Liver cancer has several subtypes, including hepatocellular carcinoma (HCC), cholangiocarcinoma, hepatoblastoma, and angiosarcoma. HCC accounts for between 85% and 90% of all liver cancers, while most of the remaining liver cancers are cholangiocarcinoma (6,7). Major risk factors for liver cancer include hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and alcohol abuse, which together may be responsible for up to 90% of incident cases (6-8,9).

To examine the trends of liver cancer over the period of study, we used the codes ICD–9 155, ICD–O–3 C22 and ICD–10 C22 for liver cancer. First, we contrasted the average 3–year age-adjusted incidence and mortality rates for the period 1972–74 with that for 2004–06 for men and women separately. We then compared the incidence and mortality rates for five specific age groups that is 35–44, 45–54, 55–64, 65–74 and 75–84 years. We evaluated secular trends in the incidence and mortality of liver cancer through linear regression models using logarithms of the annual rates for all ages as well as for the five age groups. Correspondingly, the annual percent changes (APC) during the study period were derived from the regression coefficients of those models. All age-adjusted incidence and mortality rates were calculated using 1991 Canadian population serving as the standard.

Analyses integrating age at diagnosis, time period of diagnosis and birth cohort were conducted separately for men and women. We grouped age at diagnosis into 5-year intervals (35–39 years to 80–84 years) and categorized the period of diagnosis into 5-year intervals from 1972 through 2006 (1972–76 to 2002–06). Corresponding to these age intervals and time periods, 16 overlapping 10-year birth cohorts (1888–97 to 1963–72) were derived for the ageperiod- cohort analysis of the incidence. We thus computed and plotted the age-specific incidence rates for all the 16 birth cohorts. A Poisson regression model was used to estimate the age, period and cohort effects; the model assumes that the number of incident cases follows a Poisson distribution and that the incidence rates are a multiplicative function of the included model parameters, making the logarithm of the rates an additive function of the parameters (17-19). For example, the form of the age-period-cohort model was given by

log(d_ij/p_ij) = μ + α_i + β_j + γ_k

where log (d_ij/p_ij) is the rate of interest with d_ij denoting the number of the cases in the ith age group and jth period and p_ij is the population at risk in the ith age group and jth period; α_i is the effect of the ith age group; β_j is the effect of jth period category; and γ_k is the effect of the kth cohort category (k = I – i + j when i = 1, 2,…, I). Inherent in the three-factor age-period-cohort model is the well-known non-identifiability problem: parameters for age, period and cohort can not be uniquely estimated because of the exact linear dependence of the regression variables (cohort = period − age) (20,21). Although there are several methods that can deal with the non-identifiability problem, there is no consensus in the literature as to which method is optimal. Hence, we selected two-factor models to calculate the relative risk as the log of regression coefficients by adjusting for the other factor. To test the effect of birth cohort and period of diagnosis individually after controlling for the effect of age, we compared respective two-factor models with the full model.

The increase in overall incidence rates of liver cancer among men was larger than that among women, with an APC of 2.9% and 1.2%, respectively. Among the respective age groups, men aged 45–54 years experienced the most rapid increase in incidence (APC: 4.1%), while women aged 65–74 years had the highest increase (APC: 1.7%) (Table1). The increase in mortality among men was higher than that among women (APC: 2.3% vs. 1.2%). Men aged 75–84 years had the most rapid increase (APC: 2.8%). Women aged 35– 44 years of age had a statistically significant decrease (APC: −2.2%) over the study period, however (Table 2).

Epidemiological studies found that recent immigrants from HBV–endemic areas and their descendants were at high risk of chronic HBV infection and of HBV–related liver cancer (25-27). Immigration from high-risk areas of hepatitis B infection, drug abuse and needle sharing, blood transfusion of unscreened blood or blood products, and unsafe sexual practices in the 1960s and 1970s have been associated with an increase in the HBV- and HCV- related liver cancer (9,23,28,29).

The total number of individuals born outside of Canada reached 6.2 million, 19.8% of the total population in 2006 (31). Canadian census data show an increase in immigration from Africa and Asia made up about 17% of the foreignborn population in 1981, increasing to 28% in 1996 and 42% in 2001. Concurrently, immigrants from Europe made up a decreasing proportion of the foreign-born population, beginning at 67% in 1981 and dropping to 55% in 1996 and then 42% in 2001 (28). Immigrants from high-risk areas for HBV infection showed elevated rates of several diseases including liver cancer (27,29). The highest annual percentage change (APC) among 45–65 men liver cancer could be inf luenced by immigration from high-risk areas of hepatitis B infection. Previous epidemiological studies associated an increase in immigrants from high-risk areas with the rise in incidence and mortality of liver cancer in Canada (30,32). Analysis by cultural background and region of birth revealed a high incidence of and mortality due to liver cancer for immigrants from certain specific regions. Chen et al. found that the risk of liver cancer was associated with a high proportion of immigration to the province of Ontario (28). Luo et al. examined the incidence of cancer among Chinese immigrants in Alberta and found that the overall cancer incidence was lower among immigrants, but the incidence rates of liver cancer were much higher (16.7/100 000) than that among Canadian-born residents (1.7/100 000) of Alberta (32). The increased incidence rates of liver cancer observed in those studies were likely to be associated with the high prevalence of HBV and HCV infections among high-risk groups. Immigrants might have acquired such infection before coming to Canada. One study found increased risk among immigrants from South–Eastern Asia infected with biliary liver flukes where consumption of raw fresh-water fish is a cultural practice. Biliary liver fluke has an infrequent cause of infection which the potential long-term consequences of chronic infection are highly associated with cholangiocarcinoma (33).

Liver cancer is more prevalent in men than in women worldwide (1,2). We observed a male to female ratio of around 2:1 for liver cancer incidence and mortality in Canada. We also observed that the increasing trends of incidence and mortality of liver cancer among men started at 45 years of age. The reasons for higher rates of liver cancer in males may be due to sex-specific differences in exposure to risk factors (27). Further, epidemiological studies have indicated that males are more sensitive to the effect of HBV infection than females. Wang et al. found that there was a greater risk difference between hepatitis B surface antigen carriers and noncarriers among males than among females, and that males had a significant synergistic effect for the interaction between sex and HBV infection on liver cancer mortality (34). A case-control study by Yu et al. found an inverse relation between exposure to estrogens and liver cancer, suggesting that estrogens may provide a protective effect against liver cancer (35). Naugler et al. found that estrogen-mediated inhibition of interleukin-6 production by Kupffer cells reduced the risk of liver cancer in females (36).

Heavy consumption of alcohol is a well-known risk factor for liver cancer. Donato et al. found a positive linear relation between the risk of hepatocellular carcinoma (HCC) and alcohol intake, although these was no substantial relative risk differences between men and women (37). Further, risk of liver cancer is thought to be affected by synergistic interactions between HBV or HCV infection and alcohol (38). A systematic review of epidemiological evidence concluded that HBV infection, HCV infection and alcohol intake are major causes of HCC worldwide, and the three main risk factors together account for approximately 85% of the total HCC cases (39). Boffetta et al. found that DNA damage occurred after heavy alcohol consumption, and alcohol-associated liver cirrhosis was the most important risk factor for HCC in populations with low prevalence of infection from HBV and HCV, such as in the United States and northern Europe (40). Heavy alcohol consumption may cause DNA damage by reducing intake of nutrition; this could also explain the synergistic effect of alcohol and HBV and HCV infections (41). In addition, other studies also reported a strong association between obesity and liver cancer, although the mechanisms for this association remain unknown (42,43). The metabolic abnormalities related to excess weight include high plasma triglyceride, glucose and insulin levels, as well as insulin resistance.

Period effect identif ied by our age-period-cohort regression, though statistically significant only in women, is very likely due to an overall improvement in the quality of cancer registration data that took place in the 1970s and early 1980s in most Canadian provinces/territories, especially Quebec (21,44). Changes to cancer diagnostic criteria and registration methodology over that period were already documented by the Canadian Cancer Registry; however, its impact on the cancer trends was too small to be quantified by earlier studies (11,44). In addition, the slight decrease in relative risks in the two most recent birth cohorts (Table 4) may indirectly indicate a likelihood that risks for liver cancer attributable to exposure to the risk factors identified above have yet to appear in younger generations.