Survival after liver transplantation for hepatocellular carcinoma in the model for end-stage liver disease and pre–model for end-stage liver disease eras and the independent impact of hepatitis C virus

Authors


Abstract

It has been suggested that hepatitis C virus (HCV) patients with hepatocellular carcinoma (HCC) may have worse outcomes after liver transplantation (LT) because of more aggressive tumor biology. In this study, we determined the post-LT survival of HCC patients with and without HCV using United Network for Organ Sharing data from January 1994 to March 2008. Patients with HCC were stratified into HCV (HCC-HCV) and non-HCV (HCC–non-HCV) groups. In the era before the Model for End-Stage Liver Disease (MELD), there were 1237 HCC patients (780, HCV; 373, non-HCV; 84, unknown HCV status), and during the MELD era, there were 4933 HCC patients (3272, HCV; 1348, non-HCV; 313, unknown). In the pre-MELD era, 5-year graft (58.6% versus 53.7%) and patient (61.7% versus 59.3%) survival rates were marginally higher for HCC–non-HCV patients than for HCC-HCV patients. In the MELD era also, 5-year graft (61.2% versus 55.5%) and patient (63.7% versus 58.2%) survival rates were marginally higher for HCC–non-HCV patients than for HCC-HCV patients. In patients without HCC, pre-MELD and MELD era graft/patient survival rates for non-HCV patients were higher than those for HCV patients. The differences in survival rates for HCC patients with and without HCV were lower than those for non-HCC patients stratified by their HCV status. HCV had no additional negative impact on the post-LT survival of patients with HCC, and this was further confirmed by multivariate analysis. In conclusion, the survival of HCC patients has remained unchanged in the past 2 decades. HCV patients have a lower survival rate than non-HCV patients, regardless of their HCC status, but HCV has no additional negative impact on survival in patients with HCC. Liver Transpl 15:754–762, 2009. © 2009 AASLD.

Liver transplantation (LT) is the treatment of choice for patients with cirrhosis and hepatocellular carcinoma (HCC) because of lower recurrence rates and better long-term survival.1 In 2002, with the adoption of the Model for End-Stage Liver Disease (MELD) score for organ allocation, the United Network for Organ Sharing (UNOS) also adopted a policy of transplanting patients with HCC fulfilling the Milan criteria2 in an expedited fashion. The allocation of additional MELD points to patients with HCC who fulfill Milan criteria has led to a dramatic increase in the rate of LT for HCC and decreased waiting time after listing. There has been concern among physicians that the expedited transplant policy may not provide adequate time to assess tumor biology, and hence transplanting patients with more aggressive tumor biology may result in overall lower survival in the MELD era.

There is growing evidence that the tumor biology of HCC, perhaps the most important predictor of HCC recurrence, can be highly variable. Recent data on molecular signaling suggest that hepatitis C virus (HCV) is associated with the activation of certain kinases that are indicative of aggressive behavior.3 Studies comparing the recurrence rates after resection have shown lower recurrence rates in patients with nonviral etiologies of liver disease.4 Even among patients with hepatitis C and hepatitis B, there are differences in clinical presentation. Patients with HCV tend to be older, have more advanced liver disease, and demonstrate a higher proportion of multinodular tumors at diagnosis.5 HCV infection has been shown to be an independent risk factor associated with HCC recurrence after resection in some studies.6–8 Additionally, in a recent study, HCV was associated with a high incidence of late recurrence of HCC.9

The independent impact of HCV on the post-LT survival of HCC patients remains poorly defined. Although a few studies have suggested that HCV infection has an additional negative impact on the outcomes of patients transplanted for HCC,10–13 other studies have found similar survival in HCV and non-HCV patients with HCC.14, 15 Small sample sizes, heterogeneous populations, and nonadjustment for multiple confounders in LT recipients could explain these observations. A comparison of patients with HCV and patients without HCV shows that HCV has a negative impact on survival, regardless of HCC,16 and the lower survival rate can be easily explained by recurrent HCV. If there were significant differences in tumor recurrence rates in HCC patients with HCV, there would be an additional negative impact on long-term survival. A large data set was necessary to test this hypothesis because there are multiple confounders in the LT population. We therefore examined UNOS data from 1994 to 2008 to determine whether the differences in outcomes in HCC patients with and without HCV could be attributed to the presence of HCV alone. Because MELD had an impact on the waiting time, patient selection, tumor progression, and hence outcomes, we stratified patients into pre-MELD and MELD eras.

Abbreviations

BMI, body mass index; CVA, cerebrovascular accident; DCD, donation after cardiac death; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; UNOS, United Network for Organ Sharing.

PATIENTS AND METHODS

The study was performed with data from 59,219 adult deceased-donor liver-only recipients as captured in the UNOS database from January 1994 to February 2008. HCV was determined by reported positive serology, clinical evidence of the disease, and/or a report of HCV as one of the factors contributing to a patient's cirrhosis. HCV status was ascertainable for 88% of patients. Patients with HCC were divided into 2 groups: those with HCV (HCC-HCV) and those without HCV (HCC–non-HCV). Both groups were further stratified into the pre-MELD and MELD eras for reasons explained earlier. For those patients with unknown HCV status, a third group was created, and the data were analyzed separately. As this group was relatively small and suffered from considerable missing data for other variables as well, the resultant data analysis is not reported as part of this study. Comparative analysis was also conducted of the HCV and non-HCV cohorts without HCC by stratification according to the era of LT as described previously.

Unadjusted graft and patient survival rates at 1, 3, and 5 years for the pre-MELD and MELD groups were determined with Kaplan-Meier survival analysis. Univariate and multivariate hazard ratios were also calculated with Cox models. In the multivariate analysis, we included variables that were significant on univariate analysis. Additionally, we included variables that were possibly biologically relevant to avoid the limitations of an empirically driven model. The independent effect of HCV on the graft and patient survival of HCC patients was assessed by an interaction term in multivariate analysis after adjustments for other known confounders.

RESULTS

There was a significant increase in the number of LT procedures for HCC during the study period, with a sharp increase after the introduction of MELD for organ allocation (Fig. 1). In the pre-MELD era, there were 1237 recipients (780, HCV; 373, non-HCV; 84, unknown HCV status), and in the MELD era, there were 4933 recipients of LT for HCC (3272, HCV; 1348, non-HCV; 313, unknown HCV status). The characteristics of patients in the pre-MELD and MELD groups with HCC are listed in Tables 1 and 2. In the pre-MELD and MELD eras, there were more Caucasians in the HCV group; similarly, diabetes was more common in the non-HCV group and serum albumin was lower in the HCV group during both eras (Table 1). There were no significant differences in donor characteristics in the pre-MELD era (Table 1). In the MELD era, HCV patients were younger, more likely to be men, more likely to receive higher MELD exception points, and more likely to have had a history of peritonitis (Table 2). In the MELD era, donor age was significantly lower in the HCV group, and the HCV group also had more Caucasian donors (Table 2).

Figure 1.

The number of liver transplants for HCC in the United States stratified by HCV status. Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus.

Table 1. Baseline Recipient Demographics of the Pre-MELD Group (01/94-02/02)
 HCV Status
HCV-Negative (n = 373)HCV-Positive (n = 780)P Value Comparing the Negative and Positive GroupsHCV Missing (n = 84)
  1. Abbreviations: BMI, body mass index; CVA, cerebrovascular accident; DCD, donation after cardiac death; HCV, hepatitis C virus; MELD, Model for End-Stage Liver Disease.

Recipient Characteristics    
Age (years)55.0 (1.1)54.3 (0.6)0.2355.8 (2.0)
Female (%)22.8260.2325
Ethnicity (%)    
 Caucasian60.668.6<0.00170.2
 African American5.46.4 6.0
 Hispanic12.915.5 8.3
 Other21.29.5 15.5
BMI (kg/m2)27.1 (0.5)27.4 (0.4)0.4227.5 (1.3)
Bilirubin (mg/dL)4.1 (0.7)4.7 (0.6)0.1475.4 (1.9)
Creatinine (mg/dL)1.2 (0.1)1.1 (0.1)0.521.3 (0.2)
Dialysis (%)1.92.40.653.3*
Albumin (g/dL)3.1 (0.1)3.0 (0.1)<0.0013.2 (0.2)
Hospitalized (%)31.434.70.2635.7
On life support (%)7.58.10.739.5
Diabetes (%)31.219.5<0.00127.3*
Hypertension (%)16.113.00.1721.0*
Peritonitis (%)8.58.80.867.8*
Prior transplant (%)7.26.50.6611.9
Prior abdominal surgery (%)49.750.10.9050.0
     
Donor Characteristics    
Age39.4 (1.9)41.6 (1.3)0.0639.2 (3.7)
Female (%)41.641.80.9438.1
Ethnicity (%)    
 Caucasian74.873.10.8765.1
 African American12.312.9 18.1
 Hispanic10.510.5 8.4
 Other2.43.7 8.4
Bilirubin (mg/dL)1.1 (0.3)1.0 (1.1)0.41.1 (0.2)
Cause of death (%)    
 Anoxia12.58.90.177.4
 CVA47.350.5 39.5
 Head trauma38.039.3 53.1
 Other2.21.3 0.0
BMI (kg/m2)25.3 (0.6)25.4 (0.4)0.8625.6 (1.6)
Diabetes (%)4.94.10.544.1
Hypertension (%)26.228.20.4825.0
DCD donor (%)0.51.20.312.7
Split donor (%)3.23.50.832.4
Cold ischemic time (hrs)8.6 (0.4)9.0 (0.3)0.1510.3 (1.6)
Table 2. Baseline Recipient and Donor Characteristics of the MELD Group (2/02-2/08)
 HCV Status
HCV-Negative (n = 1348)HCV-Positive (n = 3272)P Value Comparing the Negative and Positive GroupsHCV Missing (n = 313)
  1. Abbreviations: BMI, body mass index; CVA, cerebrovascular accident; DCD, donation after cardiac death; HCV, hepatitis C virus; MELD, Model for End-Stage Liver Disease.

Recipient Characteristics    
Age (years)58.4 (0.5)55.2 (0.2)<0.00157.6 (0.9)
Female (%)23.819.20.01922.4
Ethnicity (%)    
 Caucasian59.167.9<0.00167.2
 African American5.49.4 5.0
 Hispanic13.014.9 9.2
 Other22.57.7 18.5
BMI (kg/m2)27.9 (0.3)27.9 (0.2)0.8427.4 (0.5)
MELD (calculated)13.8 (0.4)14.0 (0.3)0.9214.0 (0.8)
MELD (listed)24.3 (0.3)24.4 (0.2)0.5224.4 (0.6)
MELD (exception) (%)77.581.1<0.00177.3
Albumin (g/dL)3.3 (0.1)3.1 (0.0)<0.0013.2 (0.1)
Hospitalized (%)10.59.90.3818.4
On life support (%)2.41.70.132.2
Diabetes (%)32.522.0<0.00124.3
Hypertension (%)22.720.20.0524.4
Peritonitis (%)2.74.50.0144.6*
Prior transplant (%)1.52.10.222.8
Prior abdominal surgery (%)46.845.40.6643.8
     
Donor Characteristics    
Age (years)42.6 (1.1)41.1 (0.6)0.02344.0 (2.0)
Female (%)39.438.90.9339.8
Ethnicity (%)    
 Caucasian64.968.30.00468.3
 African American15.214.0 16.0
 Hispanic14.313.7 12.9
 Other5.74.1 2.8
Bilirubin (mg/dL)0.9 (0.0)1.0 (0.1)0.121.0 (0.2)
Cause of death (%)    
 Anoxia12.914.60.5313.0
 CVA47.145.6 45.6
 Head trauma39.339.0 40.5
 Other0.70.8 0.8
BMI (kg/m2)26.2 (0.3)26.6 (0.2)0.1226.6 (0.6)
Diabetes (%)10.29.30.7710.1
Hypertension (%)34.232.00.2138.2
DCD donor (%)4.24.10.753.4
Split donor (%)1.81.40.30.6
Cold ischemic time (hrs)7.2 (0.2)7.4 (0.1)0.18.1 (0.5)*

The 1-, 3-, and 5-year graft and patient survival rates for HCC and non-HCC groups stratified by HCV status in the pre-MELD and MELD eras are shown in Tables 3 and 4. The graft and patient survival rates for non-HCC patients with and without HCV in the MELD era were marginally lower than those in the pre-MELD era (Table 3), but this decline was more pronounced in HCV patients without HCC. Although there were no significant differences in the 5-year survival of HCC patients in the MELD era versus the pre-MELD group, 1- and 3-year survival rates were significantly higher for the HCC group in the MELD era. Figures 2 and 3 show the unadjusted graft and patient survival by Kaplan-Meier analysis for the pre-MELD and MELD groups up to 5 years after LT.

Table 3. Graft and Patient Survival in Patients With and Without HCC Stratified by HCV Status and MELD Era
 Graft Survival (%)Patient Survival (%)
1 Year3 Years5 Years1 Year3 Years5 Years
  1. Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus; MELD, Model for End-Stage Liver Disease.

Pre-MELD      
 Non-HCV (no HCC) (n = 12,695)80.774.869.885.379.975.1
 HCV (no HCC) (n = 12,346)79.269.262.183.674.467.4
 Non-HCV (HCC) (n = 374)77.065.258.681.068.461.7
 HCV (HCC) (n = 781)75.461.453.781.067.659.3
MELD      
 Non-HCV (no HCC) (n = 10,532)82.475.067.986.379.672.7
 HCV (no HCC) (n = 10,582)80.968.357.384.472.461.2
 Non-HCV (HCC) (n = 1348)84.873.061.287.676.263.7
 HCV (HCC) (n = 3272)82.665.055.585.468.058.2
Table 4. Incremental Effect of a Non-HCV Diagnosis on Patient and Graft Survival in Patients With and Without HCC
 Graft Survival Difference (%)Patient Survival Difference (%)
1 Year3 Years5 Years1 Year3 Years5 Years
  1. Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus; MELD, Model for End-Stage Liver Disease.

Pre-MELD      
 Non-HCV versus HCV (no HCC)+1.5+5.6+7.7+1.7+5.5+7.7
 Non-HCV versus HCV (HCC)+1.6+3.8+4.90.0+0.8+2.4
MELD      
 Non-HCV versus HCV (no HCC)+1.5+6.7+10.6+1.9+7.2+11.5
 Non-HCV versus HCV (HCC)+2.2+8.0+5.7+2.2+8.2+5.5
Figure 2.

Unadjusted Kaplan-Meier graft and patient survival in the pre-MELD era among HCV, non-HCV, HCC-HCV, and HCC–non-HCV cohorts. The HCC cohort excluded patients with concomitant HCV. Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus; MELD, Model for End-Stage Liver Disease.

Figure 3.

Unadjusted Kaplan-Meier graft and patient survival in the MELD era among HCV, HCC, HCC-HCV, and HCC–non-HCV cohorts. The HCC cohort excluded patients with concomitant HCV. Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus; MELD, Model for End-Stage Liver Disease.

There was a lower survival of patients with HCV in both the HCC and non-HCC groups (Fig. 3B). There were differences in the survival of HCV and non-HCV patients regardless of HCC status during the pre-MELD and MELD eras, but this difference was lower for HCC patients (Table 4). These observations suggested that the negative impact of HCV on post-LT survival was not exaggerated in the presence of HCC. This was further confirmed by multivariate analysis that showed no additional negative impact on survival in patients with both HCV and HCC (Tables 5 and 6).

Table 5. Univariate and Multivariate Analysis of Graft Loss and Death in the Pre-MELD Era (01/94-02/02)
RecipientGraft LossDeath
Univariate HRMultivariate HRUnivariate HRMultivariate HR
  1. Abbreviations: BMI, body mass index; CVA, cerebrovascular accident; DCD, donation after cardiac death; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; MELD, Model for End-Stage Liver Disease.

HCV1.33 (1.28-1.38)P < 0.0011.37 (1.31-1.44)P < 0.0011.38 (1.33-1.43)P < 0.0011.43 (1.36-1.51)P < 0.001
HCC1.38 (1.28-1.49)P < 0.0011.47 (1.23-1.74)P < 0.0011.45 (1.33-1.57)P < 0.0011.56 (1.30-1.87)P < 0.001
HCC and HCV1.44 (1.31-1.58)P < 0.0010.81 (0.66-1.01)P = 0.061.47 (1.33-1.63)P < 0.0010.77 (0.62-0.96)P = 0.020
Age1.01 (1.01-1.01)P < 0.0011.01 (1.00-1.01)P < 0.0011.02 (1.01-1.02)P < 0.0011.01 (1.01-1.02)P < 0.001
Female0.95 (0.92-0.99)P = 0.0080.99 (0.95-1.04)P = 0.780.96 (0.92-0.99)P = 0.0151.02 (0.97-1.07)P = 0.51
Ethnicity        
 CaucasianReference Reference Reference Reference 
 African American1.25 (1.17-1.33)P < 0.0011.24 (1.14-1.35)P < 0.0011.21 (1.14-1.30)P < 0.0011.23 (1.13-1.35)P < 0.001
 Hispanic0.96 (0.90-1.01)P = 0.130.90 (0.84-0.97)P = 0.0060.92 (0.86-0.97)P = 0.0050.86 (0.80-0.94)P < 0.001
 Other0.92 (0.84-1.00)P = 0.0460.80 (0.71-0.91)P < 0.0010.89 (0.82-0.98)P = 0.0180.80 (0.70-0.92)P = 0.001
BMI1.00 (1.00-1.00)P = 0.631.00 (0.99-1.00)P = 0.071.00 (1.00-1.00)P = 0.311.00 (0.99-1.00)P = 0.09
Bilirubin1.01 (1.01-1.01)P < 0.0011.00 (1.00-1.00)P = 0.471.01 (1.01-1.01)P < 0.0011.00 (1.00-1.00)P = 0.33
Creatinine1.13 (1.12-1.14)P < 0.0011.06 (1.03-1.08)P < 0.0011.14 (1.13-1.16)P < 0.0011.08 (1.05-1.10)P < 0.001
Dialysis1.82 (1.70-1.96)P < 0.0011.19 (1.06-1.34)P = 0.0031.92 (1.78-2.07)P < 0.0011.21 (1.07-1.36)P = 0.002
Albumin0.91 (0.89-0.93)P < 0.0010.94 (0.91-0.97)P < 0.0010.89 (0.86-0.91)P < 0.0010.91 (0.88-0.95)P < 0.001
Hospitalized1.37 (1.32-1.42)P < 0.0011.13 (1.07-1.19)P < 0.0011.39 (1.34-1.44)P < 0.0011.13 (1.07-1.20)P < 0.001
On life support1.61 (1.54-1.69)P < 0.0011.19 (1.10-1.29)P < 0.0011.61 (1.53-1.69)P < 0.0011.19 (1.10-1.30)P < 0.001
Diabetes1.30 (1.24-1.36)P < 0.0011.22 (1.15-1.29)P < 0.0011.39 (1.32-1.45)P < 0.0011.28 (1.20-1.36)P < 0.001
Hypertension1.16 (1.09-1.22)P < 0.0011.07 (0.99-1.15)P = 0.081.25 (1.18-1.32)P < 0.0011.11 (1.03-1.19)P = 0.006
Peritonitis1.15 (1.09-1.22)P < 0.0011.06 (0.99-1.14)P = 0.101.22 (1.15-1.30)P < 0.0011.12 (1.04-1.21)P = 0.004
Prior transplant1.99 (1.90-2.09)P < 0.0011.57 (1.45-1.70)P < 0.0011.95 (1.85-2.05)P < 0.0011.55 (1.43-1.69)P < 0.001
Prior abdominal surgery1.28 (1.24-1.33)P < 0.0011.12 (1.06-1.17)P < 0.0011.30 (1.25-1.35)P < 0.0011.12 (1.06-1.17)P < 0.001
Donor        
Age1.01 (1.01-1.01)P < 0.0011.01 (1.01-1.01)P < 0.0011.01 (1.01-1.01)P < 0.0011.01 (1.01-1.01)P < 0.001
Female1.14 (1.10-1.18)P < 0.0011.01 (0.96-1.06)P = 0.621.10 (1.06-1.14)P < 0.0010.99 (0.94-1.04)P = 0.72
Ethnicity        
 CaucasianReference Reference Reference Reference 
 African American1.13 (1.07-1.19)P < 0.0011.15 (1.07-1.24)P < 0.0011.08 (1.02-1.15)P = 0.0051.10 (1.02-1.19)P = 0.015
 Hispanic1.01 (0.96-1.08)P = 0.631.03 (0.95-1.12)P = 0.411.02 (0.96-1.09)P = 0.531.02 (0.94-1.11)P = 0.64
 Other1.16 (1.02-1.31)P = 0.0221.04 (0.86-1.24)P = 0.711.09 (0.95-1.25)P = 0.201.06 (0.88-1.28)P = 0.55
 Other 51.12 (0.95-1.32)P = 0.181.06 (0.84-1.34)P = 0.611.16 (0.98-1.38)P = 0.091.06 (0.83-1.36)P = 0.63
BMI1.01 (1.00-1.01)P < 0.0011.00 (0.99-1.00)P = 0.141.01 (1.00-1.01)P < 0.0011.00 (0.99-1.00)P = 0.29
Cause of death       
 AnoxiaReference Reference Reference Reference 
 CVA1.21 (1.13-1.29)P < 0.0010.99 (0.90-1.08)P = 0.761.19 (1.10-1.27)P < 0.0011.00 (0.91-1.11)P = 0.93
 Head trauma0.87 (0.81-0.93)P < 0.0010.89 (0.81-0.97)P = 0.0080.90 (0.83-0.96)P = 0.0030.90 (0.82-0.99)P = 0.024
 Other1.13 (0.95-1.34)P = 0.161.10 (0.88-1.38)P = 0.401.09 (0.91-1.32)P = 0.351.03 (0.81-1.31)P = 0.83
Inotropes1.02 (0.98-1.06)P = 0.400.95 (0.90-1.00)P = 0.051.05 (1.01-1.10)P = 0.0190.98 (0.92-1.04)P = 0.44
Diabetes1.33 (1.23-1.45)P < 0.0011.14 (1.02-1.27)P = 0.0241.31 (1.20-1.43)P < 0.0011.12 (1.00-1.27)P = 0.06
Hypertension1.34 (1.29-1.39)P < 0.0011.02 (0.96-1.09)P = 0.451.27 (1.22-1.33)P < 0.0010.97 (0.91-1.03)P = 0.33
DCD1.48 (1.22-1.79)P < 0.0011.54 (1.21-1.96)P < 0.0011.30 (1.06-1.61)P = 0.0141.26 (0.96-1.65)P = 0.09
Split/partial1.16 (1.01-1.33)P = 0.0301.48 (1.23-1.78)P < 0.0011.02 (0.87-1.18)P = 0.821.15 (0.94-1.43)P = 0.18
Cold ischemic time1.01 (1.01-1.01)P < 0.0011.01 (1.01-1.02)P < 0.0011.01 (1.00-1.01)P < 0.0011.01 (1.00-1.02)P < 0.001
Table 6. Univariate and Multivariate Analysis of Graft Loss and Death in the MELD Era (02/02-02/08)
RecipientGraft LossDeath
Univariate HRMultivariate HRUnivariate HRMultivariate HR
  1. Abbreviations: BMI, body mass index; CVA, cerebrovascular accident; DCD, donation after cardiac death; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; MELD, Model for End-Stage Liver Disease.

HCV1.24 (1.18-1.31)P < 0.0011.38 (1.28-1.48)P < 0.0011.33 (1.26-1.40)P < 0.0011.47 (1.36-1.59)P < 0.001
HCC1.06 (1.00-1.13)P = 0.051.23 (1.05-1.43)P = 0.0111.14 (1.06-1.21)P = 0.0011.27 (1.08-1.51)P = 0.005
HCC and HCV1.13 (1.05-1.22)P < 0.0010.90 (0.75-1.07)P = 0.241.21 (1.12-1.31)P = 0.0010.89 (0.74-1.08)P = 0.25
Age1.01 (1.00-1.01)P < 0.0011.01 (1.00-1.01)P = 0.0041.02 (1.01-1.02)P < 0.0011.01 (1.01-1.02)P < 0.001
Female1.01 (0.96-1.06)P = 0.791.00 (0.93-1.07)P = 0.911.03 (0.97-1.08)P = 0.351.03 (0.95-1.11)P = 0.48
Ethnicity        
 CaucasianReference Reference Reference Reference 
 African American1.35 (1.25-1.46)P < 0.0011.29 (1.16-1.43)P < 0.0011.30 (1.20-1.42)P < 0.0011.28 (1.14-1.44)P < 0.001
 Hispanic0.94 (0.87-1.01)P = 0.100.86 (0.78-0.95)P = 0.0030.95 (0.88-1.03)P = 0.230.86 (0.77-0.96)P = 0.008
 Other0.92 (0.83-1.03)P = 0.140.82 (0.70-0.97)P = 0.0170.94 (0.83-1.05)P = 0.280.85 (0.72-1.01)P = 0.06
BMI1.00 (1.00-1.01)P = 0.321.00 (0.99-1.00)P = 0.761.00 (1.00-1.01)P = 0.151.00 (0.99-1.01)P = 0.91
MELD1.02 (1.01-1.02)P < 0.0011.01 (1.00-1.01)P = 0.0081.02 (1.02-1.03)P < 0.0011.01 (1.01-1.02)P < 0.001
Albumin0.89 (0.86-0.92)P < 0.0010.91 (0.87-0.95)P < 0.0010.87 (0.83-0.90)P < 0.0010.88 (0.83-0.92)P < 0.001
Hospitalized1.49 (1.42-1.56)P < 0.0011.19 (1.09-1.30)P < 0.0011.58 (1.50-1.67)P < 0.0011.23 (1.12-1.35)P < 0.001
On life support2.13 (1.97-2.31)P < 0.0011.66 (1.43-1.93)P < 0.0012.17 (2.00-2.34)P < 0.0011.73 (1.48-2.02)P < 0.001
Diabetes1.23 (1.16-1.30)P < 0.0011.20 (1.11-1.30)P < 0.0011.33 (1.25-1.41)P < 0.0011.27 (1.17-1.38)P < 0.001
Hypertension1.11 (1.04-1.25)P = 0.0061.01 (0.93-1.10)P = 0.791.19 (1.11-1.27)P < 0.0011.05 (0.96-1.14)P = 0.32
Peritonitis1.10 (1.00-1.22)P = 0.061.06 (0.94-1.19)P = 0.351.20 (1.09-1.33)P = 0.0041.08 (0.95-1.23)P = 0.23
Prior transplant1.99 (1.86-2.14)P < 0.0011.64 (1.44-1.86)P < 0.0012.03 (1.88-2.19)P < 0.0011.67 (1.46-1.91)P < 0.001
Prior abdominal surgery1.27 (1.22-1.34)P < 0.0011.17 (1.09-1.25)P < 0.0011.33 (1.27-1.40)P < 0.0011.20 (1.12-1.29)P < 0.001
Donor        
Age1.01 (1.01-1.01)P < 0.0011.01 (1.01-1.02)P < 0.0011.01 (1.01-1.01)P < 0.0011.01 (1.01-1.02)P < 0.001
Female1.12 (1.07-1.18)P < 0.0011.11 (1.04-1.18)P = 0.0031.07 (1.02-1.13)P = 0.0071.07 (0.99-1.15)P = 0.07
Ethnicity        
 CaucasianReference Reference Reference Reference 
 African American1.13 (1.06-1.21)P < 0.0011.16 (1.06-1.26)P = 0.0021.07 (0.99-1.15)P = 0.071.10 (1.00-1.22)P = 0.05
 Hispanic1.10 (1.02-1.18)P = 0.0101.16 (1.05-1.28)P = 0.0031.13 (1.05-1.22)P = 0.0011.17 (1.05-1.30)P = 0.003
 Other1.30 (1.12-1.51)P < 0.0011.23 (1.00-1.51)P = 0.051.35 (1.19-1.59)P < 0.0011.25 (1.00-1.56)P = 0.045
BMI1.00 (1.00-1.01)P = 0.0151.00 (0.99-1.01)P = 0.931.00 (1.00-1.01)P = 0.0201.00 (1.00-1.01)P = 0.50
Cause of death:        
 AnoxiaReference Reference Reference Reference 
 CVA1.21 (1.12-1.30)P < 0.0011.08 (0.97-1.20)P = 0.171.18 (1.09-1.28)P < 0.0011.04 (0.93-1.17)P = 0.49
 Head trauma0.87 (0.80-0.94)P < 0.0011.01 (0.91-1.13)P = 0.170.87 (0.80-0.95)P = 0.0010.99 (0.88-1.12)P = 0.49
 Other0.97 (0.74-1.29)P = 0.860.86 (0.58-1.27)P = 0.450.97 (0.72-1.31)P = 0.840.79(0.51-1.22)P = 0.91
Inotropes0.97 (0.93-1.02)P = 0.251.05 (0.98-1.12)P = 0.170.96 (0.91-1.01)P = 0.111.00 (0.93-1.08)P = 0.93
Diabetes1.35 (1.25-1.45)P < 0.0011.12 (1.01-1.25)P = 0.0371.29 (1.18-1.40)P < 0.0011.12 (1.00-1.26)P = 0.06
Hypertension1.34 (1.27-1.40)P < 0.0010.96 (0.89-1.04)P = 0.301.27 (1.21-1.34)P < 0.0010.94 (0.86-1.03)P = 0.17
DCD1.63 (1.47-1.82)P < 0.0011.98(1.70-2.31)P < 0.0011.34 (1.18-1.52)P < 0.0011.50 (1.25-1.80)P < 0.001
Split/partial0.96 (0.79-1.17)P = 0.711.44 (1.11-1.86)P = 0.0060.91 (0.73-1.14)P = 0.411.30 (0.97-1.73)P = 0.08
Cold ischemic time1.02 (1.01-1.03)P < 0.0011.02 (1.01-1.03)P < 0.0011.02 (1.01-1.02)P < 0.0011.02 (1.01-1.03)P < 0.001

Many recipient and donor factors were significant predictors of graft and patient survival on both univariate and multivariate analysis (Tables 5 and 6). These factors have been previously reported and analyzed in more detail by our group and others. It is important to note that African Americans had 21% to 30% lower survival in both the pre-MELD and MELD eras after adjustments for other confounders.

DISCUSSION

The examination of UNOS data showed that there was a marked increase in the number of LT procedures for HCC after the introduction of MELD. There was a decline in 5-year graft (−4.8%) and patient (−6.2%) survival rates for HCV patients without HCC in the MELD era. Although there was an improvement in graft and patient survival rates for HCC patients, regardless of their HCV status, at 1 and 3 years in the MELD era, this survival advantage nearly disappeared at 5 years. As expected, the survival was lower in the HCV group, regardless of the HCC status, but there was no additional negative impact on patients with both HCV and HCC over what would be expected from the presence of HCV or HCC alone. The survival of HCC patients has not declined since the introduction of MELD for organ allocation, and moreover, our findings do not support the recent suggestions that HCV patients with HCC may have more aggressive tumor biology and hence may have relatively worse outcomes after LT. We believe that our observations are more robust than single-center studies because of the large sample size and the unselected patient population. Additionally, we were able to analyze survival after adjusting for many known confounders that could negatively affect survival, and this would not be possible without a large sample size.

From our study, we cannot specifically comment on recurrence-free survival rates after LT, as the information on recurrence was not reliably recorded in the data set. This is not a major limitation because we can assume that 5-year survival rates represent tumor-free status as most tumors recur in the first year after LT. We do, however, acknowledge that the time to recurrence of HCC after LT may vary widely. Studies validating the Milan criteria have shown very low recurrence rates at 3 years after LT with a strong correlation between patient survival and recurrence-free rates.17, 18 A recent single-center study19 has also shown a very low recurrence rate (3.6%, 4/110) among those transplanted within the Milan criteria. In their cohort of 267 patients with HCC, the median time to recurrence was 10.7 months, with only 8% of recurrences occurring beyond 3 years.19 In our study, there was a significant improvement in graft and patient survival at 1 and 3 years for HCC patients in the MELD era versus the pre-MELD era, but this was not sustained at 5 years. This observation could be due to multiple reasons. One major concern will be late recurrences, or alternatively, it could be a skewed observation due to the relatively small number of patients at risk at 5 years. Further examination of UNOS data at a later date will clarify these concerns.

Before the MELD era, significant numbers of patients with HCC were removed from the transplant registry because of tumor progression secondary to a prolonged waiting time on the transplant list. One study reported that the cumulative probability of dropout from the transplant list could be as high as 25% per year for patients with HCC.20 When UNOS implemented MELD criteria for organ allocation in February 2002, additional MELD points were given to patients with HCC, provided that they fulfilled Milan criteria, to expedite the transplantation of patients with HCC. The significant increase in the number of patients undergoing LT for HCC in the MELD group is a reflection of the increased priority afforded to this group in the MELD era.

There was a concern that patients with noncancerous tumor nodules or aggressive tumors might be transplanted because of this policy change. The initial UNOS policy was to allocate 24 MELD points for T1 tumors and 29 points for T2 tumors. This policy change resulted in a dramatic increase in LT for presumed HCC, but an examination of explants showed that a significant number of LT procedures for HCC under this policy were performed for small false-positive nodules.21 In April 2003, UNOS decided to allocate only 20 MELD points for T1 lesions (nodules < 2 cm) and 24 for T2 lesions (nodules ≥ 2 cm), and they further refined this in 2006 by eliminating MELD points for T1 tumors. Despite the reduced priority scores for HCC, there has been no detrimental impact on the wait-list survival rates.22 However, the concern that patients with more aggressive tumors will undergo transplantation because of the shorter waiting period remained among transplant physicians. We did not find a decline in survival in the MELD era, and in fact, there was a significant improvement in 3-year survival rates. A firm conclusion could be made only with further follow-up because only a minority of the patients were available for 5-year survival analysis.

It is possible that a significant minority of patients transplanted for HCC in the MELD era may not have had HCC as histological confirmation was not necessary to obtain MELD exception points. With a large sample size, we assume that these patients were equally distributed in the HCV and non-HCV groups. It is possible that the overall improvement in 1- and 3-year survival of HCC patients in the MELD era may be partly due to this reason. In a previous study, we reported an improvement in survival of HCC patients between 1988 and 2001, and we attributed this improvement to the adoption of the Milan criteria.23 The current study shows that there has been no further improvement of survival of HCC patients. More importantly, the differences in the 3-year survival rates in non-HCC and HCC patients were only 4.4% in the HCV groups and 3.4% in the non-HCV groups (Tables 3 and 4). These data suggest that early diagnosis may have a dramatic impact on the long-term survival of patients with HCC if they are able to undergo LT, and they reconfirm that LT is the treatment of choice for patients with cirrhosis and HCC.

A number of studies have examined the impact of tumor characteristics, including tumor size, number of nodules, extent of tumor involvement (unilobar versus bilobar), tumor differentiation, vascular involvement, and neo-adjuvant treatment, on tumor recurrence rates and patient survival.24–27 However, the impact of HCV on the outcome after LT for HCC has not been well defined. Shimoda et al.10 reported the outcomes of LT in 463 patients with HCV who underwent LT, and of these, 67 patients had concomitant HCC and HCV. As expected, they found that patients with HCC had lower survival rates than their non-HCC counterparts at 1, 3, and 5 years. The reason for this reduction in post-LT survival was recurrent HCC in 12% and recurrent HCV in 4.5%. On multivariate analysis, the authors did not find HCV to be an independent predictor of lower post-LT survival for HCC patients. In contrast, 2 other studies have found HCV to be an independent negative predictor of survival after LT for HCC.11, 12 Although 1 of these studies concluded that the lower survival was related to early mortality from recurrent HCV,11 the other study12 found the rate of tumor recurrence to be significantly higher in the HCV group in comparison with their non-HCV cohort. In the second study,12 the authors claimed that only 6% of the post-LT mortality in the HCV group could be attributed to recurrent HCV, and yet the tumor-free survival among patients who fulfilled the Milan criteria was similar in the HCV and non-HCV groups. The small sample size and heterogeneity of the patient population could explain these discrepant observations as previous studies evaluating the outcomes after LT for HCC have not found HCV status to be an independent factor in post-LT recurrence rates.13, 15, 16 Our study is the first to examine this question in a large unselected population obtained from a nationwide database. We did not find any additional negative impact in HCV patients transplanted for HCC. The difference in survival between HCC patients with and without HCV was similar to or lower than that in non-HCC patients with and without HCV. Moreover, with adjustments for other confounding predictors, HCV had no additional impact on the survival of HCC patients. On the basis of this study, we cannot firmly conclude that the tumor biology in HCV patients is similar to non-HCV etiologies, but we can unequivocally conclude that any differences, if they exist, have no impact on post-LT survival.

In addition to the aforementioned observation, our study reconfirms that African Americans with HCC have 30% lower survival than others after adjustments for other factors. We made this important observation in a previous study in the pre-MELD era.28 Socioeconomic status and education are not important determinants of this negative impact,29, 30 and the lower survival in African Americans merits careful prospective studies that use newer developments in transplant immunology and pharmacogenomics.31

Ancillary