ORIGINAL ARTICLE

Increasing Disparity in Waitlist Mortality RatesWith Increased Model for End-Stage Liver DiseaseScores for Candidates With HepatocellularCarcinoma Versus Candidates WithoutHepatocellular CarcinomaDavid Goldberg,1,2 Benjamin French,2,3 Peter Abt,4 Sandy Feng,5 and Andrew M. Cameron6

1Division of Gastroenterology, Department of Medicine, 2Clinical Center for Epidemiology and Biostatistics,3Leonard Davis Institute for Health Economics, and 4Division of Transplantation, Department of Surgery,University of Pennsylvania, Philadelphia, PA; 5Division of Transplant Surgery, Department of Surgery,University of California San Francisco, San Francisco, CA; and 6Comprehensive Transplant Center, JohnsHopkins University School of Medicine, Baltimore, MD

Candidates with hepatocellular carcinoma (HCC) within the Milan criteria (MC) receive standardized Model for End-StageLIver Disease (MELD) exception points because of the projected risk of tumor expansion beyond the MC. Exception pointsat listing are meant to be equivalent to a 15% rusj if 90-day mortality, with additional points granted every 3 months, equiva-lent to a 10% increased morality risk. We analyzed the United Network for Organ Sharing database (January 1, 2005 toMay 31, 2009) to compare the 90-day waitlist outcomes of HCC candidates and non-HCC candidates with similar MELDscores. Two hundred fifty-nine HCC candidates (4.1%) who were initially listed with 22 MELD exception points wereremoved because of death or clinical deterioration within 90 days of listing, whereas 283 non-HCC candidates (11.0%) withinitial laboratory MELD scores of 21 to 23 were removed. Ninety-three HCC candidates (4.6%) with 25 exception points (af-ter 3-6 months of waiting) were removed because of death or clinical deterioration within 90 days, whereas 805 non-HCCcandidates (17.3%) with laboratory MELD scores of 24 to 26 were removed. Twenty HCC candidates (3.0%) with 28 excep-tion points (after 6-9 months of waiting) were removed for death or clinical deterioration within 90 days, whereas 646 non-HCC candidates (23.6%) with laboratory MELD scores of 27 to 29 were removed. In multivariate logistic regression models,HCC candidates had significantly lower 90-day odds of waitlist removal for death or clinical deterioration (P < 0.001). Overtime, the risk of waitlist removal for death or clinical deterioration was unchanged for HCC candidates (P ¼ 0.17), whereasit increased significantly for non-HCC candidates. The current allotment of HCC exception points should be re-evaluatedbecause of the stable risk of waitlist dropout for these candidates. Liver Transpl 18:434-443, 2012. VC 2012 AASLD.

Received November 3, 2011; accepted January 7, 2012.

Additional Supporting Information may be found in the online version of this article.

Abbreviations: CI, confidence interval; HCC, hepatocellular carcinoma; MC, Milan criteria; MELD, Model for End-Stage LiverDisease; OPTN, Organ Procurement and Transplantation Network; OR, odds ratio; UNOS, United Network for Organ Sharing.

This study was supported by the National Institutes of Health (grant 1-F32-DK-089694-01 from the National Institute of Diabetesand Digestive and Kidney Diseases to David Goldberg) and by the Health Resources and Services Administration (contract 234-2005-370011C). The contents of this article are the responsibility of the authors alone and do not necessarily reflect the views orpolicies of the Department of Health and Human Services, nor does mention of trade names, commercial products, ororganizations imply endorsement by the US Government.

Address reprint requests to David Goldberg, M.D., M.S.C.E., Division of Gastroenterology, Department of Medicine, University of Pennsylvania,3400 Civic Center Boulevard, 9 Penn Tower, Philadelphia, PA 19104. Telephone: 215-746-8598; FAX: 215-349-5915;E-mail: david.goldberg@uphs.upenn.edu

DOI 10.1002/lt.23394View this article online at wileyonlinelibrary.com.LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

LIVER TRANSPLANTATION 18:434-443, 2012

VC 2012 American Association for the Study of Liver Diseases.

See Editorial on Page 381

Since February 27, 2002, the United Network forOrgan Sharing (UNOS) has relied on the Model forEnd-Stage Liver Disease (MELD) to prioritize candi-dates listed for liver transplantation in the UnitedStates. Initially developed and validated to predict 90-day waitlist mortality from the time of the initial list-ing, the MELD score has subsequently been shown toaccurately predict 90-day waitlist mortality for candi-dates throughout their time on the wait list.1-6

There are candidates for whom the risk of waitlistremoval for death or clinical deterioration is notadequately captured by the MELD score; these candi-dates include patients with extrahepatic manifesta-tions of liver disease such as hepatopulmonary syn-drome and metabolic liver disease and, most notably,hepatocellular carcinoma (HCC). For patients whoseperceived and/or actual clinical risk the MELD scoredoes not address, policymakers have instituted stan-dardized criteria and algorithms by which candidatesreceive MELD exception points.7

Candidates with HCC whose tumors are within theMilan criteria (MC; either 1 tumor < 5 cm in diameteror 3 tumors with each < 3 cm in diameter) receivestandardized MELD exception points. When MELDallocation was initiated, it was agreed that mortalitywas not the appropriate endpoint for HCC candidates,but instead tumor expansion beyond the MC wouldnecessitate dropout from the wait list. As a result,candidates with HCC within the MC and with T2lesions were assigned 29 points at the time of the ini-tial listing with incremental points granted every 3months (corresponding to a 10% increase in waitlistdropout). The initial point allocation was decreased to24 in April 2003 and to 22 in January 2005. Bothdecreases occurred because it was noted that the allo-cated MELD score did not correlate with the risk ofwaitlist dropout for these candidates. There have,however, been no further changes in the allocation ofincremental exception points over time. The currentpolicy states that an HCC candidate with a tumorwithin the MC may receive an exception MELD score(‘‘equivalent to a 15% probability of candidate deathwithin 3 months’’) and 3 additional points every 3months (‘‘equivalent to a 10% increase in candidatemortality’’).7

Two recent publications have addressed the issue ofdifferences in waitlist mortality between HCC candi-dates and non-HCC candidates, and they have dem-onstrated that non-HCC candidates have a greaterrisk of waitlist dropout.8,9 However, these studies didnot specifically address the systematic upgrades inexception points based on the waiting time; this issueremains unresolved.

The goal of this study was to explore the appropri-ate allocation of exception points for HCC candidatesby (1) comparing the 90-day waitlist outcomes of can-didates with an initial HCC exception score of 22 tonon-HCC candidates with similar initial MELD scores;

(2) determining whether HCC candidates with aMELD exception score of 22 have a 15% risk of wait-list dropout; (3) determining of whether HCC candi-dates with MELD exception scores of 25 and 28 infact have 25% and 35% risks, respectively, of waitlistdropout; and (4) the comparing of the 90-day waitlistoutcomes of HCC candidates with MELD exceptionscores of 25 and 28 to non-HCC candidates with simi-lar MELD scores.

PATIENTS AND METHODS

Study Population

Analyses were based on data from the Organ Procure-ment and Transplantation Network (OPTN)/UNOSdatabase as of May 31, 2009. We included all adults(�18 years old) who were listed for initial liver trans-plantation between January 1, 2005 and May 31,2009. January 1, 2005 marked the implementationdate for the current MELD allocation policy. The HCCgroup included all candidates who received exceptionpoints for T2 stage HCC (within the MC) according tothe current exception policy. The non-HCC cohortincluded all candidates without a diagnosis of HCCafter the exclusion of candidates with any otherapproved non-HCC exception. This enabled a compar-ison of HCC candidates and candidates with compa-rable laboratory MELD scores. All status 1 candidateswere excluded.

Outcomes

The primary outcome was waitlist removal for deathor clinical deterioration within 90 days. This endpointincluded all candidates who were removed with the‘‘died’’ code as well as candidates who were removedbecause they were too sick or medically unsuitable.We considered candidates who were removed fromthe wait list because of clinical deterioration asequivalent to candidates who died because chronicliver disease is almost uniformly fatal without trans-plantation. This grouping is consistent with previousresearch.10,11 After the exclusion of clinical deteriora-tion, death on the wait list was also evaluated as asecondary outcome.

For the cohort of candidates who were evaluatedfrom the time of the initial listing, the 90-day out-comes were determined from the date of receipt of 22MELD exception points for HCC candidates or fromthe date of listing for non-HCC candidates. For analy-ses of HCC candidates and non-HCC candidates whohad already been listed, the period of 90 days wasdetermined from the receipt of additional HCC excep-tion points (MELD scores of 25 and 28) for HCCcandidates or from the updating of the MELD score(24-26 or 27-29; see the next section) for non-HCCcandidates.

The current analysis used the binary outcome ofwaitlist removal (yes/no) within 90 days for death orclinical deterioration rather than the time to waitlist

LIVER TRANSPLANTATION, Vol. 18, No. 4, 2012 GOLDBERG ET AL. 435

removal because the MELD score is meant to predict90-day waitlist mortality. Also, because HCC candi-dates are granted additional MELD exception pointsevery 3 months, we wanted to determine the 90-dayrisk of waitlist removal for HCC candidates after thereceipt of 22, 25, or 28 exception points.

MELD Categories

All HCC candidates listed with 22 MELD exceptionpoints were compared to all non-HCC candidateslisted with an initial laboratory MELD score of 21 to23. A comparison group of non-HCC candidates witha calculated MELD score of 21 to 23 at listing waschosen because if the HCC exception MELD scoreaccurately predicts 90-day waitlist survival from theinitial listing, these 2 groups would be expected tohave similar 90-day risks of waitlist removal for deathor clinical deterioration. A MELD score range of 21 to23 was chosen because limiting the analysis solely tonon-HCC candidates with a calculated MELD score of22 resulted in a sample size substantially smallerthan the HCC cohort (n ¼ 877). To ensure a lack ofselection bias in the non-HCC group, a secondaryanalysis was conducted to compare candidates with22 HCC MELD exception points to all non-HCC candi-dates with a MELD score of 21 to 23, regardless of theinitial MELD score. This demonstrated a 90-day riskof waitlist removal or death similar to that demon-strated by the analysis of non-HCC candidates with

an initial laboratory MELD score of 21 to 23 (data notshown).

The 90-day outcomes for HCC candidates withMELD scores of 25 and 28 were also compared tonon-HCC candidates with MELD scores of 24 to 26and 27 to 29, respectively. The non-HCC cohortsincluded all candidates with MELD scores of 24 to 26and 27 to 29, regardless of the initial MELD score (seethe flowchart in Fig. 1). This can be exemplified by acandidate who first enters the wait list with a MELDscore of 14 but whose score subsequently escalates to25. This candidate would have the same expected 90-day mortality as a patient who first enters the wait listwith a different MELD score but also subsequentlyarrives at a MELD score of 25.1 Candidates with labo-ratory MELD scores of 24 to 26 and 27 to 29 at anypoint in time on the wait list were chosen to enable acomparison of non-HCC candidates and HCC candi-dates with equivalent MELD scores and thus similarpredicted risks of waitlist removal for death or clinicaldeterioration. Non-HCC candidates could have a cal-culated MELD score of 24 to 26 or 27 to 29 at morethan 1 point in time. Therefore, within each MELDcategory (24-26 and 27-29), we included only the firsttime point at which the MELD score met the criteriafor that stratum.

To ensure that candidate outcomes were notincluded in more than 1 MELD category (eg, a candi-date who was listed with a MELD score of 21 on Jan-uary 1, 2006, whose MELD score increased to 25 on

Figure 1. Flowchart describing the non-HCC candidates included in the study.

436 GOLDBERG ET AL. LIVER TRANSPLANTATION, April 2012

February 1, 2006, and who died on March 1, 2006,ie, within 90 days of MELD scores of 21 and 25), weincluded non-HCC candidates in a subsequent cate-gory only if they remained on the wait list for morethan 90 days after their inclusion in the precedingcategory (eg, a candidate listed with a MELD score of21 that was subsequently increased to 24 wasincluded in the cohort of patients with MELD scoresof 24 to 26 only if the listing date for the MELD scoreof 24 was at least 90 days after the listing date for theMELD score of 21).

Statistical Analysis

The characteristics of HCC and non-HCC candidateswere compared with Fisher’s exact test and chi-squaretests for dichotomous variables and with 2-sample ttests or Wilcoxon rank-sum tests for continuous vari-ables. Chi-square tests were used to compare theunadjusted 90-day risk of removal for death or clini-cal deterioration between HCC and non-HCC candi-dates within each MELD category and between HCCcandidates in the 3 different MELD categories. Stu-dent t tests were used to compare the MELD scores atthe time of waitlist removal for HCC and non-HCCcandidates. For comparisons of outcomes after wait-list removal, we used Social Security Death MasterFile data included in the OPTN/UNOS data set(updated as of March 14, 2011). For candidatesremoved from the wait list for clinical deterioration,Wilcoxon rank-sum tests were used to compare theaverage times between waitlist removal and actualdeath. As a supplementary analysis, chi-square testswere used to determine whether the 90-day risk ofwaitlist removal for death or clinical deterioration forHCC candidates listed with a MELD score of 22 wassimilar to the risk for non-HCC candidates with initialMELD scores of less than 21.

Logistic regression models were used to determinewhether the odds of waitlist removal for death or clini-cal deterioration within 90 days of listing differedbetween HCC candidates and non-HCC candidates.Separate models were fitted to compare HCC candi-dates with exception MELD scores of 22, 25, and 28 tonon-HCC candidates with MELD scores of 21 to 23, 24to 26, and 27 to 29, respectively. Adjustment variableswere selected for inclusion if they were independentlyassociated with the outcome (P < 0.05), if their removalfrom the model changed the coefficient for HCC by�10%, or if they were needed for clinical validity. Thevariables tested with these criteria included the recipi-ent’s age at listing, sex, race/ethnicity, blood type, andinsurance type (private or public). We included fixedeffects for the UNOS region to account for unobservedheterogeneity in the risk of waitlist removal acrossregions and for any correlations due to the clusteringof candidates within regions.12

The unadjusted posttransplant survival of HCC liverrecipients was compared with log-rank testing. Allanalyses were conducted with Stata 11.13

This study received an exempt review from theinstitutional review board of the University ofPennsylvania.

RESULTS

Initial Listings

Between January 1, 2005 and May 31, 2009, 6246candidates were listed with T2 HCC exception points.The demographics and primary diagnoses of the HCCand non-HCC cohorts are displayed in Table 1. Com-pared to non-HCC candidates, HCC candidates wereolder (P < 0.001), more likely to be male (P < 0.001),and less likely to be white (P < 0.001) or Asian (P <0.001). The primary diagnoses of the HCC cohorts dif-fered from the diagnoses of each of the non-HCCcohorts. According to the UNOS primary diagnosiscodes, HCC candidates were less likely to have alco-holic cirrhosis, nonalcoholic steatohepatitis/crypto-genic cirrhosis, or cholestatic cirrhosis. Although28.7% (1793/6246) of the HCC candidates were listedwith HCC as the primary diagnosis without a clearspecification of the background liver disease etiology,863 (48.1%) were positive for hepatitis C virus anti-body. The inclusion of these candidates with HCCpatients listed with hepatitis C virus as the primarydiagnosis yielded 3526 HCC patients (56.4%) withhepatitis C virus (ie, a significantly greater proportionthan the proportion of the non-HCC cohort).

Wait List Mortality

Figure 2 depicts the rates of waitlist removal for deathor clinical deterioration within 90 days for candidateswith HCC and candidates without HCC in the 3MELD categories. Two hundred fifty-nine of 6246HCC candidates (4.1%) who were listed with 22 excep-tion points were removed from the wait list because ofdeath or clinical deterioration within 90 days of list-ing, whereas 283 of 2564 non-HCC candidates(11.0%) with an initial MELD score of 21 to 23 wereremoved. Similar data were obtained when all non-HCC candidates with a MELD score of 21 to 23,regardless of the initial MELD score, were analyzed(data not shown). Ninety-three of the 2009 HCC can-didates (4.6%) with a MELD score of 25 were removedfrom the wait list for death or clinical deteriorationwithin 90 days, whereas 805 of the 4655 non-HCCcandidates (17.3%) with a MELD score of 24 to 26were removed. Lastly, 20 of the 675 HCC candidates(3.0%) with a MELD score of 28 were removed fromthe wait list for death or clinical deterioration within90 days, whereas 646 of the 2737 non-HCC candi-dates (23.6%) with a MELD score of 27 to 29 wereremoved.

The risk of death alone differed between HCC andnon-HCC candidates (P < 0.001) within each MELDstratum (2.0% for a MELD score of 22 versus 7.6% fora MELD score of 21-23, P < 0.001; 2.1% for a MELDscore of 25 versus 11.4% for a MELD score of 24-26,P < 0.001; and 1.3% for a MELD score of 28 versus15.6% for a MELD score of 27-29, P < 0.001).

LIVER TRANSPLANTATION, Vol. 18, No. 4, 2012 GOLDBERG ET AL. 437

However, the risk of death alone for HCC candidateswith exception MELD scores of 22, 25, and 28 werestatistically similar (2.0% versus 2.1% versus 1.3%, P¼ 0.42).

In the HCC cohorts, the proportion of waitlistremovals for death equaled the proportion for clinicaldeterioration (2.0% versus 2.1% for a MELD score of22, P ¼ 0.49; 2.1% versus 2.5% for a MELD score of25, P ¼ 0.46; and 1.3% versus 1.7% for a MELD scoreof 28, P ¼ 0.65). Conversely, in each of the non-HCCMELD cohorts, the proportion of waitlist removals fordeath was approximately twice the proportion for clin-

ical deterioration (7.6% versus 3.4% for a MELD scoreof 21-23, P < 0.001; 11.4% versus 5.9% for a MELDscore of 24-26, P < 0.001; and 15.6% versus 8.0% fora MELD score of 27-29, P < 0.001).

There was regional variability in the 90-day rates ofwaitlist removal for death or clinical deteriorationamong the HCC and non-HCC cohorts (SupportingFig. 1). The variability was similar among the HCCcohorts with MELD scores of 22 and 25, but it wasmuch more pronounced among the non-HCC cohorts.

Among the HCC candidates who were removed fordeath or clinical deterioration, the mean laboratoryMELD score at removal was 22.4 6 10.2, and thescores were similar across all 3 MELD categories.However, among the non-HCC candidates, the MELDscore at removal increased from 29.2 6 7.7 for thecohort with MELD scores of 21 to 23 to 31.9 6 9.0 forthe cohort with MELD scores of 24 to 26 and to 32.26 6.5 for the cohort with MELD scores of 27 to 29.Among the HCC candidates removed for death or clin-ical deterioration, the laboratory MELD score at re-moval was higher than the exception MELD score for106 of the 259 candidates (40.9%) with a MELD scoreof 22, for 22 of the 93 candidates (23.7%) with aMELD score of 25, and for 5 of the 20 candidates(25.0%) with a MELD score of 28.

Among the HCC and non-HCC waitlist candidatesin each MELD stratum who were removed for clinical

TABLE 1. Patient Demographics and Primary Diagnoses

HCC Candidates

With a MELD

Score of 22

(n ¼ 6246)

Non-HCC Candidates

MELD Score

of 21-23

(n ¼ 2564)

MELD Score

of 24-26

(n ¼ 4655)

MELD Score

of 27-29

(n ¼ 2737)

Age at listing (years)* 56.5 6 7.5 52.6 6 9.9 53.1 6 9.5 52.9 6 9.6Male sex [n (%)] 4817 (77.1) 1700 (66.3) 3017 (64.8) 1747 (63.8)Race/ethnicity [n (%)]White 4087 (65.4) 1790 (69.8) 3325 (71.4) 1901 (69.5)Hispanic 913 (14.6) 378 (14.7) 735 (15.8) 466 (17.0)Black 533 (8.5) 299 (11.7) 432 (9.3) 247 (9.0)Asian 643 (10.3) 73 (2.8) 123 (2.6) 87 (3.2)Other† 69 (1.1) 24 (0.9) 40 (0.9) 36 (1.3)

Blood type [n (%)]O 2923 (46.8) 1224 (47.7) 2260 (48.5) 1363 (49.8)A 2316 (37.1) 935 (36.5) 1790 (38.5) 1014 (37.0)B 783 (12.5) 304 (11.9) 500 (10.7) 285 (10.4)AB 224 (3.6) 101 (3.9) 105 (2.3) 75 (2.7)

Private insurance [n (%)] 3977 (63.7) 1492 (58.2) 2805 (60.3) 1655 (60.5)Primary diagnosis [n (%)]Hepatitis C 2663 (42.6) 892 (34.8) 1711 (36.8) 997 (36.4)HCC 1793 (28.7) 0 (0.0) 0 (0.0) 0 (0.0)Alcoholic 454 (7.3) 562 (21.9) 836 (18.0) 507 (18.5)Nonalcoholic steatohepatitis/cryptogenic 371 (5.9) 395 (15.4) 707 (15.2) 389 (14.2)Hepatitis B 291 (4.7) 55 (2.1) 75 (1.6) 65 (2.4)Cholestatic 100 (1.6) 180 (7.0) 401 (8.6) 202 (7.4)Metabolic/autoimmune 114 (1.8) 148 (5.8) 217 (4.7) 126 (4.6)Other 460 (7.4) 332 (12.9) 708 (15.2) 451 (16.5)

*The data are presented as means and standard deviations.†Other includes patients whose ethnicity was defined as Hawaiian, Native American, or multiracial.

Figure 2. Patients who died or were removed from the list(because they were too sick) within 90 days.

438 GOLDBERG ET AL. LIVER TRANSPLANTATION, April 2012

deterioration, similar proportions subsequently diedduring follow-up. However, in each MELD stratum,HCC candidates survived longer after delisting thannon-HCC candidates (Table 2). The median survivaltimes were as follows: 27 days (interquartile range ¼3-187 days) for patients with a MELD score of 22 ver-sus 2 days (interquartile range ¼ 1-14 days) forpatients with a MELD score of 21 to 23 (P < 0.001),87 days (interquartile range ¼ 8-202 days) forpatients with a MELD score of 25 versus 3 days(interquartile range ¼ 1-13 days) for patients with aMELD score of 24 to 26 (P < 0.001), and 32.5 days(interquartile range ¼ 1-175 days) for patients with aMELD score of 28 versus 1 day (interquartile range ¼0-6 days) for patients with a MELD score of 27 to 29(P ¼ 0.02).

To explore whether the risk of waitlist dropout forHCC candidates varied according to the initial listinglaboratory MELD scores, we stratified HCC candidatesinto 2 groups: laboratory MELD scores � 15 and labo-ratory MELD scores < 15.14 Candidates with a labora-tory MELD score � 15 at the initial listing had ahigher 90-day risk of removal for death or clinicaldeterioration (8.4% versus 2.5% for the cohort with aMELD score of 22, P < 0.001; 7.8% versus 3.6% forthe cohort with a MELD score of 25, P < 0.001; and5.2% versus 2.3% for the cohort with a MELD score of28, P ¼ 0.06). However, according to a comparison ofall candidates with an initial laboratory MELD score� 15, the risk of waitlist dropout remained higher fornon-HCC candidates versus HCC candidates.

Multivariate Analysis

In univariate regression models, all tested recipientvariables (except for the blood type) were significantlyassociated with the risk of 90-day waitlist removal fordeath or clinical deterioration. Nevertheless, the bloodtype was included in multivariate models because ofthe potential association with the outcome of inter-est.15 In the multivariate regression models assessingthe 90-day survival of HCC candidates, each of the

other tested independent variables (age at listing, sex,race/ethnicity, and insurance) was significantly asso-ciated with the odds of waitlist removal for death orclinical deterioration within 90 days.

Table 3 provides unadjusted and adjusted oddsratios (ORs) of 90-day waitlist removal due to death orclinical deterioration for HCC and non-HCC candi-dates within each MELD stratum. The adjusted oddsof waitlist removal were substantially and consistentlylower for HCC candidates versus non-HCC candi-dates, and they decreased with increasing MELDscores [for a MELD score of 22, OR ¼ 0.32, 95% confi-dence interval (CI) ¼ 0.27-0.39; for a MELD score of25, OR ¼ 0.21, 95% CI ¼ 0.17-0.27; and for a MELDscore of 28, OR ¼ 0.09, 95% CI ¼ 0.05-0.14]. Weobtained similar results when we examined 90-daywaitlist removal for death alone.

Transplantation for HCC Candidates

and Non-HCC Candidates

Transplantation rates within 90 days were higher foreach of the non-HCC cohorts versus the HCC cohortswith similar MELD scores, with increasing rates corre-lating with increasing MELD scores (data not shown).The median donor risk index, the mean donor age,and the use of donation after cardiac death organswere similar for all 6 groups of patients. There wasincreased use of regionally shared organs in the non-HCC cohorts with MELD scores of 24 to 26 and 27 to29 versus their respective HCC cohorts (data notshown). Across the 3 HCC cohorts, similar propor-tions of patients underwent transplantation with labo-ratory MELD scores of <15 (65.0%-70.5%), 15 to 21(23.7%-28.3%), and >22 (5.8%-7.7%).

Posttransplant Outcomes for HCC Candidates

With MELD Exception Scores of 22, 25, and 28

For HCC candidates who underwent transplanta-tion, posttransplant patient survival did not differ

TABLE 2. Removal Due to Clinical Deterioration During Follow-Up and Time to Death

Category Removed (n)*

Died During

Follow-Up

[n (%)]

Time From

Delisting to

Death (Days)† P Value‡

HCC MELD score of 22 134 114 (85.1) 27 (3-187) <0.001Non-HCC MELD score of 21-23 91 74 (81.3) 2 (1-14)HCC MELD score of 25 50 43 (86.0) 87 (8-202) <0.001Non-HCC MELD score of 24-26 274 245 (89.4) 3 (1-13)HCC MELD score of 28 12 12 (100.0) 32.5 (1-175) 0.016Non-HCC MELD score of 27-29 220 192 (87.3) 1 (0-6)

*Candidates were removed because they were too sick or were medically unsuitable.†The data are presented as medians and interquartile ranges.‡Comparison of the number of days from delisting to death for HCC and non-HCC candidates within each MELD category(Wilcoxon rank-sum test).

LIVER TRANSPLANTATION, Vol. 18, No. 4, 2012 GOLDBERG ET AL. 439

between the 3 MELD strata (log-rank P ¼ 0.20; Ta-ble 4 and Fig. 3). By the end of the follow-up, 465,161, and 48 HCC transplant recipients (16.5%,17.1%, and 13.1%) with exception MELD scores of22, 25, and 28, respectively, had died. The causesof graft failure are not well coded for determiningthe risk of recurrent HCC in transplant patients.Although the risk of posttransplant mortality washigher for non-HCC recipients versus HCC trans-plant recipients in the corresponding MELD cate-gory, the time to death was longer for non-HCCrecipients (data not shown).

Risk of Wait List Removal for HCC Candidates

With a MELD Score of 22 Versus Non-HCC

Candidates With a MELD Score < 21

We compared the 90-day risk of waitlist removal fordeath or clinical deterioration for HCC candidateswith an initial MELD score of 22 and 4 groups of non-HCC candidates with initial MELD scores less than 21(Table 5). According to a comparison with non-HCCcandidates with MELD scores of <15, 15 to 16, 17 to18, and 19 to 20, the unadjusted 90-day risk of wait-list removal for death or clinical deterioration forpatients with an HCC MELD score of 22 was mostcomparable to the risk for non-HCC candidates withan initial MELD score of 15 to 16 (4.2% versus 4.1%).

DISCUSSION

We have shown that under the current allocation pol-icy, the odds of waitlist removal for death or clinicaldeterioration are significantly lower for HCC candi-dates versus non-HCC candidates. The observed dif-ferences increase steeply as the analysis progressesfrom low MELD strata to high MELD strata. Theseresults not only reinforce previous work that hasquestioned the initial MELD exception pointsbestowed upon HCC candidates within the MC, but

TABLE 3. ORs Comparing 90-Day Wait List Mortality and Removal Due to Clinical Deterioration for HCC Candidates

and Non-HCC Candidates Within Each MELD Category

HCC MELD

Score Reference Group

Unadjusted

OR (95% CI)

Adjusted

OR (95% CI)* P Value

22 Non-HCC MELD score of 21-23 0.35 (0.29-0.41) 0.32 (0.27-0.39) <0.00125 Non-HCC MELD score of 24-26 0.23 (0.19-0.29) 0.21 (0.17-0.27) <0.00128 Non-HCC MELD score of 27-29 0.10 (0.06-0.16) 0.09 (0.05-0.14) <0.001

*The multivariate model was adjusted for the recipient’s age at listing, sex, race/ethnicity, blood type, and insurance status(private versus public); the UNOS region was treated as a fixed effect.

TABLE 4. Posttransplant Outcomes of Recipients With HCC

Exception MELD

Score for HCC at the

Time of Transplantation

Alive at

Follow-Up

[n (%)]

Died During

Follow-Up

[n (%)]

Time to

Death (Days)*

22 (n ¼ 2822)† 2145 (76.0) 465 (16.5) 282 (94-604)25 (n ¼ 944)‡ 730 (77.3) 161 (17.1) 237 (113-548)28 (n ¼ 367)§ 294 (80.1) 48 (13.1) 179 (26-585)

NOTE: P was 0.20 for the proportion of patients who died versus the proportion of patients who survived in the 3 MELDgroups.*The data are presented as medians and interquartile ranges.†The follow-up status was incomplete for 78 patients.‡The follow-up status was incomplete for 19 patients.§The follow-up status was incomplete for 10 patients.

Figure 3. Posttransplant survival of recipients with HCC withinthe MC.

440 GOLDBERG ET AL. LIVER TRANSPLANTATION, April 2012

also newly challenge the incremental MELD exceptionpoints granted at 3-month intervals. Our data suggestthat neither the initially awarded MELD exceptionpoints for HCC nor the incrementally awarded pointsaccurately reflect the risk of waitlist removal for HCCcandidates, particularly when they are juxtaposedagainst non-HCC candidates.

The current MELD allocation system is based on aprinciple set forth by the Department of Health andHuman Services in 1998: an organ allocation policyshould be based on medical urgency.16 The Instituteof Medicine resoundingly echoed this sentiment 1year later with its recommendation to eliminate wait-ing time as an allocation criterion. An allocation policyshould ensure equitable access to organs based oncandidates’ medical characteristics and disease prog-nosis rather than waiting times.3,17 Our analysesshow that with respect to HCC candidates versusnon-HCC candidates, the current allocation policyfails in both ways.

Although OPTN policy states that the initial 22MELD exception points allocated to HCC candidatesare meant to be equivalent to a 15% probability ofwaitlist dropout within 3 months, the data do notsupport this contention.7 Only 4.1% of the HCC can-didates with T2 stage HCC tumors who were listedwith a MELD score of 22 were removed from the waitlist within 90 days because of death or clinical deteri-oration, whereas 11.0% of the non-HCC candidateswith MELD scores of 21 to 23 were removed. Althoughthe data presented here are similar to the datareported by Washburn et al.,8 the 2 studies differ inthat Washburn et al. compared HCC candidates to allnon-HCC candidates, regardless of the MELD scores.Massie et al.9 recently reported similar data as well.

However, their HCC comparator group included allHCC candidates with 22 MELD exception points andnot only those candidates within the MC. From Janu-ary 1, 2005 to March 23, 2011, 7360 HCC candidateswithin the MC were accepted with 22 MELD exceptionpoints. Another 1034 candidates (14.0%) were catego-rized according to the UNOS coding criteria as ‘‘HCCnot meeting criteria’’ but received 22 MELD exceptionpoints through a petition to a regional review board[ie, they received the exception diagnosis code of 3(‘‘HCC not meeting criteria’’), but the exception HCCcode was listed as yes]. These candidates, who werepresumably outside the MC, were not included in ouranalysis. This difference may explain the higher wait-list dropout rate reported by Massie et al.

We extended our analyses of HCC candidates andnon-HCC candidates to provide a novel assessment ofthe differences in the risk of waitlist removal betweenHCC candidates with 25 MELD exception points andHCC candidates with 28 MELD exception points andbetween these HCC candidates and non-HCC candi-dates with comparable laboratory MELD scores.

The magnitude of the difference in the risk of deathbetween HCC candidates and non-HCC candidateswas staggering, especially at the higher MELD levels.With increasing MELD scores, the risk of waitlist re-moval was stable for HCC candidates (4.6% forpatients with a MELD score of 25 versus 3.0% forpatients with a MELD score of 28), whereas itincreased significantly for non-HCC candidates(17.3% for patients with MELD scores of 24-26 versus23.6% for patients with MELD scores of 27-29). Theadditional exception points granted to HCC candi-dates every 3 months are meant to reflect the increas-ing risk of tumor extension beyond acceptable MCboundaries, with the number of points meant toreflect a 10% increase in the risk of waitlist dropout.7

The data that we have presented clearly contradictthe notion that waitlist dropout secondary to tumorprogression increases over time. Point increases inthe calculated MELD score directly correspond to anatural log increase in the risk of death. The fact thatwaitlist dropout for HCC does not escalate in thesame manner calls into question the entire premise ofgranting exception MELD points to HCC candidates.Survival after waitlist removal was significantly longerfor HCC candidates who were delisted for clinicaldeterioration rather than death versus non-HCCcandidates.

Despite similar MELD scores at listing, the candi-dates with HCC consistently had lower laboratoryMELD scores (13.2 for the patients with a MELD scoreof 22 versus 22.0 for the patients with a MELD scoreof 21-23, 13.1 for the patients with a MELD score of25 versus 24.8 for the patients with a MELD score of24-26, and 13.2 for the patients with a MELD scoreof 28 versus 27.8 for the patients with a MELD scoreof 27-29). The fact that the proportion of waitlistremovals was stable across the 3 cohorts of HCC can-didates but increased significantly for the non-HCCcandidates suggests that the risk of waitlist removal

TABLE 5. Risk of Death or Removal Due to Clinical

Deterioration for HCC Candidates and Non-HCC

Candidates With MELD Scores of 6 to 20 at the

Time of Listing

Category

Died or

Removed

Within

90 Days

[n (%)]*

Died or

Removed

During Time

on the Wait

List [n (%)]†

HCC MELD score of 22(n ¼ 6246)

259 (4.1) 637 (10.2)

Non-HCC MELD score‡

<15 (n ¼ 12,570) 277 (2.2) 1719 (13.7)15-16 (n ¼ 3548) 146 (4.1) 590 (16.6)17-18 (n ¼ 2894) 166 (5.7) 486 (16.8)19-20 (n ¼ 2164) 185 (8.7) 378 (17.5)

*Removal due to death or clinical deterioration within 90days of listing.

†Removal due to death or clinical deterioration during theentire period of time on the wait list.

‡Calculated MELD score at the time of the initial listing.

LIVER TRANSPLANTATION, Vol. 18, No. 4, 2012 GOLDBERG ET AL. 441

is directly related to the severity of the underlyingliver disease rather than tumor progression. Furthersupport for this concept is the fact that the 90-dayrisk of waitlist removal for death or clinical deteriora-tion was similar for HCC candidates listed with 22exception points and non-HCC candidates listed witha laboratory MELD score of 15 to 16.

Although additional exception points are given toHCC candidates according to the waiting timebecause of concerns about tumor progression, thecurrent MELD exception point policies were created inan era when locoregional therapies for HCC were notas widespread, and they have not been altered despiteevidence that these therapies have decreased waitlistdropout rates.18-20 Current locoregional strategieshave been shown to improve the survival of patientswith HCC (both within and beyond the MC). Amongpatients with HCC who are not transplant candidatesand receive only locoregional therapy, those with a ra-diographic response have a median survival of 2years.21 Furthermore, recent Italian data demon-strated that candidates with T2 stage tumors whoresponded to locoregional therapy had a lower risk ofwaitlist dropout and decreased posttransplant HCCrecurrence.20 This correlation between the responseto therapy and posttransplant HCC recurrence likelyexplains our finding that the posttransplant survivalrates of HCC recipients with 22, 25, and 28 exceptionpoints were similar, with the recurrence risk relatedmore to the therapy response than the waiting time.The waitlist mortality for HCC candidates decreasedwith rising exception scores, which correlated withlonger wait times. The available data do not support adefinitive rationale for this finding. Although this ob-servation may be due to a more favorable tumor bio-logy, an alternative explanation is that these candi-dates received additional locoregional therapies asthey accrued exception points. Altogether, there iscompelling evidence that current policies of auto-matic, incremental upgrades in exception points mustbe thoroughly re-evaluated.

Our study has several limitations. The use of theOPTN/UNOS database limited the data elementsavailable for covariate adjustments. However, theOPTN/UNOS database not only has been used forprevious research evaluating this question but also isused in the design and alteration of allocation policy.For our outcome definition, we relied on the outcomesof HCC candidates under the current allocation sys-tem. We would have been unable to determine theirrisk of death or clinical deterioration if they had notbeen given the same exception points. Although it istheoretically possible that fewer HCC candidateswould have undergone transplantation and more HCCcandidates would have been removed from the waitlist for death or clinical deterioration if they had notreceived exception points, it is unlikely that thisexplains the results that we see. Because of the mag-nitude of the difference in the risk of death for HCCcandidates versus non-HCC candidates, the risk ofdeath for HCC candidates who underwent transplan-

tation would have needed to be substantially largerthan the risk for non-HCC candidates who underwenttransplantation to alter our current results. Our anal-yses focused only on candidates’ 90-day outcomesfrom a single point in time. Although this has thepotential for introducing a time-dependent misclassifi-cation bias, a candidate’s current MELD score is thesingle most important determinant of mortality riskon the waiting list.1,9 Moreover, our goal was to evalu-ate the 90-day risk of waitlist dropout for HCC candi-dates from the time of receiving exception points todetermine the appropriateness of current policies.1,9

We do not have data on the impact of locoregionaltherapies, which directly correlate with survival andcould help us to stratify candidates with HCC forexception points.21 UNOS provides some data onwhether candidates have received locoregional ther-apy, but detailed data on the number of treatmentsand the success of treatments are limited. Lastly,although we could compare posttransplant survivalacross the 3 HCC MELD cohorts, we could not evalu-ate differences in recurrent HCC because these dataare not reliably coded in the OPTN/UNOS database.

In conclusion, our data suggest that HCC candi-dates have substantially lower odds of waitlist re-moval for death or clinical deterioration than non-HCC candidates across a broad range of MELDscores. The initial allocation of 22 MELD exceptionpoints to HCC candidates is too high according totheir actual risk of 90-day waitlist dropout from list-ing. The steep increase in the risk differential betweenHCC patients and non-HCC patients within higherMELD strata (25 and 28) challenges the notion thatan increased waiting time for HCC candidates is asso-ciated with an increased risk of waitlist dropout justi-fying the systematic addition of acceptance points ev-ery 3 months. These data highlight the urgent need toreconsider the equitable treatment of HCC patientsand non-HCC patients by our national allocation pol-icy. Although the intention of bestowing HCC excep-tion points to accurately reflect the risk of waitlist re-moval for tumor expansion beyond acceptable listingcriteria appears eminently reasonable, practice hasdemonstrated that the risk has been grossly overesti-mated. Without question, certain HCC candidatesmerit exception points, but other factors, includingtheir response to locoregional therapy, the severity ofthe underlying liver disease, and regional access totransplantation, must be taken into account.Although future research is planned to determineoptimal allocation policies for HCC candidates withrespect to non-HCC candidates, our data stronglyindicate that the current number of exception pointsallocated for HCC should be lowered.

REFERENCES

1. Bambha K, Kim WR, Kremers WK, Therneau TM,Kamath PS, Wiesner R, et al. Predicting survival amongpatients listed for liver transplantation: an assessment ofserial MELD measurements. Am J Transplant 2004;4:1798-1804.

442 GOLDBERG ET AL. LIVER TRANSPLANTATION, April 2012

2. Kamath PS, Kim WR; for Advanced Liver Disease StudyGroup. The Model for End-Stage Liver Disease (MELD).Hepatology 2007;45:797-805.

3. Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Ther-neau TM, Kosberg CL, et al. A model to predict survivalin patients with end-stage liver disease. Hepatology 2001;33:464-470.

4. LeiseMD, KimWR, KremersWK, Larson JJ, Benson JT, Ther-neau TM. A revised Model for End-Stage Liver Disease opti-mizes prediction of mortality among patients awaiting livertransplantation. Gastroenterology 2011;140:1952-1960.

5. Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J,ter Borg PC. A model to predict poor survival in patientsundergoing transjugular intrahepatic portosystemicshunts. Hepatology 2000;31:864-871.

6. Wiesner R, Edwards E, Freeman R, Harper A, Kim R,Kamath P, et al.; for United Network for Organ SharingLiver Disease Severity Score Committee. Model for End-Stage Liver Disease (MELD) and allocation of donor liv-ers. Gastroenterology 2003;124:91-96.

7. Organ Procurement and Transplantation Network. Alloca-tion of livers. http://optn.transplant.hrsa.gov/Policiesand-Bylaws2/policies/pdfs/policy_8.pdf. Accessed January2012.

8. Washburn K, Edwards E, Harper A, Freeman R. Hepato-cellular carcinoma patients are advantaged in the cur-rent liver transplant allocation system. Am J Transplant2010;10:1643-1648.

9. Massie AB, Caffo B, Gentry SE, Hall EC, Axelrod DA,Lentine KL, et al. MELD exceptions and rates of waitinglist outcomes. Am J Transplant 2011;11:2362-2371.

10. Moylan CA, Brady CW, Johnson JL, Smith AD, Tuttle-Newhall JE, Muir AJ. Disparities in liver transplantationbefore and after introduction of the MELD score. JAMA2008;300:2371-2378.

11. Austin MT, Poulose BK, Ray WA, Arbogast PG, FeurerID, Pinson CW. Model for End-Stage Liver Disease: didthe new liver allocation policy affect waiting list mortal-ity? Arch Surg 2007;142:1079-1085.

12. French B, Heagerty PJ. Analysis of longitudinal data toevaluate a policy change. Stat Med 2008;27:5005-5025.

13. Stata Statistical Software [computer program]. Version11. College Station, TX: StataCorp; 2010.

14. Berg CL, Merion RM, Shearon TH, Olthoff KM, Brown RSJr, Baker TB, et al. Liver transplant recipient survival bene-fit with living donation in the Model for Endstage Liver Dis-ease allocation era. Hepatology 2011;54:1313-1321.

15. Scientific Registry of Transplant Recipients. Organ sum-mary. http://srtr.org/csr/current/NatPublic201106/pdf/LI201106.pdf. Accessed January 2012.

16. Organ Procurement and Transplantation Network—HRSA. Final rule with comment period. Fed Regist 1998;63:16296-16338.

17. Analysis of waiting times. In: Institute of Medicine Com-mittee on Organ Procurement and Transplantation Pol-icy, eds. Organ Procurement and Transplantation:Assessing Current Policies and the Potential Impact ofthe DHHS Final Rule. Washington, DC: National Aca-demies Press; 1999:57-78.

18. Golfieri R, Cappelli A, Cucchetti A, Piscaglia F, Carpen-zano M, Peri E, et al. Efficacy of selective transarterialchemoembolization in inducing tumor necrosis in small(<5 cm) hepatocellular carcinomas. Hepatology 2011;53:1580-1589.

19. Otto G, Herber S, Heise M, Lohse AW, M€onch C, Bittinger F,et al. Response to transarterial chemoembolization as a bi-ological selection criterion for liver transplantation in hepa-tocellular carcinoma. Liver Transpl 2006;12:1260-1267.

20. Cucchetti A, Cescon M, Bigonzi E, Piscaglia F, Golfieri R,Ercolani G, et al. Priority of candidates with hepatocellu-lar carcinoma awaiting liver transplantation can bereduced after successful bridge therapy. Liver Transpl2011;17:1344-1354.

21. Memon K, Kulik L, Lewandowski RJ, Wang E, Riaz A,Ryu RK, et al. Radiographic response to locoregionaltherapy in hepatocellular carcinoma predicts patientsurvival times. Gastroenterology 2011;141:526-535.

LIVER TRANSPLANTATION, Vol. 18, No. 4, 2012 GOLDBERG ET AL. 443