ORIGINAL ARTICLE. Received September 7, 2013; accepted January 6, 2014.

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1 LIVER TRANSPLANTATION 20: , 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. Nguyen 1 1 Liver Transplant Program, Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, CA; 2 Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA; 3 Department of Internal Medicine, Detroit Medical Center/Wayne State University, Detroit, MI; and 4 Department of Medicine, Stanford University School of Medicine, Stanford, CA Hepatocellular carcinoma (HCC) is a leading cause of morbidity and mortality. After the implementation of the Model for End- Stage 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 ( ), we retrospectively analyzed trends for LT among HCC patients in 3 time periods: , , and 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 , 50.4% in , and 51.7% in ; P < 0.001). Although the proportion of HCC patients within the Milan criteria also increased with time (22.8% in , 31.8% in , and 37.1% in ; P < 0.001), the proportion of those patients undergoing LT increased from to but decreased from to However, the actual frequencies of LT were similar in (208.2 per year) and (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 versus [odds ratio (OR) , 95% confidence interval (CI) ]. Blacks (OR , 95% CI ), Asians (OR , 95% CI ), and Hispanics (OR , 95% CI ) 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 alternatives to LT. Liver Transpl 20: , VC 2014 AASLD. Received September 7, 2013; accepted January 6, Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. 1,2 Despite advances in HCC screening and surveillance for earlier detection 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 Telephone: ; FAX: ; mindiehn@stanford.edu DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2014 American Association for the Study of Liver Diseases.

2 LIVER TRANSPLANTATION, Vol. 20, No. 5, 2014 WONG ET AL. 529 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 was not reported, and thus the current study used the 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 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 cohort was separated into 3 time periods so that we could evaluate trends in LT rates: the pre-meld exception era ( ) and 2 MELD exception eras ( and ). 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 ( and ) to allow a more representative estimation of LT rates in the more recent period. Preliminary analyses demonstrated that the 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

3 530 WONG ET AL. LIVER TRANSPLANTATION, May 2014 significant underreporting. A preliminary analysis of the 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 ( , , and ). 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 < 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 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 (n 5 20,004) (n 5 27,571) (n 5 13,200) P Value Sex: male (%) <0.001 Age (years)* <0.01 Age categories (%) <0.001 <50 years years years Race/ethnicity (%) <0.001 Non-Hispanic white Black Asian Hispanic Number of tumors (%) < Size of largest tumor (cm) 6.9 ( ) 6.5 ( ) 6.1 ( ) <0.001 Tumor stage (%) <0.001 Localized Regional Distant Within Milan criteria (%) <0.001 Localized stage within Milan criteria (%) <0.001 Localized HCC within Milan criteria and age < 70 years (%) <0.001 *The data are presented as means and standard deviations. The data are presented as medians and ranges.

4 LIVER TRANSPLANTATION, Vol. 20, No. 5, 2014 WONG ET AL. 531 more recent time periods (Table 1). In addition, there were significant increases in the proportions of black HCC patients (11.4% in , 12.6% in , and 13.4% in ; P < 0.001) and Hispanic HCC patients (15.8% in , 17.6% in , and 18.9% in ; P < 0.001), but there was a decrease in the proportion of Asian HCC patients (Table 1). The median size of the largest tumor decreased, but there was a significant trend toward fewer solitary tumors and more multifocal tumors in more recent times (Table 1). The proportion of localized-stage tumors increased with each time period (45.0% in , 50.4% in , and 51.7% in ; P < 0.001), whereas the proportion of distant/advanced tumors decreased. In addition, the proportion of tumors meeting the Milan criteria also significantly and consistently increased across the analyzed time periods (22.8% in , 31.8% in , and 37.1% in ; P < 0.001). HCC Treatment Among all HCC patients, there was an increase in all forms of therapy received from to , but there was a subsequent decrease in treatment in (Table 2). A similar trend was seen in HCC patients within the Milan criteria (Table 2). However, what is most striking is the unacceptably high rate of no therapy among HCC patients within the Milan criteria (61.5% in , 56.1% in , and 65.3% in ; P < 0.001). Even among patients with more favorable characteristics (localized HCC within the Milan criteria and age < 70 years), there remained unacceptably high rates of no therapy (55.0% in ) and low rates of LT (15.3% in ; Table 2). In addition, across all HCC categories, LT rates increased from to , but they declined in (Table 2). To investigate whether this trend was reflective of a true decrease in LT for HCC or a result of an increasing imbalance between organ availability and wait-listed HCC patients, we compared the actual number of transplants with LT rates across the 3 time periods and stratified them by race/ethnicity, sex, and age groups (Fig. 1A-C). Among patients < 70 years old with localized HCC within the Milan criteria, the number of actual LT procedures increased from 75.5 per year in to per year in , and the number remained stable at per year in However, among all racial/ethnic groups, the proportion of patients < 70 years old with localized HCC within the Milan criteria undergoing LT increased from to but declined in , with the lowest rates of LT seen among Asians (Fig. 1A). Similar trends were seen when the patients were stratified by sex (Fig. 1B) and age groups (Fig. 1C), and this suggests that the decline in the rates of LT for HCC in the more recent time period may be largely a result of the increasing number of HCC patients on the LT wait list, which was compounded by the shortage of available donor organs. TABLE 2. Treatment of HCC by Time Periods P Value All HCC (n 5 20,004) (n 5 27,571) (n 5 13,200) <0.001 None Local tumor destruction Surgical resection LT Within Milan Criteria (n ) (n ) (n ) <0.001 None Local tumor destruction Surgical resection LT Localized Stage Within Milan Criteria (n ) (n ) (n ) <0.001 None Local tumor destruction Surgical resection LT Localized Stage Within Milan Criteria (n ) (n ) (n ) <0.001 and Age < 70 Years None Local tumor destruction Surgical resection LT NOTE: The data are presented as percentages.

5 532 WONG ET AL. LIVER TRANSPLANTATION, May 2014 Figure 1. Trends in LT among patients less than 70 years old with localized HCC within the Milan criteria: (A) race/ethnicity, (B) sex, and (C) age. Predictors of LT In comparison with the period, HCC patients in the period were less likely to undergo LT [odds ratio (OR) , 95% confidence interval (CI) , P < 0.001], whereas patients in were just as likely to undergo LT (OR , 95% CI , P ; Table 3). In comparison with non-hispanic whites, blacks (OR , 95% CI , P < 0.001), Asians (OR , 95% CI , P < 0.001), and Hispanics (OR , 95% CI , P < 0.001) were all significantly less likely to undergo LT. As expected, HCC patients within the Milan criteria were significantly more likely to undergo LT in comparison with those outside the Milan criteria. Older patients and patients with more advanced tumor stages were less likely to undergo LT (Table 3). DISCUSSION The current study evaluated trends in LT for HCC in a large population-based cohort in the United States from 1998 to In comparison with the pre-meld exception era of , the MELD exception time periods of and demonstrated increasing proportions of localized HCC and decreasing proportions of distant/advanced HCC. In addition, the proportion of HCC patients who had tumors within the Milan criteria continued to rise. Although the actual number of LT cases increased significantly from the pre-meld exception era of (75.5 per year) to the MELD exception period of (208.2 per year) and stabilized in (201.5 per year), the proportion of HCC patients undergoing LT increased from to but declined in HCC patients in the more recent time period ( ) and patients of racial/ ethnic minorities were significantly less likely to undergo LT. With the implementation of the MELD exception policy for HCC patients within the Milan criteria, the rates of LT for HCC rose significantly. Using UNOS data from 1997 to 2007, Ioannou et al. 9 reported a 6- fold increase in the proportion of LT recipients with HCC resulting from MELD exception policy implementation (4.6% in versus 26.0% in ). Similar trends were seen in data from the Scientific Registry of Transplant Recipients. 8 Thuluvath et al. 8 reported a steady increase in the number of LT recipients with HCC in similar time periods (999 in 2002 versus 1656 in 2008). Despite the increasing proportion of LT procedures for HCC, the number of HCC patients who remained on the LT wait list at the end of the year also continued to rise in that study (382 in 2002 versus 890 in 2008). In the current study, the number of HCC patients undergoing LT also rose from 75.5 per year in to per year in , but the trend did not continue into the period with only transplants per year. Correspondingly, the proportion of transplant-eligible HCC patients who underwent LT increased from 13.3% in to 15.2% in (P < 0.01) but then declined to 10.2% in (P < 0.001; Table 2 and Fig. 1A-C). Furthermore, more than 65% of transplant-eligible HCC patients did not receive any form of surgical therapy in the most recent era (Table 2). Although these findings are limited by the exclusion of TACE from the treatment categories, it is still a concern that such a large proportion of transplant-eligible HCC patients did not undergo curative surgical resection or LT. These findings clearly indicate that although LT has been offered more to HCC patients since the implementation of MELD exception policies, the shortage of available organs is contributing to an increasing imbalance between HCC patients eligible for LT and those who actually undergo LT. 1,4,13-16 As a result of this imbalance, longer wait-list times and, consequently, risk progression of disease beyond

6 LIVER TRANSPLANTATION, Vol. 20, No. 5, 2014 WONG ET AL. 533 TABLE 3. Univariate and Multivariate Logistic Regression Analyses of Predictors of LT Univariate Analysis Multivariate Analysis Variable OR 95% CI P Value OR 95% CI P Value Sex Female 1.00 Reference 1.00 Reference Male < Age category <50 years 1.00 Reference 1.00 Reference years < years < <0.001 Race/ethnicity Non-Hispanic white 1.00 Reference 1.00 Reference Black < <0.001 Asian < <0.001 Hispanic <0.001 Within Milan criteria < <0.01 Number of tumors Reference 1.00 Reference < Tumor size < <0.001 Tumor stage Localized 1.00 Reference 1.00 Reference Regional < <0.001 Distant < <0.001 Time period Reference 1.00 Reference < <0.001 transplantation eligibility and subsequent dropout from the wait list are expected. 13,15-17 The evolving changes in the number of MELD exception points allocated to transplant-eligible HCC patients may be another potential factor contributing to the decreasing proportion of HCC patients undergoing LT. When MELD exception points for HCC were initially implemented, patients with stage 1 HCC (1 tumor < 2 cm in diameter) were allocated 24 points, and patients with stage 2 HCC (1 tumor 2-5 cm in diameter or 2-3 tumors, each 3cm in diameter) were allocated 29 points. 7 With time, the number of points allocated to HCC has been gradually reduced, so that patients with stage 2 HCC currently are allocated 22 points. 7 Despite these modifications, transplant-eligible HCC patients may still continue to possess a disproportionate advantage over patients with other chronic liver diseases, and the exception point advantage allocated to HCC patients on LT wait lists may need to be further modified. Although the increasing utilization of TACE has been effective in bridging HCC patients to LT, TACE is neither a curative treatment nor a comparable treatment endpoint for transplant-eligible HCC patients Living donor liver transplantation (LDLT) is an alternative approach that has a potentially unlimited supply of available organs, but early studies reported significantly higher rates of HCC recurrence associated with LDLT cohorts (5-year HCC recurrence rate 5 29%). 23,24 However, more recent studies have demonstrated recurrence and survival comparable to those associated with deceased donor LT. 25,26 A recent meta-analysis by Liang et al. 14 demonstrated no significant difference in overall 5-year survival (OR , 95% CI ) or 5-year HCC recurrence (OR , 95% CI ) between LDLT recipients and deceased donor LT recipients. 14 Nevertheless, risks to living liver donors are real, and the recent media emphasis on complications from LDLT have hampered the expansion of LDLT programs across the United States. 27 Clearly, LDLT will not be the final solution to the current shortage of available organs, and future efforts should focus on enhancing donor recruitment through education and outreach as well as novel therapies that may eventually prevent the development of HCC and thus preclude the need for LT for HCC. Before the implementation of the MELD allocation system for LT, significant racial disparities in the receipt of LT existed Siegel et al. 29 demonstrated that blacks (OR , 95% CI ) and Asians (OR , 95% CI ) were significantly less likely to undergo LT in comparison with whites in an early cohort of transplant-eligible HCC patients from 1998 to Reid et al. 30 reported similar observations based on an analysis of UNOS data from 1994 to According to standardized

7 534 WONG ET AL. LIVER TRANSPLANTATION, May 2014 transplantation ratios that compared the racial distribution of LT recipients with the racial distribution of the US population, blacks were significantly less likely to undergo LT in comparison with whites (black/white ratio /1.05). Whether the implementation of the MELD system, which was intended to be a more objective tool placing more emphasis on the severity of disease and less emphasis on the waiting time, has been successful in reducing racial disparities in LT is not clear. In a large, retrospective cohort study, Moylan et al. 28 used the UNOS database to compare LT patterns in the pre-meld period of and the MELD period of In comparison with whites in the pre-meld era, blacks were significantly more likely to die or become too sick for LT (OR , 95% CI ) and were less likely to undergo LT (OR , 95% CI ). However, in the MELD era ( ), blacks no longer had an increased likelihood of dying or becoming too sick for LT (OR , 95% CI ) and had a similar likelihood of undergoing LT (OR , 95% CI ). In the current study, which included only HCC patients, blacks, Asians, and Hispanics all had significantly lower rates of LT than non-hispanic whites; this included those presenting in a fairly recent time period ( ; Fig. 1A). Although this disparity was most prominent in the pre-meld exception period of , the differences persisted in all 3 time periods studied. Even after correction for multiple demographic characteristics (age and sex), tumor characteristics (tumor stage and Milan criteria), and time periods, blacks, Asians, and Hispanics were all significantly less likely to undergo LT in comparison with non-hispanic whites (Table 3). Clearly, racial disparities in LT for HCC patients persist. Whether these differences result from disparities in HCC screening among high-risk groups that subsequently lead to more advanced disease at presentation precluding curative therapy or from disparities in access to care that prevent transplant-eligible patients from an initial LT evaluation is not clear. Future research on the management of HCC should target resources to address such disparities. The strengths of the current study are highlighted by the large sample, which represents a sizeable proportion of the US population. The SEER cancer registry is globally recognized as an authoritative source of cancer statistics. The focus on the cohort ensured consistent reporting of tumor staging and treatment data and allowed an accurate comparison of pre-meld exception and MELD exception eras, including a precise evaluation of the most recent time period ( ). However, the current study is limited by factors typical of large registry-based studies. Most importantly, the etiology of HCC was not available for analysis; and although previous studies have demonstrated differences in posttransplant survival with different HCC etiologies, disparate rates of LT by HCC etiology have not been reported. In addition, locoregional therapy (specifically TACE) is increasingly used for treating HCC patients not eligible for resection or LT and for down-staging or bridging HCC patients to LT However, data for TACE are a relatively new addition to the SEER registry and suffer from significant underreporting and inconsistencies in reporting. In the SEER registry, the date of treatment was not readily available, and this prevented a time-to-event Cox regression model to evaluate predictors of undergoing LT. Thus, our study used a binary logistic regression model to evaluate predictors of LT. In summary, the MELD exception policy significantly increased the number of LT procedures for HCC patients immediately after its implementation, but this did not continue into the more recent time period ( ). The proportion of transplant-eligible HCC patients also increased in the more recent time period, but the proportion of those actually undergoing LT actually decreased, and this was most likely due to the donor organ shortage. In addition, substantial racial disparities in the receipt of LT persisted for HCC patients after the implementation of the MELD exception policy, even in the more recent time period ( ). Blacks and Asians continued to have the lowest rates of LT. Most striking is that more than 65% of transplant-eligible HCC patients in the more recent time period did not receive any form of curative therapy. Further efforts are needed to promote education and outreach among potential organ donors to improve the availability of LT. In addition, quality improvement efforts should target research and education to address the persisting racial disparities in LT as well as the dismally low rates of curative therapy for transplanteligible HCC patients in the United States. REFERENCES 1. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012;379: Siegel R, Naishadham D, Jemal A. Cancer statistics, CA Cancer J Clin 2013;63: Croswell JM, Ransohoff DF, Kramer BS. Principles of cancer screening: lessons from history and study design issues. Semin Oncol 2010;37: Bruix J, Sherman M; for American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011;53: Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334: Llovet JM, Bruix J, Fuster J, Castells A, Garcia-Valdecasas JC, Grande L, et al. Liver transplantation for small hepatocellular carcinoma: the tumor-node-metastasis classification does not have prognostic power. Hepatology 1998;27: United Network for Organ Sharing Organ Procurement and Transplantation Network. hrsa.gov/policiesandbylaws2/policies/pdfs/policy_8.pdf. Accessed June Thuluvath PJ, Guidinger MK, Fung JJ, Johnson LB, Rayhill SC, Pelletier SJ. Liver transplantation in the United States, Am J Transplant 2010;10(pt 2): Ioannou GN, Perkins JD, Carithers RL Jr. Liver transplantation for hepatocellular carcinoma: impact of the

8 LIVER TRANSPLANTATION, Vol. 20, No. 5, 2014 WONG ET AL. 535 MELD allocation system and predictors of survival. Gastroenterology 2008;134: Surveillance, Epidemiology, and End Results Program. SEER data, (including July-December 2005 Hurricane Katrina impacted Louisiana cases). seer.cancer.gov/data. Published April Accessed January Fritz A, Percy C, Jack A, Shanmugaratnam K, Sobin L, Parkin DM, Whelan S, eds. International Classification of Diseases for Oncology. 3rd ed. Geneva, Switzerland: World Health Organization; Young JL Jr, Roffers SD, Ries LAG, Fritz AG, Hurlbut AA, eds. SEER Summary Staging Manual 2000: Codes and Coding Instructions. Bethesda, MD: National Cancer Institute; NIH publication Freeman RB, Edwards EB, Harper AM. Waiting list removal rates among patients with chronic and malignant liver diseases. Am J Transplant 2006;6: Liang W, Wu L, Ling X, Schroder PM, Ju W, Wang D, et al. Living donor liver transplantation versus deceased donor liver transplantation for hepatocellular carcinoma: a meta-analysis. Liver Transpl 2012;18: Adler M, De Pauw F, Vereerstraeten P, Fancello A, Lerut J, Starkel P, et al. Outcome of patients with hepatocellular carcinoma listed for liver transplantation within the Eurotransplant allocation system. Liver Transpl 2008; 14: Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30: Smith JM, Biggins SW, Haselby DG, Kim WR, Wedd J, Lamb K, et al. Kidney, pancreas and liver allocation and distribution in the United States. Am J Transplant 2012; 12: De Luna W, Sze DY, Ahmed A, Ha BY, Ayoub W, Keeffe EB, et al. Transarterial chemoinfusion for hepatocellular carcinoma as downstaging therapy and a bridge toward liver transplantation. Am J Transplant 2009;9: Ha BY, Ahmed A, Sze DY, Razavi MK, Simpson N, Keeffe EB, Nguyen MH. Long-term survival of patients with unresectable hepatocellular carcinoma treated with transcatheter arterial chemoinfusion. Aliment Pharmacol Ther 2007;26: Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003;37: Alba E, Valls C, Dominguez J, Martinez L, Escalante E, Llado L, Serrano T. Transcatheter arterial chemoembolization in patients with hepatocellular carcinoma on the waiting list for orthotopic liver transplantation. AJR Am J Roentgenol 2008;190: Llovet JM, Mas X, Aponte JJ, Fuster J, Navasa M, Christensen E, et al. Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation. Gut 2002;50: Lo CM, Fan ST, Liu CL, Chan SC, Ng IO, Wong J. Living donor versus deceased donor liver transplantation for early irresectable hepatocellular carcinoma. Br J Surg 2007;94: Fisher RA, Kulik LM, Freise CE, Lok AS, Shearon TH, Brown RS Jr, et al.; for A2ALL Study Group. Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation. Am J Transplant 2007;7: Bhangui P, Vibert E, Majno P, Salloum C, Andreani P, Zocrato J, et al. Intention-to-treat analysis of liver transplantation for hepatocellular carcinoma: living versus deceased donor transplantation. Hepatology 2011;53: Sandhu L, Sandroussi C, Guba M, Selzner M, Ghanekar A, Cattral MS, et al. Living donor liver transplantation versus deceased donor liver transplantation for hepatocellular carcinoma: comparable survival and recurrence. Liver Transpl 2012;18: Miller C, Smith ML, Fujiki M, Uso TD, Quintini C. Preparing for the inevitable: the death of a living liver donor. Liver Transpl 2013;19: Moylan CA, Brady CW, Johnson JL, Smith AD, Tuttle- Newhall JE, Muir AJ. Disparities in liver transplantation before and after introduction of the MELD score. JAMA 2008;300: Siegel AB, McBride RB, El-Serag HB, Hershman DL, Brown RS Jr, Renz JF, et al. Racial disparities in utilization of liver transplantation for hepatocellular carcinoma in the United States, Am J Gastroenterol 2008;103: Reid AE, Resnick M, Chang Y, Buerstatte N, Weissman JS. Disparity in use of orthotopic liver transplantation among blacks and whites. Liver Transpl 2004;10: Eckhoff DE, McGuire BM, Young CJ, Sellers MT, Frenette LR, Hudson SL, et al. Race: a critical factor in organ donation, patient referral and selection, and orthotopic liver transplantation? Liver Transpl Surg 1998;4: