Cancer: Global Burden, Trends, and Projections

Cancer: Global Burden, Trends, and Projections Freddie Bray and Kevin D Shield, Section of Cancer Surveillance, International Agency for Research on Cancer, Lyon, France Ó 2017 Elsevier Inc. All rights reserved. This article is an updated version of the previous edition article by Freddie Bray, volume 1, pp. 424–451, Ó 2008, Elsevier Inc.

Nomenclature AFCRN African Cancer Registry Network ASR Age-standardized rate CI5 Cancer Incidence in Five Continents HDI Human Development Index

IARC International Agency for Research on Cancer PSA Prostate-specific antigen TURP Transurethral resection of the prostate WHO World Health Organization

Glossary Cancer Incidence in Five Continents (CI5) A serial publication (currently in its tenth iteration) of high-quality cancer incidence data from cancer registries. Case fatality (cancer) The probability of dying from cancer within a given period of time after diagnosis (1 – survival rate). GLOBOCAN A global cancer database that provides data for 184 countries on cancer incidence, mortality, and prevalence for 27 cancer sites by age and sex. Incidence rate (cancer) The frequency of occurrence of new cases of cancer in a defined population for a given period of time. The numerator is the number of new cancer cases and the denominator is the person-time at risk from which the cases in the numerator arose.

Introduction Cancer is a leading cause of death and disability globally (Lozano et al., 2013; World Health Organization, 2016; Soerjomataram et al., 2012; Ferlay et al., 2015), the scale and profile of which can be linked to the Human Development Index (HDI) (Bray et al., 2012). Population growth (Torre et al., 2015), population aging (particularly in developing societies) (Lutz et al., 2008; Lloyd-Sherlock et al., 2012), changes in lifestyle behaviors that increase the risk of cancer (such as smoking, obesity, alcohol consumption), and reproductive changes among women (including a decrease in parity and an increase in the age at first birth) (McCormack and Boffetta, 2011) have led, and will continue to lead, to an increase in the magnitude of the cancer burden at all geographical levels (Bray et al., 2015). The current cancer burden is not uniform however, and nor will be the expected future increase in this burden (Bray, 2016). Therefore, an understanding of how cancer incidence, mortality, and prevalence are measured, together with robust statistics on the variations in the historical and current cancer burdens as well as predictions of future cancer burdens, is critical for cancer prevention, early detection, and the development of risk reduction programs. This article aims to summarize (1) the methodology used to collect information on global cancer incidence, mortality,

International Encyclopedia of Public Health, 2nd edition, Volume 1

Mortality rate The number of deaths in a population from a given cause over a given period of time. Prevalence (cancer) The number of people alive as of a given date who have been diagnosed with cancer (complete or lifetime prevalence), or who have been diagnosed with cancer within a given number of previous years (partial prevalence). This measure reflects both incidence and prognosis. Survival (cancer) The time that elapsed between the diagnosis of and death from cancer. Survival (cancer) proportion The percentage of people who are alive after a given period of time after having been diagnosed with cancer.

and prevalence as well as how to estimate these statistics where data are sparse or nonexistent; (2) global variations in cancer incidence, mortality, and prevalence; (3) trends in cancer incidence and mortality based on high-quality data from worldwide cancer registries; and (4) the expected changes in the global profile of cancer by 2030 due to anticipated changes in population age structures and to population growth.

Routine Measures of Cancer Burden Various measures are used to quantify the cancer burden at the local, national, regional, and global levels (Ferlay et al., 2015), with numerous data sources available to enable quantification of this burden. These measures include cancer incidence (the number of new cancer cases over a given period of time), cancer prevalence (the number of people living with cancer over a given period of time), and cancer mortality (the number of cancer deaths over a given period of time).

Incidence Differences in the incidence of various cancers over a given period of time are useful in providing clues as to the

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Cancer: Global Burden, Trends, and Projections

underlying etiology of cancer incidence. These differences are also useful in providing data on cancer occurrences and transitions (Ferlay et al., 2015) for the purposes of assessing and controlling the impact of cancer in the community through planning, evaluating, and prioritizing resources for primary prevention where the aim is to reduce cancer incidence by means of changes in cultural and personal patterns of behavior (Weir et al., 2003). Data on the incidence of new cancer cases are collected by population-based (regional or national) cancer registries which classify such information in a defined population. The comparability, completeness, and accuracy of these data are essential for making reliable inferences regarding geographical and temporal variations in incidence rates. Cancer Incidence in Five Continents (CI5) (see Relevant Websites), published by the International Agency for Research on Cancer (IARC) and the International Association of Cancer Registries, is considered to be the most comprehensive and accurate source of cancer incidence data and only includes data from high-quality population-based cancer registries. Specifically, CI5, which was first published in 1966 (Doll et al., 1966), is now in its tenth volume (Forman et al., 2013), containing information from 290 cancer registries in 68 countries about cancers diagnosed from 2003–07. Additionally, the CI5plus database compiles comparable incidence rates across time, allowing for the analysis of rate trends in cancer incidence.

Mortality Cancer mortality (for a given cancer) is a key measure of the cancer’s impact and is determined based on both cancer incidence and fatality (1 – survival rate). As data on cancer mortality are dependent upon cancer survival, in countries with a high HDI, where both treatment and cancer management have markedly improved (De Angelis et al., 2014), trends in incidence and mortality can be divergent. Data on mortality are collected through vital registration systems, where, typically, a medical practitioner certifies the occurrence and cause of death (Mathers et al., 2005); however, in many resource-poor areas of the world, data on occurrence and cause of mortality are often collected through verbal autopsies (Mathers et al., 2005; Dikshit et al., 2012). The International Classification of Diseases (ICD) provides a standardized system of nomenclature and coding for mortality data, as well as a suggested format for death certificates (World Health Organization, 2007). The quality of mortality data, in general, is affected by both the degree of detail and the quality of the information, namely, the accuracy of the recorded cause of death, the completeness of registration, and the population coverage of the databases; indeed, mortality data are more comprehensively available than are incidence data. Data on cancer mortality are also available from the cancer mortality database of the World Health Organization (WHO) and held at IARC, which contains national cancer mortality data from 120 countries, covering, in many cases, extended periods of time (International Agency for Research on Cancer, 2016); however, these data are typically from more developed

countries, with the quality of the data varying in its completeness and coverage.

Prevalence Cancer prevalence is a combined measure of cancer incidence and fatality, knowledge of which assists in the quantification and development of the strategies needed for treating and supporting cancer patients (Bray et al., 2013). As such, data on cancer prevalence are estimated based on cancer incidence and fatality data; where such data are not available or are incomplete, they are based on mathematical modeling (Bray et al., 2013). However, unlike the measures of incidence and mortality, there is no universal definition of prevalence. Total (or complete) prevalence indicates the number of people in a defined population who are alive and have a previous diagnosis of cancer. Limited-duration (or partial) prevalence is estimated based on the number of people who are alive in a population and who have a previous diagnosis of cancer and is based also on the number of years since diagnosis, i.e., initial cancer treatment (within 1 year), clinical follow-up (2–3 years), and possible cure (4–5 years).

Trends in Incidence and Mortality Investigations of cancer trends have important applications in epidemiological research and in planning and evaluating cancer prevention strategies. Analyses of how rates of different cancers are changing in different populations over time can provide clues to the underlying determinants and serve as aids in formulating, implementing, or further developing population-based preventative strategies. Genetic factors have only a minor impact on time trends of cancer in the absence of large migration influxes and exoduses within the population under study. Issues concerning data quality and other detectable artifacts in interpreting time trends have been comprehensively addressed (Saxen, 1982; Muir et al., 1993), and cancerspecific artifacts and their likely effects on time trends are reasonably well understood. The efforts of cancer registries in standardizing procedures and data definitions have been important in providing consistently high-quality cancer incidence data and ensuring comparability of these data over time. Global trends in the five most common cancers are presented herein as age-standardized rates (ASR) using data compiled in successive volumes of the CI5. While these figures can only provide a broad overview of trends, references are made to trends in cancer mortality (where the trends diverge from incidence), in the age-specific rates by calendar period or birth cohort (where the age-adjusted trends are partially misleading), and according to subsite or histological groups (where they differ from the overall trend).

Data Synthesis: Global Estimates of Cancer Burden National cancer incidence, mortality, and prevalence data are available for a minority of countries, so estimation procedures are necessary to obtain a comprehensive global picture of cancer. The GLOBOCAN 2012, which used multiple data

Cancer: Global Burden, Trends, and Projections

Figure 1

Map depicting sources of incidence data and methods of estimation worldwide for GLOBOCAN.

sources, provides data for 184 countries by sex and age on cancer incidence, mortality, and prevalence (based on cancer survival) for 27 major cancer sites (Ferlay et al., 2015). The available sources and methods used to derive the GLOBOCAN 2012 by country estimates are summarized in Figure 1 (incidence) and Figure 2 (mortality). The preferable data for the compilation of cancer statistics are high-quality and high-coverage cancer incidence, mortality, and survival data sets for a given country. Incidence rates for a country are obtained wherever possible from cancer registries, and national mortality data are obtained from the WHO’s cancer mortality database. Adjustments are

Figure 2

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made where underreporting of mortality is suspected, and deaths recorded as due to uterine cancer are reallocated to the specific sites of the cervix or corpus uteri (Ferlay et al., 2015). When incidence data are unavailable or inaccurate, such data may be estimated by applying a registry-based incidence:mortality ratio to national mortality data; however, this ratio is dependent on country-level factors, as large survival differences exist between countries (Sankaranarayanan et al., 2010; De Angelis et al., 2014). Lastly, global prevalence is estimated by combining the estimated incidence data with corresponding estimates of survival (Pisani et al., 2002).

Map depicting sources of mortality data and methods of estimation worldwide for GLOBOCAN.

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Data from GLOBOCAN 2012 are provided as numbers, crude and age-adjusted rates, including ASRs based on population weights using the world standard (Doll et al., 1966). While the crude rates can be important as measures of the cancer ‘load,’ for planning purposes, the use of ASRs allows for differing population age structures between countries and regions. Data on cancer incidence, mortality, and prevalence are also provided in GLOBOCAN 2012 according to 21 geographical regions. Furthermore, countries can also be grouped according to their HDI, a summary measure of the average achievement in three dimensions of human development: (1) a long and healthy life, (2) knowledge (i.e., educational achievement), and (3) a decent standard of living (i.e., gross national income per capita, adjusted for purchase power parity) (Anand, 1994).

Global Cancer Burden in 2012 Excluding nonmelanoma skin cancers, 14.1 million people were diagnosed with cancer in 2012, 8.2 million people died of cancer, and 32.5 million people were living with cancer (5-year prevalence) (see Table 1). The five leading contributors to cancer incidence in terms of all new cancer cases were lung cancer (13.0%), breast cancer (11.9%), colorectal cancer (9.7%) prostate cancer (7.8%), and stomach cancer (6.8%); these cancers contributed almost 50% of all new cancers in

Table 1

2012. Indeed, over one-half of the total cancer mortality burden in 2012 was caused by four of the five above-noted leading contributors to cancer incidence. Lung cancer was the most common cause of cancer mortality, responsible for close to one in every five cancer deaths (19.4%), followed by liver (9.1%), stomach (8.8%), colorectal (8.5%), and breast cancer (6.4%). Lastly, the top five cancers within the 5-year prevalence category (taking into account both incidence and prognosis) contributed more than 50% of total cancer prevalence: breast cancer accounted for close to one in every five cancer cases (19.2%), followed by cancers of the prostate (11.9%), colorectum (10.9%), lung (5.8%), and cervix (4.8%). Men had a higher cancer incidence (7.4 vs. 6.7 million new cancer cases among men and women, respectively) and a higher cancer mortality (4.7 vs. 3.5 million cancer deaths of men and women, respectively) in 2012, whereas women had a higher 5-year prevalence of cancer (15.3 vs. 17.2 million among men and women, respectively). The distribution and frequency of the different cancer types varied also by sex (see Figure 3). In women, breast and colorectal cancer ranked first and second for both new cancer cases and 5-year cancer prevalence, while breast and lung cancer ranked first and second for cancer deaths. For men, lung and prostate cancer ranked first and second for new cancer cases, lung and liver cancer ranked first and second for cancer mortality, and prostate and colorectal cancer ranked first and second for 5-year cancer prevalence.

Estimated new cancer cases, deaths, and 5-year prevalence by cancer site in 2012

Cancer site (ICD-10 code)

Incident cases

%

Deaths

%

5-year prevalence

%

Lip, oral cavity (C00–08) Nasopharynx (C11) Other pharynx (C09, 10, C12–14) Esophagus (C15) Stomach (C16) Colorectal (C18–21) Liver (C22) Gallbladder (C23, 24) Pancreas (C25) Larynx (C32) Lung (C33, 34) Melanoma of skin (C43) Kaposi sarcoma (C46) Breast (C50) Cervix uteri (C53) Corpus uteri (C54) Ovary (C56) Prostate (C61) Testis (C62) Kidney (C64–66) Bladder (C67) Brain, nervous system (C70–72) Thyroid (C73) Hodgkin lymphoma (C81) Non-Hodgkin lymphoma (C82–85, C96) Multiple myeloma (C88, C90) Leukemia (C91–95) All cancers excluding nonmelanoma skin cancer (C00–97 excluding C44)

300 000 87 000 142 000 456 000 952 000 1 361 000 782 000 178 000 338 000 157 000 1 825 000 232 000 44 000 1 671 000 528 000 320 000 239 000 1 095 000 55 000 338 000 430 000 256 000 298 000 66 000 386 000 114 000 352 000 14 068 000

2.1 0.6 1.0 3.2 6.8 9.7 5.6 1.3 2.4 1.1 13.0 1.7 0.3 11.9 3.8 2.3 1.7 7.8 0.4 2.4 3.1 1.8 2.1 0.5 2.7 0.8 2.5 100.0

145 000 51 000 96 000 400 000 723 000 694 000 746 000 143 000 330 000 83 000 1 590 000 55 000 27 000 522 000 266 000 76 000 152 000 307 000 10 000 143 000 165 000 189 000 40 000 25 000 200 000 80 000 265 000 8 202 000

1.8 0.6 1.2 4.9 8.8 8.5 9.1 1.7 4.0 1.0 19.4 0.7 0.3 6.4 3.2 0.9 1.9 3.7 0.1 1.7 2.0 2.3 0.5 0.3 2.4 1.0 3.2 100.0

702 000 229 000 310 000 464 000 1 538 000 3 544 000 633 000 206 000 212 000 442 000 1 893 000 870 000 80 000 6 232 000 1 547 000 1 217 000 587 000 3 858 000 215 000 907 000 1 320 000 343 000 1 206 000 189 000 833 000 229 000 501 000 32 455 000

2.2 0.7 1.0 1.4 4.7 10.9 2.0 0.6 0.7 1.4 5.8 2.7 0.2 19.2 4.8 3.7 1.8 11.9 0.7 2.8 4.1 1.1 3.7 0.6 2.6 0.7 1.5 100.0

Data source: Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D., Bray, F., 2015. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386.

Cancer: Global Burden, Trends, and Projections

Figure 3

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Cancer burden in 2012 among men and women.

Cancer incidence, prevalence, and mortality also varied greatly by geographic region and human development level, the latter measured by four-level HDI aggregate of countries (see Table 2). The largest number of new cancer cases occurred in countries indexed with very high HDI levels (40.9% of all cases), followed by countries indexed as medium (37.2%), high (15.1%), and low (6.7%) HDI. Conversely, the largest number of cancer deaths occurred in countries with medium HDI scores (contributing 44.6% of all cancer deaths), followed by very high HDI (31.8%), high HDI (15.2%), and low HDI (8.4%) countries. Adjusting for population size and age structure, a clear increase in the ASRs of cancer incidence can be observed between low HDI countries (with 112.8 cases per 100 000 people) compared to very high HDI countries (with 278.1 cases per 100 000 people). The ASRs for mortality, although lower for low HDI countries (86.7 cancer deaths per 100 000 people) were relatively similar for countries with medium, high and, very high HDI scores (100.8, 102.3, and 105.5 cancer deaths per 100 000 people, respectively). The observed increase in cancer incidence rates as HDI increases is partially

attributable to population growth and aging (see cancer projections section). The relative contribution of different cancer sites to the burden also varied between HDI regions (Figures 4 and 5). For example, in very high HDI countries, breast, prostate, lung, colorectal, and stomach cancers were the largest contributors to the overall incidence, while in low HDI countries, the corresponding five cancers were breast, cervix, liver, prostate, and esophagus. The mortality in terms of leading sites was similar in very high HDI countries, although cancer of the prostate was displaced by pancreas within the top five cancers, while the very same five cancers contributed to the mortality burden in low HDI countries as was seen for incidence. In 2012, the cancer burden was greatest in eastern Asia (including China), where approximately 3 in 10 of the new cancer cases (4.1 million new cancer cases) and 2.8 million cancer deaths occurred. After adjusting for population size and structure, the ASRs showed a large geographical variation in the number of new cancer cases and cancer deaths. Specifically, the ASRs for new cancer cases were highest in Australia/ New Zealand, northern America, and western Europe, while

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Table 2

Estimated new cancer cases and deaths by geographical region and Human Development Index (HDI) designation in 2012 Incidence

World region

ASR

Casesa

World Low HDI Medium HDI High HDI Very high HDI Africa Eastern Middle Northern Southern Western Latin America and Caribbean Caribbean Central America South America Northern America Asia Eastern Southeastern South-central Western Europe Central and eastern Northern Southern Western Oceania Melanesia Micronesiab Polynesiab Australia/New Zealand

182.0 112.8 144.2 180.2 278.1 123.4 137.8 100.8 129.7 177.5 95.4 177.0 185.4 133.6 190.6 315.6 152.2 186.0 138.2 100.1 168.3 253.6 216.1 277.4 253.6 292.1 298.4 164.7 171.4 200.7 318.5

14 068 000 943 000 5 232 000 2 126 000 5 759 000 847 000 287 000 74 000 221 000 83 000 182 000 1 096 000 91 000 198 000 808 000 1 786 000 6 763 000 4 145 000 786 000 1 514 000 318 000 3 420 000 1 037 000 526 000 769 000 1 088 000 155 000 10 000 800 1 200 143 000

Mortality % of global cancers 100.0 6.7 37.2 15.1 40.9 6.0 2.0 0.5 1.6 0.6 1.3 7.8 0.6 1.4 5.7 12.7 48.1 29.5 5.6 10.8 2.3 24.3 7.4 3.7 5.5 7.7 1.1 0.1 0.0 0.0 1.0

ASR

Casesa

102.4 86.7 100.8 102.3 105.3 89.9 106.5 81.3 86.8 112.5 71.6 94.9 102.0 73.7 101.2 105.5 100.1 117.7 94.8 69.3 103.0 113.1 123.4 108.2 105.2 105.0 102.5 116.4 79.7 108.1 97.6

8 202 000 690 000 3 657 000 1 244 000 2 607 000 591 000 208 000 57 000 143 000 51 000 131 000 603 000 53 000 111 000 440 000 692 000 4 500 000 2 758 000 529 000 1 023 000 189 000 1 756 000 638 000 245 000 390 000 483 000 60 000 7 000 400 700 52 000

% of global cancers 100.0 8.4 44.6 15.2 31.8 7.2 2.5 0.7 1.7 0.6 1.6 7.4 0.6 1.4 5.4 8.4 54.9 33.6 6.4 12.5 2.3 21.4 7.8 3.0 4.8 5.9 0.7 0.1 0.0 0.0 0.6

Most common cancer (% of regional cancers) Lung Breast Lung Breast Breast Breast Cervix uteri Cervix uteri Breast Breast Breast Prostate Prostate Breast Breast Prostate Lung Lung Breast Breast Breast Breast Colorectum Prostate Colorectum Prostate Prostate Breast Lung Prostate Prostate

13.0 15.6 16.4 13.2 13.0 15.8 15.9 15.6 17.9 12.4 21.8 13.9 20.6 12.6 14.3 14.6 15.5 19.2 13.7 14.8 13.4 13.4 13.5 15.5 13.7 14.9 16.8 13.7 19.7 18.4 17.6

Most common death (% of regional cancers) Lung Breast Lung Lung Lung Breast Cervix uteri Cervix uteri Liver Lung Liver Lung Lung Stomach Lung Lung Lung Lung Lung Breast Lung Lung Lung Lung Lung Lung Lung Cervix uteri Lung Lung Lung

19.4 10.8 21.4 15.7 22.2 10.7 13.5 13.9 13.0 13.0 16.9 12.4 16.7 10.4 12.8 27.1 20.8 25.8 17.7 10.2 18.1 20.1 19.1 21.4 20.4 20.7 17.8 10.3 38.2 22.7 19.0

a

Rounded to the nearest 1000. rounded to the nearest 100. ASR, age-standardized rate. Data source: Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D., Bray, F., 2015. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386.

b

the ASRs for new cancer cases were lowest in central and middle Africa, and south-central Asia. The highest ASRs for cancer deaths were observed for central and eastern Europe, eastern Asia, and southern Africa. The overall risk in different regions reflected the additive contribution of different forms of cancer. In northern Africa, although incidence and mortality rates were low, cancers associated with infections were more common relative to other types of cancer (De Martel et al., 2012). In contrast, in southern Africa, where incidence rates were elevated relative to other regions in continent, there were high rates of a prostate, cervical, breast, lung, and colorectal cancer.

Incidence of and Mortality Trends for the Five Most Common Cancers Lung Cancer For decades, lung cancer has ranked as the most important neoplasm in terms of both incidence and mortality (Parkin et al., 1999; Torre et al., 2015, Murray and Lopez, 1997).

Indeed, in 2012, lung cancer ranked as the leading contributor to cancer incidence, with over 1.8 million new lung cancer cases diagnosed annually, accounting for more than one in eight of all new cancer cases. Lung cancer was also the leading form of cancer mortality, with 1.6 million cancer deaths, or almost one in five of all cancer deaths. There was a clear association between lung cancer and human development, with the ASRs for new cancer cases and cancer deaths being 5.9 and 4.9 times higher in very high HDI countries when compared to low HDI countries, respectively. Geographically, lung cancer incidence ranked first in few geographical regions; however, lung cancer was the largest contributor to new cancer cases in eastern Asia, the region which experienced the highest overall incidence in 2012. In contrast, lung cancer was the largest contributor to cancer mortality in the majority of geographical regions. At the country level, the highest ASRs of new lung cancer cases and deaths were observed in Hungary and Serbia (see Figure 6). Temporal studies of smoking and the resulting lung cancer incidence and mortality have played an important part in

Cancer: Global Burden, Trends, and Projections

353

Lung Breast Colorectum Prostate Stomach Liver Cervix uteri Esophagus Bladder Non-Hodgkin lymphoma Leukemia Pancreas Kidney Corpus uteri Lip, oral cavity Thyroid Brain, nervous system Ovary Melanoma of skin Gallbladder Larynx Other pharynx Multiple myeloma Nasopharynx Hodgkin lymphoma Testis Kaposi sarcoma 0

2

4

6

8

10

12

14

16

18

Cancer cases (100 000)

Figure 4

Low

Medium

High

Very high

New cancer cases in 2012 for 27 different cancer sites and by Human Development Index (HDI) designation.

determining the role of smoking as the primary cause of the disease (Proctor, 2012). The contrasting trends observed in different parts of the world largely reflect the changing profile of tobacco use – the number of cigarettes smoked, the duration of the habit, and the composition of the tobacco – within different populations over time. Among men, overall lung cancer ASRs in many high and very high HDI countries – in Europe, northern America, and Australia – peaked between 1980 and 2000 and subsequently declined, although there is a distinct variability between countries in terms of the magnitude of the ASRs and the year of peak incidence (Figure 7). Additionally, previous research observed a dramatic increase in ASRs among men in many eastern European countries (Brennan and Bray, 2002). In the low and medium HDI countries, ASRs tend to be reasonably stable or decreasing; however, there is a consistent and large variation in lung cancer risk (e.g., ASRs in Uganda are more than 10 times lower than ASRs in the Philippines). The global profile of female lung cancer trends is some what different. ASRs are steadily increasing with time in most high and very high HDI countries, an observation that reflects historic increases in smoking by women (Thun et al., 2012); however, in some Western populations – including the United States and Denmark, where a long-established decrease in the prevalence of smoking among women has been observed – plateaus and recent declines can be seen in lung cancer rates. The proportion of lung cancer cases due to smoking ranges from greater than 80% of cases in the United States (US

Department of Health and Human Services, 2014) and France (Ribassin-Majed and Hill, 2015) to 61% of cases in Asia (pooled analysis of cohorts) (Zheng et al., 2014). In countries with low-to-medium smoking prevalence, smoking and smoking-related mortality due to causes which include lung cancer are currently rather low but likely to increase (Thun et al., 2012). For example, based on the projected increases in lung cancer and other tobacco-related diseases, an increased burden from tobacco-related cancers and other diseases, as observed in very high HDIs, may be expected, in the absence of intervention, in many countries in Asia, Africa, and South America (Peto et al., 1999). Since the 1950s, trends in lung cancer incidence and mortality are correlated with birth cohorts, namely incidence rates in a given birth cohort can be related to the smoking habits of the same generation (Holford et al., 2014). The ‘smoking epidemic’ (i.e., the increase in smoking rates and the subsequent increase in smoking-related mortality) produced changes in ASRs which were first observed within younger age groups, leading to increasingly higher overall ASRs as these generations reached the older age groups where lung cancer was most common (Jemal et al., 2003; Bray and Weiderpass, 2010; Islami et al., 2015). There are intriguing differences in time trends by the histological type of lung cancer (Devesa et al., 2005; Govindan et al., 2006; Lortet-Tieulent et al., 2014). Squamous cell carcinoma incidence rates among men have declined in North America

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Lung Liver Stomach Colorectum Breast Esophagus Pancreas Prostate Cervix uteri Leukemia Non-Hodgkin lymphoma Brain, nervous system Bladder Ovary Lip, oral cavity Kidney Gallbladder Other pharynx Larynx Multiple myeloma Corpus uteri Melanoma of skin Nasopharynx Thyroid Kaposi sarcoma Hodgkin lymphoma Testis 0

2

4

6

8

10

12

14

16

Cancer deaths (100 000)

Figure 5

Low

Medium

High

Very high

Cancer deaths in 2012 for 27 different cancer sites and by Human Development Index (HDI) designation.

and in some European countries, whereas among women they have generally increased (Devesa et al., 2005). In contrast, lung adenocarcinoma rates have increased in both sexes in many areas of the world (Devesa et al., 2005). Such observations are probably explained by shifts in cigarette composition toward low-tar, low-nicotine, and filtered cigarettes (Wynder and Muscat, 1995).

Breast Cancer Among women, breast cancer is the leading contributor to both new cancer cases and to cancer deaths globally, with 1.7 million new cases and 0.5 million deaths in 2012. Thus, among women, close to approximately one in four new cancer cases and one in seven cancer deaths are caused by breast cancer. Furthermore, when considering cancers among both sexes, breast cancer is the second most frequently diagnosed cancer and the fifth most common cause of cancer death. The ASRs for new breast cancer incidence in very high HDI countries are 2.5 times those of low HDI countries; however, no difference in breast cancer mortality rates was observed by HDI level. Breast cancer incidence and mortality ASRs deviated by geographical region. The ASRs for new breast cancer cases were higher in northern America, western Europe, and northern Europe, while the ASRs for breast cancer deaths were higher in western Africa, Melanesia (a subregion of Oceania), and northern Africa (Figure 8). This was exemplified at the country level where the highest ASRs for new breast cancer cases were

observed in Belgium, Denmark, and the Netherlands, respectively, while the highest ASRs for breast cancer deaths were observed in Fiji, Bahamas, and Nigeria. The ASRs for new breast cancer cases among women have increased in many countries in the last few decades, regardless of HDI level (see Figure 9). For breast cancer deaths, however, increases in ASRs for breast cancer deaths are observed for countries indexed at low-to-medium HDI levels, while in countries with high and very high HDI scores, both increases (e.g., Japan and Colombia) and decreases (e.g., Australia, Denmark, France, and the United States) have been observed. Furthermore, increases in breast cancer death ASRs were observed in many European countries from the 1950s to 1980s, particularly in eastern and southern Europe, followed by a plateau and subsequent decline (observed for both younger and older women) (Althuis et al., 2005; Bray et al., 2004). A similar trend for breast cancer has been observed also in the United States (among people who identify as both white and black) and Canada. However, breast cancer mortality has increased in several eastern European countries, including the Russian Federation, Estonia, and Hungary (Bray et al., 2004). These temporal patterns in European and North American countries are complex and are likely due to numerous and interactive risk factors (Soerjomataram et al., 2008, World Cancer Research Fund International and American Institute for Cancer Research, 2011), to the introduction of screening (Harding et al., 2015; Independent UK Panel on Breast Cancer

Cancer: Global Burden, Trends, and Projections

Figure 6

355

Age-standardized (world) rates of lung cancer, by country in 2012.

Screening, 2012), and to improved therapies and the establishment of therapeutic guidelines (Webb et al., 2004). The observed screening-related increases in incidence seen in the 1980s in some countries were attributable, in part, to the implementation of screening programs; however, in several Nordic countries, and in England, Wales, and the Netherlands, incidence rates had been rising before the introduction of national screening programs in the mid- to late-1980s (Botha et al., 2003). Furthermore, screening-related increases in incidence have not been observed in all countries following their implementation of screening programs. In addition, despite an international consensus that there is sufficient evidence for the efficacy of mammography screening of 50- to 69-year-old women in reducing breast cancer mortality (International Agency for Research on Cancer, 2002), quantification of screening’s contribution to the observed decline in mortality has been problematic. While some of the overall reduction in breast cancer mortality has been attributed directly to screening via prediction models, the observed declines (e.g., a 25% reduction

in mortality by 2000 in the United Kingdom and United States (Peto et al., 2000)) began in 1986, before screening was introduced. Indeed, some recent decreases in mortality are also seen in several countries without national screening programs, although these trends tend to be confined mainly to younger age groups (Bray et al., 2004). Some of the greatest increases in breast cancer mortality have been observed in non-Western countries, whose populations have historically been at relatively low risk for breast cancer (Bray et al., 2004). For instance, breast cancer rates in Japan of both incidence and mortality have been increasing fairly rapidly (Figure 9), an observation which is consistent with the reported increasing risk among successive generations of women (Wakai et al., 1995). The reported increases in mortality are often attributed to childbearing, dietary habits, and exposure to exogenous estrogen, resulting in a movement toward a distribution closer in profile to that of women of the very high HDI countries in Europe and North America. Again in Japan, decreasing age at menarche, increasing age at

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Low/medium HDI

High/very high HDI

Low/medium HDI

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Trends in age-standardized (world) rates of lung cancer, by Human Development Index (HDI).

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Figure 8

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Age-standardized (world) rates of female breast cancer, by country in 2012.

menopause, decreasing fertility, increasing age at first birth, and increases in both height and weight have been noted as factors contributing to an increased risk of breast cancer (Wakai et al., 1995; World Cancer Research Fund International and American Institute for Cancer Research, 2011).

Colorectal Cancer There were 1.3 million new colorectal cancer cases and 0.7 million colorectal cancer deaths in 2012. A similar number of men and women were affected, with colorectal cancer accounting for almost 1 in 10 cancer cases diagnosed and for approximately 1 in 12 cancer deaths. Due to the large difference between colorectal cancer incidence and mortality, colorectal cancer was the third most prevalent cancer globally. Colorectal cancer was strongly correlated with HDI, with colorectal cancer constituting 12.1% and 12.5% of all new cancer cases and cancer deaths, respectively, in very high HDI countries; however, in contrast, colorectal cancer constituted 4.2% and 5.3% of all new cancer cases and cancer deaths, respectively, in low HDI

countries. The burden of colorectal cancer also showed a large geographical variation, with higher ASRs for new colorectal cancer cases in Australia/New Zealand, western Europe, and southern Europe; the ASRs for colorectal cancer deaths were higher in central and eastern Europe, northern Europe, and southern Europe (Figure 10). At the country level, the Republic of Korea, Slovakia, and Hungary experienced the highest ASRs for new cancer cases, while Hungary, Croatia, and Slovakia experienced the highest ASRs for cancer deaths. While there are some important differences in the epidemiological characteristics of colon cancer compared to rectal cancer, Figure 11 depicts the sex-specific trends for colon cancer and rectum cancer combined, thus avoiding the recognized problems of varying subsite allocations of cancers found at the rectosigmoid junction. The most notable features of global trends are the rather rapid increases in male and female ASRs in countries formerly at low risk. With respect to the most recent 10-year period, there are three general groupings of countries based on the temporal

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Low/medium HDI

Figure 9

High/very high HDI

Trends in age-standardized (world) rates of female breast cancer, by Human Development Index (HDI).

pattern of new colorectal cancer cases and colorectal cancer deaths (Arnold et al., 2016). Firstly, several eastern European countries, and also populations in Latin America and Asia (including Philippines, China, and Colombia), have had increasing incidence and mortality trends. Secondly, several European countries, as well as Canada and Singapore, have experienced an increase in the ASRs for new colorectal cancer cases and a decline in the ASRs for colorectal cancer deaths. Thirdly, for countries with the highest HDI, such as Australia, Iceland, New Zealand, and Japan, decreases in both the ASRs for new colorectal cancer cases and for colorectal cancer deaths have been observed. Declines in mortality may be a consequence of changes in incidence, a result of progress in therapy, and a result of the effects of improved early detection; however, the pattern in the United States is probably due to more widespread screening, resulting in stage-specific shifts in incidence and a subsequent increase in survival (Troisi et al., 1999). In high-risk Western countries, there has been a notable shift in the subsite distribution within the colorectum, with increases in the incidence of proximal (ascending colon) compared to distal (descending and sigmoid colon) cancers (Thörn et al., 1998; Troisi et al., 1999). In low-risk populations, such as Singapore, the reverse subsite distribution has been

reported (Huang et al., 1999), while the trend in rates of proximal and distal cancers was similar in Shanghai to that found in high-risk Western countries (Ji et al., 1998). For rectal cancers, the countries with the most rapid increases in incidence are Japan and countries in eastern Europe. In the United States, there has been a decline in incidence and mortality for several decades among white and black females and among white men, although an increase in rectal cancer is apparent in black males (Troisi et al., 1999). The risk factors that could explain the geographical and temporal variations in colorectal cancer are likely numerous and interactive. The observed declines in distal cancer incidence in some Western populations may be the result of increased detection and treatment of premalignant polyps; however, overall screening of at-risk groups remains low (Meissner et al., 2006). Where colorectal cancer incidence rates are increasing, as is the case in Asia and eastern Europe, a Westernization of lifestyle may be responsible, in part, particularly as a result of the adoption of a more Westernized diet.

Prostate Cancer An estimated 1.1 million new cases of prostate cancer and 0.3 million prostate cancer deaths occurred worldwide in 2012

Cancer: Global Burden, Trends, and Projections

Figure 10

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Age-standardized (world) rates of colorectal cancer, by country in 2012.

(Table 2), making prostate cancer the fourth and seventh most frequent cancer globally in terms of new cancer cases and deaths. The incidence of prostate cancer varies with HDI, with high and very high HDI countries having ASRs 1.5 times higher than low and medium HDI countries. Geographically, the ASRs for incidence were notably elevated in central and eastern Europe and in northern Europe, while the ASRs for prostate cancer deaths were elevated in Melanesia (a subregion of Oceania) and in central and eastern Europe (Figure 12). The magnitude of such variations in incidence reflects the high prevalence of prostate-specific antigen (PSA) testing in some Western countries – as a means to detect latent cancers in asymptomatic individuals – rather than real differences in risk (Draisma et al., 2003). In this respect, mortality rates may be a better guide to true geographical differences than are incidence rates. For example, the ASR for new prostate cancer cases in the United States was 4.7 times that of China in 2012. At the country level, Martinique, France, Norway,

and Trinidad and Tobago had the highest rates of new prostate cancer cases, while Trinidad and Tobago, Guyana, and Barbados had the highest rates of prostate cancer deaths. The ASRs for new prostate cancer cases have increased in many countries regardless of their HDI. In several low-risk countries, including China, Thailand, and Japan, an increase in prostate cancer incidence over the past 20 years parallels the growth of breast and colorectal cancer incidence in those countries (Figure 13). However, for countries with higher ASRs such as the United States, ASRs for new prostate cancer cases have stabilized. In many very high HDI countries, the ASRs for prostate cancer deaths increased from 1980 to a peak in approximately 1995, after which time they decreased. For countries with a high HDI, such as Russia and Bulgaria, the ASRs for prostate cancer deaths did not peak in 1995, and further increases in mortality have been observed (Center et al., 2012). The large increases in prostate cancer incidence in high-risk countries, as illustrated in Figure 13, can be attributed

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Figure 11

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High/very high HDI

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High/very high HDI

Trends in age-standardized (world) rates of colorectal cancer, by Human Development Index (HDI).

Cancer: Global Burden, Trends, and Projections

Figure 12

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Age-standardized (world) rates of prostate breast cancer, by country in 2012.

primarily to increased detection following transurethral resection of the prostate (TURP), and, due to the use of PSA testing (Potosky et al., 1990, 1995). In the United States, incidence rates increased slowly up to the 1980s (Figure 13), probably due to a genuine increase in risk, coupled with an increased diagnosis of latent, asymptomatic cancers in prostatectomy specimens due to the increasing use of TURP (Potosky et al., 1990). Beginning in 1986, and accelerating after 1988, there was a rapid increase in incidence, coinciding with the introduction of PSA testing, allowing the detection of preclinical (asymptomatic) disease (Potosky et al., 1995). With the introduction of PSA screening, and the dramatic surge of incidence it precipitated, there was an increase in the rate of mortality, but this latter increase was much less marked than the change in incidence (Figure 13). In the United States (since 1992 in white men, and since 1994 in black men), mortality rates have decreased. The contribution that PSA screening and/or improved treatments have made to the slow, steady decline in mortality continues to be the subject of

much debate (Gavin et al., 2004). The increased mortality observed from the 1970s into the 1990s is probably partly due to misclassification of the cause of death among the large number of men who were diagnosed with latent prostate cancer in the late 1980s and early 1990s (Feuer et al., 1999). The later decline in mortality may be attributable, in part, to a reversal of this effect, as it seems unlikely that screening was entirely responsible for the initial decrease in prostate cancer mortality observed in 1992 (Center et al., 2012). Similar mortality trends have been reported in Australia, Canada, the United Kingdom, France, and the Netherlands, although, in general, they are less pronounced, or occurred later, than in the United States (Center et al., 2012). In some of the countries concerned (Canada, Australia), there has been considerable screening activity, but this is not the case in other countries where falling prostate cancer mortality rates are just as marked (France, Germany, Italy, and the United Kingdom) (Oliver et al., 2001). The rapid growth in prostate cancer incidence observed in some low-risk countries may be the result, in part, of greater

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Figure 13

Trends in age-standardized (world) rates of prostate breast cancer, by Human Development Index (HDI).

awareness of the disease and of the diagnosis of small and latent cancers. Although it remains likely that there have been genuine increases in risk in many countries related to the aforementioned Westernization of lifestyles, mortality rate increases in these populations are also large and are of a similar magnitude to the observed increases in incidence (Center et al., 2012).

Stomach Cancer Stomach cancer has historically ranked as one of the most frequently diagnosed cancers worldwide (Jemal et al., 2011; Parkin et al., 1984; Torre et al., 2015), and, according to 2012 estimates, the disease ranked fifth (1.0 million new cases). Furthermore, stomach cancer ranks as the third most common cause of mortality from cancer, with 0.7 million deaths occurring worldwide in 2012 (Table 2). The majority of stomach cancer cases and deaths affected men, with roughly twice the number of the new stomach cancer cases and deaths occurring in men compared to women. Incidence and mortality rates were highest in eastern Asia; however, these rates were also elevated in central and eastern Europe and South America (Figure 14). Furthermore, at the country level, the Republic of Korea, Mongolia, and Japan had the highest incidence of

new stomach cancer cases, and Mongolia, Guatemala, and Tajikistan had the highest rates of stomach cancer deaths. Declines in the ASRs for new stomach cancer cases and for stomach cancer deaths have been observed in most populations worldwide, a trend which has been observed for both men and women (Figure 15). This relative decline has been greatest for countries with lower ASRs for new stomach cancer cases when compared to countries with higher ASRs, such as Japan, China, Korea, Columbia, Ecuador, Ukraine, and Russia (Bertuccio et al., 2009). The reason for this decline in the ASRs in incidence and mortality is not fully understood. The temporal profile is consistent with improved food preservation techniques and better nutrition, particularly the invention of refrigeration for the transport and storage of food, making obsolete salting, smoking, and pickling. There is also evidence that, at least in countries with a higher HDI, there has been a progressive decline in Helicobacter pylori infection rates between successive birth cohorts, likely as a result of continual changes within the childhood environment (Kobayashi et al., 2004). Some studies have reported that the declines in gastric cancer are dependent on histology as they are restricted to intestinal-type adenocarcinoma, with stable incidence trends observed for the diffuse-type carcinomas (Liu et al., 2004; Wu

Cancer: Global Burden, Trends, and Projections

Figure 14

363

Age-standardized (World) rates of stomach breast cancer, by country in 2012.

et al., 2009); however, this pattern may not be universal (Ekström et al., 2000). There has been particular interest in the distinct trends of stomach cancer by site, with rates of cancer of the gastric cardia increasing in several populations (Powell et al., 2002), and concomitant increases in the prevalence of Barrett’s esophagus and adenocarcinoma of the lower third of the esophagus. It is possible, therefore, that much of the increase in gastric cardia cancer incidence represents misclassification of cancers at the gastroesophageal junction (Ekström et al., 1999).

Predicting Cancer Incidence in 2030 It is expected that future cancer burden will continue to increase over time due to changes in population risk, population growth, and aging (Bray et al., 2015). As such, the prediction of the number of new cancer cases and cancer deaths is a necessary tool for advocating and implementing cancer prevention strategies, early detection protocols, and risk reduction

programs, as well as for determining future resource allocation. Commonly, these predictions are determined by extrapolating recent trends, while accounting for anticipated population changes; however, historical patterns are not always a sound basis for future projections. Indeed, for several cancer sites, trends differ depending on the region of the world being considered, and these trends can change direction even on a short-term basis, as has been observed for lung cancer in the last decade. Irrespective of changing risks, population growth and aging are large determinants of future burden, and foreseeable demographic changes are projected to substantially increase the magnitude of global cancer incidence in the coming decades. The GLOBOCAN model predicts the cancer burden in 2030 by applying 2012 sex- and age-specific cancer incidence rates to population projections. In the absence of changing risk or intervention, it is projected that by 2030 there will be 21.6 million new cases of cancer worldwide per year, an approximate 53.9% increase from 2012 (Figure 16). The

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Figure 15

Trends in age-standardized (World) rates of stomach breast cancer, by Human Development Index (HDI).

Cancer: Global Burden, Trends, and Projections

Figure 16

Cancer Incidence Projected to 2030, by age and Human Development Index (HDI).

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greatest relative increase in cancer cases in transitioning countries will occur among the elderly (defined herein as 65 years of age or older): a 76.9% increase is projected from the 6.7 million cases in 2012 to 11.8 million by 2030. Given the projected large increase in the burden of cancer over the next decades, there is a need to provide for an older and disproportionately larger number of people who will be diagnosed with cancer within the developing and developed regions, and (although not modeled) a need to increase the capacity to reduce and nullify expected risk factor increases, such as expected increases in tobacco smoking in lower-HDI countries. This latter consideration is a particularly important strategy to combat the burden of cancer in the vast populations living in Asia, Africa, and South America, where the destructive effects of tobacco to health are beginning to be realized.

Other Considerations Other Cancer Burden Measures Cancer survival and survival proportions are also important in assessing the cancer burden in a given country, as they are partial measures of the success of early detection programs used to screen for cancer (i.e., the stage at which tumors are diagnosed and treated) (Independent UK Panel on Breast Cancer Screening, 2012; Shaukat et al., 2013; Gakidou et al., 2008), as well as of the quality and coverage of cancer treatment resources in a country. Analyses of available survival estimates from countries in Africa, Asia, and Central America (Sankaranarayanan et al., 2010), as well as from Europe (De Angelis et al., 2014), indicate that there are geographical, cancer-specific, and temporal differences in cancer survival. Increases in cancer survival, in settings where medium-level and high-level resources exist, have brought to light the relevance of changes in quality of life due to cancer-related sequelae (Van De Poll-Franse et al., 2011; Soerjomataram et al., 2012). These changes are typically measured in years lived with disability (YLD), a measure of both the magnitude of the disability experienced and the duration of this disability. YLD can be combined with data on years of life lost due to premature mortality, to estimate the disability-adjusted life years (DALYs) lost, a measure of both cancer mortality and disability experienced by long-term survivors (Murray, 1994) (see Soerjomataram et al., 2012 for global estimates of cancer DALYs lost).

Limitations in Incidence, Mortality, and Prevalence Data There are several limitations to the cancer registry incidence data. Firstly, changes in registration practices, accuracy of case ascertainment, likelihood of diagnosis of cancer, which definition of malignancy is employed, and which classification system is used (such as the revision of the ICD) can artificially impact the reported incidence rate(s) (Muir et al., 1993). Additionally, cancer incidence reporting (especially in instances such as prostate cancer) is impacted by issues of overdiagnosis (as indicated by a rise in the incidence of early stage cancer (indolent cases) without a decrease in the incidence of later stage cancer) and, consequently, patients are susceptible to overtreatment (Esserman et al., 2013). Furthermore, with

respect to CI5 data, there remains low coverage of highquality data in certain world regions. In North America, 99% of the population is covered by cancer registries included in the CI5, while only 7%, 5%, and 2% of the populations in the South American, Asian, and African regions, respectively, are covered by the cancer registries included in the CI5. The Global Initiative for Cancer Registry Development (GICR, see Relevant Websites), a partnership of funding and technical organizations led by IARC, is bringing about the needed improvement in the quantity and quality of cancer incidence through investment in PBCR. There are also several limitations to the cancer mortality data. Firstly, consistent usage of the coding systems for cause of death reporting, such as the ICD, is known to vary considerably both between countries and over time, making comparisons difficult (Janssen and Kunst, 2004). Secondly, the detail and accuracy of mortality coding is an issue with data collected through population-based cancer registries, especially with respect to the elderly and people with advanced diseases where cause of death classification is susceptible to miscoding (Schaffar et al., 2013). Data on the prevalence of cancer is limited through the requirement of both cancer registration and vital data linkage for multiple years, with long-term partial prevalence typically requiring data on cancer incidence and mortality over a long period of time. Furthermore, the utility of prevalence is limited for some cancer cases, such as where there has been a previous diagnosis of female breast cancer or prostate cancer where the risk of death remains higher than for the general population beyond 4–5 years (i.e., possible cure) from their initial treatment (Brenner and Hakulinen, 2002).

Summary Globally, cancer is a leading cause of death, with the burden expected to increase in the future. However, the burden of cancer is not uniform. Geographical and HDI-based variations are evident when one examines the distribution of common cancers outlined in this article. Furthermore, trends in incidence and mortality differ by geographical region and HDI, indicating the complex diversity of cancer as well as future cancer transitions that will see the incidence and mortality of certain (Westernization-related) cancers to increase and corresponding rates of a number of (infectionorientated) cancers to decrease. Many countries lack both formal cancer registries and the interoperability of health information systems to capture data on cancer incidence, mortality, and prevalence. Furthermore, for countries and regions where such data are available, there are often problems with data accuracy and whether they are representational (Ferlay et al., 2015). Thus, there is a need for surveillance systems to collect accurate data on cancer incidence, mortality, and prevalence (as part of populationbased systems collecting data on the occurrence of all cancers and on all-cause deaths), as well as to determine the risk factors for various cancers. These data are critical for cancer prevention and early detection and for the establishment of risk reduction programs (Glaser et al., 2005). The GICR as a collaboration of international partners working with

Cancer: Global Burden, Trends, and Projections

governments to ensure cancer registries becomes a cornerstone of cancer control; the focus is to strengthen cancer registration in the very countries in transition where surveillance is limited and for which an increasingly high proportion of the global cancer burden will be observed, as documented here.

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Further Reading Bray, F., Soerjomataram, I., November 01, 2015. The changing global burden of cancer: transitions in human development and implications for cancer prevention and control. In: Gelband, H., Jha, P., Sankaranarayanan, R., Horton,, S. (Eds.), Cancer: Disease Control Priorities, third ed., vol. 3. The International Bank for Reconstruction and Development/The World Bank, Washington, DC. Chapter 2. PubMed PMID: 26913347.

Relevant Websites http://www.afcrn.org/ – African Cancer Registry Network (AFCRN) (last accessed 06.07.16.). http://www.ci5.iarc.fr – Cancer Incidence in Five Continents (CI5) (last accessed 06.07.16.). http://www.encr.com.fr/ – European Network of Cancer Registries (ENCR) (last accessed 06.07.16.). http://www.gicr.iarc.fr – Global Initiative for Cancer Registry Development (GICR) (last accessed 06.07.16.). http://www.gco.iarc.fr – IARC’s Cancer Surveillance Website. The Global Cancer Observatory Includes “Cancer Today” (Data on Cancer Incidence, Cancer Mortality), “Cancer Over Time” (Data on Changes in Cancer Incidence and Mortality Rates Over Time), “Cancer Tomorrow” (Data on Projected Cancer Incidence and Mortality), and “Cancer Causes” (Data on Cancer Incidence and Mortality Attributable to Various Risk Factors) (last accessed 06.07.16.). http://www.iacr.com.fr/ – International Association of Cancer Registries (IACR) (last accessed 06.07.16.).