In recent decades, cancer has become one of the leading causes of death worldwide in both sexes, with significant geographic variations in frequency and distribution [1–3]. Based on GLOBOCAN 2012 estimates, overall cancer mortality in Serbia (147.8 per 100,000) ranks among the highest in the world after Mongolia (161.0 per 100,000), Hungary (152.1 per 100,000), and Armenia (150.3 per 100,000) [2]. The lowest mortality rates have been recorded in countries of South-Central Asia and Western Africa (approximately 70.0 per 100,000).

Since the late 1980s, cancer mortality rates have been declining in most developed countries [4–7]. In contrast, cancer mortality trends in some Eastern and Southern European countries have risen continuously [7, 8]. It is considered that the decrease in overall cancer mortality rates in developed countries is attributable to the reduction in tobacco smoking-related cancers (i.e., lung, intestinal, prostate, and cervical cancers, among others) [3, 5, 7]. The reduction in cancer mortality in Western countries might also be attributed to reductions in other major risk factors (e.g., dietary habits, alcohol use, occupational exposure to carcinogens, infection, and so on) as well as the availability and use of screening, early diagnosis, and improved treatment. The increased cancer mortality in developing countries probably reflects lifestyle changes that accompany industrialization, including greater consumption of animal fats, increased obesity, and physical inactivity [8, 9].

Serbia (officially the Republic of Serbia) is a small country in southeastern Europe, where the previous 25 years have been marked by dramatic socioeconomic and political upheaval, such as civil wars from 1991 to 1999, the break-up of the former Yugoslavia, influx of more than a million refugees, damaging effects of economic sanctions imposed by the United Nations from 1992 to 1995, a 78-day bombing campaign by NATO (North Atlantic Treaty Organization) in 1999, the collapse of the economy, decline of the living standard of the population, degradation of health services (with a lack of drugs and other medical materials), democratic changes in social and political circumstances in 2000, and the global financial crisis in 2007. With democratic political changes since 2000, there have been some general improvements of the social conditions in Serbia. Despite some enhancements of the health system, however, the Serbian population continues to experience significant health problems [10]. As yet, there are no corresponding data for cancer mortality in the Serbian population for that period.

In this nationwide study, we assessed cancer mortality trends in Serbia over a 25-year period, which includes the time of civil war in the country and the global economic crisis. In addition, we obtained comprehensive estimates of the nationwide cancer mortality pattern in Serbia.

Serbia’s mortality rates owing to cancer place it among the countries with the highest cancer mortality in the world. In the period from 1991 to 2015, approximately 266,000 males and 200,000 females died from cancer in Serbia. The overall cancer mortality rate increased nearly equally in both sexes.

GLOBOCAN estimated that there were 8.2 million deaths from cancer in both sexes worldwide in 2012, with an age-standardized mortality rate of 102.4 per 100,000 [2]. The overall cancer mortality in both sexes varies more than three-fold across the world, ranging from about 150.0 per 100,000 in Mongolia, Hungary, Armenia, and Serbia to approximately 50.0 per 100,000 in Namibia and Cape Verde. In males, rates vary more than four-fold, ranging from 209.6 per 100,000 in Armenia to 46.4 per 100,000 in Kuwait. Zimbabwe had the highest cancer mortality rate among females (146.5 per 100,000) and Maldives had the lowest rate (42.3 per 100,000) in 2012. Of 174 countries worldwide, Serbia had the fourth highest cancer mortality rate for both sexes in the same year.

The significant differences in cancer mortality observed between countries could be explained by different prevalence of risk factors; variations in cancer prevention, diagnosis and treatment; the availability and use of high-quality cancer care and resources; and management of health expenditure [18, 19]. In addition, mortality rates partly reflect the varying data quality worldwide [11]. Tobacco smoking is the strongest environmental risk factor known to cause cancer. Tobacco exposure in Serbia is higher than in developed countries [20]. Based on World Health Organization 2013 estimates, the prevalence of tobacco smoking among males was 59.8% in the Russian Federation, 48.7% in China and Mongolia, 44.6% in Serbia, and 24.6% in Finland [20]. In females, the highest prevalence of tobacco smoking was recorded in Serbia (39.7%) and the lowest prevalence was in Bangladesh (0.9%). In 2013, more than one-half (56.3%) of the Serbian population was overweight, classified as pre-obese (35.1%) and obese (21.2%) [21]. Contrary to the overweight category, which included about the same percentage of men and women (20.1 and 22.2%, respectively), the pre-obese category more frequently included men (41.4%) than women (29.1%). According to the 2013 Serbian National Health Survey, conducted by the Institute of Public Health of Serbia, 4.7% of the adult population of Serbia drinks alcohol on a daily basis (8.3% of men and 1.3% of women) [21]. Every other Serbian citizen (54.4%) either does not consume fruit or consumes fruit rarely. Women, more often than men, spent their time at work sitting or standing (48.3% against 38.7%). The share of people aged 65 years and over in the total population of Serbia is 17.4%, indicating an advanced phase of demographic aging [22]. In the period between the censuses of 2002 and 2011, the average age of the entire Serbian population increased by 2 years (from 39.0 to 40.9 years in men and from 41.5 to 43.5 years in women, respectively) [21].

Unfortunately, the prolonged effects of war, manifested in collapsed health care infrastructures, lack of medicines and medical supplies, together with a large number of wounded individuals, created circumstances in which cancer prevention, diagnosis and treatment have been a major challenge in medical practice. One recent meta-analysis pointed out that wars around the globe are making the impact of war-related stress on mortality especially important [23]. However, it is difficult to separate the impact of threats caused by wars on health from the impact of economic sanctions against Serbia, similar to those already seen in Nicaragua and Cuba [24].

According to the 2011 Global Report of the United Nations High Commissioner for Refugees, during the study period, Serbia ranked among the top countries in the world by the number of refugees [25]. The wars in the former Yugoslavia during the 1990s ended with the exile and persecution of many people (around 1,000,000). Twenty years after the first war broke out in the former Yugoslavia, Serbia remains at the top of the list of European countries in terms of forced migration, as well as one of the five countries in the world facing a prolonged refugee crisis [26]. According to the results of the last census in 2011, there are nearly 300,000 forced migrants living in Serbia, equaling 3.9% of the total population. However, neither the age nor sex structure of the refugee population is different from that of the domestic population. Data for refugees were included in the Serbian population in the present study and could not be set apart as a special contingent.

Since the 1980s, mortality rates from all cancers have been falling rapidly for both sexes in North America and many Western European countries [2, 3, 8]. In some countries, however, such as Brazil, Cuba, and Malaysia, the cancer mortality trends have continued to rise in the last decade in both sexes [27]. After two decades of increase, mortality rates for all cancers have been decreasing since 2009 among both males and females in Serbia, similar to its neighbors and many other countries of the former Eastern communist bloc [28]. Reasons for the substantial decline of cancer mortality rates in Serbia since 2009 have not been completely elucidated. Stabilization of the political, social, and economic situation in the country after the 2000s, as well as the implementation of several national guidelines of good practice for the diagnosis and treatment of malignant tumors might, at least partly, explain the observed period effect.

The overall cancer mortality in Serbia can be attributed mainly to mortality from lung to colon cancer in both sexes, prostate cancer in males, and breast and cervical cancer in females. In 2012, Serbia was among the countries with the highest mortality rates from cancers of the lung, colon, pancreas, and brain in both sexes, as well as breast and ovarian cancer in females; other countries with high mortality rates in that year include Hungary, Armenia, Slovakia, Croatia, and Slovenia [2]. Globally, Serbia has the second highest mortality rate from brain cancer for both sexes, after Albania. The high mortality rate owing to brain cancer among women in Serbia is particularly worrisome. On the other hand, mortality rates from cancers of the stomach and prostate are lower in Serbia compared with other European countries.

Lung cancer is the leading cause of cancer death globally. There are different trends of lung cancer mortality in Serbia, mostly reflecting different phases of the smoking epidemic among males and females. These rates in males have recently decreased whereas they have increased in females. The cohort effects observed for both males and females born after 1951 suggest the start of a lung cancer epidemic associated with a high prevalence of tobacco smoking in Serbia. According to data for the population of Belgrade, 49% of males and 25% of females were smokers during 1976–1977, and 51% of males and 37% of females were smokers during 1988–1989 [29].

The Serbian National Health Survey recorded that the overall prevalence of daily smokers was lower in 2013 (29.2%) than in 2000 (33.0%), although a considerable increase was noted in the percentage of daily smokers among women in comparison with 2006 (26.0% in 2013 versus 22.6% in 2006) (21). Thanks to the antismoking campaign that has intensified since 2000 in the country, a decrease in the prevalence of smokers in recent years suggests that the decreasing trend in cancer mortality initiated in 2009 will continue as long as smoking prevalence continues to decline. Our results are in agreement with previous data indicating that international disparities in lung cancer mortality trends most likely reflect different rates of tobacco use in both sexes [30].

The findings of the present study suggest that mortality trends for cancer of the colon, breast, and cervix uteri had already begun to decrease in Serbia before implementation of a national screening program in 2013. The cohort effect has been decreasing for breast cancer mortality in younger generations (those born from 1961 to 1980), indicating that the generative characteristics (such as parity, use of hormonal contraceptives or hormone replacement treatment) and exposures to other risk factors are homogeneous in Serbian females. The use of hormone replacement therapy was very low (less than 1.0%) [31] whereas 1 in 20 women (5.4%) aged 20–49 years used oral contraceptives [21]. In comparison with the previous National Health Survey in 2000, physical inactivity was reduced by 12% in 2006 [21]. The findings of other studies are similar to our results [32].

In Serbia, the noted increase in cancer mortality trends among the oldest birth cohorts (for prostate cancer in males, as well as for pancreatic and hematological malignancies in both sexes) might be attributed to aging and specific exposure to risk factors in early life. The period effects in the mortality trend for hematological malignancies among males only in Serbia are not fully understood. Considering the shorter latency time than for solid organ tumors, the increased mortality trend for hematological malignancies in males during 2006–2015 might be associated with a higher exposure to numerous risk factors during this period, including participation in war and the cleaning and decontamination of fields that were contaminated by various chemicals and other pollutants during bombings [33].

This study revealed an increase in the relative risk for brain cancer mortality in both sexes among the oldest birth cohorts (from 1911 to 1935) in Serbia. This could be attributed to aging and exposure to different environmental factors (especially in agricultural occupations) in cohorts born between the First and Second World Wars, when the Serbian population was mostly rural. In addition, the contribution toward cancer development of exposure to unknown risk factors (such as infectious diseases and so forth) during early life is unclear. Although not significant, the highest increase in mortality for brain cancer was observed in cohorts born from 1946 to 1959, which some researchers have linked with the campaign for eradication of tinea capitis in Serbia during 1950–1959, in which nearly 50,000 children aged 5–15 years were subjected to X-ray treatment of the scalp [34]. The increasing period effects on mortality trends from brain cancer since 1991 could be the result of improved diagnostic procedures. These findings are similar to results reported in other studies [35].

The strength of this study is that it provides the first comprehensive nationwide estimates of cancer mortality in Serbia over a period of 25 years. Another strength is that it covers the entire Serbian population using quality data on cancer mortality, with temporal trends analyzed by both joinpoint and age-period-cohort analysis. However, there were several sources of limitations in this study. We acknowledge that a longer study period might be better for a more accurate assessment of mortality time trends; however, there were no available data for a longer period in Serbia. Of course, there is always a question of whether the cancer mortality trends were a consequence of variations in the process of registering the causes of death, as well as the reliability and validity of death certificates. However, the proportion of cases with uncertain death cause during the study period was non-significantly decreased, so a significant increase in cancer mortality in the observed period can hardly be attributed only to improvement in the quality of mortality statistical data in Serbia. There are no separate data on cancer mortality among refugees, which could possibly confound the cancer mortality pattern in Serbia. Another weakness of this study is related to the inherent limitations of age-period-cohort analysis (such as collinearity among age, period, and cohort effects or ecological fallacy).

This study represents the first nationwide estimates of cancer mortality in Serbia. The cancer mortality rates place Serbia among the countries with the highest cancer mortality worldwide. Overall cancer mortality has undergone a significant increase in the past decades. The increase in cancer mortality among males during 1991–2009 could be attributed to the increase in mortality from cancers of the lung, colon, and prostate whereas the decrease from 2009 onwards could be attributed to decreased mortality from stomach to lung cancers. In females, the increase in cancer mortality during 1991–2009 could be attributed to the increase in mortality from lung, brain, pancreas, breast, and colon cancers, whereas the decrease in mortality from 2009 onwards could be attributed to decreased mortality from breast to cervical cancers. However, after increasing for two decades, cancer mortality rates in Serbia are finally declining. Nevertheless, the increasing trend in mortality owing to lung cancer among women is particularly worrisome. These rising trends in cancer mortality indicate that improvement in primary and secondary prevention measures is needed.