Katherine A. McGlynn

Hepatocellular Carcinoma Incidence, Mortality, and Survival Trends in the United States From 1975 to 2005

PURPOSE Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Incidence rates are increasing in the United States. Monitoring incidence, survival, and mortality rates within at-risk populations can facilitate control efforts. METHODS Age-adjusted incidence trends for HCC were examined in the Surveillance, Epidemiology, and End Results (SEER) registries from 1975 to 2005. Age-specific rates were examined for birth cohorts born between 1900 and 1959. Age-adjusted incidence and cause-specific survival rates from 1992 to 2005 were examined in the SEER 13 registries by race/ethnicity, stage, and treatment. United States liver cancer mortality rates were also examined. RESULTS Age-adjusted HCC incidence rates tripled between 1975 and 2005. Incidence rates increased in each 10-year birth cohort from 1900 through the 1950s. Asians/Pacific Islanders had higher incidence and mortality rates than other racial/ethnic groups, but experienced a significant decrease in mortality rates over time. From 2000 to 2005, marked increases in incidence rates occurred among Hispanic, black, and white middle-aged men. Between 1992 and 2004, 2- to 4-year HCC survival rates doubled, as more patients were diagnosed with localized and regional HCC and prognosis improved, particularly for patients with reported treatment. Recent 1-year survival rates remained, however, less than 50%. CONCLUSION HCC incidence and mortality rates continue to increase, particularly among middle-aged black, Hispanic, and white men. Screening of at-risk groups and treatment of localized-stage tumors may contribute to increasing HCC survival rates in the United States. More progress is needed.

The Continuing Increase in the Incidence of Hepatocellular Carcinoma in the United States: An Update

Context Incidence rates of hepatocellular carcinoma have been increasing in the United States. Contribution This large, retrospective, population-based cohort study confirmed an almost 2-fold increase in the incidence of hepatocellular carcinoma from 1975 to 1998. Increases were seen in all ethnic groups and in most age groups after 40 years of age. Although black people and older people remained most at risk, the largest recent increase in rates (from 1995 to 1998) occurred in white men 45 to 54 years of age. Implications The incidence of hepatocellular carcinoma continues to increase rapidly in the United States, especially in white, middle-aged men. The Editors We previously reported an increase in the incidence and mortality rates of hepatocellular carcinoma in the United States (1). Studies among U.S. hospitalized veterans, as well as those conducted in large single centers, indicated that approximately half of the observed increase was attributable to hepatitis C virus (HCV) infection, whereas the incidence of hepatocellular carcinoma related to hepatitis B virus (HBV), alcoholic liver disease, or idiopathic cirrhosis remained relatively stable (2, 3). If HCV were indeed responsible for the increasing rates of hepatocellular carcinoma, this increase would be expected to continue for at least several more years since 2 to 4 decades of chronic HCV infection is required to develop cirrhosis and subsequent hepatocellular carcinoma (4). On the other hand, if the increased rates of hepatocellular carcinoma were related to better detection due to technologically improved diagnostic testing, such an effect would be expected to plateau at some point in the future. The observed increase in hepatocellular carcinoma could have other explanations. Changes in the demographic structure (age, sex, ethnicity, and geography) of the underlying population may have resulted in an increasing number of persons at high risk for hepatocellular carcinoma (older age and increased number of ethnic and racial minorities). Hepatocellular carcinoma is an age-dependent cancer that peaks in incidence between 75 and 79 years of age, and direct standardization methods may not have been sufficient to control for the effect of aging in the underlying population (5). The observed increase could also have resulted from an increase in high-risk sex or racial or ethnic groups or the population residing in 1 or a few high-risk geographic regions (6). For example, rates of hepatocellular carcinoma were severalfold higher in Asian Americans than in white people, and African Americans had rates between those of the other 2 groups (1). The current study was designed to update the recent trends in hepatocellular carcinoma incidence by using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registries and to examine the temporal trends in hepatocellular carcinoma through adjustments for potential changes in several influential factors. Methods Data Sources: SEER Beginning in 1973, the SEER registry program was established to identify all new cancer cases diagnosed in 7 geographic areas. By 1975, SEER included 9 geographic regions, 5 states (Connecticut, Hawaii, Iowa, New Mexico, and Utah) and 4 metropolitan areas (San FranciscoOakland in California; SeattlePuget Sound in Washington; Detroit, Michigan; and Atlanta, Georgia). In 1992, the Los Angeles County and San JoseMonterey areas in California joined the SEER program, expanding the representation to approximately 14% of the U.S. population. Overall, the SEER population is similar to the general U.S. population, particularly in measures of poverty and education. However, SEER regions are more urban and have a higher proportion of foreign-born persons than the general U.S. population. Data for this study were obtained from SEER*STAT public-use data files (National Cancer Institute, Bethesda, Maryland), available on CD-ROM from the National Cancer Institute (7). Data from the SEER public-use CD-ROM were converted into SAS datasets for further analyses (SAS software, version 8.2, SAS Institute, Inc., Cary, North Carolina). Demographic and cancer-related information included in this database are obtained by medical record review. Studies are conducted annually at each SEER registry site to verify that data are being collected accurately and that case ascertainment is at least 98%. Types of cancer are coded according to the International Classification of Disease for Oncology (ICD-O) (8). There are several categories of race or ethnicity, including Hispanic white, non-Hispanic white, Chinese, Japanese, Filipino, Pacific Islander, and American Indian. However, accurate information on the underlying population in the areas covered by the SEER program is available only on race classified as white (which includes Hispanic), black, or other (which includes all other ethnic groups listed). As a result, valid incidence rates can be calculated for only these 3 broad racial or ethnic groups (white, black, and other). Study Sample Patients eligible for inclusion in this study were all individuals with hepatocellular carcinoma (ICD-O code 8170) identified from 9 SEER registries between 1975 and 1998. Patients younger than 20 years of age were excluded to avoid including those with hepatoblastoma (<1% of total cases). Cases in which the patients race or ethnicity was unknown (<1% of total cases) also were excluded. To examine the potential role of diagnostic bias, we calculated the proportion of cases with microscopic confirmation, which is defined by SEER as the presence of a confirmatory histologic or cytologic evidence of hepatocellular carcinoma. Statistical Analysis The age-adjusted incidence rates for hepatocellular carcinoma were calculated for 3-year periods between 1975 and 1998. Sex- and ethnicity-specific, age-adjusted incidence rates and their 95% CIs were calculated. Adjustment was made to the 1990 U.S. population. Age-specific incidence rates were calculated for all patients and for each of the 3 broad categories of race or ethnicity (white, black, and other). Among patients with hepatocellular carcinoma, we calculated the proportions of cases belonging to the following racial or ethnic groups: Hispanic white, non-Hispanic white, Asian (Chinese, Japanese, Filipino, or Pacific Islander), and others. We also calculated the proportion of patients with liver cancer who had microscopic confirmation for each time period. These calculations were made by using the SEER*STAT statistical software (7). The temporal trends of the incidence of hepatocellular carcinoma were examined in linear Poisson multivariate regression models. We used SAS PROC GENMOD for this task. The model was used to analyze the effect of the period of diagnosis (independent variable) on the incidence of hepatocellular carcinoma (dependent variable), while controlling for several other independent variables including age (20 to 49, 50 to 64, 65 to 74, or 75 years), sex, race or ethnicity (white, black, or other), and differences in the geographic regions (9 SEER registries). Similar categories were assembled for the underlying population and were included as an offset variable in the model. Risk estimates (incidence rates and incidence rate ratios) and 95% CIs were calculated for all the independent variables in the final model. The model was tested for interactions between time of diagnosis and each variable of age, sex, and race or ethnicity. Role of the Funding Source The funding source had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Results Between 1975 and 1998, there were 11 547 cases of hepatocellular carcinoma. The overall age-adjusted incidence rates of hepatocellular carcinoma started to increase in the early 1980s, from 1.3 per 100 000 persons in 1981 to 1983 to 3.0 per 100 000 persons in 1996 to 1998 (Figure 1). This is equivalent to a 114% overall increase throughout the study period. There was a 25% increase during the last 3 years of the study (1996 to 1998) compared with the previous 3 years (1993 to 1995). The proportions of patients with liver cancer who underwent microscopic confirmation were relatively stable during the study period: 86%, 86%, 84%, 82%, 78%, and 80% in consecutive 3-year periods between 1981 and 1998, respectively. All hepatocellular carcinoma cases were included in subsequent analyses regardless of microscopic confirmation. Figure 1. The overall age-adjusted incidence rates for hepatocellular carcinoma for consecutive 3-year periods between 1975 and 1998. In addition to the variable of more recent time period, age, sex, race or ethnicity, and geographic region were statistically significant determinants of the incidence of hepatocellular carcinoma. Hepatocellular carcinoma was rare among individuals younger than 40 years of age, and the incidence peaked at 75 to 79 years of age. Concomitant with the increase in incidence, the age distribution of patients with hepatocellular carcinoma progressively shifted toward relatively younger persons. Figure 2 shows the temporal changes in the age distribution of new cases of hepatocellular carcinoma in men, with age-specific incidence rates for consecutive 3-year periods from 1975 to 1998. The incidence has increased in most age groups older than 40 years; the greatest increase occurred in patients 45 to 55 years of age. For example, in the 1990s, the incidence rates increased 110% among white men 45 to 49 years of age and 60% among white men 50 to 54 years of age (Figure 3). Similar trends were seen for women (data not shown); the greatest increase in incidence occurred in women 60 to 69 years of age. Figure 2. Age-adjusted incidence rates for hepatocellular carcinoma broken down by sex and race or ethnicity for consecutive 3-year periods between 1975 and 1998. Figure 3. Temporal trends in the age distribution of hepatocellular carcinoma. Throughout

Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study

Background: Diabetes has been associated with an increased risk of hepatocellular carcinoma (HCC) in studies of referred patients. This is the first population based case control study in the USA to examine this association while adjusting for other major risk factors related to HCC. Methods: We used the Surveillance Epidemiology and End-Results Program (SEER)-Medicare linked database to identify patients aged 65 years and older diagnosed with HCC and randomly selected non-cancer controls between 1994 and 1999. Only cases and controls with continuous Medicare enrolment for three years prior to the index date were examined. Inpatient and outpatient claims files were searched for diagnostic codes indicative of diabetes, hepatitis C virus (HCV), hepatitis B virus (HBV), alcoholic liver disease, and haemochromatosis. HCC patients without these conditions were categorised as idiopathic. Unadjusted and adjusted odds ratios were calculated in logistic regression analyses. Results: We identified 2061 HCC patients and 6183 non-cancer controls. Compared with non-cancer controls, patients with HCC were male (66% v 36%) and non-White (34% v 18%). The proportion of HCC patients with diabetes (43%) was significantly greater than non-cancer controls (19%). In multiple logistic regression analyses that adjusted for demographics features and other HCC risk factors (HCV, HBV, alcoholic liver disease, and haemochromatosis), diabetes was associated with a threefold increase in the risk of HCC. In a subset of patients without these major risk factors, the adjusted odds ratio for diabetes declined but remained significant (adjusted odds ratio 2.87 (95% confidence interval 2.49–3.30)). A significant positive interaction between HCV and diabetes was detected (p<0.0001). Similar findings persisted in analyses restricted to diabetes recorded between two and three years prior to HCC diagnosis. Conclusions: Diabetes is associated with a 2–3-fold increase in the risk of HCC, regardless of the presence of other major HCC risk factors. Findings from this population based study suggest that diabetes is an independent risk factor for HCC.

International trends and patterns of primary liver cancer

Primary liver cancer (PLC) is common in many areas of the developing world, but uncommon in most of the developed world. Some evidence suggests, however, that the global pattern of PLC may be changing. To clarify this issue, we examined incidence rates for PLC over the 15‐year time period, 1978–92, in selected cancer registries around the world. With some exceptions, developed countries have experienced PLC increases in incidence whereas developing countries have experienced declines. Although the reasons for the trends are not entirely clear, the increased seroprevalence of HCV in the developed world and the elimination of HBV‐cofactors in the developing world are likely to have contributed to the patterns. Further progress against PLC may be seen in the developing world once the HBV‐vaccinated segment of the population reaches adulthood. Published 2001 Wiley‐Liss, Inc.

Metabolic syndrome increases the risk of primary liver cancer in the United States: A study in the SEER‐medicare database

Incidence rates of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) have increased in the United States. Metabolic syndrome is recognized as a risk factor for HCC and a postulated one for ICC. The magnitude of risk, however, has not been investigated on a population level in the United States. We therefore examined the association between metabolic syndrome and the development of these cancers. All persons diagnosed with HCC and ICC between 1993 and 2005 were identified in the Surveillance, Epidemiology, and End Results (SEER)‐Medicare database. For comparison, a 5% sample of individuals residing in the same regions as the SEER registries of the cases was selected. The prevalence of metabolic syndrome as defined by the U.S. National Cholesterol Education Program Adult Treatment Panel III criteria, and other risk factors for HCC (hepatitis B virus, hepatitis C virus, alcoholic liver disease, liver cirrhosis, biliary cirrhosis, hemochromatosis, Wilsons disease) and ICC (biliary cirrhosis, cholangitis, cholelithiasis, choledochal cysts, hepatitis B virus, hepatitis C virus, alcoholic liver disease, cirrhosis, inflammatory bowel disease) were compared among persons who developed cancer and those who did not. Logistic regression was used to calculate odds ratios and 95% confidence intervals. The inclusion criteria were met by 3649 HCC cases, 743 ICC cases, and 195,953 comparison persons. Metabolic syndrome was significantly more common among persons who developed HCC (37.1%) and ICC (29.7%) than the comparison group (17.1%, P < 0.0001). In adjusted multiple logistic regression analyses, metabolic syndrome remained significantly associated with increased risk of HCC (odds ratio = 2.13; 95% confidence interval = 1.96‐2.31, P < 0.0001) and ICC (odds ratio = 1.56; 95% confidence interval = 1.32‐1.83, P < 0.0001). Conclusion: Metabolic syndrome is a significant risk factor for development of HCC and ICC in the general U.S. population. (HEPATOLOGY 2011;)

Trends in the incidence of testicular germ cell tumors in the United States

Recent reports have suggested that the increasing rates of testicular germ cell tumors in some populations have begun to plateau. This study was conducted to examine whether rates among white men in the United States have begun to stabilize and whether rates among black men in the United States have remained low.

Use of surveillance for hepatocellular carcinoma among patients with cirrhosis in the United States

Surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is recommended but may not be performed. The extent and determinants of HCC surveillance are unknown. We conducted a population‐based United States cohort study of patients over 65 years of age to examine use and determinants of prediagnosis surveillance in patients with HCC who were previously diagnosed with cirrhosis. Patients diagnosed with HCC during 1994‐2002 were identified from the linked Surveillance, Epidemiology, and End‐Results registry–Medicare databases. We identified alpha‐fetoprotein (AFP) and ultrasound tests performed for HCC surveillance, and examined factors associated with surveillance. We identified 1,873 HCC patients with a prior diagnosis of cirrhosis. In the 3 years before HCC, 17% received regular surveillance and 38% received inconsistent surveillance. In a subset of 541 patients in whom cirrhosis was recorded for 3 or more years prior to HCC, only 29% received routine surveillance and 33% received inconsistent surveillance. Among all patients who received regular surveillance, approximately 52% received both AFP and ultrasound, 46% received AFP only, and 2% received ultrasound only. Patients receiving regular surveillance were more likely to have lived in urban areas and had higher incomes than those who did not receive surveillance. Before diagnosis, approximately 48% of patients were seen by a gastroenterologist/hepatologist or by a physician with an academic affiliation; they were approximately 4.5‐fold and 2.8‐fold, respectively, more likely to receive regular surveillance than those seen by a primary care physician only. Geographic variation in surveillance was observed and explained by patient and physician factors. Conclusion: Less than 20% of patients with cirrhosis who developed HCC received regular surveillance. Gastroenterologists/hepatologists or physicians with an academic affiliation are more likely to perform surveillance. HEPATOLOGY 2010

The Global Epidemiology of Hepatocellular Carcinoma: Present and Future

The global risk of hepatocellular carcinoma (HCC) has been largely driven by hepatitis B virus (HBV) infection for the past century, along with hepatitis C virus (HCV), aflatoxin, excessive alcohol consumption, and obesity/diabetes. The dominant effect of HBV on global HCC risk should decline as the population vaccinated against HBV grows older. Infection with HCV is also expected to decline. Projections of HCV-related HCC rates remaining high for another 30 years may be overly pessimistic. Alcohol may be less of a factor in HCC in coming years. However, obesity and diabetes may become even more important risk factors for HCC.

Sex Disparities in Cancer Incidence by Period and Age

Background: Cancer epidemiology articles often point out that cancer rates tend to be higher among males than females yet rarely is this theme the subject of investigation. Methods: We used the Surveillance, Epidemiology and End Results program data to compute age-adjusted (2000 U.S. standard population) sex-specific incidence rates and male-to-female incidence rate ratios (IRR) for specific cancer sites and histologies for the period 1975 to 2004. Results: The 10 cancers with the largest male-to-female IRR were Kaposi sarcoma (28.73), lip (7.16), larynx (5.17), mesothelioma (4.88), hypopharynx (4.13), urinary bladder (3.92), esophagus (3.49), tonsil (3.07), oropharynx (3.06), and other urinary organs (2.92). Only 5 cancers had a higher incidence in females compared with males: breast (0.01), peritoneum, omentum, and mesentery (0.18), thyroid (0.39), gallbladder (0.57), and anus, anal canal, and anorectum (0.81). Between 1975 and 2004, the largest consistent increases in male-to-female IRR were for cancers of the tonsil, oropharynx, skin excluding basal and squamous, and esophagus, whereas the largest consistent decreases in IRR were for cancers of the lip and lung and bronchus. Male-to-female IRRs varied considerably by age, the largest increases of which were for ages 40 to 59 years for tonsil cancer and hepatocellular carcinoma. The largest decreases in male-to-female IRR by age, meanwhile, were for ages 30 to 49 years for thyroid cancer, ages >70 years for esophageal squamous cell carcinoma, and ages >30 years for lung and bronchus cancer. Conclusion: These observations emphasize the importance of sex in cancer etiopathogenesis and may suggest novel avenues of investigation. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1174–82)

International trends in the incidence of testicular cancer, 1973–2002

Background: Whereas testicular cancer incidence rates have been widely reported in populations of Northern European ancestry, rates in other populations have been less frequently examined. In a prior report, global testicular cancer incidence rates and trends for the years 1973 to 1997 were summarized. The current report extends these analyses with an additional 5 years of data from Cancer Incidence in Five Continents. Methods: Age-standardized incidence rates over successive 5-year time periods were obtained for populations in the Americas, Asia, Europe, and Oceania. Results: In general, testicular cancer incidence remained highest in Northern European populations (8.0-9.0 per 100,000) and lowest in Asian and African populations (<1 per 100,000). One notable exception to this pattern, however, was the very high rate reported by the Valdivia, Chile registry (8.8 per 100,000). In many populations, rates rose between 1973 and 2002, although the increases were strongest and most consistent among populations of European ancestry. In certain European populations, such as those of Denmark and of Geneva, Switzerland, some recent plateauing of rates was evident. There was little evidence of increase and possible evidence of a modest decline in rates among east Asian populations. Trends by histology (seminoma and nonseminoma) were generally similar to one another. Conclusions: Risk of testicular cancer remains relatively high in Northern European populations and low in Asian and African populations. Similar trends by histology suggest common risk factors. Effect: Reasons for increasing rates among Northern Europeans and stable or declining rates among East Asians are unexplained, supporting the need for future etiologic studies. Cancer Epidemiol Biomarkers Prev; 19(5); 1151–9. ©2010 AACR.