National Trends in Surgical Procedures for Hepatocellular Carcinoma:

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1 National Trends in Surgical Procedures for Hepatocellular Carcinoma: Hari Nathan, MD; Dorry L. Segev, MD, PhD; Skye C. Mayo, MD, MPH; Michael A. Choti, MD; Andrew M. Cameron, MD, PhD; Christopher L. Wolfgang, MD, PhD; Kenzo Hirose, MD; Barish H. Edil, MD; Richard D. Schulick, MD; and Timothy M. Pawlik, MD, MPH BACKGROUND: The incidence of hepatocellular carcinoma (HCC) is rising, and the options for surgical therapy of HCC have evolved recently, but use of surgical therapy has not been characterized on a representative, nationwide basis. We quantified trends in use, mortality, and patient and hospital characteristics for 3 surgical therapies for HCC (resection, ablation, and transplantation) in the United States from 1998 to METHODS: Hospital discharge data from the Nationwide Inpatient Sample were used to quantify procedure-related data for each year. Trends over time were summarized as the average annual percent change (AAPC) and corresponding 95% confidence interval (CI). RESULTS: The number of surgical procedures for HCC increased from 1416 to 6769 (AAPC, 13.5%; 95% CI, 10.2%-16.8%). Volumes increased for all surgical procedures, most notably for ablation (AAPC, 17.3%; 95% CI, 6.6%- 29.2%) and transplantation (AAPC, 20.9%; 95% CI, 14.1%-28.1%). When analyzed as a proportion of total procedures, there were declines in the relative use of major hepatectomy (35% to 16%; AAPC, 7.2%, 95% CI, 8.8% to 5.6%) and wedge resection (37% to 22%; AAPC, 4.8%; 95% CI, 6.2% to 3.4%), while the proportion accounted for by transplantation increased (16% to 35%; AAPC, 4.4%; 95% CI, 0.2%-8.9%). Inpatient mortality decreased for each procedure individually and overall from 7.3% to 4.6% (AAPC, 7.7%; 95% CI, 10.8% to 4.5%), despite increasing age and comorbidity burden. CONCLUSIONS: The use of surgical therapy for HCC has increased dramatically over the last decade, with a relative shift away from liver resection and toward liver transplantation. These therapeutic modalities must be better targeted to make the most appropriate use of limited health care resources. Cancer 2012;118: VC 2011 American Cancer Society. KEYWORDS: hepatocellular carcinoma, surgery, liver ablation, liver resection, liver transplantation. INTRODUCTION Hepatocellular carcinoma (HCC) is the sixth most common cancer and, due to its poor prognosis, the third leading cause of cancer death worldwide. 1 Although HCC has historically been a disease of the underdeveloped world, it is becoming more common in the West. Its incidence in the United States has risen at a rate of 4.5% per year from 1980 to 2005 and is currently 4.9 per 100,000 persons. 2 Hospital charges for HCC more than doubled from 1988 to This increase has largely been driven by the hepatitis C epidemic; 4 in fact, the prevalence of HCC among patients with chronic hepatitis C infection has increased 20-fold over the last decade. 5 Mortality from primary liver cancer in the United States has increased faster than that of any other major type of cancer, accounting for nearly 20,000 deaths annually. 6 The survival of patients with HCC remains dismal even in recent years, with cause-specific survival <50% at 1 year and 13% at 5 years. 2 However, the subgroup of patients who are candidates for surgical therapy have significantly better survival, reportedly as high as 39% at 5 years in population-based series. 7 Importantly, the proportion of HCC diagnosed at a localized stage, making it potentially amenable to surgical therapy, is increasing (44% in versus 28% in ). 2 Simultaneously, the therapeutic options for localized HCC have evolved considerably over the last 15 years. 8 Advances in hepatic surgery have made liver resection safer, even in patients with cirrhosis. 9 HCC is an accepted indication for liver transplantation, and its HCC indication was further refined following publication of the Milan experience in Radiofrequency ablation is also being used with increasing frequency to treat HCC. 11 Corresponding author: Timothy M. Pawlik, MD, MPH, FACS, Associate Professor of Surgery, The Johns Hopkins Hospital, 600 North Wolfe Street, Harvey 611, Baltimore, MD 21287; Fax: (410) ; tpawlik1@jhmi.edu Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Presented in part at the 9th Annual Meeting of the American Hepato-Pancreato-Biliary Association, March 13, 2009, Miami, FL. DOI: /cncr.26501, Received: March 4, 2011; Revised: June 19, 2011; Accepted: July 6, 2011, Published online August 25, 2011 in Wiley Online Library (wileyonlinelibrary.com) 1838 Cancer April 1, 2012

2 Trends in Surgery for Hepatocellular Carcinoma/Nathan et al Despite this evolution in the surgical approach to HCC, changes in the use of these surgical therapies have not been characterized on a representative, nationwide basis. We quantified the nationwide use of the 3 primary surgical therapies for HCC liver resection, liver ablation, and liver transplantation in the United States over the period We also identified trends in the use of these procedures, associated inpatient mortality, and characteristics of both the patients and hospitals involved. MATERIALS AND METHODS We analyzed hospital discharge data from the Nationwide Inpatient Sample (NIS), compiled and distributed by the Healthcare Cost and Utilization Project. The NIS database is the largest all-payor inpatient care database in the United States, representing an approximately 20% stratified sample of 1044 nonfederal hospitals in 40 states. 12 The NIS databases from years were used to identify all adult (age 18 years) inpatients with a diagnosis of HCC, as determined by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD- 9) codes. Patients were considered to have HCC if they had ICD-9 diagnosis code (primary liver carcinoma). Patients with ICD-9 diagnosis code (liver carcinoma, not specified as primary or secondary) were included only if they also had a diagnosis or procedure code indicative of underlying liver disease (eg, viral hepatitis or ligation of esophageal varices). This strategy has been used previously 3 and was intended to differentiate patients with primary liver cancer from those with metastatic disease to the liver, because the vast majority of patients with HCC have underlying liver disease such as cirrhosis or viral hepatitis. The NIS quantifies inpatient discharges and does not link patients across hospital discharges. As such, patient with multiple discharges are counted multiple times. The unit of analysis in this study was the discharge record (except for analysis of hospital volumes), which for simplicity is hereafter referred to as a patient. Liver-directed surgical procedures performed on these patients were then identified using ICD-9 procedures codes. Procedures of interest were major hepatectomy (50.3), hepatic wedge resection (50.22), liver ablation ( ), and liver transplantation (50.5x). Although it was not a primary focus of the study, analyses were also performed for inpatient transcatheter arterial chemoembolization (TACE) (99.25, chemotherapy, and either 38.91, arterial catheterization, or 88.4 / / 88.47, arteriography, on the same day). The resulting data were used to calculate nationwide estimates of hospitalizations, inpatient surgical procedures, and inpatient mortality for patients with HCC during the period Patient and hospital characteristics were used as coded in the NIS, except for hospital procedure volumes, which were calculated for each hospital for each year. The number of comorbidities for each patient was calculated using the Elixhauser index. 13 Because some patients underwent more than 1 inpatient procedure per admission, inpatient mortality for each procedure was calculated using the subset of patients who underwent only that procedure. NIS estimates were compared against estimates derived from United Network for Organ Sharing (UNOS) data for the annual number of liver transplantations for HCC. These UNOS-derived estimates were only calculated for because the allocation of exception points for HCC began in 2002, such that some cases of HCC would be missed by UNOS data before UNOS-derived estimates included patients who received exception points for HCC, had a primary or secondary diagnosis of HCC at the time of transplant listing, or had a diagnosis of HCC at the time of discharge after liver transplantation. We tested for trends in NIS estimates using an approach that has been described previously. 14 Nationwide estimates and associated standard errors were calculated using Stata/MP 10.0 (StataCorp, College Station, TX) and accounted for the stratified sampling design of the NIS using hospital weights (for hospital volume analyses) or discharge weights (for all other data). 15 These estimation procedures do not allow the calculation of median values of variables, so mean values were calculated for all variables. Trends over time were analyzed using the Joinpoint Regression Program, Version (April 2010, Statistical Research and Applications Branch, National Cancer Institute) with a log-linear model and a Monte Carlo permutation method incorporating heteroscedastic errors and a maximum of 1 joinpoint (allowing for 2 distinct temporal trends). 16 This is the software used by the Surveillance, Epidemiology, and End Results program to determine changes in cancer incidence. Changes were summarized as the average annual percent change (AAPC) and corresponding 95% confidence interval (CI) over the entire 11-year period. All tests of statistical significance were 2-sided, and statistical significance was established at P<.05 for Wald tests comparing proportions or CI excluding 0 for trends analyses. This study was deemed Cancer April 1,

3 Table 1. Patient and Hospital Characteristics for All Inpatient Procedures for Hepatocellular Carcinoma, Procedure AAPC (%) CI Procedure-related hospitalizations Total, no to 16.9 Mortality, % to 4.5 Surgical procedures Total, no to 16.8 Mean patient demographics Age, y to 0.5 Sex, % men to 1.5 Elixhauser comorbidities, no to 2.8 Hospital characteristics a Teaching hospital, % to 0.5 Liver transplant hospital, % to 2.8 Urban hospital, % to 0.16 AAPC, average annual percent change; CI, confidence interval. a Percent of patients treated at hospitals with the relevant characteristics. exempt from review by The Johns Hopkins University School of Medicine Institutional Review Boards. RESULTS The number of hospitalizations of adult patients with HCC in the United States increased from 17,510 in 1998 to 47,943 in 2008 (AAPC, 8.1%; 95% CI, 6.3%-10.0%). Over the same time period, the number of HCC surgeryrelated hospitalizations increased from 1363 (7.8% of all HCC hospitalizations) to 6531 (13.6% of all HCC hospitalizations) (AAPC, 13.5%; 95% CI, 10.1%-16.9%). The number of surgical procedures for HCC increased from 1416 to 6769 (AAPC, 13.5%; 95% CI, 10.2%-16.8%), and the number of procedures per hospitalization remained constant at 1.04 (AAPC, 0.02%; 95% CI, 0.2%-0.1%). The mean age of patients undergoing surgical procedures increased slightly from 60 years in 1998 to 61 years in 2008 (AAPC, 0.3%; 95% CI, 0.06%- 0.5%), and the mean number of comorbidities increased from 3.2 to 3.7 (AAPC, 2.2%; 95% CI, 1.5%-2.8%). The proportion of patients that were men increased from 64% to 71% (AAPC, 0.9%; 95% CI, 0.4%-1.5%). Overall, 91% of patients underwent their procedures at teaching hospitals, and this figure did not significantly change over time (AAPC, 0.2%; 95% CI, 0.8%-0.5%). Similarly, 69% of patients underwent their procedures at hospitals that perform liver transplantation, and this figure also did not significantly change over time (AAPC, 0.4%; 95% CI, 1.8%-2.8%). Importantly, the majority of nontransplant procedures 55% of major hepatectomies, 56% of wedge resections, and 55% of ablations were performed at liver transplant hospitals. Of the hospitals that performed inpatient surgical procedures for HCC over the course of the study, 70% were teaching hospitals, and 21% were liver transplant hospitals. Overall inpatient mortality associated with surgery-related hospitalizations for HCC decreased from 7.3% in 1998 to 4.6% in 2008 (AAPC, 7.7%; 95% CI, 10.8% to 4.5%). The overall patient and hospital characteristics are summarized in Table 1. Trends in individual surgical procedures were analyzed next (Table 2). The number of major hepatectomies for HCC increased from 480 in 1998 to 1039 in 2008 (AAPC, 5.6%; 95% CI, 2.0%-9.4%) (Figure 1). Teaching hospitals performed 88% of major hepatectomies, a proportion that did not change over time (AAPC, 0.4%; 95% CI, 0.5%-1.3%). The mean annual hospital volume of major hepatectomy for HCC increased from 1.9 in 1998 to 3.3 in 2008 (AAPC, 4.3%; 95% CI, 0.8%- 7.9%), which reflected a significant increase in hospital volume at nonteaching hospitals from 1.0 to 1.5 (AAPC, 4.3%; 95% CI, 2.1%-6.5%). the mean annual hospital volume at teaching hospitals remained constant at 2.6 (AAPC, 3.6%; 95% CI, 0.1%-7.4%). The mean age of patients undergoing major hepatectomy remained constant at 61 years (AAPC, 0.1%; 95% CI, 0.3%- 0.2%), whereas the number of comorbidities increased from 2.8 to 3.4 (AAPC, 2.2%; 95% CI, 1.2%-3.1%). Despite these trends, inpatient mortality after major hepatectomy for HCC decreased from 11.0% in 1998 to 7.4% in 2008 (AAPC, 5.2%; 95% CI, 9.4% to 0.8%), 1840 Cancer April 1, 2012

4 Trends in Surgery for Hepatocellular Carcinoma/Nathan et al Table 2. Volume and Mortality of Inpatient Procedures for Hepatocellular Carcinoma, Procedure AAPC (%) CI Total, no , Major hepatectomy Total, no Mortality, % to 0.8 Hepatic wedge resection Total, no Mortality, % to 0.2 Liver ablation Total, no Mortality, % to 3.1 Liver transplantation Total, no Mortality, % to 1.1 AAPC, average annual percent change; CI, confidence interval. Figure 1. Trends in national volumes of inpatient surgical procedures for hepatocellular carcinoma are shown. Statistically significant changes are indicated by an asterisk (*). driven primarily by a decrease at teaching hospitals from 11.2% to 7.0% (AAPC, 5.5%; 95% CI, 10.1% to 0.6%). There was no significant change in mortality at nonteaching hospitals (14.6%; AAPC, 6.1%; 95% CI, 14.0%-2.5%). There was no statistically significant difference in mortality based on teaching hospital status (P ¼.06). However, mortality after major hepatectomy was lower at transplant hospitals than at nontransplant hospitals (5.9% versus 14.1%; P<.001). The number of hepatic wedge resections for HCC increased from 499 in 1998 to 1444 in 2008 (AAPC, 10.8%; 95% CI, 7.2%-14.5%) (Figure 1). The proportion of wedge resections performed at teaching hospitals was 88% and did not change significantly (AAPC, 0.6%; 95% CI, 1.4%-0.2%). The mean annual hospital volume of wedge resection for HCC increased from 1.9 in 1998 to 4.2 in 2008 (AAPC, 5.5%; 95% CI, 2.8%- 8.3%), reflecting increases both at teaching hospitals (2.1 to 5.0; AAPC, 6.6%; 95% CI, 3.9%-9.3%) and nonteaching hospitals (1.0 to 1.5; AAPC, 3.8%; 95% CI, 1.7%-5.8%). The mean age of patients undergoing wedge resection remained constant at 62 years (AAPC, 0.4%; 95% CI, 0.1%-0.8%), whereas the number of comorbidities increased from 3.2 to 3.7 (AAPC, 1.9%; 95% CI, 0.8%-3.0%). However, inpatient mortality after wedge resection for HCC decreased from 5.2% to 4.9% (AAPC, 5.4%; 95% CI, 10.4% to 0.2%) and did not differ between teaching and nonteaching hospitals (P ¼.1) or between transplant and nontransplant hospitals (5.1% versus 5.8%; P ¼.6). There was a dramatic increase in the number of inpatient liver ablations for HCC from 226 to 2009 over the period of the study (AAPC, 17.3%; 95% CI, 6.6%- 29.2%) (Figure 1). The proportion of ablations performed at teaching hospitals decreased slightly over this period (AAPC, 1.2%; 95% CI, 2.1% to 0.2%). The mean annual hospital volume of inpatient ablation for HCC increased from 1.5 in 1998 to 5.1 in 2008 (AAPC, 7.8%; 95% CI, 3.6%-12.2%), reflecting increases both at teaching hospitals (1.6 to 6.1; AAPC, 8.6%; 95% CI, 3.7%-13.7%) and nonteaching hospitals (1.4 to 2.7; AAPC, 7.1%; 95% CI, 3.7%-10.6%). The mean age of patients undergoing ablation remained constant at Cancer April 1,

5 Figure 2. Estimates of liver transplantation for hepatocellular carcinoma derived from Nationwide Inpatient Sample (NIS) data, with 95% confidence intervals, versus United Network for Organ Sharing (UNOS) data are shown. Figure 3. Trends in proportions of all hepatocellular carcinoma surgery-related admissions are shown. Statistically significant changes are indicated by an asterisk (*). 63 years (AAPC, 0.04%; 95% CI, 0.37%-0.29%), whereas the number of comorbidities increased from 3.0 to 3.5 (AAPC, 2.1%; 95% CI, 1.1%-3.1%). Inpatient mortality after ablation for HCC decreased from 6.5% in 1998 to 3.1% in 2008 (AAPC, 7.6%; 95% CI, 11.9% to 3.1%) and did not differ between teaching and nonteaching hospitals (P ¼.3) or between transplant and nontransplant hospitals (P ¼.4). The number of liver transplantations for HCC increased from 212 in 1998 to 2277 in 2008 (AAPC, 20.9%; 95% CI, 14.1%-28.1%) (Figure 1). The vast majority (>98%) of liver transplantations for HCC were performed at teaching hospitals in all years. The mean annual hospital volume of transplantation for HCC increased from 2.4 in 1998 to 19.6 in 2008 (AAPC, 20.6%; 95% CI, 15.1%-26.2%). The mean age of patients undergoing transplantation increased slightly from 51 to 58 years (AAPC, 1.0%; 95% CI, 0.6%-1.4%), whereas the number of comorbidities remained constant at 3.8 (AAPC, 0.5%; 95% CI, 0.5%-1.4%). Inpatient mortality after liver transplantation for HCC decreased from 6.4% in 1998 to 4.6% in 2007 (AAPC, 10.1%; 95% CI, 18.2% to 1.1%). Estimates derived from NIS data versus UNOS data were similar (Figure 2). To assess general shifts in therapeutic choices for HCC, we also calculated the proportion of all HCC procedure-related admissions that involved each procedure for each year (Figure 3). There were declines in the relative use of major hepatectomy (35% to 16%; AAPC, 7.2%; 95% CI, 8.8% to 5.6%) and wedge resection (37% to 22%; AAPC, 4.8%; 95% CI, 6.2% to 3.4%), whereas the proportion accounted for by transplantation increased significantly from 16% to 35% (AAPC, 4.4%; 95% CI, 0.2%-8.9%). There was no significant trend in the relative use of ablation, which accounted for 33% of procedure-related admissions over all years (AAPC, 7.9%; 95% CI, 5.3%-22.9%). Although TACE use was not a primary focus of our study, similar analyses were performed for illustrative purposes. The number of inpatient TACE procedures for HCC increased from 474 in 1998 to 3465 in 2008 (AAPC, 10.7%; 95% CI, 3.7%-18.2%) (Figure 1). Most (93%) TACE procedures were performed at teaching hospitals, a proportion that did not change over time (AAPC, 0.1%; 95% CI, 0.6%-0.4%). The mean annual hospital volume of inpatient TACE for HCC remained constant at 8.3 (AAPC, 4.9%; 95% CI, 2.3%-12.6%). Hospital volumes at teaching hospitals (10.4; AAPC, 5.8%; 95% CI, 0.9%-13.0%) and nonteaching hospitals (2.2; AAPC, 5.5%; 95% CI, 0.2%-11.4%) similarly remained constant. The mean age of patients undergoing TACE remained constant at 61 years (AAPC, 0.7%; 95% CI, 0.02%-1.5%), whereas the number of comorbidities increased from 2.6 to 3.0 (AAPC, 2.8%; 95% CI, 1.3%-4.4%). Inpatient mortality after TACE was 1.2% 1842 Cancer April 1, 2012

6 Trends in Surgery for Hepatocellular Carcinoma/Nathan et al and did not change significantly over time (AAPC, 3.3%; 95% CI, 15.2%-10.4%). DISCUSSION The surgical approach to HCC has evolved significantly over the past 15 years. Acceptable long-term survival can be achieved in appropriately selected patients using liver resection, 7,17,18 liver ablation, and liver transplantation. 10,22-25 Most reports detailing the use of these procedures arise from specialized centers. The pattern of use of surgical procedures for HCC in the United States has not been previously characterized on a nationwide basis. In this analysis, we demonstrate significant increases in the use of all 3 surgical procedures over the past decade. We also document reductions in the inpatient mortality associated with all of these procedures, despite advancing patient age and increased comorbidity burden. Finally, we illustrate a shift in the surgical treatment paradigm of HCC in the era of the Milan criteria. Although absolute numbers of all procedures increased, there was a relative shift away from liver resection and toward liver transplantation in terms of the proportion of all HCC-related procedures. 10 Growth in HCC surgery-related hospitalizations outpaced growth in HCC-related hospitalizations as a whole, indicating that more patients are receiving surgical treatment of HCC even when accounting for a rise in overall hospital use for HCC. Using data from the Surveillance, Epidemiology, and End Results (SEER) database, several investigators have documented that an increasing proportion of patients with HCC have received therapeutic interventions in recent years. 2,11 In particular, this increase is attributable to an increase in the proportion of patients with localized disease receiving therapy (from 44% in to 62% in ). 2 Our data quantify this increase in surgical procedures for HCC on a nationally representative basis, which the SEER data do not allow due to its geographic sampling scheme. 26 SEER data may also not capture treatments received outside SEER areas, such as when patients travel to referral centers. The high proportion of HCC surgical procedures performed at urban and teaching hospitals throughout the study period suggest that many patients are traveling to specialized centers for care. Our data demonstrate a nearly 5-fold increase in HCC surgical procedures over the last decade, which can be explained by the confluence of several factors: the increasing number of patients being diagnosed with localized disease, the increasing proportion of those with localized disease receiving surgical therapy, and the increased number of therapeutic options for patients with localized disease. Throughout the study period, surgical procedures for HCC were highly concentrated at urban and teaching hospitals. Of note, the majority of nontransplant procedures were performed at hospitals that also perform liver transplantation, even though only 21% of hospitals that performed surgical procedures for HCC were transplant hospitals. Although mortality after wedge resection and ablation did not differ based on transplant hospital status, inpatient mortality after major hepatectomy was significantly lower at transplant versus nontransplant centers. A previous study demonstrated that mortality after liver resection for HCC is lower among patients treated at high-volume transplant hospitals, even after accounting for the effect of hepatectomy volume itself. 27 Taken together, these data suggest that patients who are anticipated to have complex surgical interventions for HCC may benefit from referral to specialized centers, and one marker of such expertise may be the presence of a liver transplant program. Our data indicate that, over the course of this study, there was a dramatic rise in the use of liver transplantation relative to liver resection. Since the adoption of an allocation system based on the model for end-stage liver disease (MELD) in 2002, certain patients with HCC have received special consideration in the allocation of organs. The policy has been amended several times and continues to be a subject of debate and refinement. 28 Future changes to this policy are likely to determine the extent to which this rise in liver transplantation for HCC continues. Although liver transplantation clearly offers superior outcomes to other locoregional therapies, 8 use of liver transplantation will continue to be limited by the availability of donor organs. As such, the choice between liver transplantation, liver resection, and liver ablation should be made carefully and consistently. However, the criteria used to choose between liver resection and liver transplantation for the treatment of HCC vary considerably between providers. 29 It is imperative that future studies better delineate which patient subgroups would benefit most from each type of surgical therapy for HCC while considering the overall limitations that will exist on use of liver transplantation. Our study has several limitations that should be emphasized. Although a major strength of NIS data is the ability to quantify nationwide inpatient use of procedures, NIS does not allow quantification of Cancer April 1,

7 outpatient procedures. 26 Although the focus of our analysis was on potentially curative procedures for localized disease, which usually occur on an inpatient basis, a more complete picture of therapy for HCC would include a quantification of all types of intra-arterial therapies, some of which occur on an outpatient basis. Another limitation of our study is the unavailability of data on tumor burden (such as size and number) and severity of cirrhosis, both of which affect potential therapeutic options. Finally, our study describes trends in the use of surgical therapy for HCC but cannot discern the reasons for these trends or assess the appropriateness of therapies used. Likewise, differences in survival attributable to shifts in therapeutic patterns cannot be assessed using these data. In conclusion, significant increases have occurred in the use of major hepatectomy, hepatic wedge resection, liver ablation, and liver transplantation for the treatment of HCC over the past decade. There has been a relative shift away from liver resection and toward liver transplantation. This trend is unlikely to continue unabated, especially given the limited availability of organs for transplantation. Future work will be necessary to identify candidates who are most likely to benefit from each of these therapeutic modalities to make the most appropriate use of limited health care resources. REFERENCES 1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, CA Cancer J Clin. 2005;55: Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to J Clin Oncol. 2009;27: Kim WR, Gores GJ, Benson JT, Therneau TM, Melton LJ 3rd. Mortality and hospital utilization for hepatocellular carcinoma in the United States. Gastroenterology. 2005;129: Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study. Gastroenterology. 2004;127: Kanwal F, Hoang T, Kramer JR, Asch SM, Goetz MB, Zeringue A, et al. Increasing prevalence of HCC and cirrhosis in patients with chronic hepatitis C virus infection. Gastroenterology. 2010;140: Altekruse S, Kosary C, Krapcho M, Neyman N, Aminou R, Waldron W, et al. SEER Cancer Statistics Review, seer.cancer.gov/csr/1975_2007/. Accessed June 1, Nathan H, Schulick RD, Choti MA, Pawlik TM. Predictors of survival after resection of early hepatocellular carcinoma. Ann Surg. 2009;249: Jarnagin W, Chapman WC, Curley S, D Angelica M, Rosen C, Dixon E, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB (Oxford). 2010;12: Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg. 1999;229: ; discussion 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: Massarweh NN, Park JO, Farjah F, Yeung RS, Symons RG, Vaughan TL, et al. Trends in the utilization and impact of radiofrequency ablation for hepatocellular carcinoma. J Am Coll Surg. 2010;210: Healthcare Cost and Utilization Project Databases. Accessed February 1, Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with administrative data. Med Care. 1998;36: Wiener RS, Welch HG. Trends in the use of the pulmonary artery catheter in the United States, JAMA. 2007;298: Houchens R, Elixhauser A. Final report on calculating Nationwide Inpatient Sample (NIS) variances. reports/calculatingnisvariances pdf Accessed October 15, Kim HJ, Fay MP, Feuer EJ, Midthune DN. Permutation tests for joinpoint regression with applications to cancer rates. Stat Med. 2000;19: Zhou XD, Tang ZY, Yang BH, Lin ZY, Ma ZC, Ye SL, et al. Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer. 2001;91: Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg. 2002;235: Chen MS, Li JQ, Zheng Y, Guo RP, Liang HH, Zhang YQ, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg. 2006;243: Cho YK, Kim JK, Kim MY, Rhim H, Han JK. Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies. Hepatology. 2009;49: Cho YK, Kim JK, Kim WT, Chung JW. Hepatic resection versus radiofrequency ablation for very early stage hepatocellular carcinoma: a Markov model analysis. Hepatology. 2010;51: Bismuth H, Majno PE, Adam R. Liver transplantation for hepatocellular carcinoma. Semin Liver Dis. 1999;19: Iwatsuki S, Dvorchik I, Marsh JW, Madariaga JR, Carr B, Fung JJ, et al. Liver transplantation for hepatocellular carcinoma: a proposal of a prognostic scoring system. J Am Coll Surg. 2000;191: Figueras J, Ibanez L, Ramos E, Jaurrieta E, Ortiz-de-Urbina J, Pardo F, et al. Selection criteria for liver transplantation in earlystage hepatocellular carcinoma with cirrhosis: results of a multicenter study. Liver Transpl. 2001;7: Todo S, Furukawa H. Living donor liver transplantation for adult patients with hepatocellular carcinoma: experience in Japan. Ann Surg. 2004;240: ; discussion Nathan H, Pawlik TM. Limitations of claims and registry data in surgical oncology research. Ann Surg Oncol. 2008; 15: Nguyen GC, Thuluvath NP, Segev DL, Thuluvath PJ. Volumes of liver transplant and partial hepatectomy procedures are independently associated with lower postoperative mortality following resection for hepatocellular carcinoma. Liver Transpl. 2009;15: Pomfret EA, Washburn K, Wald C, Nalesnik MA, Douglas D, Russo M, et al. Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl. 2010;16: Nathan H, Bridges JF, Schulick RD, Cameron AM, Hirose K, Edil BH, et al. Understanding surgical decision making in early hepatocellular carcinoma. J Clin Oncol. 2011;29: Cancer April 1, 2012