Background

Gallbladder cancer (GBC) and extra-hepatic duct cholangiocarcinoma are rare diseases with age standardized incidence rates of around 2 to 3 per 100,000 populations in both gender separately worldwide [1, 2]. GBC is a highly fatal malignancy, with a 5-year survival rate around 13%, and the only effective treatment is early diagnosis [3, 4]. GBC has a prominent geographic variability associated with the prevalence of risk factors [5] such as cholelithiasis [6]. GBC has a higher incidence in Latin America, the Caribbean, and Asia, according to previous studies [5]. GBC has other known characteristics apart from this geographic issue, such as age [7], race, and gender [8], suggesting that the age-standardized rate (ASR) is more reliable than the crude rate as a method for disease evaluation of GBC.

The known risk factors of GBC are gallbladder disease (including gallstones [6], porcelain gallbladder [9], and gallbladder polyps [10]); chronic inflammation of the bile duct (e.g., primary sclerosing cholangitis [11], choledochal cysts, and abnormal pancreaticobiliary duct junctions [12]); and chronic bacterial infections (e.g., Salmonella [13] and Helicobacter infections [14]) [15]. In terms of these risk factors, congenital abnormalities and chronic bacterial infections are common mainly in low socioeconomic areas, whereas high-fat diets and Caucasian ethnicity [16] increase the possibility of GBC in high socioeconomic countries.

The only treatment that provides a good outcome for GBC is early curative resection. The 5-year mortality rate is around 50% in cases with peri-muscular connective tissue involvement [17], regardless of the treatment choice of surgical resection or adjuvant chemotherapy. The poor response of current chemotherapy regimens means that once GBC invades beyond the gallbladder, the outcome becomes poor and the median survival is only around 3 years [4, 18]. Chemoradiotherapy is another approach for treatment of systemically spreading GBCs, but no randomized trials have yet directly compared the effectiveness of chemotherapy alone versus concomitant chemoradiotherapy [19].

Technical and equipment improvements suggest that health care systems may be able to improve early lesion detection. Better socioeconomic conditions can prevent delays in surgical cholecystectomy, thereby avoiding the extra-gallbladder spread of GBC. We considered that the mortality-to-incidence (MIR) ratio for GBC would be low in a country with a good health care system, as a similar concept has recently been confirmed for prostate and colon cancers [20,21,22,23]. The aim of the present study was to clarify the association between World Health Organization (WHO) ranking, geographic region, total expenditure on health/gross domestic product (GDP; e/GDP), and the ASR of GBC incidence and mortality. Our results provide an overview of the MIR and health disparities worldwide for GBC.

Methods

The data acquisition protocol was described previously [20]. In brief, the cancer incidence and mortality data were obtained from the GLOBOCAN 2012 database, which presented estimates for 2012. The crude rate and ASR are multiplied by 100,000 (cases per 100,000 populations). The database is maintained by the International Agency for Research on Cancer (http://gco.iarc.fr/). The WHO rankings are the World Health Organization’s ranking of the health systems based on an index of factors including health, responsiveness, and fair financial contribution. The health expenditure and life expectancies were obtained from the World Health Statistics 2015 of WHO.

The GLOBOCAN 2012 database contains information for 184 countries. We excluded countries that lacked WHO ranking data (22 countries) or that had a low availability level of data (i.e., a ranking of E to G for incidence or a ranking of 4 to 6 for mortality; 105 countries). Ultimately, 57 countries were used for our analyses. The MIR was defined previously as the ratio of the crude rate of mortality to the incidence [23].

The method used for statistical analysis was described previously [20]. We evaluated the association between the MIRs and variants via linear regression using SPSS statistical software version 15.0 (SPSS, Inc., Chicago, IL). P values < 0.05 were considered statistically significant. Scatter plots were produced using Microsoft Excel 2010.

Results

The distribution of incidence and mortality numbers/rates in gallbladder cancer according to regions

The incidence/mortality numbers, crude rates, ASR, and MIRs are listed in Table 1. The survey included 178,101 incidences and 142,823 mortalities worldwide. The more developed regions had higher crude rates of incidence/mortality, but favorable ASR and MIRs, when compared with the less developed regions. In the categories of WHO regions, the WHO Western Pacific region had the highest number, crude rates, and ASR of incidence/mortality. However, when we grouped the countries via continent, the highest crude rates of incidence/mortality were in Europe and the highest ASR of incidence/mortality was in Asia. In both categories, Africa had the highest MIR and the WHO Americas region and North America had the lowest MIR.

Table 1 Summary of the case number, rates and mortality-to-incidence ratio of the incidence and mortality according to regions in gallbladder cancer
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The World Health Organization ranking and total health expenditure are correlated with the mortality-to-incidence ratios in gallbladder cancer

The data for 57 selected countries are summarized in Table 2. The mean e/GDP was 8.0%, with a standard deviation of 2.6 (ranging from 4.0% [Malaysia and Fiji] to 17.0% [United States of America]). Among the 57 countries, Japan had the highest incidence and mortality number for GBC. For both the incidence and mortality rates, Japan had the highest incidence and mortality crude rates and Chile had the highest incidence and mortality ASR. Five countries had MIR values greater than or equal to 1.00, including Sweden (1.23), Estonia (1.12), Egypt (1.00), the Republic of South Africa (1.00), and Oman (1.00).

Table 2 Summary of World Health Organization rankings, total expenditure on health/GDP, life expectancy, gallbladder cancer incidence, mortality, and mortality-to-incidence ratio of selected countries
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The association between crude rate/age-standardized rate of incidence/mortality and the WHO ranking or e/GDP is illustrated in Additional file 1: Figure S1 and S2. No significant association was noted, except between the e/GDP and the crude rate of incidence (p = 0.031, Additional file 1: Figure S2A). The favorable MIRs of 57 countries were significantly associated with good WHO ranking and high e/GDP (R2 = 0.176, p = 0.001; R2 = 0.083, p = 0.030, respectively, Fig. 1).

Fig. 1
figure 1

The (a) World Health Organization rankings and (b) total expenditures on health/GDP are significantly associated with the MIR in gallbladder cancer

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Discussion

In this study, we analyzed the correlation of incidence, mortality, and MIRs for GBC with WHO rankings and total expenditures on health/GDP. A correlation between MIR and health care disparities was confirmed previously for many cancers [20, 23]. Our analysis showed that the more developed regions have higher crude rates of incidence and mortality but favorable ASR and MIRs when compared with the less developed regions. The developed regions and countries have greater numbers of elderly people and older age is one important risk factor of GBC; consequently, the crude rates of incidence and mortality were higher in the more developed regions, but the condition was reversed for ASR and MIRs. The geographic continent analysis revealed that the WHO Western Pacific region and Asia had the highest ASR of incidence and mortality for GBC and these results were similar to those of previous studies of geographic regions [5, 24] published decades ago. Both the WHO America region and North America showed a median ASR of incidence and the lowest age-standardized mortality and MIRs. These results imply an importance of economic level and e/GDP in GBC prognosis.

The best treatment choice is early diagnosis, so screening programs and high probability population for GBC have been established in some studies [25, 26]. The availability of precision instruments and experienced physicians are known key factors for the early diagnosis of GBC. Africa had the lowest crude rates and ASR of incidence/mortality, but the highest MIR around the world.

The WHO ranking and e/GDP showed no significant correlations with the crude rate and ASR of incidence/mortality, except for the crude rate of incidence. We found an association between a higher e/GDP and a higher crude rate of incidence for GBC in our analysis. We believe that the higher e/GDP countries have better or more frequent screening programs, which lead to more GBC diagnoses. Furthermore, the favorable MIRs of 57 countries are significantly associated with good WHO ranking and high e/GDP (R2 = 0.176, p = 0.001; R2 = 0.083, p = 0.030, respectively, Fig. 1).

This study has some limitations. First, many countries, and especially those in the least developed areas in the world, do not participate in the WHO, and this may influence the impact of total e/GDP on GBC incidence. Second, the ethnicity, geographic region, and national health insurance issues (especially for e/GDP) could not be fully analyzed in our study, and these issues may add some bias to our study. Third, the use of MIR for predicting disease outcome has many limitations, since MIR was calculated from the cross-sectional data of mortality and incidence for a certain period causing different patients calculated in the incidence and mortality. MIR would not substitute for prognostic data from long-term follow up or from a cohort study. Forth, we excluded countries with relatively poor or unknown data quality which changes the distribution of countries according to the regions or continents. We analyzed the main results without country selection, the conclusion remains unchanged. The favorable MIRs of all countries were significantly associated with good WHO ranking and high e/GDP (R2 = 0.309, p < 0.001; R2 = 0.118, p < 0.001, respectively, Additional file 1: Figure S3). Other limitations include the lack of detailed information about the disease clinical parameters, health care facilities or policies, socioeconomic determinant, and confounding factors of cancer risks. Despite these limitations, MIR appears to provide more accessible data when compared with long-term follow up survival surveys.

Conclusions

In conclusion, the MIRs of GBC showed a significant correlation with the WHO ranking and e/GDP in this study. We successfully demonstrated that MIRs could reflect the health care disparities in GBC worldwide and could explain the differences in crude rates and ASR of incidence and mortality between WHO region categories and geographic continents.