of gene expression using microarrays to define prognostic patterns are beginning to yield potentially valuable information, but these studies are preliminary Profiling the expression of more than 6000 genes in tumors and normal tissues, Hoshida et al. 51 recently provided new insights into genome-based predictors of outcomes for patients with HCC. However, these authors did not identify any genes associated with survival after they studied tumor tissue. The most exciting finding was their ability to use paraffin-embedded tissues to profile gene expression and then identify a tissue-associated signature of a gene in noncancerous hepatic tissue that enabled the prediction of survival of patients with HCC. In contrast to frozen specimens, paraffin-embedded tissues can be easily stored and transported, and they are consequently readily available for facilitating the discovery and validation of genome-based predictors, which can enable the stratification of patients into groups that are homogeneous with respect to survival, disease etiology and recurrence, and oncogenic pathways. Significant advances are also anticipated in the management of specific liver diseases such as chronic hepatitis C. In common with chronic hepatitis B, the prevention of hepatitis C relapse or the treatment of recurrent hepatitis C should improve the overall management of patients infected with HCV and, therefore, should mitigate the need for retransplantation in some patients with recurrent hepatitis C after liver transplantation. CONCLUSIONS Liver transplantation is an effective treatment for patients with HCC when the disease meets the Milan criteria. HCC is currently a standard indication for liver transplantation in conventional clinical practice; this disease is responsible for 26% to 34% of the patients who undergo liver transplantation in Europe and the United States. A few studies have supported liver transplantation for patients whose disease exceeds the Milan criteria, but the relevant studies are limited by their retrospective design and their reliance on data that are not available before liver transplantation (eg, the histology of the noncancerous liver). The goal of liver transplantation is to maximize the benefits that can be provided to patients through the most judicious and fair use of the limited supply of donor organs. In practice, the problem of the donor organ shortage influences the indications for liver transplantation. In this context, it is necessary to make choices that favor collective benefits rather than individual benefits for patients while we attempt to gradually extend the indications for liver transplantation in patients with HCC. The recent selection system based on the MELD score is less relevant to the management of patients with HCC versus patients with end-stage chronic liver disease. The current allocation of liver allografts to patients with HCC is based on MELD exceptions (ie, the addition of a specific number of points related to the characteristics of the tumor). This system of allocation is being refined to ensure that the application of liver transplantation is as fair to the patient with HCC as it is to the patient with end-stage chronic liver disease. RECOMMENDATIONS Liver transplantation is currently an effective therapy for patients with HCC who meet the Milan criteria. Because few studies have provided support for liver transplantation in patients with HCC who exceed the Milan criteria, no recommendations can currently be made to extend the Milan criteria. Even if an individual patient with HCC who does not meet the Milan criteria might benefit from liver transplantation, the limited number of donor organs currently limits the indications for liver transplantation to patients who have the greatest likelihood of survival after surgery. Liver transplantation in patients with HCC should, therefore, be restricted to those who are expected to have the same posttransplant survival as that of patients with nonneoplastic end-stage chronic liver disease. On the basis of these considerations, a 5- year survival rate of 50% after liver transplantation for HCC seems too low. REFERENCES 1. Thuluvath PJ, Guidinger MK, Fung JJ, Johnson LB, Rayhill SC, Pelletier SJ. Liver transplantation in the United States, Am J Transplant 2010;10(pt 2): El-Serag HB, Marrero JA, Rudolph L, Reddy KR. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 2008;134: El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999; 340:

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