Jessica L. Petrick

Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability

Liver cancer is the second leading cause of global cancer mortality. The major risk factors for hepatocellular carcinoma (HCC) are being addressed with success by prevention efforts. Vaccination against hepatitis B virus has reduced incidence of HCC in Taiwan and is partly responsible for lower rates in China. New infections with hepatitis C virus are low in developed countries because of prevention of posttransfusion infections and reduced exposure to HCV by drug users. Aflatoxin exposure has been reduced by better grain storage and dietary changes. Obesity, metabolic syndrome, and diabetes are increasing in developed and developing countries and will lead to more cases of HCC.

International trends in liver cancer incidence, overall and by histologic subtype, 1978–2007

Primary liver cancer, the most common histologic types of which are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), is the second leading cause of cancer death worldwide. While rising incidence of liver cancer in low‐risk areas and decreasing incidence in some high‐risk areas has been reported, trends have not been thoroughly explored by country or by histologic type. We examined liver cancer incidence overall and by histology by calendar time and birth cohort for selected countries between 1978 and 2007. For each successive 5‐year period, age‐standardized incidence rates were calculated from volumes V‐IX of the Cancer Incidence in Five Continents electronic database (CI5plus) and the newly released CI5X (volume X) database. Wide global variations persist in liver cancer incidence. Rates of liver cancer remain highest in Asian countries, specifically Eastern and South‐Eastern Asian countries. While rates in most of these high‐risk countries have been decreasing in recent years, rates in India and several low‐risk countries of Africa, Europe, the Americas, and Oceania have been on the rise. Liver cancer rates by histologic type tend to convey a similar temporal profile. However, in Thailand, France, and Italy, ICC rates have increased while HCC rates have declined. We expect rates in high‐risk countries to continue to decrease, as the population seroprevalence of hepatitis B virus (HBV) continues to decline. In low‐risk countries, targeted screening and treatment of the hepatitis C virus (HCV), treatment of diabetes and primary prevention of obesity, will be key in reducing future liver cancer incidence.

Future of Hepatocellular Carcinoma Incidence in the United States Forecast Through 2030

PURPOSE Hepatocellular carcinoma (HCC) incidence rates have been increasing in the United States for the past 35 years. Because HCC has a poor prognosis, quantitative forecasts could help to inform prevention and treatment strategies to reduce the incidence and burden of HCC. METHODS Single-year HCC incident case and population data for the years 2000 to 2012 and ages 35 to 84 years were obtained from the SEER 18 Registry Database. We forecast incident HCC cases through 2030, using novel age-period-cohort models and stratifying by sex, race/ethnicity, and age. Rates are presented because absolute numbers may be influenced by population increases. RESULTS Rates of HCC increased with each successive birth cohort through 1959. However, rates began to decrease with the 1960 to 1969 birth cohorts. Asians/Pacific Islanders (APIs) have had the highest HCC rates in the United States for many years, but the rates have stabilized and begun to decline in recent years. Between 2013 and 2030, rates among APIs are forecast to decline further, with estimated annual percentage changes of -1.59% among men and -2.20% among women. Thus, by 2030, Asians are forecast to have the lowest incidence rates among men, and Hispanics are forecast to have the highest rates among men (age-standardized rate, 44.2). Blacks are forecast to have the highest rate among women (age-standardized rate, 12.82). CONCLUSION Although liver cancer has long had some of the most rapidly increasing incidence rates, the decreasing rates seen among APIs, individuals younger than 65 years, and cohorts born after 1960 suggest that there will be declines in incidence of HCC in future years. Prevention efforts should be focused on individuals in the 1950 to 1959 birth cohorts, Hispanics, and blacks.

Prevalence of human papillomavirus among oesophageal squamous cell carcinoma cases: systematic review and meta-analysis.

Background:Oncogenic human papillomavirus (HPV) has been hypothesised as a risk factor for oesophageal squamous cell carcinoma (OSCC), but aetiological research has been limited by the varying methodology used for establishing HPV prevalence. The aims of this systematic review and meta-analysis were to estimate the prevalence of HPV DNA detected in OSCC tumours and the influence of study characteristics.Methods:Study-level estimates of overall and type-specific HPV prevalence were meta-analysed to obtain random-effects summary estimates.Results:This analysis included 124 studies with a total of 13 832 OSCC cases. The average HPV prevalence (95% confidence interval) among OSCC cases was 0.277 (0.234, 0.320) by polymerase chain reaction; 0.243 (0.159, 0.326) by in situ hybridisation; 0.304 (0.185, 0.423) by immunohistochemistry; 0.322 (0.154, 0.490) by L1 serology; and 0.176 (0.061, 0.292) by Southern/slot/dot blot. The highest HPV prevalence was found in Africa and Asia, notably among Chinese studies from provinces with high OSCC incidence rates.Conclusions:Future research should focus on quantifying HPV in OSCC cases using strict quality control measures, as well as determining the association between HPV and OSCC incidence by conducting large, population-based case–control studies. Such studies will provide a richer understanding of the role of HPV in OSCC aetiology.

Geographic variation of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and hepatocellular carcinoma in the United States.

Background Intrahepatic (ICC) and extrahepatic cholangiocarcinomas (ECC) are tumors that arise from cholangiocytes in the bile duct, but ICCs are coded as primary liver cancers while ECCs are coded as biliary tract cancers. The etiology of these tumors is not well understood. It has been suggested that the etiology of ICC is more similar to that of another type of liver cancer, hepatocellular carcinoma (HCC), than to the etiology of ECC. If this is true, geographic incidence patterns and trends in ICC incidence should be more similar to that of HCC than ECC. Methods To examine this hypothesis, data from the North American Association of Central Cancer Registries Cancer in North America data file were analyzed. Incidence rates and joinpoint trends were calculated by demographic subgroup. County-level incidence rates were mapped. Results Overall incidence rates, racial distribution, male:female ratio, and peak ages were more similar between ICC and ECC than with HCC. During 2000–2009, average annual incidence rates of ECC increased. During 2005–2009, average annual ICC incidence rates also increased. High rates for all three cancer sites were found in the Pacific region, particularly Hawaii and Alaska. Rates of ICC and ECC were also high in the Northeast and the upper Midwest, while rates of HCC were high in the South. Conclusions Demographic patterns and geographical variation were more closely related between ICC and ECC than HCC, suggesting that the etiology of ICC and ECC may be similar. Increasing rates of both tumors suggest that further etiology studies are warranted.

Dietary intake of flavonoids and oesophageal and gastric cancer: incidence and survival in the United States of America (USA)

Background:Flavonoids, polyphenolic compounds concentrated in fruits and vegetables, have experimentally demonstrated chemopreventive effects against oesophageal and gastric cancer. Few epidemiologic studies have examined flavonoid intake and incidence of these cancers, and none have considered survival.Methods:In this USA multicentre population-based study, case participants (diagnosed during 1993–1995 with oesophageal adenocarcinoma (OEA, n=274), gastric cardia adenocarcinoma (GCA, n=248), oesophageal squamous cell carcinoma (OES, n=191), and other gastric adenocarcinoma (OGA, n=341)) and frequency-matched controls (n=662) were interviewed. Food frequency questionnaire responses were linked with USDA Flavonoid Databases and available literature for six flavonoid classes and lignans. Case participants were followed until 2000 for vital status. Multivariable-adjusted odds ratios (ORs) and hazard ratios (HRs) (95% confidence intervals (CIs)) were estimated, comparing highest with lowest intake quartiles, using polytomous logistic and proportional hazards regressions, respectively.Results:Little or no consistent association was found for total flavonoid intake (main population sources: black tea, orange/grapefruit juice, and wine) and incidence or survival for any tumour type. Intake of anthocyanidins, common in wine and fruit juice, was associated with a 57% reduction in the risk of incident OEA (OR=0.43, 95% CI=0.29–0.66) and OES (OR=0.43, 95% CI=0.26–0.70). The ORs for isoflavones, for which coffee was the main source, were increased for all tumours, except OES. Anthocyanidins were associated with decreased risk of mortality for GCA (HR=0.63, 95% CI=0.42–0.95) and modestly for OEA (HR=0.87, 95% CI=0.60–1.26), but CIs were wide.Conclusions:Our findings, if confirmed, suggest that increased dietary anthocyanidin intake may reduce incidence and improve survival for these cancers.

Functional Status Declines among Cancer Survivors: Trajectory and Contributing Factors

OBJECTIVE This study aimed to quantify functional status (FS) trajectories pre- and post-diagnosis of cancer, FS trajectories among cancer-free individuals, and factors affecting FS. MATERIALS AND METHODS Self-reported FS, scored from 0 (worst) to 100 (best), of Atherosclerosis Risk in Communities (ARIC) Study cohort participants diagnosed with incident cancer (lung (N=303), breast (N=374), prostate (N=529), colorectal (N=228)), and cancer-free participants (N=11,155) over 15 years was examined. FS was evaluated in two ways: 1) until death or follow-up year 15 (Model 1) and 2) same as survivorship model except that a FS value of zero was used for assessments after death to follow-up year 15 (Model 2). Mean FS at discrete time points were used to generate FS trajectories. Differences in repeated measures of FS were assessed using linear growth models. RESULTS Within one year after diagnosis, FS scores declined compared to the cancer-free group, except for prostate cancer. FS continued to decline beyond one year after lung or colorectal cancer diagnosis. FS was lower in all cancer groups, except prostate, compared to the cancer-free group (Model 1: lung -4.76, breast -2.28, colorectal -2.55; Model 2: lung -2.36, breast -2.46, colorectal -2.31). Predictors of decreased FS score independent of cancer diagnosis included low education, comorbidities, obesity, smoking, lack of health insurance, and age. CONCLUSION FS in all incident cancer groups declined during the first year post-diagnosis, which could be due to intensive treatments. Targeting factors related to FS declines could improve health outcomes for patients with cancer.

Nsaid use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The liver cancer pooling project

Chronic inflammation plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common types of liver cancer. A number of prior experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen, may potentially protect against liver cancer. However, no observational study has examined the association between aspirin duration and dose or other over-the-counter non-aspirin NSAIDs, such as ibuprofen, and liver cancer incidence. Furthermore, the association between NSAID use and risk of ICC is unclear. As part of the Liver Cancer Pooling Project, we harmonized data on 1,084,133 individuals (HCC = 679, ICC = 225) from 10 U.S.-based prospective cohort studies. Cox proportional hazards regression models were used to evaluate multivariable-adjusted HRs and 95% confidence intervals (CI). Current aspirin use, versus nonuse, was inversely associated with HCC (HR, 0.68; 95% CI, 0.57–0.81), which persisted when restricted to individuals not using non-aspirin NSAIDs and in a 5- and 10-year lag analysis. The association between aspirin use and HCC risk was stronger for users who reported daily use, longer duration use, and lower dosage. Ibuprofen use was not associated with HCC risk. Aspirin use was associated with a reduced ICC risk in men (HR, 0.64; 95% CI, 0.42–0.98) but not women (HR, 1.34; 95% CI, 0.89–2.01; Pinteraction = 0.01). The observed inverse association between aspirin use and liver cancer in our study, together with previous data, suggests the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC. Cancer Prev Res; 8(12); 1156–62. ©2015 AACR.

Reproductive factors, exogenous hormone use and risk of hepatocellular carcinoma among US women: results from the Liver Cancer Pooling Project

Background:Hepatocellular carcinoma (HCC) occurs less commonly among women than men in almost all regions of the world. The disparity in risk is particularly notable prior to menopause suggesting that hormonal exposures during reproductive life may be protective. Exogenous oestrogenic exposures such as oral contraceptives (OCs), however, have been reported to increase risk, suggesting that estrogens may be hepatocarcinogenic. To examine the effects of reproductive factors and exogenous hormones on risk, we conducted a prospective analysis among a large group of US women.Methods:In the Liver Cancer Pooling Project, a consortium of US-based cohort studies, data from 799 500 women in 11 cohorts were pooled and harmonised. Cox proportional hazards regression models were used to generate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of reproductive factors and exogenous hormones with HCC (n=248).Results:Bilateral oophorectomy was associated with a significantly increased risk of HCC (HR=2.67, 95% CI=1.22–5.85), which did not appear to be related to a shorter duration of exposure to endogenous hormones or to menopausal hormone therapy use. There was no association between OC use and HCC (HR=1.12, 95% CI=0.82–1.55). Nor were there associations with parity, age at first birth, age at natural menopause, or duration of fertility.Conclusions:The current study suggests that bilateral oophorectomy increases the risk of HCC but the explanation for the association is unclear. There was no association between OC use and HCC risk. Examination of endogenous hormone levels in relation to HCC may help to clarify the findings of the current study.

Coffee consumption and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma by sex: The Liver Cancer Pooling Project

Background: Coffee consumption has been reported to be inversely associated with hepatocellular carcinoma (HCC), the most common type of liver cancer. Caffeine has chemopreventive properties, but whether caffeine is responsible for the coffee–HCC association is not well studied. In addition, few studies have examined the relationship by sex, and no studies have examined whether there is an association between coffee and intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. Methods: In the Liver Cancer Pooling Project, a consortium of U.S.-based cohort studies, data from 1,212,893 individuals (HCC, n = 860; ICC, n = 260) in nine cohorts were pooled. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Results: Higher coffee consumption was associated with lower risk of HCC (HR>3 cups/day vs. non-drinker, 0.73; 95% CI, 0.53–0.99; Ptrend cups/day = <0.0001). More notable reduced risk was seen among women than men (Pinteraction = 0.07). Women who consumed more than three cups of coffee per day were at a 54% lower risk of HCC (HR, 0.46; 95% CI, 0.26–0.81), whereas men had more modest reduced risk of HCC (HR, 0.93; 95% CI, 0.63–1.37). The associations were stronger for caffeinated coffee (HR>3 cups/day vs. non-drinker, 0.71; 95% CI, 0.50–1.01) than decaffeinated coffee (HR, 0.92; 95% CI, 0.55–1.54). There was no association between coffee consumption and ICC. Conclusions: These findings suggest that, in a U.S. population, coffee consumption is associated with reduced risk of HCC. Impact: Further research into specific coffee compounds and mechanisms that may account for these associations is needed. Cancer Epidemiol Biomarkers Prev; 24(9); 1398–406. ©2015 AACR.