Decreasing disparity in liver transplantation among white and Asian patients with hepatocellular carcinoma

California, 1998-2005

Authors


  • The ideas and opinions expressed herein are those of the authors, and endorsement by the State of California, Department of Public Health, the National Cancer Institute, and the Centers for Disease Control and Prevention or their contractors and subcontractors is not intended nor should be concluded.

  • The collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute's Surveillance, Epidemiology, and End Results Program under contract N01-PC-35136 awarded to the Northern California Cancer Center, contract N01-PC-35139 awarded to the University of Southern California, and contract N01-PC-54404 awarded to the Public Health Institute (PHI); and by the Centers for Disease Control and Prevention's National Program of Cancer Registries under agreement 1U58DP00807-01 awarded to the PHI.

Abstract

BACKGROUND.

A preliminary study using national cancer surveillance data from 1998 through 2002 suggested that there were significant differences between non-Hispanic whites (‘whites’) and Asian/Pacific Islanders (APIs) in the use of liver transplantation as a treatment for hepatocellular carcinoma (HCC).

METHODS.

The objective of the current study was to examine whether differences in liver transplantation between whites and APIs with HCC were changing over time. By using a population-based, statewide cancer registry, data were obtained on all HCC cases diagnosed in California between 1998 and 2005, and the study was limited to white and API patients with nonmetastatic HCC who had tumors that measured ≤5 cm in greatest dimension (n = 1728 patients).

RESULTS.

From 1998 through 2003 (n = 1051 patients), the odds of undergoing liver transplantation were 2.56 times greater for white patients than for API patients (95% confidence interval [CI], 1.72–3.80 times higher), even after adjusting for age, sex, marital status, year of diagnosis, TNM stage, and tumor grade. In contrast, during 2004 and 2005 (n = 677 patients), there were no significant differences in the odds of undergoing liver transplantation. Between 2002 and 2004, changes in liver transplantation policy assigned priority points to patients with HCC (initially to stage I and II, then to stage II only). After the policy changes, API patients with HCC experienced a significant increase in stage II diagnoses, whereas white patients did not.

CONCLUSIONS.

In California, there was a large and significant disparity in the rate of liver transplantation among white and API patients with HCC from 1998 through 2003 but not during 2004 and 2005. Changes in liver transplantation policy from 2002 through 2004 may have played a role in decreasing this difference. Cancer 2008. © 2008 American Cancer Society.

Between 1995 and 2004, the incidence of liver cancer in the United States increased by 22%, and only thyroid cancer had a greater increase. More worrisome, the mortality rate for liver cancer increased by 17% during this period, an increase that was larger than all other cancer sites and was in stark contrast to the decreasing mortality rates for the majority of cancer sites.1 The largest contribution to these incidence and mortality trends was the rise in hepatocellular carcinoma (HCC). Unfortunately, HCC has one of the poorest survival rates of all cancers2; for patients who were diagnosed from 1995 through 1999 and were followed through 2004, the 5-year relative survival rate was only 8.8%. To date, the only potentially curative therapies for HCC are resection and liver transplantation (LT) when resection is not possible.3, 4 The use of LT to treat HCC was revitalized by Mazzaferro et al. in 1996, when they identified patients who met specific tumor criteria that clearly demonstrated a survival benefit after transplantation (no evidence of extrahepatic tumor and unifocal tumor mass <5 cm in greatest dimension or ≤3 multifocal tumors each <3 cm in greatest dimension), with an overall actuarial 4-year survival rate of 75% and a recurrence-free 4-year survival rate of 83%.5 On the basis of the success of that therapy and the small window of opportunity to gain this survival benefit, the United Network for Organ Sharing (UNOS) implemented changes in LT policy between 2002 and 2004 that assigned priority points to patients with HCC (initially to patients with stage I and II disease and then to only to patients with stage II disease). After the initial policy change in 2002, the number of transplantations for liver cancer has risen rapidly.6

Groups who may derive a large benefit from these policy changes include Asians and Pacific Islanders (APIs) and other ethnic and racial groups that are affected disproportionately by liver disease.7 Of these groups, Vietnamese men and Korean women have the highest incidence of liver cancer, and Chinese men and women have the highest liver cancer mortality rate of any demographic group in the United States.7–9 In contrast to other groups, the etiology of liver cancer in APIs is predominantly because of chronic infection with hepatitis B virus (HBV). Among those with chronic HBV infection, the majority of patients who develop HCC do not experience hepatic decompensation before or by the time of diagnosis, indicating that HCC usually arises in the clinical setting of compensated cirrhosis, which may be silent clinically.10, 11 However, before the adoption of the UNOS policy changes, in the context of a relatively large pool of patients awaiting transplantation of a limited organ supply, patients with liver cancer were only competitive for transplantation after they had developed decompensated cirrhosis. These factors may explain in part why, in a preliminary study using national cancer registry from 1998 to 2002 on adult patients with nonmetastatic HCC who had tumors that measured ≤5 cm in greatest dimension, non-Hispanic whites (‘whites’) were 1.5 times more likely than APIs to undergo LT, even after adjusting for year of diagnosis, age, marital status, tumor size, and histologic grade (P = .005).12

The state of California has the largest population of APIs in the United States (4.6 million as of July 2003).13 By using the unique resources of the California Cancer Registry (CCR), a population-based cancer registry that has covered the entire state of California since 1988, we obtained data on all HCC cases diagnosed among whites and APIs in California between 1998 and 2005. By using 3 additional years of data (2003–2005) beyond the earlier preliminary study, we examined differences in the use of LT among white and API patients who were diagnosed in California with nonmetastatic HCC and tumors that measured ≤5 cm. We also examined whether these differences were changing over time. On the basis of the considerations described above, we hypothesized that the largest benefit of the UNOS policy changes would be observed among APIs with HCC.

MATERIALS AND METHODS

Study Population

HCC cases were identified through the CCR, a population-based registry that has collected cancer incidence data for the entire population of California since 1988 through a system of regional registries. With the state's population at 33.9 million in the 2000 US Census, nearly 140,000 cases of invasive cancer are added to the CCR each year, and data on nearly 2.3 million invasive cases have been collected since 1988. The CCR is a participant in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program, which requires the highest standards of data quality, as judged by completeness, accuracy, and timeliness.

We restricted eligibility to patients who were diagnosed between 1998 and 2005, because the collection of detailed liver surgery codes began in 1998, and because 2005 was the latest year with complete case ascertainment. Cases were followed through the end of 2005, the latest year with complete cause-of-death ascertainment. Because of racial differences in the etiology of liver cancer and, thus, in the potential impact of changes in transplantation policy, we limited to study to white and API patients with HCC. Between January 1, 1998 and December 31, 2005, 6421 white adults and API adults (aged ≥18 years) were newly diagnosed in California with primary invasive cancer of the liver (SEER site recode 21071). We restricted study eligibility to patients with HCC according to the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) (histology code 8170), without lymph node or distant metastasis (ie, N0/M0 in the TNM staging nomenclature), and tumor size ≤5 cm (n = 1767). In the American Joint Committee on Cancer (AJCC) TNM staging system, the disease in these patients ranged from stage I (T1/N0/M0) to stage IIIA (T3/N0/M0) or stage IIIB (T4/N0/M0). Because of insufficient numbers for analysis, we excluded cases with unknown marital status or TNM stage. We also excluded cases that were identified by autopsy or death certificate only. Thus, the final sample included 1728 cases. Each case included detailed information on the most definitive site-specific surgery; in total, 31 surgery codes were available, with 2 codes representing transplantation (code 61, total hepatectomy and transplantation; and code 75, bile duct and hepatectomy with transplantation).

During the study period, the CCR used 2 distinct but complementary schemes for collecting data on tumor characteristics. In the beginning of 2004, the new Collaborative Staging (CS) scheme was put into place and required the collection of a large set of tumor, lymph node, and metastasis fields as well as supplementary clinical and laboratory data. For cases diagnosed during 2004 through 2005, the registry data contained values for AJCC TNM stage groups derived from the CS fields. Before 2004, a simpler Extent of Disease (EOD) system had been used for many years that required the collection of a smaller set of tumor, lymph node, and metastasis fields. For cases diagnosed during 1998 through 2003, these EOD fields were used to derive AJCC TNM stage groups using the same staging rules that were in effect during 2004 through 2005.

Statistical Methods

We used the t test and the chi-square test to compare baseline characteristics related to the probability of LT. To simultaneously assess the effect of race/ethnicity, age, sex, marital status, year of diagnosis, TNM stage, and histologic grade on the probability of undergoing LT, we used logistic regression models that included terms for all of these variables. For each term, we estimated the odds ratio (OR) and associated 95% confidence interval (CI). To assess whether the effect of race was changing over time, we performed these analyses for 3 time intervals: 1) the entire study period, 1998–2005; 2) the earlier part of the study period, 1998–2003; and 3) the later part of the study period, 2004–2005. Survival estimates were computed by the Kaplan-Meier method using deaths from all causes. All statistical analyses were conducted using SAS for Windows, version 9.1 (SAS Institute, Cary, NC).

RESULTS

Our study population consisted of 991 white patients and 737 API patients. During the entire study period (1998–2005), there were large differences in the probability of LT among white and API patients with HCC (Fig. 1), with unadjusted transplantation rates higher for whites (19.8%) than for APIs (14.1%; P = .002). In analyses that are not shown here, we observed that, in our study population, patients who underwent transplantation had a 5-year survival rate of 68.2%, versus 23.4% for patients who did not undergo transplantation.

Figure 1.

Unadjusted differences in liver transplantation among non-Hispanic white patients and Asian/Pacific Islander (API) patients with hepatocellular carcinoma in California from 1998 through 2005 (n = 1728). Only patients without lymph node or distant metastasis and tumor that measured ≤5 cm in greatest dimension were included in the analysis. *White denotes non-Hispanic white and API denotes Asian/Pacific Islander. †Only patients without nodal or distant metastasis and tumor size ≤5 cm were included in the analysis.

Table 1 shows racial differences in baseline characteristics related to the probability of LT. Compared with white patients, API patients were older, more often were women, more often were currently married, and more often were diagnosed during 1988 through 2002. There were no significant racial differences in TNM stage or histologic grade. To assess the role of race while adjusting for these potential confounding variables, we performed a multivariate logistic regression analysis, simultaneously measuring the effect of race, age, sex, marital status, year of diagnosis, TNM stage, and histologic grade (Table 2). Even after adjustment for these variables, the odds of undergoing transplantation were 1.88 times higher for whites than for APIs (95% CI, 1.40–2.53 times higher). Other factors that were associated with higher odds of transplantation were younger age, being currently married, diagnosis during 2002, TNM stage II, and histologic grade other than unknown.

Table 1. Baseline Characteristics of White Patients and Asian/Pacific Islander Patients With Hepatocellular Carcinoma: California, 1998–2005 (n = 1728)*
CharacteristicWhites (n = 991), %APIs (n = 737), %P
  • Whites indicates non-Hispanic whites; APIs, Asian/Pacific Islanders; TNM, the American Joint Committee on Cancer Tumor, Lymph Node, Metastasis classification system.

  • *

    Only patients without lymph node or distant metastasis and tumor size ≤5 cm were included in the analysis.

Mean age, y62.163.3.03
Sex
 Men74.963.6<.0001
 Women25.136.4 
Marital status
 Never married19.27.5<.0001
 Formerly married25.016.8 
 Currently married55.875.7 
Year of diagnosis
 19986.16.8.04
 19997.67.6 
 20007.86.5 
 200110.710.7 
 200211.616.2 
 200317.312.9 
 200418.817.1 
 200520.322.2 
TNM stage
 I57.754.1.32
 II38.642.1 
 III3.73.8 
Histologic grade
 Well differentiated22.318.1.16
 Moderately differentiated18.719.4 
 Poorly differentiated/undifferentiated6.07.1 
 Unknown53.155.5 
Table 2. Multivariate Model of Liver Transplantation Among White Patients and Asian/Pacific Islander Patients With Hepatocellular Carcinoma: California, 1998–2005 (n = 1728)*
VariableMultivariate OR for Liver Transplantation (95% CI)
  • OR indicates odds ratio; CI, confidence interval; White, non-Hispanic white; API, Asian/Pacific Islander; TNM, the American Joint Committee on Cancer Tumor, Lymph Node, Metastasis classification system.

  • *

    Only patients without lymph node or distant metastasis and tumor size ≤5 cm were included in the analysis.

Race
 API1.00 (Referent)
 White1.88 (1.40–2.53)
Age, 1-y increase0.93 (0.92–0.95)
Sex
 Men1.00 (Referent)
 Women1.12 (0.81–1.57)
Marital status
 Never married1.00 (Referent)
 Formerly married1.33 (0.79–2.25)
 Currently married2.58 (1.68–3.95)
Year of diagnosis
 19981.00 (Referent)
 19991.19 (0.56–2.53)
 20000.82 (0.37–1.81)
 20011.15 (0.57–2.33)
 20022.13 (1.10–4.13)
 20030.83 (0.42–1.66)
 20041.36 (0.71–2.58)
 20051.23 (0.65–2.34)
TNM stage
 I1.00 (Referent)
 II1.71 (1.29–2.26)
 III0.52 (0.20–1.36)
Histologic grade
 Well differentiated1.00 (Referent)
 Moderately differentiated0.99 (0.69–1.44)
 Poorly differentiated/undifferentiated0.84 (0.49–1.45)
 Unknown0.26 (0.19–0.37)

To examine whether these racial differences were changing over time, we performed multivariate logistic regression analyses after stratifying by year of diagnosis (2 periods: 1998–2003 and 2004–2005). Table 3 shows that, during 1998 through 2003, the odds of undergoing transplantation were 2.56 times higher for whites than for APIs (95% CI, 1.72–3.80 times higher), but that, during 2004 through 2005, there were no significant racial differences in the odds of transplantation (whites vs APIs: OR, 1.23; 95% CI, 0.77–1.96). The importance of other factors also changed over time. During 1998 through 2003, currently being married was associated with a very large increase in the odds of undergoing transplantation (OR, 4.24; 95% CI, 2.22–8.08), but it did not play a significant role during 2004 through 2005 (OR, 1.64; 95% CI, 0.89–2.99). Patients who were diagnosed in 2002 had more than a 2-fold increase in the odds of undergoing transplantation compared with patients who were diagnosed in 1998 (OR, 2.09; 95% CI, 1.08–4.03), reflecting the initial decision in 2002 to award (what were retrospectively deemed excessive) priority points to patients with HCC. The impact of UNOS policy decisions also is observed in the finding that a stage II diagnosis did not significantly increase the odds of undergoing transplantation during 1998 through 2003 (OR, 1.32; 95% CI, 0.92–1.91); however, during 2004 through 2005, the odds of undergoing transplantation were 2.61 times higher among patients with a stage II diagnosis (95% CI, 1.65–4.14 times higher).

Table 3. Decreasing Disparity in Liver Transplantation Among White and Asian/Pacific Islander Patients With Hepatocellular Carcinoma: California, 1998–2005 (n = 1728)*
VariableMultivariate OR for Liver Transplantation (95% CI)
1998-2003, n = 10512004-2005, n = 677
  • OR indicates odds ratio; CI, confidence interval; White, non-Hispanic white; API, Asian/Pacific Islander; TNM, the American Joint Committee on Cancer Tumor, Lymph Node, Metastasis classification system.

  • *

    Only patients without lymph node or distant metastasis and tumor size ≤5 cm were included in the analysis.

Race
 API1.00 (Referent)1.00 (Referent)
 White2.56 (1.72–3.80)1.23 (0.77–1.96)
Age, 1-y increase0.93 (0.91–0.95)0.93 (0.91–0.95)
Sex
 Men1.00 (Referent)1.00 (Referent)
 Women1.17 (0.77–1.79)1.06 (0.61–1.84)
Marital status
 Never married1.00 (Referent)1.00 (Referent)
 Formerly married2.13 (1.01–4.49)0.78 (0.35–1.74)
 Currently married4.24 (2.22–8.08)1.64 (0.89–2.99)
Year of diagnosis
 19981.00 (Referent) 
 19991.12 (0.53–2.37) 
 20000.78 (0.35–1.69) 
 20011.10 (0.55–2.23) 
 20022.09 (1.08–4.03) 
 20030.78 (0.39–1.56) 
 2004 1.00 (Referent)
 2005 0.88 (0.57–1.37)
TNM stage
 I1.00 (Referent)1.00 (Referent)
 II1.32 (0.92–1.91)2.61 (1.65–4.14)
 III0.64 (0.21–1.95)0.33 (0.04–2.68)
Histologic grade
 Well differentiated1.00 (Referent)1.00 (Referent)
 Moderately differentiated1.43 (0.87–2.35)0.56 (0.31–1.00)
 Poorly differentiated/undifferentiated1.05 (0.52–2.12)0.63 (0.26–1.53)
 Unknown0.38 (0.24–0.59)0.14 (0.08–0.25)

Because the UNOS policies to award priority points were targeted at patients with stage II HCC, we investigated whether there were changes in the proportion of HCC patients with stage II over time and whether these time trends differed by race. Table 4 shows that, for white patients, there was no significant change in the TNM stage of patients over time; whereas, for API patients, there was a significant shift in TNM stage. Between the earlier and later years of the study period, the proportion of API patients diagnosed with stage II HCC increased from 39.4% to 46.2%, a 17% relative increase.

Table 4. Changes in TNM Stage Among White and Asian/Pacific Islander Patients With Hepatocellular Carcinoma: California, 1998–2005 (n = 1728)*
TNM StageWhites (n = 991)APIs (n = 737)
1998-20032004-20051998-20032004-2005
  • TNM indicates the American Joint Committee on Cancer Tumor, Lymph Node, Metastasis classification system; Whites, non-Hispanic whites; APIs, Asian/Pacific Islanders.

  • *

    Only patients without lymph node or distant metastasis and tumor size ≤5 cm were included in the analysis.

I60.353.855.751.7
II36.841.339.446.2
III3.04.94.92.1
P for change over time.07 .04 

Because small tumors (<2 cm) are treated more appropriately with surgical resection rather than transplantation, we investigated whether there were racial differences in the prevalence of these tumors that might explain the racial differences in transplantation. In our study population, there were no significant racial differences in the proportion of patients who had HCC with tumors <2 cm in either the earlier years (white vs API: 16.7% vs 13.4%; P = .14) or the later years (white vs API: 14.7% vs 14.8%; P = .97) of the study period.

DISCUSSION

LT for HCC has led to dramatic improvements in survival for many patients if the tumor is detected at an early stage. Identifying these patients and assigning their priority relative to others awaiting LT has been a difficult balance. Realizing that the opportunity for LT in patients with liver cancer was small, beginning in 2002, UNOS assigned additional Model of End-Stage Liver Disease (MELD) points to these patients to increase their chances of undergoing LT. Between 2002 and 2004, the methodology for assigning these points underwent several modifications to make it equitable. The goal is that appropriate numbers of patients with liver cancer are transplanted, but not to the extent that others are excluded unfairly. Although imperfect, these policy changes have led to a remarkable improvement in the number of liver transplantations being performed for liver cancer in the United States. Although these new rules should benefit all patients with early-stage HCC, we hypothesized that APIs would benefit the most because of the frequency with which HCC develops in patients with hepatitis B in the absence of decompensated cirrhosis. Our analyses may be among the first to document the particularly favorable outcomes observed among APIs after the implementation of these policy changes.

We did observe that 5-year survival improved markedly for patients who underwent LT (68%) compared with those who did not (23%). The number of transplantations for liver cancer increased dramatically over time: A patient with HCC diagnosed in 2002 was more than twice as likely to undergo LT than a patient who was diagnosed in 1998. The UNOS policy changes were targeted toward those with stage II disease, and we observed that patients who had stage II cancer were 2.61 times more likely to undergo transplantation compared with patients who had stage I disease. Thus, the policy changes appear to have been broadly successful for patients with HCC. However, it did appear that the largest benefits were observed for API patients, because the policy changes were associated temporally with the elimination of a large disparity in LT between whites and APIs observed during 1998 through 2003. In this earlier period, the odds of transplantation were 2.56 times higher for white patients; however, during 2004 through 2005, after the UNOS policy changes, there was no significant racial difference in the odds of transplantation for HCC.

Our data also show that age, marital status, and histologic grade other than unknown improve the odds of undergoing LT for HCC. This is likely a reflection of some of the requirements for patients before undergoing LT. Although there is no specific age limitation to LT,14, 15 it has been demonstrated that older LT recipients have poorer long-term outcomes than younger patients,16 in part because of their increased risk of cancer17 and coronary artery disease.18 Medical comorbidities and functional status are important factors in deciding who will undergo LT; thus, younger patients are more likely to receive transplantation because they have fewer comorbidities and better functional status. Other important factors include the social support available to a patient who will undergo a major operation with a prolonged recovery time and the need for close adherence to medications, laboratory testing, and clinic visits after surgery. The improved odds for those who are married may be a reflection of these requirements, although it is not clear why the effect of marital status would change over time. Histology is not often a factor in deciding on LT for HCC and currently is determined infrequently, because imaging in conjunction with a serum α fetoprotein level often can make the diagnosis without the risk of tumor seeding. However, if a biopsy is done and is inconclusive, then the patient may be less likely to be offered transplantation.

In addition to changes in UNOS policy, other factors were changing during the study period. Screening for hepatitis B and surveillance for liver cancer among hepatitis B carriers (using abdominal imaging and α fetoprotein) also have increased over the past decade, especially in the API community. The American Association for the Study of Liver Diseases recommends surveillance for liver cancer in API hepatitis B carriers beginning at age 40 years for men and at age 50 years for women.19 The practice of screening has been controversial in terms of its cost-effectiveness20 and true benefit to survival. There have been many retrospective studies suggesting benefit that have suffered from potential lead- and length-time biases.21 To date, only 1 randomized trial has demonstrated a benefit from screening: That was a study of patients with hepatitis B in China which reported a 37% reduction in mortality.22

Our data suggest that, in California and particularly among APIs, screening for liver cancer is leading to an increase in diagnosis at early stages, when LT can be offered. In many parts of California, there have been major hepatitis B education and screening campaigns directed at Asians,23 and specialized centers have emerged that focus on liver disease in Asian patients. Despite these developments, screening rates for HBV infection and liver cancer among APIs remain low.24 These screening efforts must be encouraged, and new methods must be identified to reach the numerous and diverse ethnicities that comprise the API population. Reducing barriers to LT also will require different approaches across the many API ethnicities.25

The current study was subject to several limitations. We aggregated all API groups together to achieve a greater sample size, although the results may have differed for some API subgroups.13 In fact, the ‘API’ category consisted of more than 16 ethnicities, including Chinese, Japanese, Vietnamese, Korean, and Hawaiian, with various incidence of liver cancer and differing rank order of liver cancer incidence and mortality.26 Barriers to screening for these different API groups may include linguistic, cultural, and religious factors, and we must design interventions that acknowledge and incorporate these factors. Our study also was limited by the lack of data on risk factors for HCC and by the lack of clinical details on patients' liver disease, both of which may play a role in determining therapy for HCC and LT. Long-term follow-up will be necessary to determine whether the trends observed in this study continue.

It is possible that the increase in use of LT among APIs may represent over-treatment with LT and under-treatment with surgical resection. It is also possible that factors we did not measure may have made whites less competitive candidates for LT. For example, if a substantially lower proportion of API patients with HCC had cirrhosis, then we would expect fewer to undergo LT, because surgical resection is the treatment of choice in noncirrhotic patients with HCC. Conversely, if the prevalence of alcohol abuse or intravenous drug use were substantially greater among whites, then this could lead to fewer receiving LT. In a recent study of patients with HCC caused by HBV or hepatitis C virus (HCV),27 Barazani et al. reported that patients with HBV were predominantly Asian (84%), and patients with HCV were predominantly Caucasian (72%). Cirrhosis was present in 98% of patients with HCV versus 79% of patients with HBV. However, 78% of patients who had HCV had alcohol abuse or intravenous drug use compared with 13% of patients who had HBV.

Despite these limitations, our data suggest that the assignment of MELD priority points for patients with HCC has led to an increase in LT, and these policy changes were associated temporally with the elimination of a large disparity between whites and APIs that was observed during 1998 through 2003. The UNOS policy changes have provided a rational means for increasing LT among groups with historically lower use of this life-saving treatment.

Ancillary