Hepatocellular carcinoma in the setting of liver transplantation

CAQ CORNER

Hepatocellular Carcinoma in the Setting ofLiver TransplantationMaria Varela,1 William Sanchez,2 Jordi Bruix1, and Gregory J. Gores2

1Barcelona Clınic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clınic, Institut d’InvestigacionsBiomediques August Pi i Sunyer, Barcelona, Spain; 2Division of Gastroenterology and Hepatology, Miles andShirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, Rochester, MN

Received April 6, 2006; accepted April 12, 2006.

Hepatocellular carcinoma (HCC) is a frequent compli-cation and leading cause of mortality among patientswith cirrhosis. In the setting of advanced liver disease,many patients with HCC are not candidates for hepaticresection due to inadequate functional hepatic reserveand the risk of postoperative decompensation. In thesepatients, liver transplantation (LT) offers curative ther-apy, as well as amelioration of their underlying chronicliver disease. Among appropriately selected candidates,LT for HCC provides excellent technical results with5-yr overall survival rates exceeding 70%, similar topatients undergoing LT for other indications.1-4 Thesize and number of tumors plays an important role indetermining an individual patient’s candidacy for LT.However, patients on the LT waiting list are at risk fortumor progression leading to ineligibility for LT anddeath. Given the significant impact of HCC on patientswith cirrhosis, healthcare providers caring for this pa-tient population need to be familiar with the diagnosticcriteria, pretransplantation management, transplanta-tion criteria, and organ allocation policies associatedwith LT for HCC.

BURDEN OF DISEASE: CLINICALEPIDEMIOLOGY OF HCC

With the exception of patients from areas of the worldwith endemic hepatitis B virus infection, an estimated95% of HCCs arise in the setting of cirrhosis. Reportedestimates of the annual incidence of HCC among cir-

rhotic patients ranges from 2-9%.5-9 Data from a cohortof European patients with hepatitis B virus-related cir-rhosis reported that 6% of patients developed HCCwithin 5 yr of diagnosis.10 Among Asian patients withcirrhosis secondary to chronic hepatitis B virus, thereported incidence of HCC is 2.5% per yr.11,12 The ob-served incidence of HCC among patients with cirrhosissecondary to hepatitis C (HCV) ranges from 2 to 8% peryr.12-15 Patients with hereditary hemochromatosis havea reported incidence of HCC approaching 3 to 4% peryr.12,16

Globally, HCC is the third leading cause of cancer-related death and accounts for as many as 500,000deaths annually.16 The prevalence of HCC is especiallyhigh in Asia, where HCC is the second most commoncause of cancer death. In Japan, primary liver malig-nancies (95% of which are HCC) are the third and fifthleading cause of cancer death among men and women,respectively.

In Western nations, both the incidence and mortalityrate from HCC are increasing.5,17 Data from Europeancenters suggests that HCC causes 50 to 70% of liver-related mortality among patients with cirrhosis.5 In theUnited States, where approximately 50% of cases aresecondary to chronic HCV infection, the incidence ofHCC has dramatically increased over the past 2 de-cades. An estimated 8,500 to 11,500 new cases of HCCoccur in the United States each year. Data from theNational Cancer Institute Surveillance Epidemiologyand End Results registry demonstrates that the age-

Abbreviations: HCC, hepatocellular carcinoma; LT, liver transplantation; HCV, hepatitis C virus; AFP, alpha fetoprotein; CT,computerized tomography; LDLT, living donor liver transplantation; MELD, Model for End-Stage Liver Disease; TACE, transarterialchemoembolization; RFA, radiofrequency ablation; UNOS, United Network for Organ Sharing; MRI, magnetic resonance imaging.Supported by a grant from the Fundacion Cientıfica de la Asociacion Espanola Contra el Cancer (to M.V.).Maria Varela and William Sanchez are cofirst authors of this article.Address reprint requests to Gregory J. Gores, M.D., Division of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center for DigestiveDiseases, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55901. Telephone: 001-507-284-8700; FAX: 001-507-284-0762;E-mail: [email protected]

DOI 10.1002/lt.20833Published online in Wiley InterScience (www.interscience.wiley.com).

LIVER TRANSPLANTATION 12:1028-1036, 2006

© 2006 American Association for the Study of Liver Diseases.

adjusted U.S. incidence of HCC has doubled between1985 and 1998.17 Associated with the rising incidenceof HCC, healthcare expenditures for HCC have alsosignificantly increased. Hospital charges for HCC-re-lated treatments doubled from 1988 to 2000 to exceed$500 million.18 Furthermore, the incidence of HCC inthe United States is projected to continue rising due toepidemiologic factors such as the aging of the popula-tion and the rising frequency of cirrhosis in patientswith chronic HCV infection. Additionally, the obesityepidemic in the United States associated with nonalco-holic fatty liver disease will also likely contribute to theprevalence of HCC.19-21

DIAGNOSIS OF HCC

Practice guidelines recommend that patients with cir-rhotic stage liver disease be enrolled in surveillanceprograms with the aim of identifying HCC at an earlystage.12 Surveillance programs are typically based onultrasonography of the liver at 6-month intervals. Se-rum alpha fetoprotein (AFP) is also frequently mea-sured, although it has not been found to be sensitiveand efficient as a screening tool, and current guidelinesfrom the American Association for the Study of LiverDiseases do not recommend serum AFP determinationsfor HCC surveillance.12 Since HCC develops at a rela-tively high frequency among patients with cirrhosis,any new liver mass identified in a cirrhotic patientshould be considered to be HCC until proven otherwise.The detection of a lesion suspicious for HCC in thesetting of a surveillance program should prompt furtherdiagnostic and therapeutic evaluation.7

In contrast to other malignant tumors in which bi-opsy is required to guide management decisions, thediagnosis of HCC can usually be established by nonin-vasive means. HCC is characterized by a specific vas-cular pattern that in dynamic imaging studies resultsin contrast enhancement during the arterial phase (Fig.1) followed by a contrast washout in the delayed venousphase. This pattern of contrast enhancement is seldomobserved in minute nodules measuring less than 1 cmas they are not yet fully vascularized. This pathologicfeature explains why mass lesions �1 cm cannot beconfidently diagnosed by imaging studies; their smallsize also often makes a biopsy technically challenging,further confounding the diagnosis of these small nod-ules. Hence, many clinicians follow nodules �1 cm withinterval imaging studies. When the detected nodule ex-ceeds 1 cm but is still less than 2 cm, a biopsy istechnically more feasible and can be considered if thedynamic imaging studies are indeterminate.12 HCC canbe confidently diagnosed in most instances if a nodule�2 cm within a cirrhotic liver demonstrates the char-acteristic imaging pattern (rapid arterial contrast en-hancement with washout during the delayed venousphase imaging studies) in a well-done imaging study bycomputerized tomography (CT) or magnetic resonanceimaging (MRI). In nodules between 1 and 2 cm, a non-invasive diagnosis requires that 2 distinct imagingstudies (CT and MRI) both demonstrate these features.

This double confirmation helps avoid a false positivediagnosis in nodules of this size which may displaydifficult to interpret subtle findings on cross sectionalimaging studies. It has to be stressed that almost one-half of the HCC between 1 and 2 cm will not exhibit thespecific contrast enhancement pattern on CT or MRI,and, thus, a biopsy may be necessary to establish thediagnosis. Also, occasionally even large lesions may nothave arterial phase contrast enhancement and will re-quire a biopsy for the diagnosis. It should be noted,however, that a negative biopsy does not exclude thediagnosis of HCC, and hence, if the biopsy report isequivocal, repeated biopsies may be necessary to con-fidently establish a diagnosis.

The role of serum AFP determinations are of limitedusefulness.22 In patients with an increased AFP inwhom a liver mass shows a nonspecific vascular pat-tern, a biopsy should be obtained, as cholangiocarci-noma and some digestive metastases may also presentwith an increased serum AFP value. If the mass has adiagnostic imaging pattern for HCC, the diagnosis isalready established irrespective of serum AFP concen-trations. Nonetheless, studies have reported that amass in a cirrhotic liver with a serum AFP �200 ng/mLcan be confidently diagnosed as HCC with a specificityof 99.4%.23

Because noninvasive criteria may have only moder-ately specificity in diagnosing HCC �2 cm and thesesmall lesions do not rapidly progress even if they areHCC, the United Network for Organ Sharing (UNOS)does not allocate additional priority to patients awaitingLT with lesions smaller than 2 cm. This policy wasdeveloped to avoid transplantation in patients with afalse-positive HCC diagnosis.

While several recently published practice guide-lines exist with regard to diagnostic criteria for HCC,recommendations for small lesions differ somewhat.The recent guidelines from the American Associationfor the Study of Liver Diseases only recommend abiopsy for lesions that lack characteristic radio-graphic features (Fig. 2).12 However, a biopsy of smalllesions is technically more difficult and a negativebiopsy from a suspicious lesion result should be re-garded with caution (i.e., is the lesion benign or wasthe lesion missed by the biopsy needle). For lesionssmaller than 1 cm in diameter, where the risk of HCCis lower, continued observation with serial imaginghas been recommended.12 The risk of seeding from abiopsy could argue against performing this proce-dure. However, in a large multicenter series of 2,320patients undergoing repeated tumor puncture for ra-diofrequency ablation (RFA), the reported seedingrate was only 0.5%.24 Therefore, it is likely that tumorseeding is an uncommon event and needle biopsyshould be performed when necessary. Alternatively,small lesions suspicious for HCC can be followed withserial imaging studies; an enlarging lesion demon-strating characteristic features of HCC can be con-sidered diagnostic.

LIVER TRANSPLANTATION FOR HCC 1029

LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

RATIONALE FOR LT AS THERAPY FOR HCC

Treatment options for HCC include those therapieswith curative intent such as LT, hepatic resection, andablation, as well as palliative therapies such as transar-terial chemoembolization (TACE). Systemic chemother-apy and radiation therapy are of limited utility due to ahigh incidence of side effects, dose-limiting hepatotox-icity, and poor efficacy.12

There are no randomized controlled trials comparingLT to other therapies for the management of HCC. Whileearly experience with LT for HCC was disappointingwith 5-yr survival rates of approximately 25%, out-comes have significantly improved over time.25 In part,improved outcomes have been due to the application ofstringent eligibility criteria for patients undergoing LTfor HCC. Currently, patients undergoing LT for HCChave a 5 yr survival rate exceeding 70%, which is sim-ilar to survival for other indications for LT.1 The ob-served tumor recurrence rates are less than 15% at5 yr.2-4

Chronic infection with HCV is the most common in-dication for LT in the United States. Among U.S. LTrecipients, patients with HCV-related liver disease havea 23% increased mortality rate and a 30% increasedallograft failure rate.26 These data obtained from themanagement of UNOS databases are in discrepancywith those obtained from the NIH LT Database,27 inwhich long-term patient and graft survival following LTfor end-stage liver disease secondary to HCV infection arecomparable with that observed for other indications.These differences may relate to donor age in the 2 data-bases. Older donors are associated accelerated fibrosis inHCV recipients. Since the universal use of hepatitis Bimmunoglobulin and oral antiviral drugs posttransplan-

tation, the outcome of hepatitis B virus transplanted pa-tients infection has become similar to those transplantedby other than virus-related causes.28,29

Liver Resection and Salvage Transplantation

Patients with well-compensated liver disease (Child-Turcotte-Pugh class A) and localized HCC may be man-aged with hepatic resection. Among carefully selectedpatients, outcomes for hepatic resection for HCC aresatisfactory with reported 5 yr survival rates of over50%.3,30,31 In an European study performed years ago,the multivariate analysis of risk factors for cirrhoticpatients undergoing hepatic resection for HCC identi-fied a serum bilirubin greater than 1.1 mg/dL and por-tal hypertension �10 mmHg (as measured by hepaticvenous pressure gradient) as predictive of postoperativehepatic decompensation.32 For that reason, surgicalresection should, therefore, be restricted to patientswithout portal hypertension. The applicability of he-patic resection in this circumstances is low (less than5% of patients with HCC are candidates for hepaticresection), and the main drawback of this therapeuticoption is the development of tumor recurrence in theremaining liver, as high as 50% at 3 yr and 70% at5 yr.3,30,31,33-35

Unfortunately, effective strategies for prevention ofHCC recurrence following hepatic resection are lacking.Recurrence related to dissemination appear early dur-ing follow-up and are usually multifocal, thus exclud-ing patients from subsequent LT. If such patients (pa-tients with recurrence following hepatic resection) doundergo LT the results are disappointing with highpostoperative tumor recurrence and mortality ratescompared to initial LT.36 For that reason, some groupshave recommended immediate transplantation for re-sected patients in whom pathological examination ofthe surgical specimen demonstrates features placingthe patient at high risk for recurrence such as satellitelesions or microvascular invasion.37 However, in theUnited States, there is no mechanism to prioritize thesepatients for LT although a Markov decision analysismodel assuming a 12-month waiting list time for LTdemonstrated a life-expectancy for patients undergoingsalvage LT similar to those undergoing primary LT (7.8vs. 8.8 yr).38

Percutaneous Ablation

Patients ineligible for hepatic resection due to decom-pensated liver disease who have small lesions may un-dergo percutaneous ablative therapies. No randomizedcontrolled trials comparing outcomes from percutane-ous ablative therapies to hepatic resection or LT exist.There are a variety of ablative modalities, includingpercutaneous ethanol injection, cryoablation, and RFA.The particular ablative method used is influenced byavailability and local expertise. Percutaneous ablationis limited by the number of tumors that may be treated(�3), difficulty in ablating large tumors (�3 cm), andtechnical limitations for tumors in anatomically unfa-

Figure 1. Gadolinium-enhanced MRI reveals a single HCC of43 mm in diameter located in the caudal part of the righthepatic lobe (arrows).

1030 VARELA ET AL.


vorable positions (e.g., near the liver capsule, adjacentto the gallbladder or other organs). Five-year survivalrates of 50% have been reported for percutaneous eth-anol injection in tumors less than 2 cm in diameter,while RFA achieves tumor necrosis rates of over 60% fortumors up to 3 cm in diameter.39-42 Percutaneous ab-lative therapies, like hepatic resection, do not amelio-rate the underlying chronic liver disease and patientsmust be closely monitored for tumor recurrence.

SELECTION OF APPROPRIATE TRANSPLANTCANDIDATES

Liver transplant professionals have a responsibility tomake the best use of scarce donor organs. Among cir-rhotic patients with HCC, those with advanced liverdisease and/or multifocal (up to 3 nodules �3 cm) HCCderive the most benefit from LT.32 Extrahepatic meta-static disease and macroscopic vascular invasion areconsidered exclusion criteria for LT due to the high rateof tumor recurrence. Evaluation for extrahepatic me-tastases with CT and bone scans with radionuclidescintigraphy is commonly performed. As with LT for

other indications, patients with HCC must also un-dergo evaluation of their overall fitness including car-diopulmonary, psychosocial, and addiction assess-ments as appropriate. In addition, the optimalcandidates for LT are those with the lowest risk of tu-mor recurrence.

Early experience demonstrated that tumor size wasan important prognostic factor for patients undergoingLT for HCC. The commonly used tumor, nodes, metas-tases (TNM) cancer staging system has not been foundto have prognostic significance for small HCCs.43 Clin-ical experience with patients who had small, inciden-tally discovered tumors on explant pathology demon-strated that they had a survival comparable to patientsundergoing LT for nonmalignant disease.25,44 There-fore, tumor size has come to function as a noninvasiveproxy for other important prognostic factors such asmicrovascular invasion and tumor grade.1 In their sem-inal paper, Mazzaferro et al.4 determined that survivalafter LT for HCC was similar to LT for other indicationsamong patients who have a limited burden of disease.In what is now commonly referred to as the “Milancriteria,” patients undergoing LT with a single tumor

Figure 2. Suggested algorithm for evaluation of a liver mass in a cirrhotic patient detected during HCC surveillance accordingto the American Association for the Study of Liver Diseases (AASLD) guidelines. [Reproduced with permission from Bruix andSherman,12 Hepatology, 2005].



less than or equal to 5 cm in diameter or up to 3 tumorseach 3 cm or less in diameter have 4-yr overall anddisease-free survivals of 85% and 92%, respectively.

Recently, it has been suggested that the Milan criteriacould be expanded. Initial reports were based on ex-plant pathology demonstrating that patients with tu-mors exceeding these criteria had satisfactory out-comes.45 However, radiographic techniques tend tounderestimate tumor size and all available data indi-cate that larger size correlates with vascular invasion.Hence, an increase in size at the time of listing for LT asassessed by radiographic criteria should translate intoan increased risk of tumor recurrence following LT. Thiswas clearly shown by the experience at Mount Sinai.46

In their cohort of 353 patients with HCC, 221 met theMilan criteria, 37 met the University of California at SanFrancisco (USCF) criteria but not the Milan criteria, and95 patients met neither. In those 37 patients beyondthe Milan criteria, the survival was encouraging be-cause patients with advanced HCC and preserved phys-ical status had a better early posttransplant survival ascompared to end-stage patients with cirrhosis. How-ever, recurrence was increased and hence long-termoutcome was not optimal. Therefore, expansion of sizecriteria likely will not result in satisfactory outcome. Incontrast, exceeding the Milan number of 3 with smalllesions, which are likely de novo tumors, should befurther explored. Nonetheless, the potential benefit topatients with tumors exceeding established criteriamust be carefully weighed against the optimal use ofscarce donor organs. Therefore, large trials demon-strating satisfactory long-term outcomes are needed.Currently, sufficient data regarding the routine use ofexpanded criteria in LT are not available and patientsexceeding the Milan criteria should be considered for LTonly as part of clinical trials.12 At present, there areinsufficient data to establish new criteria. Finally, it isimportant that the healthcare team clearly explain to LTcandidates with HCC that tumor progression while onthe organ waiting list can occur and may exclude themfrom LT eligibility.

ORGAN ALLOCATION POLICY

In response to a mandate to reduce waitlist mortality,the Model for End-Stage Liver Disease (MELD) scorewas adopted for organ allocation in patients by UNOS inFebruary 2002. While the MELD score has been pro-spectively demonstrated to predict 3 month survival inpatients with end-stage liver disease of various etiolo-gies, it has not been demonstrated to predict survival incirrhotic patients with HCC. Many cirrhotic patientswith HCC have relatively preserved hepatic functionand, therefore, are at low risk for death from liver fail-ure. These patients, however, are at a significantlyhigher likelihood of tumor progression leading to ineli-gibility for LT, which is not captured by their MELDscore. Tumor progression is significantly impacted bythe amount of time waiting necessary for a suitabledonor organ to become available. Intention-to-treatanalyses demonstrate that outcomes for LT are nega-

tively impacted by the length of time on the organ wait-ing list. Even when limiting enlistment to patients withHCC limited to the Milan criteria (solitary tumor �5 cmor up to 3 tumors �3 cm), the risk of dropout from thewaiting list at 6 months is approximately 10%. A dura-tion of 12 months or greater is associated with a 25%chance of waitlist removal due to tumor progres-sion.3,47 If the listing criteria are expanded, the dropoutrate exceeds 50%. The need to prevent this adverseevent is the basis of developing priority policies andavoiding time on the waiting list as the major determi-nant of transplantation. In response to the risk of deathfrom tumor progression, an adjustment to the UNOSMELD score was necessary for patients awaiting LT forHCC.

Upon the adoption of the MELD system for organallocation, patients with small HCCs (�2 cm) were al-located a priority score equal to a predicted 3-monthmortality rate of 15% (MELD � 24). Larger tumors wereallocated a priority score equal to a predicted 3-monthmortality rate of 30% (MELD � 29). These adjustedscores led to a 2.4-fold increase in the number of pa-tients undergoing LT for HCC during the first yr afterMELD was adopted. Furthermore, over 85% of patientsundergoing LT for HCC were transplanted within 90days of being placed on the waiting list. This dispropor-tionate prioritization of patients with HCC led to a sig-nificantly smaller number of patients with HCC beingremoved from the waiting list compared to patients withchronic liver disease.12,48-50 In response, UNOS madeseveral adjustments to the priority scores for HCC.From April 2004 forward, UNOS has restricted the as-signment of additional priority to patients with a soli-tary 2-5-cm HCC or up to 3 tumors each �3 cm; theMELD score for these patients is equivalent to a 15%probability of death within 3 months. A prelisting bi-opsy is not obligatory but the lesion must meet thefollowing imaging criteria: an ultrasound of the candi-date’s liver, a CT or MRI scan of the abdomen thatdocuments the tumor, and a CT of the chest plus a bonescan that rules out metastatic disease. In addition, thecandidate must have at least 1 of the following: a vas-cular blush corresponding to the area of suspicion seenon the above imaging studies, an AFP level of �200ng/mL, an arteriogram confirming a tumor, a biopsyconfirming HCC, chemoembolization of the lesion, andRFA, cryoablation, or chemical ablation of the lesion.Candidates with chronic liver disease who have a risingAFP level �500 ng/mL may be listed with a MELD scoreequivalent to an 8% mortality risk without review eventhough there is no evidence of a tumor based on imag-ing studies. Candidates will receive additional MELDpoints equivalent to a 10% increase in mortality every 3months until LT or delisting due to tumor progression.

Currently, an HCC lesion greater than 2 cm is as-signed a MELD score of 22, with tumors less than 2 cmin diameter no longer receiving additional priority. Ev-ery 3 months, the MELD score is increased to accountfor an additional 10% increase in mortality risk forpatients remaining on the waiting list.12,49,50

Several concerns regarding the increased numbers of

1032 VARELA ET AL.


patients undergoing LT for HCC during the early MELDera were raised. Of theoretical concern was that pa-tients with aggressive tumor biology (i.e., those mostlikely to progress and subsequently exclude a patientfrom LT) were transplanted without an adequate timeperiod to observe their natural history. To date, thesurvival of patients undergoing LT for HCC during theearly MELD era is not significantly different than sur-vival during the pre-MELD era.49,50 More importantly, asignificant proportion (31%) of patients undergoing LTfor small (�2 cm) HCCs during the early MELD era werefound to have been misdiagnosed, with no evidence ofHCC identified in the explants, probably because rigidcriteria for the noninvasive diagnosis of HCC were notapplied. Thus, tumors smaller than 2 cm no longerreceive additional priority for transplantation.49 Theappropriate adjustment of transplantation priority forpatients with HCC under the MELD system will con-tinue to be monitored and modified as demonstrated byoutcomes related to the allocation policy.

ROLE OF PRE-LT THERAPY

Patients with HCC waiting for LT are at significant riskfor tumor progression. As the disparity between thenumber of patients awaiting LT and the number ofsuitable donor organs increases, the waiting times forpatients listed for LT will become prolonged. Accordingto UNOS data, in United States the proportion of can-didates waiting 2 yr or more has increased steadily from15% in 1993 to 46% in 2002, correlating with a near6-fold rise in the number of patients on the waiting list.Measures to increase the number of available donororgans, such as the use of expanded criteria donors,split liver grafts, and “domino” transplantation, are ap-propriate to expand the donor pool and reduce waitlistmortality. Many centers, however, also actively treatpatients with HCC prior to LT with the aim of reducingtumor progression and waitlist dropout. Intention-to-treat analyses have demonstrated that the superiorityof LT over hepatic resection diminishes with increasingwaiting time.3,47 Therefore, most centers employ pre-LTtherapy.

Transarterial chemoembolization (TACE) is per-formed by selectively cannulating the hepatic arterybranch supplying the HCC lesion and injecting a che-moembolic mixture that occludes the vessel. TACE isgenerally well tolerated and has been demonstrated in asystematic review of randomized trials to provide a sur-vival benefit in patients with unresectable HCC.51

While there is a risk of causing further hepatic decom-pensation, TACE does not appear to negatively impactthe future operability of the patient. Because of thesereasons, TACE is frequently used to manage patientsawaiting LT for HCC.52-56 In a retrospective study of 54patients treated with TACE prior to the adoption of theMELD system, Maddala et al.57 observed that 8 pa-tients (15%) were removed from the LT waiting list dur-ing a median waiting time of 211 days, 6 of them due totumor progression while 2 others were not consideredto be candidates due to other medical conditions. TACE

was complicated by a liver abscess in 1 patient, but noindividual patient developed clinically significant he-patic decompensation. This drop-out rate is lower thanthat reported by Llovet et al.3 in a cohort of patientswhere no pre-LT therapy was used (25%). In a prospec-tive trial of pre-operative TACE, Graziadei et al.53 re-ported a 0% rate of removal from the LT waiting list,with a mean time to LT of 178 days. Graziadei et al.53

selected a prospective cohort of 48 patients fulfilling theMilan criteria. All of them received TACE prior to ortho-topic liver transplantation. With a mean waiting time of178 days, at the end of the study 7 were on the waitinglist and 40 underwent orthotopic liver transplantation.Only 1 of these 40 patients presented with HCC recur-rence (2.4%), and intention to treat survival rates were98%, 98%, and 94% at 1, 2, and 5 yr, respectively. Inthis same article, Graziadei et al.53 presented 15 ex-panded-criteria HCC patients, all of them with morethan 50% reduction in size after TACE (a downstagedgroup), 3 developed tumor progression and were re-moved from the waitlist, and 10 eventually underwentLT. Of these 10 expanded-criteria downstaged HCC pa-tients, 3 patients developed HCC. Thus, in the down-staged patients, intention-to treat survival rates were93%, 78%, and 31% at 1, 2, and 5 yr, respectively.53

Based on these limited data, it would appear that down-staging patients to meet the Milan criteria results insuboptimal outcomes.

Similar to the use of TACE in the pretransplantationsetting, there are no randomized controlled studiesevaluating the utility of pre-LT percutaneous ablativetherapies. The most frequent bridging therapies appliedare RFA and percutaneous ethanol injection. In a pro-spective study,58 52 patients accepted for LT weretreated with multiple-session RFA treatments. After amean waiting time of 12.7 months (range 0.3-43.5), 3patients (5.8%) had dropped out due to tumor progres-sion. A total of 41 had undergone transplantation andnone have developed HCC recurrence. Based on posta-blation CT or MRI, radiographic local tumor control wasachieved in 69 of 77 tumors (89.6%) treated with RFA.However, there was a disparity between the assessmentof response to RFA based on pathologic explant analy-sis vs. radiographic assessment. On explant pathology,54 of 64 (70.3%) tumor nodules showed complete coag-ulation.

In a prior study,41 60 HCC in 50 patients were treatedwith single-session RFA prior to LT (mean interval ofinitial RFA to LT of 9.5 months, range 2-47). None of thepatients were excluded from LT due to tumor progres-sion. According to the pretransplant assessment of re-sponse at CT scan, 70% obtained a complete post-RFAresponse, but pathologic examination of the explantedliver demonstrated that only 33 of 60 ablated HCCs(55%) had a complete response. Tumor ablation wasmost effective in patients with lesions 3 cm in diameteror smaller, achieving a 63% of complete response on theexplant examination. Outcomes were satisfactory withpatient survival rates of 83% 3 yr following LT.41 Fi-nally, it has been demonstrated that initial completeresponse to percutaneous ablation is associated with



an improved survival in both Child-Turcotte-Pugh classA and B patients, although the probability of late failureafter initial complete response is as high as 18 to 26% at1 yr, 55 to 56% at 3 yr, and 74 to 83% at 5 yr.42,59 Thus,percutaneous ablation is also an acceptable bridgeto LT.

APPROPRIATE CANDIDATES FOR LIVINGDONOR LIVER TRANSPLANTATION

Adult-to-adult living donor LT (LDLT) is a possible wayto increase transplantation rates and reduce time onthe waiting list, but this strategy involves importantethical implications. At present, LDLT appears justifiedonly if the waiting time for cadaveric orthotopic livertransplantation is expected to exceed 7 months.60 LDLToffers the benefit of early access to LT for patients withHCC, thereby reducing the risk of tumor progressionwhile awaiting a deceased donor allograft. LDLT forHCC is widely used in Japan where outcomes are sim-ilar to deceased-donor LT.61 In the United States, LDLToffers potentially curative therapy to patients with tu-mor burdens exceeding the Milan criteria who do notreceive additional priority under current UNOS policy.In Barcelona, the expanded criteria for LDLT for HCCinclude solitary tumors up to 7 cm in diameter, 3 tu-mors each up to 5 cm in diameter, or 5 tumors each upto 3 cm in diameter, but outcome data from prospectiveapplication will be necessary before widespread appli-cation of these criteria can be recommended.62 As withthe use of LDLT for other indications, the benefits to therecipient must be weighed against the risk to the donor,which includes a mortality rate of 0.5% as well as asignificant postoperative convalescence. Although con-troversial, suboptimal outcomes have been reported forpatients with HCV-related liver disease receiving LDLTas compared to deceased donor allografts, and somecenters take this into account when patients forLDLT.63,64

CONCLUSION

HCC has become a standard indication for LT. Whenappropriately selected, patients undergoing LT for HCChave excellent outcomes that are similar to those un-dergoing LT for nonmalignant disease. Given epidemi-ologic trends, HCC will continue to be an importantindication for LT in the future. However, there are manyadvances to be made in the field of LT for HCC. Furtherprospective investigation into the expansion of tumorsize criteria for LT may allow this lifesaving therapy tobe offered to more patients. In an era of organ shortage,large prospective trials of pretransplantation therapiesand the development of novel agents to prevent progres-sion of HCC are necessary among patients awaiting LT.

ACKNOWLEDGMENTSW.S. is the 2005-2006 Miles and Shirley Fiterman Cen-ter Fellow, Division of Gastroenterology & Hepatology,

Mayo Clinic College of Medicine School of GraduateMedical Education.

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Hepatocellular carcinoma in the setting of liver transplantation

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