It is estimated that colorectal cancer causes over 600,000 deaths worldwide annually, accounting for 7.6% of cancer-related deaths among men and 8.6% among women; this makes colorectal cancer the fourth most common cause of cancer-related death [1–3]. Although the number of deaths from colorectal cancer is almost the same in both developed and developing regions, the death rates vary by more than five times around the world [3]. According to the GLOBOCAN 2008 estimates, the highest colorectal cancer mortalities in both sexes were found in Central and Eastern Europe (20.3 per 100,000 for men, 12.1 per 100,000 for women); the lowest mortalities in both sexes were found in Middle Africa (3.5 per 100,000 and 2.7 per 100,000, respectively) [1–3].

During the last decade of the twentieth century, colorectal cancer mortality declined steeply in more developed regions: western and northern European countries (the United Kingdom, France, and Sweden), countries in North America (the United States of America and Canada), and Australia [3, 4]. At the beginning of the twenty-first century, declines were also observed in Japan, Germany, and Italy [5, 6]. In contrast, most countries in Eastern Europe (such as Russia and Romania) and Southern Europe (such as Portugal and Spain) saw a steep increase in colorectal cancer mortality; however, this was not the case in all countries (e.g., the Czech Republic, Hungary, and Slovakia) [3–5]. Trends were particularly favorable in young people (under 50 years of age), especially in young women [6]. The decreasing mortality trend for colorectal cancer in developed countries after 1990 may be attributable to the implementation of screening programs and improvements in treatment [7, 8]. More recent screening programs implemented in some European countries probably have had some effect on colorectal cancer mortality [9, 10]; recent socio-economic changes may have also had a role in reducing colorectal cancer incidence and mortality [11].

Most patients who died of colorectal cancer were aged 50 years or older [3, 6, 12]. Colorectal cancer mortality was 1–2 times higher for men than for women [6]. The etiology of colorectal cancer has not been entirely elucidated, but older age, inflammatory bowel disease, family history, dietary factors, obesity, low physical activity, alcohol consumption, and tobacco smoking have been recognized as risk factors for colorectal cancer [13, 14].

The purpose of this study was to assess temporal changes in colorectal cancer mortality in Serbia between 1991 and 2010, prior to the introduction of population-based screening.

The colorectal cancer mortality in Serbia increased considerably over the past two decades. Mortality increased particularly in men, but the trends were different according to age group and subsite. The increased colon cancer mortality among younger men is particularly worrisome. The exceptions were women, in whom no significant trend in rectal and anal cancer mortality was observed.

Worldwide in 2010, Hungary had the highest colorectal cancer mortalities for both men and women (31.1 per 100,000 men and 16.1 per 100,000 women); Georgia and Egypt had the lowest mortalities for both sexes (approximately 2.1 per 100,000 men and 1.6 per 100,000 women) [3]. Serbia was among the countries with high colorectal cancer mortality; other countries with high mortality included the Russian Federation, Poland, Portugal, Slovenia, and the Czech Republic. Except in only a few countries (Kuwait, Cuba, and Qatar), the colorectal cancer mortality was higher for men than for women [3]. The large geographic differences in the global distribution of colorectal cancer are generally difficult to explain [6]. The high mortality across central and eastern European countries, as well as in Serbia and some Mediterranean countries, likely reflects fundamental changes that occurred during the transition period since the 1980s [22]. These high mortalities are most likely the result of increased risk factors associated with “westernization,” such as increased animal fat and red meat consumption, low vegetable intake, obesity, physical inactivity, tobacco use, and alcohol consumption, which, in the past few decades, characterized newly economically developed countries [5, 10]. In our study, we found that colorectal cancer mortality increased markedly with age in the cohort of people born between 1956 and 1960. This finding must be interpreted carefully, though, because these cohort values are based on fewer deaths (i.e., lower ASRs). However, since trends in birth cohort effects usually reflect risk factor trends, this increase seems to indicate an increasing colorectal cancer risk in this cohort. During this 1991–2010 period (after the separation from the Eastern Bloc), Serbia sought to accelerate economic development, urbanization, and industrialization, which led to changes in lifestyle and dietary structure. Social circumstances in Serbia were further affected by a devastating economic crisis, which was exacerbated by United Nations sanctions, civil wars in the former Yugoslavia (1991–1995), hundreds of thousands of refugees, the collapse of the dinar, the inability to purchase needed medications, the deterioration of public health, and the bombing of Serbia (1999), as well as post-2000 changes during democratization [23, 24]. In addition, the mortality partly reflects varying data quality worldwide [25].

During the last decade, the colorectal cancer mortalities for both men and women annually declined in the United States (by 2.9% per year for all races) [4] and in most countries of Western and Northern Europe (in Germany by 2.0%, France by 1.7%, and the United Kingdom and Italy by 1.5% per year) [5]. Conversely, the colorectal cancer mortalities for both men and women have shown a continuous annual rise over the last decade in some Eastern and Central European countries, such as Russia (by 0.6% per year) and Croatia and Serbia (by 1.6% per year) [5, 26]. Also, increased trends have been observed in some Central and South American countries (e.g., Mexico and Brazil) [27]. On the other hand, in Slovakia and Slovenia the colorectal cancer mortalities were very high, but they remained constant for both men and women in the last decade [6]. In most countries, colorectal cancer mortality trends for both men and women were more favorable in young people (aged under 50 years) [6]. In Spain, Poland, and Hungary, during the period 1970–2007, particularly favorable colorectal cancer mortality trends were observed in women in all age groups compared to men [6]. The decrease in colorectal cancer mortality in the United States and Western Europe (e.g., the United Kingdom and France) could be attributed to long-term screening programs and improvements in treatment protocols, as well as to positive lifestyle changes [7–9]. In some Eastern European countries, the benefits, however, of short-term colorectal cancer screening, improvements in treatment, and recent positive changes in dietary and lifestyle habits are still only estimated [9–11, 28]. The promising colorectal cancer mortality trends in women and young people may reflect recent positive changes in diet and lifestyle habits (such as reduced alcohol drinking and tobacco smoking), which have been recommended as cancer prevention measures [11, 29].

In Serbia, the lack of decline in colorectal cancer mortality indicates suboptimal levels of cancer control. In 2013, a national program for the early detection of colorectal cancer was implemented. Countrywide data are not yet available, but a single-institution analysis found that the 5-year overall survival rate was 57.8% in patients younger than 40 and 28.5% in patients over 65 years of age [30]. For patients with colorectal cancer in Europe, EUROCARE-4 study investigators reported a 5-year relative survival rate of 53.8%; in this study, the highest survival rates were observed in the Nordic and Central European countries, and the lowest survival rates were observed in Eastern Europe [31]. In central Serbia during the period 1999–2008, colorectal cancer incidence was high and showed an increasing trend [22, 25]. The analysis of disease burden in Serbia showed that, for colorectal cancer, the harmful effects of physical inactivity were higher in women than in men (31.0% vs. 20.6% of total disability-adjusted life years [DALY]), as were the harmful effects of being overweight (16.3% vs. 13.1% of total DALY) [32]. The 2006 National Health Survey found that, in Serbia, 54.5 % of people were overweight, subdivided as 18.3% obese and 36.2% pre-obese [33]. This survey also found that the average body mass index (BMI) of Serbians older than 20 years was 26.7 kg/m² (27.4 for men and 26.0 for women); this represented a substantial increase over 2000, when the average BMI was 26.0. In 2006, nearly one-third of the employed population of Serbia (31.1%) had a sedentary type of work; this, too, represented a substantial increase over 2000, when the figure was only 25.2%. Also, more than two-thirds of Serbian people (67.7%) spent their free time mainly in a sedentary manner. In 2006 in Serbia, smoking was more prevalent in men (38.1%) than in women (29.9%). On average, men drank four times more alcohol than women (8.5 vs. 2.0 drinks per week) [33]. Similarly, in 30 European countries, the level of exposure to underlying lifestyle cancer risk factors corresponds to the pattern of cancer incidence [34]. In the present study, different time trends in mortality for both sexes and for subsites in the Serbian population suggest that colorectal cancer has, at least in part, different etiological factors. Furthermore, the possibility that proximal colon cancers differ from distal colon cancers in terms of biology or carcinogenesis could be an explanation for some variations between countries in the epidemiological and clinical peculiarities of colorectal cancer, as well as differences in cancer detection, treatment, and survival [35, 36].

A strength of our study is that it provides the first nationwide estimates of colorectal cancer mortality in Serbia in last two decades. Another strength is that it is a population-based study that used high-quality cancer data with temporal trends analyzed by both joinpoint and age-period-cohort analysis. Also, this high-quality data (including a comprehensive, countrywide death registration system in Serbia) enabled us to make comparisons with other countries [25, 37]. Regarding causes of death in Serbia, the World Health Organization (WHO) assessed the quality of data as moderate [37]. For example, for the most recent year (2012), the percentage of unknown and ill-defined cancer deaths in Serbia was 3.8%, which the WHO considered as moderate quality [25]. Contrary to the trends in many countries, the colorectal cancer mortality in Serbia is increasing. Because of this rising mortality trend in Serbia, more effective cancer prevention measures (such as measures focusing on diet and the control of healthy weight, tobacco use, and alcohol consumption), more effective treatments for colorectal cancer, and more effective cancer screening programs focusing on early diagnosis are needed.

Our study did have several limitations. First, we acknowledge that a longer study period may have enabled us to better assess mortality trends, but in Serbia no data were available for this. Second, no separate data exist on colorectal cancer deaths among refugees that can possibly confound the colorectal cancer pattern in Serbia. Clearly, a higher-quality death registration system, which is available in wealthier countries, is needed in Serbia. Third, during the study period, two different revisions of the ICD were used for cancer coding. Fourth, no data are available on colorectal cancer incidence for the entire Republic of Serbia, which limited our ability to explain the increasing mortality trends. Fifth, we had no reliable data on colorectal cancer therapy in Serbia during the study period. The available literature does not have enough relevant information concerning colorectal cancer risk factors in the Serbian population. Fecal occult blood testing has been recommended as a national colorectal cancer screening test since only 2013. Therefore, the incompleteness of colorectal cancer screening data in Serbia, which could be used to explain mortality trends, is a limitation of our study. Future studies should investigate whether patterns of risk factors are present in some age cohorts. The colorectal cancer mortality in Serbia contributes to its ranking among countries with the highest mortality. Increasing trends in the colorectal cancer mortality indicate that improved primary and secondary prevention measures, which target young men, particularly, are needed. Reduction in the burden of colorectal cancer in Serbia will require the implementation of a comprehensive national screening program.