Worldwide Burden of and Trends in Mortality From Gallbladder and Other Biliary Tract Cancers

Accepted Manuscript Worldwide Burden of and Trends in Mortality From Gallbladder and Other Biliary Tract Cancers Lindsey A. Torre, Rebecca L. Siegel, Farhad Islami, Freddie Bray, Ahmedin Jemal

PII: DOI: Reference:

S1542-3565(17)30982-5 10.1016/j.cgh.2017.08.017 YJCGH 55397

To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 14 August 2017 Please cite this article as: Torre LA, Siegel RL, Islami F, Bray F, Jemal A, Worldwide Burden of and Trends in Mortality From Gallbladder and Other Biliary Tract Cancers, Clinical Gastroenterology and Hepatology (2017), doi: 10.1016/j.cgh.2017.08.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Worldwide Burden of and Trends in Mortality From Gallbladder and Other Biliary Tract Cancers

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Short title: Global gallbladder cancer mortality

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Lindsey A. Torre1*, Rebecca L. Siegel1, Farhad Islami1, Freddie Bray2, Ahmedin Jemal1

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1 Surveillance and Health Services Research, American Cancer Society, Atlanta, USA 2 Cancer Surveillance Section, International Agency for Research on Cancer, Lyon, France *Corresponding author. American Cancer Society, 250 Williams Street, Atlanta, Georgia 30303. Phone: 404-327-6591; Fax: 404-321-4669; E-mail: [email protected]

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Grant support: This work was supported by the Intramural Research Department of the American Cancer Society. The American Cancer Society had no role in the collection, analysis,

publication.

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and interpretation of data; writing of the report; and decision to submit the paper for

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Disclosures: None of the authors have any conflicts of interest to disclose. Abbreviations

AAPC average annual percent change APC annual percent change CI confidence interval

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GOB gallbladder and other biliary tract

IARC International Agency for Research on Cancer SEER Surveillance, Epidemiology, and End Results

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WHO World Health Organization

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ICD international classification of diseases

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Author contributions Study concept and design: Torre, Jemal, Siegel Data acquisition: Torre, Bray

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Statistical analysis: Torre

Analysis and interpretation of data: all authors

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Drafting of the manuscript: Torre, Siegel

Critical revision of the manuscript for important intellectual content: all authors

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Study supervision: Jemal, Siegel

All authors approved the final version to be published.

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Abstract

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Background & Aims: Gallbladder cancer has a low rate of survival, a unique geographic distribution, and is associated with lifestyle factors that have changed in recent decades. Little is known about the extent to which behavioral patterns have affected global trends in gallbladder cancer. We investigated recent mortality patterns and trends worldwide.

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Methods: We collected data from the World Health Organization’s Cancer Mortality Database to examine sex-specific, age-standardized rates of death from gallbladder and other biliary tract cancers (excluding intrahepatic bile duct cancer; ICD-9 code 156 or ICD-10 C23–24). We compiled cross-sectional rates of mortality from 2009 through 2013 from 50 countries, and also trends over time from 1985 through 2014, using joinpoint regression analysis of data from 45 countries.

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Results: Among women, from 2009 through 2013, there was a 26-fold variation in rates of mortality from gallbladder and other biliary tract cancers; rates ranged from 0.8 deaths per 100,000 in South Africa to 21.2 deaths per 100,000 in Chile. Among men, rates varied 16-fold, from 0.6 deaths per 100,000 in the United Kingdom and Ireland to 9.9 deaths per 100,000 in Chile. Rates of mortality were higher for women than men in 22 of 48 countries for which comparison was possible. Mortality rates are decreasing in most countries, with decreases in the highest-risk populations of 2% or more annually (except Croatia). However, rates continued their long-term increase in Greece, by 1.4% annually in women and 4.7% annually in men from 1985 through 2012, and began increasing in the mid-2000s by 1.9% or more annually in women in the United Kingdom and Netherlands and in men in Germany.

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Conclusion: In an analysis of the World Health Organization’s Cancer Mortality Database, we found that rates of death from gallbladder and other biliary tract cancers are decreasing in most countries but increasing in some high-income countries following decades of decline. These emerging trends may reflect lifestyle changes, such as increases in excess body weight. KEY WORDS: surveillance, cancer registries, gastrointestinal cancer, epidemiology

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INTRODUCTION

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Gallbladder cancer is highly fatal and has a unique global distribution and somewhat enigmatic

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etiology. Five-year survival is less than 20% in most countries.1, 2 It is one of only a few cancers

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generally more common in women than in men, with incidence rates two- to three-fold higher

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overall, but often greater in high-risk areas.3 Some of the highest incidence rates in the world

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have been observed in populations of the Americas with indigenous ancestry, including the

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Mapuche Indians of Chile; Alaska Natives; and Hispanics in Latin America and the US.4

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Worldwide, the highest rates have been documented among women in several countries in

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Latin America and Eastern Europe, as well as certain regions in South Asia.3 Rates among men

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are also elevated in these regions.3 Geographic variation in the prevalence of gallstones, a

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primary risk factor for the disease, contributes to worldwide gallbladder cancer patterns.4

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Decreasing rates of gallbladder cancer mortality have been reported in many countries

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worldwide, with increasing use of cholecystectomy (removal of the gallbladder) for

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symptomatic gallbladder disease proposed as an underlying reason.3, 5, 6 We report here the

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global patterns and trends in gallbladder and other biliary tract (GOB) cancer mortality by sex

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using the most recent available data from the World Health Organization (WHO) mortality

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database. Our discussion focuses on gallbladder cancer due to the relative rarity and poorly

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understood etiology of other biliary tract cancers.

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METHODS

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We used the mortality database from the WHO and International Agency for Research on

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Cancer (IARC), which contains mortality statistics for cancer from national vital registration

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systems covering about 40% of the world’s population.7 As all data are publicly available, de-

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identified, and aggregated, the study was not subject to institutional review board review. We

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compiled cross-sectional mortality rates for 2009 to 2013 and also trends over time from 1985

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to 2014. Underlying cause of death in these data was categorized according to the International

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Classification of Diseases, 9th revision (code 156) through 1991 and 10th revision (code C23–24)

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thereafter. To ensure comparability across time, we included deaths from other and

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unspecified cancers of the biliary tract (including extrahepatic bile ducts, ampulla of Vater,

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overlapping lesions of the biliary tract, and biliary tract unspecified) throughout the study

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period because these deaths were grouped with deaths from gallbladder cancer under the

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same ICD code until ICD-10. Within this grouping, gallbladder cancer forms the majority of

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deaths in most parts of the world.8 In the countries with available ICD-10 data, gallbladder

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constitutes an average of about 40% of deaths in men and 60% in women out of the total

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gallbladder and other and unspecified biliary tract cancers.9 We also examined trends for

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gallbladder cancer (C23) deaths specifically in countries with sufficiently available ICD-10 data.

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We restricted the analysis to adults age 35–74 years because gallbladder cancer is uncommon

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in those younger than 35 and to limit bias from misclassification of underlying cause of death

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among the elderly. We also limited our analyses to countries with more contemporary

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mortality data (2005 onward) and with at least 70% death registration coverage each year

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during 1990 to 2013.10 The exception was China, where we used the representative sample

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registration system; data for Hong Kong met the inclusion criteria. All rates are expressed per

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100,000 population and age-standardized to the 1960 Segi world standard population (as

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modified by Doll and colleagues).11 For cross-sectional rates (2009–2013), data were excluded if

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there were fewer than 16 deaths by sex or fewer than four years of data during the period,

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resulting in 48 countries or populations for comparison among males and 50 among females.

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We also calculated female-to-male rate ratios with 95% confidence intervals (CIs) using the

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2009–2013 rates.

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To assess trends in cancer death rates, we used joinpoint regression analysis, which fits joined

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straight lines to the observed annual age-standardized rates on a logarithmic scale.12 We report

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annual percent change (APC) for each line segment in addition to the time-weighted average

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annual percent change (AAPC) for the last five and ten years of data. Trends are “increasing” or

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“decreasing” if statistically significantly different from zero (P<0.05) and “stable” otherwise.

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Countries were excluded from the joinpoint analysis if there were fewer than ten deaths by sex

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in any year or fewer than ten continuous years of data, resulting in inclusion of 39 countries or

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populations for males and 45 for females for analysis of long-term (1985 or later through 2014)

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GOB cancer trends. These same criteria resulted in inclusion of 28 countries for males and 34

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countries for females for analysis of shorter-term (1994 or later through 2014) trends in

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gallbladder cancer death rates using ICD-10 data. We also present trends in observed GOB

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cancer mortality rates by sex from 1985 to 2014 for select populations using five-year moving

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averages.

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RESULTS

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Among women, there was a 26-fold variation worldwide in GOB cancer mortality rates during

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2009–2013, ranging from 0.8 deaths per 100,000 in South Africa to 21.2 deaths per 100,000 in

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Chile (Figure 1). Rates among Chilean women were more than three times higher than those

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among Czech women, who had the second highest rate of 6.3 deaths per 100,000. Among men,

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rates varied 16-fold, from 0.6 deaths per 100,000 in the UK and Ireland to 9.9 deaths per

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100,000 in Chile. Generally, the highest rates in both men and women were in Latin America,

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Eastern Asia, and Eastern Europe.

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GOB death rates were statistically significantly higher in women than men in all Latin American

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countries and in 22 of 48 countries overall, among which the female-to-male rate ratio ranged

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from 1.1 (95% CI 1.03-1.13) in Germany to 2.6 (95% CI 1.74-3.76) in Paraguay (Supplementary

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Table 1). In contrast, death rates were significantly higher in men than in women in Japan and

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South Korea (by as much as 37%), as well as in South Africa, Romania, Greece, Portugal, and

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Spain, while they were similar in 19 countries, predominantly in Europe.

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Over the most recent decade, GOB cancer death rates were significantly decreasing in 36 of 45

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countries among women and in 23 of 39 countries among men (Tables 1 and 2; Figure 2). Rates

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were decreasing in all included countries for women in Asia and Latin America and the

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Caribbean, although this pattern was not consistent for men. Populations with the highest

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death rates (males: Chile, Republic of Korea, Japan, Czech Republic; females: Chile, Czech

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Republic, Republic of Korea, Poland) exhibited declines ranging from 2% to greater than 3%

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annually. However, rates increased for Croatian men and Greek men and women. Trends in

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Greece were unique from all other countries in that there was a statistically significant increase

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during the entire study period that was particularly striking in men; from 1985 through 2012,

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GOB death rates rose by 1.4% per year in women and by 4.7% per year in men.

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In some countries with previous long-term declines, rates began to increase or stabilize during

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the 2000s (Tables 1 and 2; Figure 2). For example, rates in women are currently stable in

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Austria, Denmark, Germany, Mexico, and the US, and are rising in the UK and the Netherlands

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(Table 1). Similarly, the most recent joinpoint in men is stable in the UK, Hong Kong, Belgium,

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Mexico, and the US, and increasing in Germany (Table 2).

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Shorter-term trends specific for gallbladder cancer mortality (ICD-10 C23) for those countries

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with available data were generally similar to those for GOB cancer (C23-24; Supplementary

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Tables 2 and 3; Supplementary Figures 1 and 2). In several countries, the magnitude of the

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decrease was larger for gallbladder cancer mortality than for GOB cancer mortality (e.g.,

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Hungary, Poland, Sweden, and Colombia). However, in the populations for which GOB cancer

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mortality had begun to increase, trends were inconsistent. For instance, the recent rise in GOB

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cancer mortality in women in the UK and Netherlands and in men in Germany was not evident

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based on joinpoint trends confined to deaths from gallbladder cancer. Similarly, while rates

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recently stabilized for GOB cancer among women in Germany, Mexico, and the US, rates

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confined to gallbladder cancer continued to decrease.

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DISCUSSION

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There are wide variations in GOB cancer mortality rates worldwide, with the highest rates in

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Latin America, Eastern Asia, and Eastern Europe. Rates are twice as high in women as in men in

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many Latin American countries, yet are more than 30% higher in men in Japan and South Korea.

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Inconsistencies in the gender bias remain perplexing, but may be related to distinct geographic

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and genetic factors. Consistent with previous studies,5, 6, 13, 14 GOB cancer mortality continues to

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decrease in most countries, although rates appear to have recently leveled off or are even

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increasing in some populations. In contrast to long-term favorable trends in most countries, a

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steady increase in the GOB death rate in Greece among both men and women continues

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unabated. As a result of the particularly rapid rise in men of almost 5% annually, rates in men

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are currently double those in women whereas they were half those in women during the late

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1980s.

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Geographic patterns of gallbladder cancer have been correlated with the occurrence of

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gallstones (cholelithiasis), the primary known risk factor.4 One systematic review estimated that

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gallbladder disease, primarily gallstones, confers a fivefold risk of developing gallbladder

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cancer.3 However, only a small proportion (about 1%—3%) of people who have gallstones will

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go on to develop gallbladder cancer, and about 15% of gallbladder cancer patients do not have

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a history of gallstones.4 Cholesterol gallstones are the dominant form worldwide and have been

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more conclusively linked to gallbladder cancer than pigment gallstones.8 Cholesterol gallstones

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are associated with older age, obesity, and physical inactivity, as well as hormonal factors

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including multiple pregnancies and exogenous estrogen use.8 These hormonal factors at least

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partly contribute to the generally higher rates of gallbladder cancer among women.4 A genetic

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predisposition to cholesterol gallstone formation, as in the case of native peoples of the

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Americas, likely plays a role in the documented excess occurrence of gallbladder cancer in these

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populations.8 High coffee consumption, which stimulates cholecystokinin release and

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gallbladder contraction, has been associated with decreased risk of gallbladder disease15 and

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cancer.16

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In addition to gallstones, several other risk factors for GOB cancer have been identified. Factors

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associated with increased risk include obesity,17 diabetes,18 and consumption of sucrose and

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sweetened beverages.19 Numerous pathogens have also been implicated, including mycotoxins;

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Salmonella Typhi/Salmonella Paratyphi; Helicobacter bilis/Helicobacter pylori; and hepatitis B

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and hepatitis C viruses.8, 20-26 These risk factors may function wholly or partly through gallstone

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formation.

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The presence of unique risk factors may explain some of worldwide variation in gallbladder

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cancer rates. For instance, a genetic predisposition to gallstone formation among Chilean

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Hispanics and Mapuche Indians has been linked to high rates of gallbladder cancer in Chile.13

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High rates in women in countries such as Czech Republic, Poland, and Hungary may also be

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linked to a higher occurrence of gallstones.3 Disease risk in Chile has also been associated with

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aflatoxin exposure through the consumption of ají rojo (red chili peppers), a food common in

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the Chilean diet.25, 26 While no dietary factors have been consistently linked to GOB cancer risk,6

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geographic variation in eating habits, including consumption of sweetened beverages or foods

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contaminated with mycotoxins, may contribute to geographic disparities. Anomalous

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pancreaticobiliary duct junction and choledochal cysts, congenital malformations of the biliary

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tree that appear to be most common among Asians, especially the Japanese, increase risk of

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gallbladder cancer through a different carcinogenic pathway from gallstones and chronic

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gallbladder inflammation.8, 27, 28 Although the prevalence of these conditions is unknown, they

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likely contribute to the elevated rates of gallbladder cancer in Asia.3 However, hospital case

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series data indicate that the condition is more common among females;29, 30 thus, it would not

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explain the higher rates of GOB cancer mortality among males in Asia.

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Some changes in medical practice may have contributed to GOB cancer trends.

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Cholecystectomy, a long-used treatment for symptomatic gallstone disease, increased rapidly

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after the introduction of a lower-risk laparoscopic procedure in the late 1980s28, 31 and has

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become a common procedure in many countries. The increase in cholecystectomy could

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theoretically increase gallbladder cancer incidence rates by detecting prevalent disease and/or

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decrease rates by reducing the size of the population at risk. However, studies remain

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inconclusive about whether cholecystectomy rates can affect gallbladder cancer trends at the

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population level.32-35 One possible source of these conflicting results could be the lag time

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assumed between local trends in cholecystectomy and gallbladder cancer occurrence. Some

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studies examine simultaneous trends in cholecystectomy and gallbladder cancer; however, it is

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thought that gallbladder cancer develops from cholelithiasis over about 20 years.4 Statin use,

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particularly long-term, may reduce the risk of gallstone disease and cancer occurrence through

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inhibition of hepatic cholesterol biosynthesis and biliary cholesterol secretion.36 Statins have

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been widely used in high income countries since the 1990s and have been partly credited with

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substantial reductions in cardiovascular disease mortality.37 Although statin use may have

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contributed to recent decreases in gallbladder cancer mortality, rates began decreasing in many

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countries prior to widespread uptake of the drug.

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Reasons for the long-term increase in GOB mortality in Greece are unknown. A recent study

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estimated the proportion of female gallbladder cancer associated with excess body weight in

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Greece (47%) is similar to that in other European countries, and lower than that in the US

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(54%).38 Although body weight has been increasing in Greece, especially among males,39 the

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trends and prevalence of excess body weight are not dissimilar from other European countries,

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and thus do not appear to fully explain the GOB mortality trend. The recent uptick in GOB

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mortality in the UK, the Netherlands, and Germany may be partly due to the obesity epidemic.

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The prevalence of excess body weight among both children and adults has been increasing in

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most high-income countries since the late 1970s.40, 41 The relationship between body weight

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and the development of gallstones is linear, and evident with even slight excess weight as

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young as age 18 years.42 As cohorts of children born since the 1970s age into adulthood, the

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health effects of lifelong excess body weight are predicted to manifest in increased rates of

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type 2 diabetes and other conditions.43 Pediatric gallstones are increasing in high-income

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countries, including the US, Canada, and UK, due not only to new diagnostic procedures but

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also likely as a result of increasing overweight and obesity.44-46 While analysis by age is not

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feasible for this report due to the small number of deaths for many countries, a US study found

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that gallbladder cancer mortality rates from 1999–2011 were declining in men and women over

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65 years, but stable in those younger than 65 years.47 Trends in young age groups are typically

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first to reflect changes in the prevalence of environmental exposures that influence cancer

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risk.48

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The strengths of this study include the use of the most recent WHO global mortality data, which

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provides a comprehensive picture of contemporary cancer mortality around the world.

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However, vital registration is lacking in many places, particularly countries undergoing

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developmental transition. While India and Pakistan have documented high incidence rates in

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populations covered by regional cancer registries,3 mortality data are lacking. The number of

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countries included was further reduced by the limited availability of mortality data meeting

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quality and coverage standards for this study. Data limitations also precluded analysis of long-

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term temporal trends specifically in gallbladder cancer death rates. Although the majority of

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GOB cancers are gallbladder and the distribution did not change substantially over time in most

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countries, the proportion of extrahepatic bile duct cancers increased in both sexes since about

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2007 in Germany. Thus, while it is possible that temporal changes in other biliary tract tumors

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may have influenced some of the GOB trends reported here, trends in gallbladder cancer

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mortality specifically using available ICD-10 data were generally consistent with GOB cancer

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mortality trends. However, inconsistencies were noted for some countries where GOB cancer

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mortality had recently stabilized or begun to increase after a long term decline, which may

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reflect limitations in joinpoint regression in detecting emerging, short-term trends based on

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few data years and/or number of deaths.

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In summary, GOB death rates are decreasing in most countries considered in this analysis. The

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causes of more recently stabilizing or increasing rates in some countries are unknown, but may

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reflect increasing disease occurrence due to changing lifestyle patterns, such as increases in

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excess body weight. Further studies exploring age-specific trends in cholecystectomy and lag

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times are needed, in addition to examination of the underlying risk factors contributing to the

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currently diverse trends in GOB cancer mortality and inconsistences in the gender bias.

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FIGURE LEGENDS Figure 1. Gallbladder and other biliary tract (GOB) cancer mortality among males and females

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age 35–74 years, age-standardized rate (world), 2009–2013 Figure 2. Trends in gallbladder and other biliary tract cancer mortality among males and

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females age 35–74 years in select countries, age-standardized rate (world), 1985–2014

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44. Balaguer EJ, Price MR, Burd RS. National trends in the utilization of cholecystectomy in children. J Surg Res. 2006;134(1):68-73. 45. Khoo AK, Cartwright R, Berry S, et al. Cholecystectomy in English children: evidence of an epidemic (1997-2012). J Pediatr Surg. 2014;49(2):284-8. 46. Murphy PB, Vogt KN, Winick-Ng J, et al. The increasing incidence of gallbladder disease in children: A 20-year perspective. J Pediatr Surg. 2016;51(5):748-52. 47. Henley SJ, Weir HK, Jim MA, et al. Gallbladder cancer incidence and mortality, United States 1999-2011. Cancer Epidemiol Biomarkers Prev. 2015;24(9):1319-26. 48. Doll R. Progress against cancer: an epidemiologic assessment. The 1991 John C. Cassel Memorial Lecture. Am J Epidemiol. 1991;134(7):675-88.

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Table 1. Trends in gallbladder and other biliary tract (GOB) cancer mortality rates among females age 35–74

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Table 2. Trends in gallbladder and other biliary tract (GOB) cancer mortality rates among males age 35–74

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