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Age- and sex-specific spatio-temporal patterns of colorectal cancer mortality in Spain (1975-2008)
© Etxeberria et al.; licensee BioMed Central Ltd. 2014
Received: 26 November 2013
Accepted: 25 June 2014
Published: 10 July 2014
In this paper, space-time patterns of colorectal cancer (CRC) mortality risks are studied by sex and age group (50-69, ≥70) in Spanish provinces during the period 1975-2008. Space-time conditional autoregressive models are used to perform the statistical analyses. A pronounced increase in mortality risk has been observed in males for both age-groups. For males between 50 and 69 years of age, trends seem to stabilize from 2001 onward. In females, trends reflect a more stable pattern during the period in both age groups. However, for the 50-69 years group, risks take an upward trend in the period 2006-2008 after the slight decline observed in the second half of the period. This study offers interesting information regarding CRC mortality distribution among different Spanish provinces that could be used to improve prevention policies and resource allocation in different regions.
Cancer is the leading cause of death each year worldwide, and half of all deaths by cancer are due to lung, stomach, liver, colorectal, and female breast cancer . About 608,000 deaths from colorectal cancer (CRC) have been estimated worldwide annually, making it the fourth most common cause of death from cancer. In the European Union, colorectal cancer is the second most common cancer. In 2008, 450,621 people suffered from this cancer and 223,268 patients (115,624 men) died . CRC mortality rates vary among sex, age, and also among countries. Approximately 75% of colorectal cancer deaths occur in people older than 65 years of age  and in general mortality trends are falling, the decrease being generally larger in young and middle-age than in the elderly . By sex, lower mortality rates are observed for females than for males, and age- and sex-specific mortality analyses indicate that mortality rates for males are comparable with those corresponding to women approximately four to eight years older .
Some differences in colorectal cancer mortality were also found by country. In the European Union a favorable pattern in colorectal cancer mortality for both sexes was observed in countries such as Austria, France, Finland, Ireland, Italy, Netherlands, Norway, Sweden, Switzerland, and United Kingdom from the 1990s onwards, or even earlier in Belgium, Denmark, and Germany. On the other hand, colorectal cancer mortality rates were still in an upward direction in Bulgaria, Poland, and Romania (Eastern European countries), as well as in some Mediterranean countries, such as Greece, Portugal, and Spain, between 2005 and 2007 [1, 5, 6]. Different populations worldwide experience various levels of colorectal cancer, and these levels change with time . Geographical inequalities and temporal trends in small areas of CRC incidence , mortality [9, 10], or even surveillance  have been analyzed in the literature detecting interesting differences.
Age- and sex-specific CRC registered deaths and population data were obtained for 50 Spanish provinces (excluding Ceuta and Melilla) for the period 1975-2008 from the Spanish Statistical Office. Different revisions of the international classification of diseases (ICD) were involved in the studied period. Codes 153-154 and 159.0 (ICD-9) for colon and rectum cancer were used until 1998, and from 1998 onwards, codes C18-C21 and C26.0 (ICD-10) were considered.
2.1 Mortality data collection
The statistical analysis was carried out for the following four age-sex groups: males 50-69 years, females 50-69 years, males ≥70 years, and females ≥70 years. The limited number of deaths for individuals under 50 years leads us to exclude this age group for statistical analysis. Traditionally, raw measures such as the standardized mortality ratio (SMR) have been used to estimate mortality risks. However, they are highly variable in low populated areas or when the number of observed counts is small , and models are required to obtain reliable estimates by borrowing information from neighbouring areas in space and time. To analyze how the geographical patterns of the relative-risks (risks hereafter in the paper) evolve with time, a model with conditional autoregressive (CAR) distributions for space, a random walk of first order for time, and the corresponding space-time interactions [17, 18] is employed. A description of the model is briefly provided.
In these expressions - represents the Moore-Penrose generalized inverse of a matrix. The spatial neighbourhood structure (provinces are neighbours if they share a common border) determines the matrix Q s . The i th diagonal element of this matrix is equal to the number of neighbours of the i th region. The off-diagonal entries ij take the value -1 if regions i and j are neighbours and 0 otherwise. The matrix I s represents the identity matrix of dimension 50×50. The distribution of the spatial random effect is based on the parameterisation proposed by Leroux et al., where λ s is a spatial smoothing parameter that takes values between 0 and 1. Note that when λ s =0, there is no spatial variability, and when λ s =1, all the variability is spatial. Q t is determined by the temporal neighbourhood structure. Each year has two neighbours, the previous and the following one, except the first and the last years that have only one neighbour. This definition corresponds to a random walk of first order (see , p. 95). The model is estimated using penalized quasi-likelihood (PQL) [21, 22], which has been shown to perform well in a spatio-temporal setting . R code  used to fit the model is available under request.
Initially, the significance of the spatio-temporal interaction effect was assessed to decide whether or not it should be introduced in the model. This is usually achieved by testing if the variance component of the spatio-temporal random effect is zero (). As the null hypothesis lies on the boundary of the parameter space, well known likelihood ratio tests and score tests do not follow the classical χ 2 distribution [25–28]. Here, a score test and its bootstrap null distribution is used instead (see  for more detail). The probability of rejection has been calculated from the null distribution of the score test obtained with 300 bootstrap replicates for each of the datasets described at the beginning of this subsection. In all cases, the null hypothesis is rejected at 5% significance level. As a result the spatio-temporal interaction was included in the model. This completely structured interaction means that the temporal trend in a given region is similar to the average trend in neighbouring regions.
To show a general overview of colorectal cancer mortality throughout the period in Spain, the spatio-temporal pattern of CRC mortality risks are plotted for both males and females in the different age groups. Secondly, for a more detailed analysis, temporal trends are represented by sex and age groups (50-69 and ≥70) for each region. Confidence intervals for the risks are also given . These measures help us to detect extreme risk areas. To do that, the relative risks should be interpreted as follows. The risk of Spain in the whole period is represented as a horizontal line at one. A lower bound of the confidence band above the horizontal line indicates that the CRC mortality risk in that area and year is significantly higher than the risk of the whole of Spain in the studied period. On the other hand, if the upper bound of the confidence band is below the horizontal line, the risk of that area and year is significantly lower than the risk of the whole country in the studied period. Finally, if the horizontal line is between the lower and the upper bounds of the confidence band, the risk of that area is not statistically different from the risk of Spain.
Colorectal cancer mortality deaths and crude rates (100,000 inhabitants), 1975-2008, by tumour, sex and age group
Regarding males, risks are lower than one at the beginning of the study period and they increase with time. From mid-1990s onward risks are significantly higher than one in some provinces and this excess risk does not decrease at the end of the period. Provinces with excess risk are mainly located in the northern strip: the Galician provinces (La Coruña, Lugo, Ourense, and Pontevedra), Asturias, Cantabria, the Basque provinces (Álava, Guipuzcoa, and Vizcaya) and Navarra. In the East, the Catalonian provinces (Lleida, Girona, Barcelona, and Tarragona), Valencia and Baleares islands also exhibit high risks. In the central part of Spain, some provinces of Castilla and León (León, Palencia, Burgos, Valladolid, and Salamanca) display increasing trends with high risks at the end of the period, and finally, the risk is higher than one at the end of the period in some provinces in the South (Cádiz and Sevilla). However, it seems that at the end of the period there is a change in trends in most of these provinces indicating that risks could start to decrease.
For females, trends differ from those for males in the same age group. In general they are rather flat and in most provinces risk for females is not significantly different from that of females in Spain as a whole for the same age group, with the exception of Valencia and Castellón (Mediterranean area) where the risks are significantly higher than one during nearly the entire period. In other provinces such as Lleida, Girona, Barcelona, and León, risk is significantly greater than one during the 1990s. The most striking feature for females is that risk seems to start increasing from 2006 onward after the slight decline observed in the second half of the period. It would be interesting to check if this increase continues in the near future.Temporal risk trends for males and females within the age group ≥70 years are shown in Figure 5. Similar to the previous sex-age groups, trends for males increase with time, and risk is significantly greater than one from the mid-1990s onward in the northern strip, the Mediterranean area (Catalonian and Valencian provinces), central Spain, and the south (Sevilla and Cádiz). A key difference for the age-group 50-69 years is that for males ≥70, the increase in risk persists until the end of the period suggesting that is still growing for most provinces. Trends for females are again rather flat, and the same provinces, Valencia and Castellón, exhibit high risk during almost the whole period. On the other hand, Cuenca, Albacete, Granada, Córdoba, Las Palmas, and Santa Cruz de Tenerife are low-risk provinces throughout the period.
In this study, spatio-temporal patterns of colorectal cancer mortality risks are analyzed for males and females in two age groups. Maps reveal differences by sex. Risk temporal trends by provinces and age groups are also provided. For males in both age groups (50-69 and ≥70), a pronounced increase in risk is observed in the north and central part of Spain, Mediterranean area, and some provinces in the south. For males between 50 and 69 years of age, risks tend to stabilize from 2001 onward, whilst for the age-group ≥70, risks seem to be still growing. A group of high-risk provinces was found in the northwest of Spain. Some of these provinces also have a high gastric cancer mortality risk . For females, the temporal patterns are rather flat along the period, although in age group 50-69 risks seem to increase at the end of the period, a striking feature that requires further research. A clear declining gradient north to south in both the western and eastern band of the country is found in females aged between 50 and 69 years, whereas for females ≥70 years of age, the geographical pattern is not so clear.
A limitation of our study is that it is of ecological nature because we have no explanatory variables related to socioeconomic index, sociocultural habits, or diet. Hence, we can only speculate about the factors that have contributed to the provincial differences observed in the spatio-temporal CRC mortality distribution. Colorectal cancer is believed to be an environmental disease defined by lifestyle factors  including diet, physical exercise, tobacco smoking, and use of alcohol . Some studies indicate that dietary factors (such as high red meat intake , low vegetable consumption  among others) are responsible of 25% of the incident cases [35, 36]. Physical inactivity  is also associated with an increase of colorectal cancer risk. The Eurobarometer of 2006 indicated that prevalence of physical inactivity in the Spanish adult population was high in comparison with other countries with similar socio-economic level . It is also known that an excess of body mass index (kg/m 2) is also consistently associated with high CRC risk [39, 40] and some small-area studies have demonstrated that socioeconomic deprivation increases mortality risks of CRC . Temporal trends in this paper reveal different patterns of colorectal cancer mortality risks by sex. It is difficult to explain the different patterns between the two sexes, but these favorable trends in women may be attributed in part to healthier dietary and lifestyle habits. A study that analyzed the principal cancer risk factors in Spain in 2006/2007 reported that the frequency of consumption of fruit and vegetables among the women was higher than in men, 80.7% and 70.9% respectively. The percentage of the obese population (BMI ≥ 30 kg/m 2) stood at 15.2% among women and 15.5% among men and the percentage of consumers of alcohol in quantities posing a risk was 1.2% for females (out of 21-40 gr. daily ) and 3.3% for males (out of 41-60 gr. daily ) in Spain . Very recently, an ecological study was designed to examine the association between colorectal cancer mortality risk and proximity of residence to industrial installations . Those authors suggest that living near industries with pollutant emissions to air could be a risk factor for CRC, detecting higher mortality due to these tumours for both sexes.
The Spanish National Health System is decentralized, with responsibility being delegated to the health systems of the Autonomous Regions. Then, each Autonomous Region is responsible for local application of the cancer screening programs. The Spanish Health Ministry’s Strategic Plan against Cancer  following the European Guidelines  set up preventive-action programs and guidelines for high-risk groups and planned the implementation of a screening program for medium- to low-risk populations aged between 50 and 69 years, recommending biannual Fecal Occult Blood testing (FOBT) as the first screening option, and leaving each Autonomous Region to decide which specific FOBT should be used (biochemical or immunological) [46, 47].
At present, 12 out of 17 Spanish Autonomous Regions have initiated screening programs, and eight of them have results of at least one screening round . The first region initiating a population-based pilot screening program was Cataluña in 2000, followed by Valencia and Murcia over the years 2005-2006. The Basque Country, Cantabria, and the Canary Islands started in 2008-2009, La Rioja in 2010, and Aragón and Castilla-León in 2011-2012. Finally Navarre, Extremadura, and Galicia joined this group in 2013 [13, 47]. The remaining regions have undertaken to initiate these programs progressively in the short term . The initiated programs include males and females aged 50-69 years as target population except Cantabria (which starts at age 55 years), Aragón (50-59 for males and 50-54 for females), and Valencia (50-69 for males and 60-69 for females) [13, 50]. The data provided by the Spanish Statistical Office showed that the coverage of these programs in Spain was 4% in 2009, 11% in 2010, and 12% in 2011. In 2012 a coverage of 17% was achieved in the whole country. To be precise, 1,744,773 people were included in the programs from a total of 10,283,772 people aged between 50-69 according to the official national census . By regions, the highest coverage was observed in Cantabria (72%), followed by the Basque Country (71%), Aragón (50%), Valencia (46%), Canary Islands (39%), Murcia (28%), and Cataluña (21%). The coverage in the rest of the regions was between 1% and 14%. A 50% coverage is expected in the whole of Spain for 2015 .
These programs are relatively new and it is too early to assess their impact on mortality. In the future it will be interesting to examine if there is an association between mortality rates and screening uptake as has happened for breast cancer . Some studies show that the decrease in death is related to the implementation of the screening programs. For example, a reduction in mortality by 16% was achieved after 11 years compared with the neighbouring areas in Burgundy (France) when FOB screening was offered to a population of 90,000 subjects. Incidence of colorectal cancer was unaffected .
In conclusion, this updated analysis of spatio-temporal patterns of colorectal cancer mortality in Spain between 1975-2008, divided by sex and age, can offer an interesting picture from an epidemiological and public health perspective. CRC mortality trends show an increase in CRC deaths in the oldest age groups in men. The findings of this paper should be taken into account when deciding whether or not to implement screening programs in all provinces.
This research has been supported by the Spanish Ministry of Science and Innovation (project MTM 2011-22664, which is co-funded by FEDER). The authors would like to thank the National Epidemiology Center (area of Environmental Epidemiology and Cancer) for providing the data.
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