Trends in lung cancer incidence and mortality in Croatia, 1988 to 2008

Aim To describe and interpret lung cancer incidence and mortality trends in Croatia between 1988 and 2008. Methods Incidence data on lung cancer for the period 1988-2008 were obtained from the Croatian National Cancer Registry, while mortality data were obtained from the World Health Organization mortality database. Population estimates for Croatia were obtained from the Population Division of the Department of Economic and Social Affairs of the United Nations. We also calculated and analyzed age-standardized incidence and mortality rates. To describe time incidence and mortality trends, we used joinpoint regression analysis. Results Lung cancer incidence and mortality rates in men decreased significantly in all age groups younger than 70 years. Age-standardized incidence rates in men decreased significantly by -1.3% annually. Joinpoint analysis of mortality in men identified three trends, and average annual percent change (AAPC) decreased significantly by -1.1%. Lung cancer incidence and mortality rates in women increased significantly in all age groups older than 40 years and decreased in younger women (30-39- years). Age-standardized incidence rates increased significantly by 1.7% annually. Joinpoint analysis of age-standardized mortality rates in women identified two trends, and AAPC increased significantly by 1.9%. Conclusion Despite the overall decreasing trend, Croatia is still among the European countries with the highest male lung cancer incidence and mortality. Although the incidence trend in women is increasing, their age standardized incidence rates are still 5-fold lower than in men. These trends follow the observed decrease and increase in the prevalence of male and female smokers, respectively. These findings indicate the need for further introduction of smoking prevention and cessation policies targeting younger population, particularly women.

Lung cancer is the most common malignancy worldwide, accounting for one fifth of all cancer-related deaths (1). There are different trends of lung cancer incidence and mortality throughout Europe, mostly reflecting different phases of smoking epidemic in individual countries. In many European countries, the rates in men have recently decreased or stabilized, while the rates in women increased (2-4). Because the majority of lung cancer deaths are attributed to tobacco smoking, any decline or deceleration in the lung cancer death rates could be attributed to the past antismoking interventions (5,6). Early indicators of progress in tobacco-smoking control are lung cancer trends in young adults (6).
About 90% of lung cancers in men and 83% in women are caused by smoking (7). The risk of developing lung cancer is affected by the level of consumption and duration of smoking (8), as well as the level of exposure to environmental tobacco smoke (9). The second most important cause of lung cancer is radon, which was estimated to be responsible for 9% of lung cancer deaths in European countries (10). Other risk factors include exposure to asbestos (11), silica (12), nitrogen oxides (13), radiation to the chest as part of the treatment of malignant diseases (14)(15)(16), and scarring on the lungs due to tuberculosis or recurrent pneumonia (17).
Currently in Croatia, lung cancer is the most common cancer in men and the fifth most common cancer in women, accounting for more than 2000 and 600 deaths per year, respectively (18, 19). The aim of this study was to provide an overview of the temporal trends of lung cancer incidence and mortality in Croatia for the period 1988-2008.

MATeriAlS And MeThodS data sources
Incidence data for the period 1988-2008 were obtained from the Croatian National Cancer Registry. The Registry, founded in 1959, covers the whole Croatian population (approximately 4.4 million persons) and relies on mandatory cancer notifications from primary and secondary health care sources and death certificates from the Croatian Bureau of Statistics. The Registry has contributed data to the last three volumes of the Cancer Incidence in Five Continents series (20)(21)(22). In addition to incidence data, these publications report respective indices of data quality (proportion of morphologically verified cases, proportion of cases registered from death certificates only, and mortality to incidence ratio) (20)(21)(22). Lung cancer was defined as ICD-10 codes C33 and C34 and ICD-9 code 162. The number of lung cancer deaths was obtained from the World Health Organization (WHO) mortality database (19). Population estimates from Population Division of the Department of Economic and Social Affairs of the United Nations were used for calculating all incidence and mortality rates (23).

Statistical analysis
Age-standardized rates of cancer incidence in Croatia and truncated age-standardized rates (for ages 30-64) were calculated by the direct standardization method, using the world standard population as a reference (24). To describe incidence and mortality time trends, we carried out joinpoint regression analysis using the software Joinpoint Regression Program, Version 3.5.2, October 2011. The analysis included logarithmic transformation of the rates, standard error, maximum number of five joinpoints, and minimum of four years between two joinpoints. All other program parameters were set to default values. The aim of the approach is to identify possible joinpoints where a significant change in the trend occurs. The method identifies joinpoints based on regression models with 0-5 joinpoints. The final model selected was the most parsimonious of these, with the estimated annual percent change (EAPC) based on the trend within each segment (25). To quantify the trend over the whole period, the average annual percent change (AAPC) was calculated. The AAPC is computed as a geometric weighted average of the EAPC trend analysis, with the weights equal to the lengths of each segment during the pre-specified fixed interval. If an AAPC lies entirely within a single joinpoint segment, the AAPC is equal to the EAPC for that segment. In these cases we reported the EAPCs (26).

Women
In women, there was an increase in the number of cases and ASRs (Figure 2). Age-standardized incidence rates increased by 26.5%, from 9.8/100 000 in the first five-years (1988)(1989)(1990)(1991)(1992)   incidence, with EAPC of 1.7% (95% CI, 0.8% to 2.5%) ( Table  2). Joinpoint analysis of mortality (Table 3) identified one joinpoint in 1994. The first trend showed non-significant decrease, with EAPC of -1.0% (95% CI, -4.1% to 2.2%), followed by a significant increase, with EAPC of 3.1% (95% CI, 2.3% to 3.9%) from 1994 to the end of the study pe-riod. AAPC was 1.9% (95% CI, 0.9% to 2.9%) throughout the whole period. Analysis by ten-year age groups showed that both incidence and mortality increased significantly in all age groups older than 40 years and decreased in younger women (30-39 years). (Tables 2 and 3) diSCuSSion This study confirmed the findings that, despite the overall decreasing trend, Croatia is still among the European countries with the highest male lung cancer incidence and mortality rate (27,28). With male ASR incidence and mortality of 59.6 and 57.6/100 000 men, respectively, it is in the top five of the 40 analyzed European countries. Hungary has the highest estimated male ASR of mortality, of 73.5/100 000, while Cyprus has the lowest, of 21.3/100 000. Incidence and mortality in women are considerably lower. Compared to other European countries, Croatia has an intermediate incidence and mortality rate (12.4 and 12.5/100 000, respectively). Denmark has the highest mortality rate of 30/100000 and Belarus the lowest -3.7/100 000 (28).
More than a quarter of all adult inhabitants of Croatia are every-day smokers (29). A survey conducted in 1972  showed a prevalence of daily cigarette smoking of 56.9% in men and 10.1% in women. In the period between 1972 and 1997, the prevalence decreased among men and increased among women. During the last decade, there has been a reduction in the frequency of smokers of both sexes (29,30). Our results show that lung cancer incidence and mortality rates in men have been constantly decreasing in most of the age groups. This trend is in agreement with the decrease in the prevalence of male smokers observed during the same period (29). On the other hand, women showed an increasing incidence trend, although their age standardized incidence rates are still five times lower than those of men. This increasing incidence trend follows the increase in the prevalence of female smokers (29) and reflects a lung cancer epidemic in women. Still, though not significant, we observed a stabilization and beginning of a decreasing trend in younger women (30-39 years). Together with the initial reduction in the frequency of smokers among women during the last decade (30), this might be an early indicator that lung cancer incidence and mortality in women will reach a plateau or start declining in the future.  (27).
Croatia still bears a major smoking-related health burden. Some of the most obvious barriers to implementing successful smoking prevention program initiatives include very limited resources, recent transnational tobacco industry's interest in the Croatian market, and the social acceptability of smoking. By ratifying the Framework Convention for Tobacco Control, Croatia did integrate European tobacco bans, but smoking is still allowed in most of the bars and cafes (31). Because of a large number of older Croatians who have been smoking for decades, the rise in the number of tobacco-related deaths is expected to continue (31). Such trends encourage the imple- mentation of smoking prevention and cessation policies, particularly those targeting younger population, especially women.