Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide.1 The incidence of HCC is rising in the United States and is projected to further increase over the next 2 decades.2 Patients with cirrhosis are at the highest risk for developing this malignancy, with chronic hepatitis C virus (HCV) infection being the primary etiology responsible for the increasing incidence of HCC.3 Surveillance programs in patients with cirrhosis enable the detection of HCC at stages at which curative treatments, such as liver transplantation, can be applied.4
In appropriately selected patients with HCC, orthotopic liver transplantation (OLT) has been shown to be an excellent treatment, and it is the only therapy that simultaneously treats the cancer and the underlying liver disease. In the early experience of liver transplantation for HCC, the outcomes were often dismal, largely because of transplantation of recipients with advanced tumors resulting in high rates of tumor recurrence and poor survival.5 In a seminal study by Mazzaferro and colleagues,6 a 4-year survival of 85% among 35 HCC patients was reported for liver recipients with a solitary tumor ≤ 5 cm or with 3 or fewer tumors each ≤ 3 cm; these criteria are now commonly called the Milan criteria. Subsequent to these findings, the United Network for Organ Sharing (UNOS) in the United States adopted these criteria to determine priority for transplanting patients with HCC. In 2002, UNOS adopted the Model for End-Stage Liver Disease (MELD) system for the allocation of deceased donor livers. Patients with HCC within the Milan criteria are given priority by being assigned a higher exception MELD score, currently 22 points for liver candidates with stage II HCC.
The majority of the data on outcomes with OLT for HCC have been derived from single-center studies. The 5-year survival rates from the time of listing have ranged from 47% to 62% when withdrawals from the waiting list are included and from 61% to 74% when withdrawals from the waiting list are excluded.7 Expanding the criteria for HCC has been proposed by some authors in light of favorable results noted in single-center studies with variable durations of follow-up.8 However, in most regions, candidates that exceed the Milan criteria are not given priority on the transplant waiting list in comparison with those that meet the Milan criteria. The rate of removal from the transplant waiting list due to either tumor progression or death is an important factor to consider when one is evaluating organ allocation policy and has been estimated to range from 20% to 30%.4
The aims of the present study were to evaluate the waiting list removal rates for liver candidates with HCC, the intent-to-treat survival of liver candidates with HCC, and to identify predictors of survival for both candidates on the waiting list and liver transplant recipients through the use of pooled data collected by the Organ Procurement Transplant Network (OPTN). While many studies have evaluated posttransplant survival, an intention-to treat analysis starting at the time of listing was utilized to provide a better understanding of the overall efficacy of liver transplantation for patients with HCC.
AFP, alpha-fetoprotein; CI, confidence interval; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; MELD, Model for End-Stage Liver Disease; OLT, orthotopic liver transplantation; OPTN, Organ Procurement Transplant Network, RFA, radiofrequency ablation; TACE, transarterial chemoembolization; TNM, Tumor-Node-Metastasis; UNOS, United Network for Organ Sharing.
PATIENTS AND METHODS
Data from all adult patients 18 years of age or older with an initial date of registration for deceased donor liver transplantation between January 1998 and March 2006 with a primary, secondary, or tertiary diagnosis of HCC were captured from the OPTN/UNOS database. Identified study subjects included those that developed HCC while waiting for transplantation. Patients with incidental tumors were excluded because the diagnosis of HCC was not known until after transplantation. Demographic, UNOS region, diagnosis, laboratory data, Child-Pugh class, underlying liver disease etiology, tumor burden, and pretransplant treatment data were recorded at the time of initial listing. Candidates listed since 1998 were included because it was the first year in which the Milan criteria were adopted by UNOS and transplant centers in the United States. Overall survival and time to removal from the transplant waiting list were available for all patients. Patients were followed to death, loss to follow-up, withdrawal from the waiting list, or the end of the observation period on December 31, 2006. All deaths were confirmed by evaluation of the Social Security Death Master File. Tumor staging was performed according to the American Liver Tumor Study Group Modified Tumor-Node-Metastasis Staging Classification (http://www.unos.org/policiesandbylaws2/policies/docs/policy_8.doc; accessed December 18, 2007), which is currently being utilized by UNOS.
The pre-MELD era was defined as the era of those listed for OLT prior to February 27, 2002, and the post-MELD era was defined as the era of those listed on or after February 27, 2002. Waiting time was defined as the time from initial listing until removal from the list due to a transplant being performed from either a living or deceased donor. Dropouts were defined as those patients removed from the list because of tumor progression and/or death. The waiting time before dropout was the time from initial listing until removal from the list due to tumor progression or death.
Data were expressed as mean ± standard deviation unless otherwise indicated. We compared the pre-MELD and post-MELD eras with respect to demographics, laboratory and tumor data, pretransplant treatment, and overall survival. The Mann-Whitney test was utilized to compare continuous variables without a normal distribution; otherwise, these variables were compared by t tests. Categorical variables were compared with chi-square tests. Survival was analyzed from the initial date of listing and included dropouts from the waiting list (ie, intent-to-treat analysis), unless otherwise indicated. Unadjusted patient survival following liver transplantation for HCC was compared with Kaplan-Meier analysis with a log-rank test to evaluate for significance. Overall probability of survival was evaluated for potential confounding factors at the time of listing, such as demographic data, etiology of liver disease (hepatitis C versus non–hepatitis C), alpha-fetoprotein (AFP), laboratory MELD score, Child-Pugh class, tumor size, tumor number, donor type, organ allocation policy, portal vein thrombosis, meeting Milan criteria, pretransplant treatment, and UNOS regions. The cutoff for continuous variables was determined by the median value. All variables with a P value < 0.05 were then entered into an adjusted Cox proportional hazards model to evaluate for independent predictors of survival. All analyses were done with the SAS System for Windows, version 9.1 (SAS Institute, Inc., Cary, NC). P values ≤ 0.05 were considered statistically significant.
During the study period, a total of 4482 patients with a diagnosis of HCC were placed on the liver transplant waiting list. The characteristics of the patients at the time of listing are listed in Table 1. The majority of the patients were male (79%) and non-Hispanic white (61%) with a median age of 55 years (range, 18-80). Chronic HCV infection was the most common cause of underlying liver disease, being identified in 57% of the 3923 patients with a reported diagnosis. The median AFP was 19 ng/mL (range, 1-44,279), and the median laboratory MELD score was 11 (range, 6-57). Region 5 (Arizona, California, New Mexico, Nevada, and Utah) accounted for 26% of the patients listed with HCC. The majority of the patients (68%) were listed in the post-MELD era. The number of patients who underwent HCC treatment while awaiting OLT was 1155 (26%), with transarterial chemoembolization being the most common treatment.
Table 1. Clinical Features at Listing for 4482 Patients with Hepatocellular Carcinoma in the United States from January 1998 Through March 2006
n (% or as indicated)
Abbreviations: AFP, alpha-fetoprotein; MELD, Model for End-Stage Liver Disease; OLT, orthotopic liver transplantation, RFA, radiofrequency ablation; TACE, transarterial chemoembolization.
The diagnosis was reported in 3923 of the 4482 patients.
The pre-MELD era is defined as the era of those listed between 1998 and February 26, 2002; the post-MELD era is defined as the era of those listed on or after February 27, 2002.
Patients were removed from the liver waiting list because of death or tumor progression.
Patients who dropped out because of tumor progression
Patients who dropped out because of death
Patients who were removed from the list for unknown reasons
Patients actively waiting
Of the 4482 patients listed, 65% (n = 2898) underwent liver transplantation, 10% (n = 492) were actively waiting as of January 2006, 18% (n = 798) dropped out because of tumor progression (n = 500) and/or death (n = 298), and 7% (n = 294) were removed from the waiting list for unknown reasons that were not detailed within the OPTN database. Figure 1 depicts the number of patients with HCC on the waiting list and those undergoing OLT per year. As a result of the MELD allocation policy, there was approximately a 2-fold increase in the number of patients transplanted for HCC in 2002, and this number continued to increase through 2006. Clinical, demographic, and laboratory data for patients listed in the pre-MELD and post-MELD eras are listed in Table 2. In addition, patients listed in the pre-MELD era were noted to have decreased survival at 1 and 3 years after listing in comparison with those listed in the post-MELD era (72.1% and 59.1% versus 76.9% and 64.1%, P = 0.007; Fig. 2).
Table 2. Clinical, Demographic, and Laboratory Data for Patients Listed in the Pre-MELD and Post-MELD Eras
Pre-MELD (n = 1433)
Post-MELD (n = 3049)
NOTE: Values are presented as mean ± standard deviation.
Abbreviations: AFP, alpha-fetoprotein; MELD, Model for End-Stage Liver Disease; OLT, orthotopic liver transplantation.
Data were available for only 846 patients pre-MELD.
The Child class was available for 3273 patients with MELD information.
Tumor information at the time of listing was available for 3136 of the 4482 (70%) candidates (Table 3). The median maximum tumor diameter was 2.5 cm (range, 0.5-15 cm), 2226 (71%) patients had a solitary tumor, and 282 (9%) had ≥3 nodules. Only 2% (n = 72) were reported to have portal vein thrombosis by radiological imaging at the time of listing. Of the patients with available tumor information, 2790 (89%) met the Milan criteria, with the majority (85%) being at the T2 stage. A total of 346 (11%) HCC patients exceeded the Milan criteria, with the proportion exceeding the Milan criteria increasing steadily since 1998 (Fig. 3).
Table 3. Tumor Information at the Time of Listing for Liver Candidates with Hepatocellular Carcinoma
NOTE: Data were available for 3136 of the 4482 (70%) candidates.
Abbreviation: TNM, Tumor-Node-Metastasis.
Maximum tumor diameter, cm [median (range)]
Number of tumor nodules [median (range)]
Portal vein thrombosis
Met the Milan criteria
Dropout from the Liver Waiting List
The overall median time on the OLT waiting list was 64 days (range, 1-2655), and the median time to dropping out from the transplant waiting list because of death or tumor progression was 140 days (range, 1-1928). Considerable variability was noted for removal rates from the liver transplant waiting list based on the UNOS region (Table 4). For all candidates with HCC, the 1- and 3-year probability of dropping out because of tumor progression and/or death was 12% and 20%, respectively, as shown in Fig. 4. Compared to those with tumors meeting the Milan criteria, candidates with tumors exceeding the Milan criteria were significantly more likely to be removed from the waiting list for tumor progression and/or death (P < 0.0001).
Table 4. Rate of Removal from the Liver Transplant Waiting List for Tumor Progression or Death According to the UNOS Region
Abbreviation: UNOS, United Network for Organ Sharing.
Removal from the liver waiting list for either tumor progression or death.
Significant predictors of removal from the liver waiting list based on univariate analysis are listed in Table 5. The factors that predicted dropout were age > 55 years, blood type, nonviral etiology of liver disease, AFP > 20 ng/mL, laboratory MELD score > 10, Child classes B and C, the diameter of the largest tumor being greater than 2.5 cm, presence of portal vein thrombosis, being listed in the pre-MELD organ allocation era, and being listed in region 9. Univariate factors predicting a decreased risk for waiting list removal included meeting the Milan criteria and being listed within region 3. The independent predictors of dropout (Table 5), based on multivariate analysis, included nonviral etiology of liver disease [hazard ratio (HR), 1.1; 95% confidence interval (CI), 1.001-1.16], Child class B (HR, 1.7; 95% CI, 1.16-2.62), Child class C (HR, 4.4; 95% CI, 2.79-6.85), AFP > 20 ng/mL (HR, 1.6; 95% CI, 1.2-2.3), and being listed in the pre-MELD era (HR, 1.6; 95% CI, 1.29-2.89). The only independent predictor of being transplanted or remaining on the list rather than dropping out was having a tumor meeting the Milan criteria (0.37; 95% CI, 0.23-0.59).
Table 5. Univariate and Multivariate Analyses for Predictors of Waiting List Dropout for Liver Candidates with Hepatocellular Carcinoma
HR (95% CI)
Abbreviations: AFP, alpha-fetoprotein; CI, confidence interval; HR, hazard ratio; MELD, Model for End-Stage Liver Disease.
The pre-MELD era is defined as the era of those listed between 1998 and February 26, 2002.
The median duration of follow-up from listing was 29 months (1-58 months). The overall 1-, 3-, and 5-year intent-to-treat survival for the 4482 patients listed was 81%, 65%, and 51%, respectively (Fig. 5). The intent-to-treat survival was further evaluated for the 3136 patients for whom tumor data were available according to whether patients met or exceeded the Milan criteria (Fig. 6). On an intent-to-treat basis, candidates listed with tumors within the Milan criteria demonstrated a significant survival advantage in comparison with subjects exceeding the Milan criteria (P value < 0.001).
An unadjusted univariate analysis of predictors of survival included age < 55 years, HCV as the etiology of the underlying liver disease, lower Child class, lack of portal vein thrombosis, receiving a deceased donor organ (versus a living donor), being listed in the pre-MELD era (versus the post-MELD era), UNOS region, having a tumor within the Milan criteria, and undergoing OLT (Table 6). To identify independent risk factors for survival on an intention-to treat basis for all liver transplant candidates with HCC, a multivariate analysis was performed that was adjusted for age, gender, UNOS region, organ allocation system, and length of follow-up. As shown in Table 7, the independent predictors of survival were age < 55, Child class, having a tumor within the Milan criteria, and undergoing OLT.
Table 6. Unadjusted Analysis of Baseline Predictors of Survival in Patients with Hepatocellular Carcinoma Listed for Liver Transplantation
Number of Patients
Median Survival (Months)
NOTE: A dash (—) indicates that the median survival could not be calculated because the last cumulative survival was greater than 50%.
Abbreviations: AFP, alpha-fetal protein; MELD, Model for End-Stage Liver Disease; OLT, orthotopic liver transplantation; UNOS, United Network for Organ Sharing.
Data were available for 2914 patients.
Treatment pre-OLT is defined as the treatment of a tumor prior to transplantation, including radiofrequency ablation and transarterial chemoembolization.
The pre-MELD era is defined as the era of those listed between 1998 and February 26, 2002; the post-MELD era is defined as the era of those listed on or after February 27, 2002.
When we took into account only the 2898 patients who underwent OLT, the 1- and 5-year post-OLT survival was 88% and 62%, respectively, and this was significantly better than the 1- and 5-year survival among those not transplanted (30% and 3%, respectively; P < 0.0001). The 1-, 3-, and 5-year survival was 89%, 75% and 65%, respectively, for those that met the Milan criteria versus 82%, 65%, and 38%, respectively, for those that exceeded the Milan criteria (P < 0.0001).
Before the use of the Milan criteria, OLT for HCC was associated with disappointing results, including a 5-year survival rate of 36% or less and a tumor recurrence rate of up to 54%.5, 9 In 1996, Mazzaferro and colleagues6 published the Milan criteria, which allowed the identification of a group of patients with HCC that had a low likelihood of developing recurrent tumors and an acceptable survival rate after OLT. Other studies have demonstrated that the best long-term results and the lowest recurrence rates are achieved when those undergoing liver transplantation have early-stage HCC (ie, stage T2).6, 8, 10–12 Therefore, the Milan criteria have been adopted by many countries, including the United States, in an attempt to maximize the efficacy of a therapy that is significantly limited by donor availability. Researchers have attempted to expand the Milan criteria while still aiming for acceptable results.8, 13–18 While numerous single-center studies have been reported on liver transplantation and HCC, the present study uses a national database to evaluate survival and dropout on an intention-to-treat basis.
The present retrospective study utilized registry data from UNOS/OPTN to analyze the outcome of candidates listed for HCC over an 8-year period. Almost two-thirds of the study population were transplanted within the MELD organ allocation era, and the majority (89%) met the Milan criteria at listing. The median waiting time was 64 days with a 12% dropout rate at 1 year. While the survival rate at 5 years post-transplant for those with tumors within the Milan criteria was 61%, for recipients with tumors exceeding these criteria, the 5-year posttransplant survival rate was significantly less at 32%. In addition, a multivariable analysis controlling for confounding factors demonstrated that patients transplanted with tumors within the Milan criteria had a significantly decreased relative risk of death in comparison with those transplanted beyond the Milan criteria (HR, 0.49; P = 0.0002). Our data show that for those listed for HCC, undergoing OLT is an independent predictor of survival, but the best survival rates are achieved in HCC patients that meet the Milan criteria. These data need to be interpreted carefully. In the current liver allocation system, candidates with tumors exceeding the Milan criteria are not given preferential MELD exceptions and, as a result, may not have equal access to liver transplantation in comparison with those with tumors within the Milan criteria.
There are several limitations of the current retrospective study using the UNOS/OPTN national registry database. Since the database does not capture tumor recurrences, we were not able to evaluate this important endpoint. Furthermore, preoperative imaging techniques and interpretation may not be comparable from one center to another. There is also substantial variability in transplant center candidate selection policies and donor availability that could not be controlled for in our retrospective analysis. Furthermore, the effects of down-staging with neoadjuvant treatment are also difficult to evaluate from the UNOS/OPTN database. Finally, HCC staging data were available for only 70% of the HCC OLT candidates during this study period, and this introduced potential selection bias. However, the intent of this study was to evaluate outcomes among HCC patients on the waiting list in an intention-to-treat manner by using information available on over 4000 patients from multiple centers. Of note, this study was not meant to be a comparison of HCC patients within or beyond the Milan criteria because the current organ allocation system assigns different priorities, making a meaningful comparison difficult if not impossible. While these limitations exist, the present study shows an important national view of the overall efficacy of OLT for HCC as it pertains to patient survival in an intent-to-treat analysis, accounting for dropouts.
In conclusion, the present study demonstrates that the current criteria for liver transplantation of patients with HCC have an acceptable 5-year survival while minimizing the rate of removal from the waiting list for either tumor progression or death. Expansion of the radiographic criteria for transplanting HCC requires careful consideration in light of the higher potential risk of tumor recurrence with lower patient survival19 and the impact on the many other non-HCC patients with liver failure.20