LIVER TRANSPLANTATION 20:528–535, 2014
ORIGINAL ARTICLE
Ethnic Disparities and Liver Transplantation Rates in Hepatocellular Carcinoma Patients in the Recent Era: Results from the Surveillance, Epidemiology, and End Results Registry Robert J. Wong,1,2 Pardha Devaki,3 Long Nguyen,4 Ramsey Cheung,1,2 and Mindie H. Nguyen1 Liver Transplant Program, Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, CA; 2Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA; 3Department of Internal Medicine, Detroit Medical Center/Wayne State University, Detroit, MI; and 4Department of Medicine, Stanford University School of Medicine, Stanford, CA
1
Hepatocellular carcinoma (HCC) is a leading cause of morbidity and mortality. After the implementation of the Model for EndStage Liver Disease system, rates of liver transplantation (LT) for HCC patients increased. However, it is not clear whether this trend has continued into recent times. Using the Surveillance, Epidemiology, and End Results registry (1998-2010), we retrospectively analyzed trends for LT among HCC patients in 3 time periods: 1998-2003, 2004-2008, and 2009-2010. A total of 60,772 HCC patients were identified. In the more recent time periods, the proportion of localized-stage HCC increased (45.0% in 1998-2003, 50.4% in 2004-2008, and 51.7% in 2009-2010; P < 0.001). Although the proportion of HCC patients within the Milan criteria also increased with time (22.8% in 1998-2003, 31.8% in 2004-2008, and 37.1% in 2009-2010; P < 0.001), the proportion of those patients undergoing LT increased from 1998-2003 to 2004-2008 but decreased from 20042008 to 2009-2010. However, the actual frequencies of LT were similar in 2004-2008 (208.2 per year) and 2009-2010 (201.5 per year). A multivariate logistic regression, including sex, age, ethnicity, Milan criteria, tumor stage, tumor size and number, and time periods, demonstrated a lower likelihood of LT in 2009-2010 versus 1998-2003 [odds ratio (OR) 5 0.63, 95% confidence interval (CI) 5 0.57-0.71]. Blacks (OR 5 0.48, 95% CI 5 0.41-0.56), Asians (OR 5 0.65, 95% CI 5 0.57-0.73), and Hispanics (OR 5 0.76, 95% CI 5 0.68-0.85) were all less likely to undergo LT in comparison with non-Hispanic whites. Despite the increasing proportion of patients with HCC diagnosed at an earlier stage, LT rates declined in the most recent era. In addition, ethnic minorities were significantly less likely to undergo LT. The growing imbalance between the number of transplanteligible HCC patients and the shortage of donor livers emphasizes the need to improve donor availability and curative alternaC 2014 AASLD. tives to LT. Liver Transpl 20:528-535, 2014. V Received September 7, 2013; accepted January 6, 2014. Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide.1,2 Despite advances in HCC screening and surveillance for earlier detec-
tion and treatment, recent studies still report an overall 5-year survival rate of only 16%.2 Although improvements in HCC screening among high-risk
Additional Supporting Information may be found in the online version of this article. Abbreviations: CI, confidence interval; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; OR, odds ratio; SEER, Surveillance, Epidemiology, and End Results; TACE, transarterial chemoembolization; UNOS, United Network for Organ Sharing. There was no funding or support for this study, and the authors have no conflicts of interest to disclose. Address reprint requests to Mindie H. Nguyen, M.D., M.A.S., Liver Transplant Program, Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, 750 Welch Road, Suite 210, Palo Alto, CA 94304. Telephone: 650-498-5691; FAX: 650498-5692; E-mail: [email protected] DOI 10.1002/lt.23820 View 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
C 2014 American Association for the Study of Liver Diseases. V
LIVER TRANSPLANTATION, Vol. 20, No. 5, 2014
populations do allow the diagnosis of earlier stage, localized HCC in patients who would benefit more from curative therapies, the success of any screening program hinges on its ability to offer effective treatment options with good long-term outcomes, such as liver transplantation (LT).1,3,4 Previous studies have demonstrated that HCC patients meeting the Milan criteria (a single tumor no more than 5 cm in diameter or fewer than 3 tumors, each no more than 3 cm in diameter) can achieve good long-term survival after LT with 5-year survival rates greater than 70% to 80%.4-6 As a result, starting in 2002, the United Network for Organ Sharing (UNOS) allocated additional Model for End-Stage Liver Disease (MELD) exception points to HCC patients with tumors meeting the Milan criteria and thereby improved their priority on the LT wait list.7 Although the initial MELD exception system assigned 24 points to patients with stage 1 HCC (1 tumor < 2 cm in diameter) and 29 points to patients with stage 2 HCC (1 tumor 2-5 cm in diameter or 2 or 3 tumors, each 3 cm in diameter), this was subsequently modified in April 2003 to assign 20 points for stage 1 HCC and 24 points for stage 2 HCC. In March 2005, another revision was enacted, and it assigned 22 points for stage 2 HCC. LT rates for HCC immediately rose in the years after the introduction of the MELD exception status.8,9 However, with the increasing shortage of donor livers available for transplantation, it is not known whether the rates of LT for HCC have continued to rise in more recent years. Furthermore, although the MELD exception status allotted to HCC patients meeting the Milan criteria in principle standardized the prioritization for LT, it is not clear whether sex-specific or race/ethnicity-specific disparities in the receipt of LT persist in this cohort. Using a large, ethnically diverse population-based cohort in the United States, the current study evaluated trends in LT among transplanteligible HCC patients in the most recent time period.
PATIENTS AND METHODS Study Design and Patient Population The current retrospective cohort study used data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) cancer registry. The most recent version of the SEER registry (SEER*Stat 8.0.4, November 2012 submission) includes data from 1973 to 2010 and from 18 registries (Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco–Oakland, Los Angeles, San Jose–Monterey, greater California, Seattle–Puget Sound, Utah, Alaska Native Tumor Registry, Kentucky, Louisiana, New Jersey, rural Georgia, and greater Georgia)10 and represents approximately 28% of the US population. Our analyses used data from the entire registry cohort. However, detailed site-specific treatment data for the liver (eg, local tumor destruction, surgical resection, and LT) were available only from 1998 onward. Before 1998, the detailed surgical treatment of liver cancers
WONG ET AL. 529
was not reported, and thus the current study used the 1998-2010 patient cohort.
Definitions SEER identifies HCC according to International Classification of Diseases for Oncology, 3rd edition.11,12 Expanded race and ethnicity classifications were used for the 1998-2010 cohort: non-Hispanic whites, blacks, Asians/Pacific Islanders (Asians), and white Hispanics (Hispanics). Smaller numbers of HCC patients in other race/ethnicity groups (American Indian/Alaskan Natives, black Hispanics, and Asian Hispanics) precluded a precise estimation of LT rates, and thus they were not included in the current study. The 1998-2010 cohort was separated into 3 time periods so that we could evaluate trends in LT rates: the pre-MELD exception era (1998-2003) and 2 MELD exception eras (2004-2008 and 2009-2010). The year 2003 was chosen as the cutoff for the pre-MELD exception era to account for the lag time in the effect of the implementation of the MELD exception status in late 2002 due to the multiple revisions since the initial policy was introduced. The MELD exception period was separated into 2 periods (2004-2008 and 2009-2010) to allow a more representative estimation of LT rates in the more recent period. Preliminary analyses demonstrated that the 2009-2010 period included more than 13,000 patients with HCC; this was a sufficient sample size for statistical analyses of LT trends, and the time period was still sufficiently close to the present time. The SEER registry provides data regarding the number and size of each tumor present in the liver. Using these data, we were able to determine whether each patient’s HCC disease burden was within or outside the Milan criteria. HCC staging definitions were based on the SEER staging system, which is unique to the SEER registry and used primarily for describing the extent of disease.12 Localized stage describes tumors confined to 1 lobe of the liver with or without vascular invasion. Regional-stage tumors include the involvement of more than 1 lobe via the contiguous growth of a single lesion, an extension to local structures (the diaphragm, extrahepatic bile ducts, or gallbladder), or an extension to regional lymph nodes. Distant-stage tumors include metastatic disease, an extension of the cancer to nearby organs (pancreas, pleura, or stomach), or the involvement of distant lymph nodes. Treatment categories were analyzed with SEER sitespecific surgery definitions (no therapy, local tumor destruction, surgical resection, and LT).12 Local tumor destruction included radiofrequency ablation and percutaneous ethanol injection but not transarterial chemoembolization (TACE). According to communication with the SEER registrar, data on TACE treatment are categorized separately under radiation and are not distinguishable from other types of radiation-based therapy (eg, brachytherapy or beam radiation). Furthermore, the SEER registrar indicated that the inclusion of TACE is relatively new, and the data quality is hindered by the consistency of the reporting and
530 WONG ET AL.
LIVER TRANSPLANTATION, May 2014
significant underreporting. A preliminary analysis of the 1998-2010 HCC cohort indicated that 95.8% of the HCC patients were categorized as receiving no form of radiation therapy or having an unknown radiation therapy status. Because of concerns about the inconsistency of data reporting and the underreporting of therapy, radiation treatment was not included to preserve the accuracy of the analyses and conclusions.
Statistical Analysis Clinical and demographic characteristics were compared across the 3 time periods (1998-2003, 20042008, and 2009-2010). Chi-square tests were used to compare categorical variables, and an analysis of variance was used to compare continuous variables in each time period. Multivariate logistic regression models were used to evaluate independent predictors of undergoing LT. Forward stepwise logistic regression methods included variables that were biologically important (eg, age and sex) or demonstrated significant associations (P < 0.1) in the univariate models. The final model included sex, age, race/ethnicity, Milan criteria, tumor number and size, tumor stage, and time period. Statistical significance was met with a 2-tailed P value < 0.05. All statistical analyses were performed with the Stata 10 statistical package (StataCorp, College Station, TX). Review by the institutional review
board was not required for this study because human subjects were not involved, as per U.S. Department of Health and Human Services guidelines and the SEER database is publicly available without individually identifiable private information.
RESULTS Overview In all, there were 60,772 HCC patients in the 19982010 cohort, and 30% (n 5 18,215) were within the Milan criteria. Among HCC patients meeting the Milan criteria, only 13.4% underwent LT during this period.
HCC Trends Across Time Periods Age-adjusted HCC incidence rates were highest for Asians and lowest for non-Hispanic whites (Supporting Fig. 1); however, HCC incidence rates for Asians appeared fairly stable over time, whereas the rates for other racial/ethnic groups increased. As of the year 2000, although Asians still had the highest HCC incidence rates, the rates of other groups were close behind: the HCC incidence rates per 100,000 personyears in 2010 were 12.4 for Asians, 11.8 for Hispanics, 8.9 for blacks, and 5.2 for non-Hispanic whites. The majority of the HCC patients were men, and the mean age at the diagnosis of HCC was slightly lower in the
TABLE 1. Clinical Characteristics of HCC Patients From 1998 to 2010
Sex: male (%) Age (years)* Age categories (%)
ORIGINAL ARTICLE
Ethnic Disparities and Liver Transplantation Rates in Hepatocellular Carcinoma Patients in the Recent Era: Results from the Surveillance, Epidemiology, and End Results Registry Robert J. Wong,1,2 Pardha Devaki,3 Long Nguyen,4 Ramsey Cheung,1,2 and Mindie H. Nguyen1 Liver Transplant Program, Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, CA; 2Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA; 3Department of Internal Medicine, Detroit Medical Center/Wayne State University, Detroit, MI; and 4Department of Medicine, Stanford University School of Medicine, Stanford, CA
1
Hepatocellular carcinoma (HCC) is a leading cause of morbidity and mortality. After the implementation of the Model for EndStage Liver Disease system, rates of liver transplantation (LT) for HCC patients increased. However, it is not clear whether this trend has continued into recent times. Using the Surveillance, Epidemiology, and End Results registry (1998-2010), we retrospectively analyzed trends for LT among HCC patients in 3 time periods: 1998-2003, 2004-2008, and 2009-2010. A total of 60,772 HCC patients were identified. In the more recent time periods, the proportion of localized-stage HCC increased (45.0% in 1998-2003, 50.4% in 2004-2008, and 51.7% in 2009-2010; P < 0.001). Although the proportion of HCC patients within the Milan criteria also increased with time (22.8% in 1998-2003, 31.8% in 2004-2008, and 37.1% in 2009-2010; P < 0.001), the proportion of those patients undergoing LT increased from 1998-2003 to 2004-2008 but decreased from 20042008 to 2009-2010. However, the actual frequencies of LT were similar in 2004-2008 (208.2 per year) and 2009-2010 (201.5 per year). A multivariate logistic regression, including sex, age, ethnicity, Milan criteria, tumor stage, tumor size and number, and time periods, demonstrated a lower likelihood of LT in 2009-2010 versus 1998-2003 [odds ratio (OR) 5 0.63, 95% confidence interval (CI) 5 0.57-0.71]. Blacks (OR 5 0.48, 95% CI 5 0.41-0.56), Asians (OR 5 0.65, 95% CI 5 0.57-0.73), and Hispanics (OR 5 0.76, 95% CI 5 0.68-0.85) were all less likely to undergo LT in comparison with non-Hispanic whites. Despite the increasing proportion of patients with HCC diagnosed at an earlier stage, LT rates declined in the most recent era. In addition, ethnic minorities were significantly less likely to undergo LT. The growing imbalance between the number of transplanteligible HCC patients and the shortage of donor livers emphasizes the need to improve donor availability and curative alternaC 2014 AASLD. tives to LT. Liver Transpl 20:528-535, 2014. V Received September 7, 2013; accepted January 6, 2014. Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide.1,2 Despite advances in HCC screening and surveillance for earlier detec-
tion and treatment, recent studies still report an overall 5-year survival rate of only 16%.2 Although improvements in HCC screening among high-risk
Additional Supporting Information may be found in the online version of this article. Abbreviations: CI, confidence interval; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; OR, odds ratio; SEER, Surveillance, Epidemiology, and End Results; TACE, transarterial chemoembolization; UNOS, United Network for Organ Sharing. There was no funding or support for this study, and the authors have no conflicts of interest to disclose. Address reprint requests to Mindie H. Nguyen, M.D., M.A.S., Liver Transplant Program, Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, 750 Welch Road, Suite 210, Palo Alto, CA 94304. Telephone: 650-498-5691; FAX: 650498-5692; E-mail: [email protected] DOI 10.1002/lt.23820 View 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
C 2014 American Association for the Study of Liver Diseases. V
LIVER TRANSPLANTATION, Vol. 20, No. 5, 2014
populations do allow the diagnosis of earlier stage, localized HCC in patients who would benefit more from curative therapies, the success of any screening program hinges on its ability to offer effective treatment options with good long-term outcomes, such as liver transplantation (LT).1,3,4 Previous studies have demonstrated that HCC patients meeting the Milan criteria (a single tumor no more than 5 cm in diameter or fewer than 3 tumors, each no more than 3 cm in diameter) can achieve good long-term survival after LT with 5-year survival rates greater than 70% to 80%.4-6 As a result, starting in 2002, the United Network for Organ Sharing (UNOS) allocated additional Model for End-Stage Liver Disease (MELD) exception points to HCC patients with tumors meeting the Milan criteria and thereby improved their priority on the LT wait list.7 Although the initial MELD exception system assigned 24 points to patients with stage 1 HCC (1 tumor < 2 cm in diameter) and 29 points to patients with stage 2 HCC (1 tumor 2-5 cm in diameter or 2 or 3 tumors, each 3 cm in diameter), this was subsequently modified in April 2003 to assign 20 points for stage 1 HCC and 24 points for stage 2 HCC. In March 2005, another revision was enacted, and it assigned 22 points for stage 2 HCC. LT rates for HCC immediately rose in the years after the introduction of the MELD exception status.8,9 However, with the increasing shortage of donor livers available for transplantation, it is not known whether the rates of LT for HCC have continued to rise in more recent years. Furthermore, although the MELD exception status allotted to HCC patients meeting the Milan criteria in principle standardized the prioritization for LT, it is not clear whether sex-specific or race/ethnicity-specific disparities in the receipt of LT persist in this cohort. Using a large, ethnically diverse population-based cohort in the United States, the current study evaluated trends in LT among transplanteligible HCC patients in the most recent time period.
PATIENTS AND METHODS Study Design and Patient Population The current retrospective cohort study used data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) cancer registry. The most recent version of the SEER registry (SEER*Stat 8.0.4, November 2012 submission) includes data from 1973 to 2010 and from 18 registries (Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco–Oakland, Los Angeles, San Jose–Monterey, greater California, Seattle–Puget Sound, Utah, Alaska Native Tumor Registry, Kentucky, Louisiana, New Jersey, rural Georgia, and greater Georgia)10 and represents approximately 28% of the US population. Our analyses used data from the entire registry cohort. However, detailed site-specific treatment data for the liver (eg, local tumor destruction, surgical resection, and LT) were available only from 1998 onward. Before 1998, the detailed surgical treatment of liver cancers
WONG ET AL. 529
was not reported, and thus the current study used the 1998-2010 patient cohort.
Definitions SEER identifies HCC according to International Classification of Diseases for Oncology, 3rd edition.11,12 Expanded race and ethnicity classifications were used for the 1998-2010 cohort: non-Hispanic whites, blacks, Asians/Pacific Islanders (Asians), and white Hispanics (Hispanics). Smaller numbers of HCC patients in other race/ethnicity groups (American Indian/Alaskan Natives, black Hispanics, and Asian Hispanics) precluded a precise estimation of LT rates, and thus they were not included in the current study. The 1998-2010 cohort was separated into 3 time periods so that we could evaluate trends in LT rates: the pre-MELD exception era (1998-2003) and 2 MELD exception eras (2004-2008 and 2009-2010). The year 2003 was chosen as the cutoff for the pre-MELD exception era to account for the lag time in the effect of the implementation of the MELD exception status in late 2002 due to the multiple revisions since the initial policy was introduced. The MELD exception period was separated into 2 periods (2004-2008 and 2009-2010) to allow a more representative estimation of LT rates in the more recent period. Preliminary analyses demonstrated that the 2009-2010 period included more than 13,000 patients with HCC; this was a sufficient sample size for statistical analyses of LT trends, and the time period was still sufficiently close to the present time. The SEER registry provides data regarding the number and size of each tumor present in the liver. Using these data, we were able to determine whether each patient’s HCC disease burden was within or outside the Milan criteria. HCC staging definitions were based on the SEER staging system, which is unique to the SEER registry and used primarily for describing the extent of disease.12 Localized stage describes tumors confined to 1 lobe of the liver with or without vascular invasion. Regional-stage tumors include the involvement of more than 1 lobe via the contiguous growth of a single lesion, an extension to local structures (the diaphragm, extrahepatic bile ducts, or gallbladder), or an extension to regional lymph nodes. Distant-stage tumors include metastatic disease, an extension of the cancer to nearby organs (pancreas, pleura, or stomach), or the involvement of distant lymph nodes. Treatment categories were analyzed with SEER sitespecific surgery definitions (no therapy, local tumor destruction, surgical resection, and LT).12 Local tumor destruction included radiofrequency ablation and percutaneous ethanol injection but not transarterial chemoembolization (TACE). According to communication with the SEER registrar, data on TACE treatment are categorized separately under radiation and are not distinguishable from other types of radiation-based therapy (eg, brachytherapy or beam radiation). Furthermore, the SEER registrar indicated that the inclusion of TACE is relatively new, and the data quality is hindered by the consistency of the reporting and
530 WONG ET AL.
LIVER TRANSPLANTATION, May 2014
significant underreporting. A preliminary analysis of the 1998-2010 HCC cohort indicated that 95.8% of the HCC patients were categorized as receiving no form of radiation therapy or having an unknown radiation therapy status. Because of concerns about the inconsistency of data reporting and the underreporting of therapy, radiation treatment was not included to preserve the accuracy of the analyses and conclusions.
Statistical Analysis Clinical and demographic characteristics were compared across the 3 time periods (1998-2003, 20042008, and 2009-2010). Chi-square tests were used to compare categorical variables, and an analysis of variance was used to compare continuous variables in each time period. Multivariate logistic regression models were used to evaluate independent predictors of undergoing LT. Forward stepwise logistic regression methods included variables that were biologically important (eg, age and sex) or demonstrated significant associations (P < 0.1) in the univariate models. The final model included sex, age, race/ethnicity, Milan criteria, tumor number and size, tumor stage, and time period. Statistical significance was met with a 2-tailed P value < 0.05. All statistical analyses were performed with the Stata 10 statistical package (StataCorp, College Station, TX). Review by the institutional review
board was not required for this study because human subjects were not involved, as per U.S. Department of Health and Human Services guidelines and the SEER database is publicly available without individually identifiable private information.
RESULTS Overview In all, there were 60,772 HCC patients in the 19982010 cohort, and 30% (n 5 18,215) were within the Milan criteria. Among HCC patients meeting the Milan criteria, only 13.4% underwent LT during this period.
HCC Trends Across Time Periods Age-adjusted HCC incidence rates were highest for Asians and lowest for non-Hispanic whites (Supporting Fig. 1); however, HCC incidence rates for Asians appeared fairly stable over time, whereas the rates for other racial/ethnic groups increased. As of the year 2000, although Asians still had the highest HCC incidence rates, the rates of other groups were close behind: the HCC incidence rates per 100,000 personyears in 2010 were 12.4 for Asians, 11.8 for Hispanics, 8.9 for blacks, and 5.2 for non-Hispanic whites. The majority of the HCC patients were men, and the mean age at the diagnosis of HCC was slightly lower in the
TABLE 1. Clinical Characteristics of HCC Patients From 1998 to 2010
Sex: male (%) Age (years)* Age categories (%)
