Should we expand the criteria for liver transplantation for hepatocellular carcinoma Yes, of course!

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1 Forum on Liver Transplantation 569 Should we expand the criteria for liver transplantation for hepatocellular carcinoma Yes, of course! Christoph Erich Broelsch*, Andrea Frilling, Massimo Malago Department of General Surgery and Transplantation, University Hospital Essen, Hufelandstr. 55, D Essen, Germany Liver transplantation for non-resectable hepatocellular carcinoma (HCC), generally associated with pre-existing cirrhosis presents a well-established and widely accepted therapeutic option. Due to a lack of appropriate selection of candidates, the results obtained in the early series were disappointing [1]. This discouraging experience and the scarcity of deceased donor liver grafts have forced the medical community to establish specific selection criteria with an aim to predict post-transplant survival. In 1996, Mazzaferro et al. in Milan have shown that consideration of stringent morphologic criteria (a single tumor %5 cm in diameter or 2 3 tumors all % 3 cm in diameter) yields 83% overall patient survival and 75% overall tumor-free survival at 4 years [2]. Applying the Milan criteria, which were also adopted by the United Network of Organ Sharing (UNOS) or similar criteria for candidate selection, several groups confirmed subsequently that for patients with HCC posttransplant survival is comparable to that obtained in recipients with non-malignant liver disease [3,4]. Reviewing survival data for HCC patients transplanted at different time periods, an increase of 5-year survival from 25.3% in the late 1980s to 61.1% in the late 1990s was documented [5].Fora patient with HCC transplanted at present, 1-year survival rates of 77 80% and 5-year survival rate of approximately 70% can be expected [5]. The improvement of survival reported in the past decade and the encouraging experience of groups offering transplantation to candidates with tumors beyond the limits of generally accepted selection criteria, in some settings in combination with pre-operative loco-regional treatment or chemotherapy, called the current listing policy into question regarding its rigidity since it excludes a significant cohort of patients from their only promising therapeutic option [7 9]. Using extended criteria (single tumor less than 6.5 cm in size, or more than three tumors, the largest less than 4.5 cm, * Corresponding author. Tel.: C ; fax: C address: christoph.broelsch@uni-essen.de (C.E. Broelsch). Abbreviations: A2ALL, adult-to-adult living donor liver transplantation cohort study; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; LITT, laser therapy; MELD, model for end-stage liver disease; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation; TACE, transarterial chemoembolization; UNOS, United Network of Organ Sharing. and a total diameter for all tumors less than 8 cm), Yao et al. reached a 1- and 5-year survival of 90 and 75.2%, respectively [10]. The impact of transplantation on survival of patients with larger HCC was further underlined by the Mount Sinai Hospital transplant cohort in which patients receiving a liver transplant had a 44% survival at 5 years compared to 3% at 3 years in those being denied this treatment option [11]. In addition, limitations of clinical staging systems based solely on the results of the pre-transplantation imaging techniques and contradictory results when comparing different criteria became evident leading to a presumption of understaging in 15 20% of patients identified as meeting standard criteria [10,12,13]. Our experience comparing preoperative imaging results and post-operative pathological examination demonstrates accurate tumor burden in 34.2% of patients only [14]. In the series reported by Yao et al. radiologic investigations underestimated HCC stage in 21.5% and overestimated tumor stage in nearly 10% [8]. A similar experience was had by Todo et al. who reported 16% of their patients as underestimated and about 10% as overestimated in pre-transplant radiologic work up [15]. These observations were confirmed in a multi-centric study comparing pre and post-transplantation variables by showing that 84.1% of the patients were classified preoperatively as meeting the Milan criteria while postoperatively this rate dropped to 64.7% [16]. A critical evaluation of these data implies than other prognostic tools, such as tumor grading or vascular invasion, rather than size of the lesion and number of tumors are needed as a surrogate marker of biological behavior of HCC [7,17,18]. As shown by Tamura et al. poorly differentiated HCC were associated with significantly shorter median recurrence-free survival after liver transplantation when compared with moderately differentiated tumors (175 days versus 430 days) [19]. In a study from Spain vascular invasion, bilobar disease and lymph node metastases, but not the tumor size and number were factors associated with high post-transplant recurrence rates [20]. The clinical utility of some of these parameters is limited, however, since they can only be evaluated at the time of histological examination of the explanted liver. More important, further understanding of biological behaviour of HCC and identification of genes associated

2 570 Forum on Liver Transplantation with survival is expected in the future as demonstrated by Marsh et al. who predict accurate prognosis in 88.3% of transplanted patients by using microdissection genotyping technique and confirmed recently by Lee et al. [21,22]. The pitfalls of current listing criteria were clearly pointed out in a retrospective analysis of the University of Pittsburgh Medical Center data on explanted livers of patients in whom HCC accounted for transplant indication [13]. Of the patients transplanted in the past, but who would have be not eligible candidates according to the standard Milano/UNOS criteria, 27 49% experienced long term survival and were potentially cured. Interestingly, of the 36.9% of the patients who were beyond the Milano/UNOS criteria at the time of transplantation nearly 50% remained tumor-free at mean follow-up of 3.3 years. A conclusion was reached that given the too rigid selection criteria a significant portion of HCC patients would be excluded from a potentially beneficial treatment option. Regardless of the debate whether current criteria should be maintained or expanded, dropout on the waiting list because of tumor progression presents the main drawback of liver transplantation for HCC, especially when intention-totreat data are analysed. Yao et al. reported the cumulative probabilities of dropout at 6, 12, and 24 months to be 7.3, 25.3, and 43.6%, respectively, with a peak monthly dropout between 9 and 15 months [23]. In the study from Barcelona, in accordance, the intention-to-treat survival at 2 years was solely 54% with a 6- and 12-month dropout likelihood of 11 and 38%, respectively [24]. For patients with tumors beyond classic criteria the dropout rate exceeded even 50% [25]. The adoption of the model for end-stage liver disease (MELD) scoring system in 2002 in the United States and the possibility of higher-assigned MELD scores for patients with HCC, i.e. a patient with a stage 1 tumor (solitary%2 cm) would be assigned a MELD score of 24, while a stage 2 lesion (solitary 2 5 cm or up to three tumors each%3 cm) would increase the MELD scoring to 29, lead to a significant rise in transplantations performed in this cohort of individuals on the waiting list. Whereas in the pre- MELD period the annual rate of HCC candidates receiving a liver transplant was approximately 7% of all deceased donor transplantations, in the post-meld period 22% of deceased donor liver transplantations took place in patients with HCC [26,27]. Moreover, the waiting time decreased from 2.28 to 0.69 years and the 5-month dropout rate declined from 16.5 to 8.5%. Since the initial post-meld results disclosed that due to the new allocation system candidates with HCC were transplanted earlier than MELD score comparable patients with non-hcc indication, a modification of the MELDbased allocation policy was carried out in 2003, leading to a marked reduction of HCC patients (14% at present) on the total amount of standard transplantations [27,28]. So far, the European transplant community lacks experience with the impact of MELD score on the HCC liver transplant candidates, since the new allocation policy is going to be introduced in the Eurotransplant International Foundation organ procurement system in 2006 first (Eurotransplant, pers. commun). With the aim of reducing dropout rates on the waiting list, locoregional control therapies can be offered to patients at risk for tumor progression. Various techniques namely transarterial chemoembolization (TACE), radiofrequency ablation (RFA), laser therapy (LITT), percutaneous ethanol injection (PEI), cryotherapy and transarterial radiotherapy are currently available. Patients with tumors exceeding standard listing criteria may not be appropriate candidates for local ablative therapies such as RFA, LITT or PEI, since due to technical issues these techniques are effective in general only in lesions up to 5 cm. Concerning TACE in transplant candidates, controversial data have been reported. While favorable results in terms of local tumor necrosis and improved recurrence -free survival were observed in some centers, others made the experience that apart from poor efficacy of TACE as bridging treatment to transplantation, amelioration of liver function and increased rates of posttransplant septic complications can occur. A recent report involving 168 patients from two centers suggests that pretransplant loco-regional treatment has no prognostic impact in patients with small HCC, however, it achieves improved survival in tumors at intermediate risk for progression [29]. Although no prospective, randomized study has been undertaken to evaluate the efficacy of pre-transplant bridging therapies, data available support the use of locoregional therapies for tumor downstaging. To escape the dilemma of limited organ availability, attempts have been made to enlarge the donor pool by implementing living donor liver transplantation (LDLT) in the treatment concept of patients with HCC. In some centers, particularly in the Asian countries where the rate of deceased donations is negligible, HCC has emerged as the most frequent indication for LDLT [15]. Taking into account a waiting time of 7 months or more, a dropout rate of 4% per month and a donor mortality of 1%, a decision analytic model revealed that LDLT not only offers a gain of life expectancy for patients with early HCCs but also presents a tool for costeffective treatment approach [30]. Data on 422 patients with HCC in whom LDLT was performed are available at present [15,31 36]. In the largest series published by Todo et al. presenting cumulative experience from Japan, 1-year and 3-year survival rates of 78.1 and 69.0%, respectively, and only slightly lower recurrent-free survival rates were achieved in a cohort of 316 patients [15] (Table 1). Since 73.4% of the Japanese patients underwent pre-transplant anti-tumor treatments, it appears possible that this approach contributed to the encouraging survival. In the largest series from United States, Gondolesi et al. from The Mount Sinai Hospital reported their experience with LDLT in 36 patients with HCC [31]. The patients who underwent LDLT for HCC had a mean waiting time of 62 days, compared to 459 days in deceased donor recipients. Regarding Milan /UNOS criteria, in most of the LDLT series published more than half of the patients had advanced

3 Forum on Liver Transplantation 571 Table 1 Series on living donor liver transplantation in HCC patients Author Year Patients Survival Overall (%) Recurrence-free (%) 1-year 2-year 3-year 1-year 2-year 3-year Todo [15] n.a n.a Gondolesi [31] n.a n.a. Lo [34] n.a. 66 n.a. n.a. n.a. Malago [35] n.a n.a. n.a. tumors [15,31,35]. In the Japanese study the 3-year patient survival was 78.7% when the Milan criteria were fulfilled and 60.4% if not. While 53% of patients in the report from Gondolesi et al. had advanced tumors no difference in recurrence-free survival was seen between living donor and deceased donor recipient groups [31]. These figures suggest that the standard criteria may be too restrictive, since a significant portion of patients with more advanced tumors would be denied treatment offering them realistic life prolongation. Although the advantage of LDLT for HCC patients, particularly those with advanced tumors appears obvious, a documented donor morbidity of 14 21% and mortality of % remain a serious concern [6,15]. In addition to a debate on continuing ethical dilemma, whether potential harm to a healthy individual is justified by the expected benefit for the recipient and the presumption made by some that the regeneration of a transplanted liver lobe may expedite tumor recurrence, two recent studies questioned the long-term efficacy of LDLT. Thuluvath et al. and Abt et al. reported significantly lower graft survival rates after LDLT when compared with deceased donor liver transplantation [37,38]. These data contradict the experience from Hong Kong (Lo C., pers. comm.) and the recent survey on 1588 LDLT documented by the European Liver Transplant Registry displaying a 72% 3-year graft survival rate in deceased donor liver transplantation versus 67% in LDLT for adult cirrhotic patients and a 67% 3-year graft survival rate in LDLT versus 63% in standard transplantation in HCC patients [6]. It should be stressed, however, that in adult recipients the high rate of biliary tract complications still has to be considered as a major obstacle of the procedure. Another controversial issue relates to whether patients who undergo LDLT while exceeding standard criteria, but have primary non-functioning grafts should be considered for a retransplantation with a deceased donor graft. At present, there are no well-defined criteria for potential candidates for LDLT in the setting of tumours exceeding conservative listing criteria. According to the policy of our center, patients with a single tumor not larger than 8 10 cm, or not more than five tumours, none O5 cm in size, and no portal vein invasion/tumor thrombosis are considered as acceptable recipients. In our pre-transplant evaluation protocol special attention is given to detection of extrahepatic tumor spread. Our preliminary data indicate that positron emission tomography might be of particular diagnostic value in detecting distant HCC metastases. This strategy enabled us to offer 62% 3-year survival to a selected group of candidates who would not have a chance on the regular list (data in press). It should be stressed that although the autonomy of the person willing to donate must be respected, the potential risk to a living donor must primarily trigger the decision making of the transplant physician involved in living organ donation. Further results are necessary so that experience achieved so far may be strengthened and our current criteria revised accordingly. Interestingly, in the United States the number of LDLT increased by over 450% within 3 years in the pre-meld era, however, it dropped by 38% after the new allocation rules had been in place for 24 months [39]. The decline in the number of the procedures could be related to two reasons: the recent increase of HCC patients eligible for deceased donor transplantations and reports on fatal complications in living donors. Further insight into the role of LDLT in the treatment of HCC patients is expected to be provided by the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL), initiated by The National Institutes of Health in Preliminary data confirmed the experience made by others in the past already, namely that a significant proportion of HCC patients were understaged by current pre-transplant radiological criteria when compared with explant assessment (Table 2). The disparity between the number of patients awaiting transplantation and the shortage of available organs from deceased donors forced the transplant community to broaden the donor criteria towards acceptance of marginal donors. While in the past donor age over 70 years has been considered a risk factor for early graft dysfunction, nowadays several centers accept donors aged 80 years and more. It has also been shown that grafts with mild to moderate steatosis can be utilized with an acceptable risk for the recipient. Furthermore, gender mismatch, prolonged ischemia, hypotension, hypernatremia, pathologic liver tests, hepatitis positive donor grafts and prolonged stay on the intensive care unit are no longer variables appraised as contraindication for organ allocation. Immunosuppression is one of the key issues of liver transplantation in oncologic patients. In a recent study published by Kneteman et al., the authors conclude that the Milan criteria could be extended,

4 572 Forum on Liver Transplantation Table 2 Summary of reasons for the expandation of the criteria for hepatocellular carcinoma with living-donor liver transplantation 1 Liver transplantation is the most rational treatment for non-resectable HCC since it offers the option to cure not only the malignant condition but also the underlying cirrhosis 2 Tumor size and number of lesions are not per se indicators for biological HCC behavior 3 Current clinical staging systems are not reliable. It can be presumed that 15 20% of HCC patients identified as meeting standard transplant listing criteria are understaged 4 The fact of understaging in pre-operative imaging studies did obviously not impair the post-transplant long-term results achieved in the past 5 Under consideration of extended criteria 5-year survival of 50% is a realistic goal 6 Living donor organ transplantation and usage of marginal deceased donors contribute to the expansion of the donor pool and offer the perspective for patients with tumors exceeding strict established criteria since sirolimus would contribute to the positive outcome [40]. The data in regard to the beneficial effect of sirolimus on the tumor growth in the transplant setting need further confirmation because in none of the other studies reporting similar long term results for extended indications sirolimus was a component of the immunosuppressive protocol. Given the fact that favorable recurrent-free survival is achievable in HCC patients exceeding Milan criteria and the possibility of not only timely transplantation but also sparing of the deceased donor organ resources offered by LDLT forces us to reconsider the standard listing criteria. The disparity of the pre-transplant evaluation results indicates that in the past a significant proportion of transplant procedures were performed beyond regular listing rules. Obviously, the post-transplant outcomes were not hampered much. The question if the medical community is willing to offer a tumor patient being at risk of disease recurrence a donor organ that could be allocated for a candidate with a non-malignant indication is unjust. A significant number of patients transplanted for a benign disorder, i.e. hepatitis C induced cirrhosis will also develop recurrence of their disease leading frequently even to a necessity of retransplantation. We need to decide rather, whether a patient with a malignant disease should be offered a chance of life prolongation. Any other oncological treatment for a large, not resectable HCC would experience unrestricted acceptance if providing the same efficiency as liver transplantation does. The possibility of living organ donation opens new perspectives for patients with advanced tumors. To achieve a well-balanced proportion between the potential risks to a living donor and the benefit to a recipient revision of current selection criteria towards estimation of risk factors specific for an individual transplant candidate is necessary. Irrespectively of the transplant technique applied, prospective protocols combining liver transplantation with neoadjuvant and adjuvant treatments would be recommendable in order to further evaluate the justification to expand the criteria for listing of HCC patients. References [1] Iwatsuki S, Starzl TE, Sheahan DG, Yokoyama I, Demetris AJ, Todo S, et al. Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg 1991;214: [2] Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzeti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334: [3] Jonas S, Bechstein WO, Steinmueller T, Herrmann M, Radke C, Berg T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 2001;33: [4] Hemming AW, Cattral MS, Reed AI, Van der Werf WJ, Greig PD, Howard RJ. Liver transplantation for hepatocellular carcinoma. Ann Surg 2001;233: [5] Yoo HY, Patt CH, Geschwind J-F, Thuluvath PJ. The outcome of liver transplantation in patients with hepatocellular carcinoma in the United States between 1988 and 2001: 5-year survival has improved significantly with time. J Clin Oncol 2003;21: [6] European Liver Transplant Registry. Accessed 15 January [7] Iwatsuki S, Dvorchik I, Marsh JW, et al. Liver transplantation for hepatocellular carcinoma: a proposal of prognostic scoring system. J Am Coll Surg 2000;191: [8] Yao FY, Kinkhabwala M, LaBerge JM, Bass NM, Brown Jr R, Kerlan R, et al. The impact of pre-operative loco-regional therapy on outcome after liver transplantation for hepatocellular carcinoma. Am J Transplant 2005;5: [9] Ravaioli M, Ercolani G, Cescon M, Vetrone G, Voci C, Grigioni WF, et al. Liver transplantation for hepatocellular carcinoma: further considerations on selection criteria. Liver Transplant 2004;10: [10] Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33: [11] Roayaie S, Frischer JS, Emre SH, Fishbein TM, Sheiner PA, Sung M, et al. Long-term results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinomas larger than 5 centimeters. Ann Surg 2002;235: [12] Marrero JA, Fontana RJ, Barrat A, Askari F, Conjeevaram HS, Su GL, et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology 2005;41: [13] Marsh JW, Dvorchik I. Liver organ allocation for hepatocellular carcinoma: are we sure? Liver Transpl 2003;9: [14] Sotiropoulos GC, Malagó M, Molmenti E, Paul A, Nadalin S, Brokalaki E, et al. Liver transplantation for hepatocellular carcinoma in cirrhosis: is clinical tumor classification before transplantation realistic? Transplantation 2005;79: [15] Todo S, Furukawa H. Living donor liver transplantation for adult patients with hepatocellular carcinoma. Ann Surg 2004;240: [16] Leung JY, Zhu AX, Gordon FD, Pratt DS, Mithoefer A, Garrigan K, et al. Liver transplantation outcome for early stage hepatocellular carcinoma: results of a multicentric study. Liver Transpl 2004;10: [17] Cillo U, Vitale A, Bassanello M, Boccagni P, Brolese A, Zanus G, et al. Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma. Ann Surg 2004;239: [18] De Carlis L, Giacomoni A, Lauterio A, Slim A, Sammartino C, Pirotta V, et al. Liver transplantation for hepatocellular cancer: should the current indication criteria be changed? Transpl Int 2003;16:

5 Forum on Liver Transplantation 573 [19] Tamura S, Kato T, Berho M, Misiakos EP, O Brien C, Reddy KR, et al. The impact of histological grade of hepatocellular carcinoma on the outcome of liver transplantation. Arch Surg 2001;136: [20] Herreo JI, Sangro B, Quiroga J, Parado F, Herraiz M, Cienfuegos JA, et al. Influence of tumor characteristics on the outcome of liver transplantation among patients with liver cirrhosis and hepatocellular carcinoma. Liver Transpl 2001;7: [21] Lee JS, Chu IS, Heo J, Calvisi DF, Sun Z, Roskams T, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology 2004;40: [22] Marsh JW, Finkelstein SD, Demetris AJ, Swalsky PA, Sasatomi E, Bandos A, et al. Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determining recurrence-free survival. Liver Transpl 2003;9: [23] Yao FY, Bass NM, Nikolai B, Merriman R, Davern TJ, Kerlan R, et al. A follow-up analysis of the pattern and predictors of dropout from the waiting list for liver transplantation in patients with hepatocellular carcinoma: implications for the current organ allocation policy. Liver Transpl 2003;9: [24] Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30: [25] Roayaie S, Schwartz JD, Sung MW, Emre SH, Miller CM, Gondolesi GE, et al. Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis. Liver Transpl 2004;10(4): [26] Sharma P, Balan V, Hernandez JL, Harper AM, Edwards EB, Rodriguez-Luna H, et al. Liver transplantation for hepatocellular carcinoma: the MELD impact. Liver Transpl 2004;10: [27] Yao FY, Bass NM, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: lessons from the first year under the Model of End-Stage Liver Disease (MELD) organ allocation policy. Liver Transpl 2004;10: [28] Sala M, Varela M, Bruix J. Selection of candidates with HCC for transplantation in the MELD era. Liver Transpl 2004;10:S4 S9. [29] Yao FY, Kinkhabwala M, LaBerge JM, Bass NM, Brown R, Kerlan R, et al. The impact of pre-operative loco-regional therapy on outcome after liver transplantation for hepatocellular carcinoma. Am J Transpl 2005;5: [30] Sarasin FP, Majno PE, Llovet JM, Bruix J, Mentha G, Hadengue A. Living donor liver transplantation for early hepatocellular carcinoma: a life-expectancy and cost-effectiveness perspective. Hepatology 2001;33: [31] Gondolesi G, Munoz L, Matsumoto C, Fishbein T, Sheiner P, Emre S, et al. Hepatocellular carcinoma: a prime indication for living donor liver transplantation. J Gastrointest Surg 2002;6: [32] Lee KW, Park JW, Joh JW, Kim SJ, Choi SH, Heo JS, et al. Can we expand the Milan criteria for hepatocellular carcinoma in living donor transplantation? Transplant Proc 2004;36: [33] Axelrod D, Koffran A, Kulik L, Al-Saden P, Mulcahy M, Baker T, et al. Living donor liver transplant for malignancy. Transplantation 2005;79: [34] Lo CM, Fan ST, Liu CL, Chan SC, Wong J. The role and limitation of living donor liver transplantation for hepatocellular carcinoma. Liver Transpl 2004;10: [35] Malagó M, Testa G, Frilling A, Nadalin S, Valentin-Gamazo C, Paul A, et al. Right living donor liver transplantation: an option for adult patients. Ann Surg 2003;238: [36] Kaihara S, Kiuchi T, Ueda M, Oike F, Fujimoto Y, Ogawa K. Livingdonor liver transplantation for hepatocellular carcinoma. Transplantation 2003;75:S37 S40. [37] Abt PL, Mange KC, Olthoff KM, Markmann JF, Reddy KR, Shaked A. Allograft survival following adult-to-adult living donor liver transplantation. Am J Transpl 2004;4: [38] Thuluvath PJ, Yoo HY. Graft and patient survival after adult live donor liver transplantation compared to a matched cohort who received a deceased donor transplantation. Liver Transpl 2004;10: [39] Hanto DW, Fishbein TM, Pinson CW, Olthoff KM, Shiffman ML, Punch JD, Goodrich NP. Liver and intestine transplantation: summary analysis Am J Transpl 2005;5(Part2): [40] Kneteman NM, Oberholzer J, Al Saghier M, Meeberg GA, Blitz M, Ma MM, et al. Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transpl 2004;10: doi: /j.jhep Should we expand the criteria for hepatocellular carcinoma with living-donor liver transplantation? No, never Jonathan R. Hiatt, Ian C. Carmody, Ronald W. Busuttil* From the Dumont-UCLA Liver Transplant Center, Department of Surgery, David Geffen School of Medicine at UCLA, LeConte Ave., CHS, Los Angeles, CA 90095, USA Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide [1], and recent data show its increasing incidence in the United States and other Western countries [2]. The reasons for the increase are * Corresponding author. Tel.: C ; fax: address: rbusuttil@mednet.ucla.edu (R.W. Busuttil). Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LDLT, living-donor liver transplantation; OLT, orthotopic liver transplantation; RFA, radiofrequency ablation; TACE, transarterial chemoembolization; UCSF, University of California San Francisco; UNOS, United Network for Organ Sharing. primarily related to the increasing prevalence of infections with hepatitis C virus (HCV) [3], and possibly to longer survival of patients with liver disease owing to advances in medical and surgical care [4]. Observations that the I5-year cumulative incidence of HCC exceeds 40% among patients with HCV-related chronic liver disease [3], combined with estimates that HCV prevalence among U.S. residents exceeds four million or 1.8% of the population [5,6], assure that HCC will be a common illness through the next quarter of a century [7]. Projections state that patients with HCC awaiting OLT will exceed the total number of available donors in the near future [8].