Disease burden, risk factors, and trends of primary central nervous system (CNS) cancer: A global study of registries data

Abstract

Background

This study aimed to evaluate the global incidence, mortality, associated risk factors, and temporal trends of central nervous system (CNS) cancer by sex, age, and country.

Methods

We extracted incidence and mortality of CNS cancer from the GLOBOCAN (2020), Cancer Incidence in Five Continents series I–X, WHO mortality database, the Nordic Cancer Registries, and the Surveillance, Epidemiology, and End Results Program. We searched the Global Health data exchanges for the prevalence of its associated risk factors. We tested the trends by Average Annual Percentage Change (AAPC) from Joinpoint regression analysis with 95% confidence intervals in different age groups.

Results

The age-standardized rates (ASRs) of CNS cancer incidence and mortality were 3.5 and 2.8 per 100,000 globally. Southern Europe (ASR = 6.0) and Western Asia (ASR = 4.2) had the highest incidence and mortality, respectively. The incidence was associated with Human Development Index, Gross Domestics Products per capita, prevalence of traumatic brain injuries, occupational carcinogens exposure, and mobile phone use at the country level. There was an overall stable and mixed trend in the CNS cancer burden. However, increasing incidence was observed in younger male population from five countries, with Slovakia (AAPC = 5.40; 95% CI 1.88, 9.04; P = .007) reporting the largest increase.

Conclusions

While the overall global trends of cancer have been largely stable, significant increasing trends were found in the younger male population. The presence of some higher-HDI countries with increasing mortality suggested an ample scope for further research and exploration of the reasons behind these epidemiological trends.

Graphical Abstract

Graphical Abstract.

Key Points.

• Brain cancer burden was higher in more developed countries and male population.

• Brain cancer was related to HDI, GDP, brain injuries, carcinogens, and phone use.

• There was an increasing trend of brain cancer in the younger male population.

Importance of the Study.

Primary central nervous system (CNS) cancer had very poor survival. Most CNS cancers are not linked with any known risk factors and have no obvious cause. Some reported data limited to a certain country or region, while another study reported relatively old data and did not investigate the trends of subsets of different age groups. In this study, we aim to inform policy makers of the preventive interventions and facilitate the development of a tailor-made strategy for countries, with the evaluation of its updated distribution and temporal trends for different age groups, genders, and geographical regions, and the investigation on the possible associative risk factors, using high-quality data from global and national cancer registries and databases.

Primary central nervous system (CNS) tumors are relatively rare, compared to other cancer sites, accounting for less than 2% of cancer cases reported worldwide in 2020.¹ Despite the improvement in medical care and the development of novel therapies in some high-income countries,² it has one of the worst 5-year survival rates among all cancers at 12.8% as reported in a cohort study in England.³ The high mortality of the cancer is particularly evident in the younger population, as it led to the third-most deaths, only after leukemia and breast cancer.¹

Most CNS cancers are not linked with any known risk factors and have no obvious cause. There are some possible risk factors associated with CNS cancer, which include ionizing radiation exposures (inclusive of atomic bomb radiation exposure, childhood nasopharyngeal radium exposure, etc.),^4–6 exposure to infections, viruses, and allergens,⁷ environmental agents such as exposure to contaminated drinking water,⁸ and lead,⁹ and having a weakened immune system.¹⁰ Other controversial risk factors may include home and work exposures (solvents, pesticides, oil products, rubber, or vinyl chloride) and cell phone use.¹¹

Previous studies on the global trends of CNS cancer were limited. Some reported data limited to a certain country or region,^12,13 while another study reported relatively old data and did not investigate the trends of subsets of different age groups.¹⁴ In this study, we aim to inform policy makers of the preventive interventions and facilitate the development of a tailor-made strategy for countries, with the evaluation of its updated distribution and temporal trends for different age groups, genders, and geographical regions, and the investigation on the possible associative risk factors, using high-quality data from global and national cancer registries and databases.

Methods

Data Sources

For descriptive analysis, the incidence and mortality data of primary central nervous system (CNS) cancer were retrieved from Global Cancer Observatory (GLOBOCAN), International Agency for Research on Cancer, World Health Organization (IARC, WHO), which specialized in cancer data to facilitate international collaboration in cancer research.¹⁵ For risk factors associations analysis, the Human Development Index (HDI),¹⁶ mobile phone use,¹⁷ gross domestic product (GDP) figures¹⁸ in 2019 for each country were obtained from the United Nations and the World Bank. HDI is a composite measure based on life expectancy, expected years of schooling and income per capita, while rates of < 0.550, 0.550–0.699, 0.700–0.799, and ≥ 0.800 are considered low, medium, high, and very high, respectively.¹⁹ The Global Health data exchanges (GHDx) was searched for the sex-specific and age-adjusted prevalence of traumatic brain injuries, occupational carcinogens exposure, and unsafe water exposure in 2019 for each country. The GHDx contains comprehensive catalog of surveys, censuses, vital statistics, and other health-related data for different countries globally.²⁰ For incidence trend analysis, data from the Cancer Incidence in Five Continents (CI5) volumes I–XI for CNS cancer were utilized.²¹ For mortality trend analysis, the WHO mortality database was used for data on cancer-related death for each country and region.²² The Nordic Cancer Registries (NORDCAN) and the Surveillance, Epidemiology, and End Results (SEER) Program were accessed for updated cancer incidence and mortality data of Scandinavian countries and the United States, respectively.^23,24 The period of data used in the trend analysis was included in the Supplementary Table 1. To ensure the accuracy of the data, the extracted data of incidence and mortality for CNS cancer in this research adopted the International Classification of Disease and Related Health Problems, 10th Revision codes of CNS cancer: Malignant neoplasm of brain, CNS (ICD-10, C70-72).²⁵ To ensure that the data in this study of different populations and sub-populations can be compared over time, the data were standardized with the Segi-Doll standard population to eliminate the confounding effects of differences in age structure between populations.²⁶ The age-standardized rate (ASR) is the weighted arithmetic mean of age-specific rates per 100,000 people, while the weights correspond to the ratio of people in the respective age groups of the standard population.²⁷

Procedures of Statistical Analysis

Associations between HDI, GDP per capita, the prevalence of traumatic brain injuries, occupational carcinogens exposure, unsafe water exposure, mobile phone use and CNS cancer burden were examined by univariable linear regression analysis. Beta coefficients (β) and the corresponding 95% confidence intervals (CI) were estimated from the regression. The β estimates refer to the degree of change in ASR of incidence or mortality per unit increase in the risk factors. Sensitivity analysis was conducted to evaluate the β after the exclusion of outliers for each dataset. In order to determine the cancer incidence and temporal mortality trends, the current study utilized the Joinpoint Trend Analysis Software version 4.9.0.1 to examine with Joinpoint regression the acquired ASRs data of past decade trends in incidence and mortality of CNS cancer from the aforementioned databases. For the calculation of the AAPC, logarithmic transformation was performed on the retrieved ASRs. Over the 10 years, the software divided the data into segments, and weighting would be assigned for each segment according to the length of each segment in proportion to the entire time interval. A maximum of one Joinpont was adopted in the analysis according to the software recommendations. The standard errors (SEs) of the AAPC were obtained with Poisson approximation. They were later used for the computation of the 95% CI. The AAPCs were used for the description of the epidemiological trends, with positive and negative AAPCs representing increasing and decreasing trends in cancer incidence or mortality respectively, while the significance of the trends was determined using the 95% CI. A trend with AAPC overlapping with 0 would be considered stable, while all P-values less than .05 were considered significant. To examine the differences in incidence or mortality due to age and gender, the analysis included gender-specific AAPC for individuals of four age groups (0–85+, 50 or above, below 50, and below 40).

Ethics Approval

This study was approved by the Survey and Behavioural Research Ethics Committee, the Chinese University of Hong Kong (No. SBRE-20-332).

Results

Global Incidence of CNS Cancer in 2020

In 2020, there were 308,102 newly reported CNS cancer cases globally with an incidence ASR of 3.5 per 100,000, accounting for 1.6% of the total cancer cases reported (Figure 1). There was an 8.5-fold variation across different geographical regions. Regions with high incidence were predominately located in Europe: Southern Europe (ASR = 6.0) had the highest incidence, followed by Western Europe (ASR = 5.8), and Northern Europe (ASR = 5.6). The lowest incidence was found in Middle Africa (ASR = 0.71). HDI seemed to be positively correlated with incidence of CNS cancer as the populations with very high HDI (ASR = 5.0) had the highest incidence and low HDI (ASR = 1.4) had the lowest incidence. The effect of gender on the incidence was largely consistent throughout different geographical regions with males (ASR = 3.9) having an incidence rate of about 30% higher than females (ASR = 3.0).

Fig. 1.

Global incidence and mortality of CNS cancer, both sexes, all ages, in 2020.

Global Incidence of CNS Cancer in 2020

A total of 251,329 CNS cancer-related deaths were recorded worldwide, which was around 2.5% of total deaths related to cancer (Figure 1). The mortality ASR per 100,000 was 2.8, with a six-fold variation across different geographical regions. The region with the highest mortality was Western Asia (ASR = 4.2), followed by European regions: Central and Eastern Europe, Northern Europe (ASR = 4.0), Southern Europe, and Western Europe (ASR = 3.9). The lowest mortality was found in Middle Africa (ASR = 0.64). Similar to the overall mortality rate of cancer, populations with very high HDI (ASR = 3.3) had the highest mortality, while populations with low HDI (ASR = 1.2) had significantly lower mortality.

Associations Between Risk Factors and CNS Cancer Burden

Higher CNS cancer incidence was associated with a higher-HDI (β_male = 0.87, CI 0.66–1.08, P < .001; β_female = 0.59, CI 0.45–0.73, P < .001), GDP per capita (β_male = 0.49, CI 0.32–0.66, P < .001; β_female = 0.30, CI 0.18–0.42, P < .001), and higher prevalence of traumatic brain injuries (β_male = 2.92, CI 2.47–3.37, P < .001; β_female = 2.79, CI 2.35–3.24, P < .001), occupational carcinogens (β_male = 1.39, CI 0.13–2.66, P = .031; β_female = 0.78, CI 0.06–1.49, P = .034), and mobile use (β_male = 2.07, CI 0.83–3.30, P = .001; β_female = 1.43, CI 0.61–2.24, P = .001) but not with exposure to unsafe water (P > .05 for both sexes; Figure 2).

Fig. 2.

Associations between risk factors and incidence of CNS cancer.

Higher CNS cancer mortality was associated with a higher-HDI (β_male = 0.58, CI 0.41–0.74, P < .001; β_female = 0.37, CI 0.26–0.47, P < .001), GDP per capita (β_male = 0.29, CI 0.16–0.42, P < .001; β_female = 0.18, CI 0.09–0.26, P < .001), and higher prevalence of traumatic brain injuries (β_male = 1.96, CI 1.60–2.32, P < .001; β_female = 1.64, CI 1.28–2.00, P < .001), occupational carcinogens (β_male = 1.06, CI 0.12–2.00, P = .027; β_female = 0.63, CI 0.12–1.14, P = .016), and mobile use (β_male = 1.34, CI 0.42–2.25, P = .005; β_female = 0.81, CI 0.22–1.39, P = .007) but not with the exposure to unsafe water (P > .05 for both sexes; Figure 3).

Fig. 3.

Associations between risk factors and mortality of CNS cancer.

Similar results were obtained from sensitivity analysis after excluding outliers in each dataset as the associations between higher CNS cancer incidence and mortality and HDI, GDP per capita, traumatic brain injuries, and mobile use remained significant. The full comparison between the two datasets can be found in the Supplementary Table 2.

Incidence Trends of Individuals of All Ages

For males, five countries reported significant increasing trends, Slovakia (AAPC = 4.39; 95% CI 2.28, 6.54) reported the largest increases (Figure 4). Meanwhile, significant decreasing trends were found in five countries. The largest decreases were found in Austria (AAPC = -2.69; 95% CI -3.86, -1.51).

Fig. 4.

AAPC of incidence of CNS cancer in individuals aged 0–85+ years.

For females, six countries reported significant increases, Denmark (AAPC = 3.37; 95% CI 1.67, 5.09), reported the most evident increase. In contrast, significant decreases were observed in seven countries, and the most evident decreases were observed in Philippines (AAPC = -4.89; 95% CI -8.66, -0.95).

Mortality Trends of Individuals of All Ages

For males, four countries showed evident increases, and the most remarkable increase was reported in Japan (AAPC = 3.46; 95% CI 2.49, 4.44, Figure 5). On the other hand, 4 countries reported significant decreases: Faroe Islands (AAPC = -12.59; 95% CI -21.65, -2.49; P = .022) had the largest decrease.

Fig. 5.

AAPC of mortality of CNS cancer in individuals aged 0–85+ years.

For females, seven countries showed significant increasing trends, with Japan (AAPC = 3.02; 95% CI 0.83, 5.27) reporting the largest increase. Significant decreases were observed in four countries, as Czech Republic (AAPC = -3.51; 95% CI -5.43, -1.55) reported the most remarkable decrease.

Incidence of Subsets of Different Age Groups

For males aged 50 or above, four countries reported significant increases and other four countries reported significant decreases, with Slovakia (AAPC = 3.55; 95% CI 1.80, 5.33), and Austria (AAPC = -3.08; 95% CI -4.19, -1.95) showing the largest increases and decreases respectively (Supplementary Table 3). For their younger counterparts aged below 50, significant increases and decreases were found in 5 and 2 countries, with Slovakia (AAPC = 5.40; 95% CI 1.88, 9.04), again, reporting the largest increases, while the most significant decrease was observed in Austria (AAPC = -2.22; 95% CI -3.98, -0.43). For the youngest males below 40, 4 countries and 3 countries showed significant increasing and decreasing trends respectively. Likewise, Slovakia (AAPC = 6.19; 95% CI 1.45, 11.14) reported the highest increase, and Cyprus (AAPC = -9.75; 95% CI -17.34, -1.48) was found to have the greatest decline.

For females aged 50 or above, significant increasing trends were observed in five countries, as Belarus (AAPC = 4.52; 95% CI 2.51, 6.57) reported the largest increase, significant decreases were observed in 8 countries, Faroe Islands (AAPC = -9.77; 95% CI -16.86, -2.08) was the country report the most evident decrease (Supplementary 3). For the younger age group of below 50, significant increases were reported in three countries, Turkey (AAPC = 4.15; 95% CI 1.47, 6.92) reported the most evident increases, two countries reported significant decreasing trends, Croatia (AAPC = -3.71; 95% CI -6.97, -0.34) reported the largest decline. For the youngest female subset aged below 40, three countries showed evident increasing trends, Slovakia (AAPC = 5.25; 95% CI 0.06, 10.71) had shown the greatest increase, on the contrary, only Croatia (AAPC = -4.2; 95% CI -7.58, -0.70) showed a significant decline.

Detailed AAPCs and their respective 95% CIs and P-values for all countries are listed in Supplementary Table 3.

Discussion

Summary of Findings

The current study reported the most recent data on the global CNS cancer incidence and mortality, its associated risk factors, as well as the temporal epidemiological trends by subsets of ages, genders, and countries using high-quality data retrieved from well-established cancer databases. There are some major findings: (1) there was a wide variation in the CNS cancer burden, with higher incidence and mortality observed in more developed countries and male population; (2) higher CNS cancer burden was associated with a higher-HDI, GDP per capita, prevalence of traumatic brain injuries, occupational carcinogens exposure, and mobile phone use; (3) there was an overall stable and mixed trend in the CNS cancer burden, while an increasing trend was observed in the younger male population.

Comparison with Existing Literature

We found CNS cancer burden was associated with HDI, GDP, which is in line with previous studies.^28,29 It might be attributable to the higher availability and utilization of diagnosis tools like magnetic resonance imaging (MRI) in developed countries³⁰ and CNS cancer might not be detected due to comorbidity among developing countries. Although HDI and GDP per capita were correlated, previous literature has shown that the two can have different directions or strengths of associations with cancer incidence and mortality,³¹ implying the need to conduct separate analyses. Reasons behind this phenomenon remain unexplored but may be related to multiple factors, including genetic predisposition, environmental exposures, and effects of access to health care.^14,32,33 The incidence and mortality of CNS cancer were higher in men than in women, which may be related to the differences in sex hormones and genetic features, and level of exposure to head injuries and occupational factors (e.g., pesticides, chemicals, and biological agents).^34–37 However, we found that western Asia had the highest morality despite it had a relatively low incidence. These findings are likely to be reflective of a lack of access to the highly specialized services needed to treat these complex diseases in the less developed regions.^38,39

The results on risk factors associations are comparable with some of the previous findings from the individual-level analysis. A study from Taiwan found patients with traumatic brain injuries were more likely to have brain tumors within the 3 years following their index date: 6.28 (95% CI 3.06–11.53) per 10,000 person-years in patients and 1.25 (95% CI 0.61–2.29) in controls.⁴⁰ However, a study from Denmark observed no such associations (RR = 1.14; 95% CI 0.87–1.46).¹⁴ In a study among occupations with potential exposure to occupational carcinogens, increased risks of brain cancer were observed for men employed in agricultural crop production, printing, and brick masons,⁴¹ while more recent studies did not identify such associations.^42–44 There are inconsistent results reporting by different settings of studies regarding the associations between mobile phone use and CNS cancer. Although some studies show mobile phone use was not associated with an increased risk of brain cancer,^45–47 they may have suffered from poor exposure assessment that likely contributed to exposure mis-classification.⁴⁸ A meta-analysis of 11 studies found a significant positive association between long-term ipsilateral mobile phone use and the risk of glioma (OR = 1.46, 95% CI 1.12–1.92).⁴⁹ Another meta-analysis showed a similar significant 1.33 times increase in risk.¹¹ A more recent meta-analysis of 46 studies found increased CNS cancer incidence with cumulative call time of 1000 or more hours.⁵⁰

The reasons behind the mixed trends remained unclear and maybe relate to the: changing exposure to its associated risk factors; expanded genetic screening for high-risk germline mutations; and progress in therapies. However, the mixed trends observed for different countries need a careful interpretation considering CNS cancer has different histological subtypes and the trends may be affected by changing diagnostic and registry criteria.⁵¹ In some circumstances, such comparisons may not be easy due to its diagnostic difficulties, inconsistency in definitions, and criteria advance with time.^52–54 Notably, an overall increasing trend was observed in the younger male population, which is different from previous findings that the increasing CNS cancer was primarily found in the older population.^55–57 The incidence increases may be likely due to continuous improvement in the health consciousness of the younger population, technology and capacity of detection for CNS cancer so that more cases were diagnosed and recorded.

Limitations

Some limitations need to be noted. First, there could be under-reporting of cancer cases in lower-income countries compared to higher-income countries due to variations in the reporting system and lack of a well-established cancer registry/ infrastructure. On the other hand, higher-income countries have more frequent health checks, such that more cases could be identified. Second, there might be over-reporting if the incidence and mortality data of a particular country were derived from registries in the capital/ major city. Third, direct comparison of the rates between different countries might be difficult as the cancer registration might have changed over time. However, such limitations should not be a major concern when incidence and mortality were compared across different age groups and sex groups within the same region. Despite differences in registration practices and coding may make it necessary to interpret trends with caution, an important feature of the databases selected is that the users can be confident that differences in rates between countries or over time are unlikely to be due to variability in the quality of the data.⁵⁸ The databases had used quality control measures to ensure that observed trends are not simply caused by the changes in the completeness of ascertainment or coding. Lastly, detailed data and research on subtypes and stages of CNS cancer were not included in the study.

Conclusions

The largest incidence and mortality of CNS cancer were found in populations with very high HDI. The high incidence could be attributable to the ample resources in early detection with advanced diagnostic techniques and regular health check-ups while the high mortality could be ascribed to higher exposure to its related risk factors, such as traumatic brain injuries, occupational carcinogens exposure, and mobile phone use. While the overall global trends of cancer have been largely stable, significant increasing trends were found in the younger male population. The presence of some higher-HDI countries with increasing mortality suggested an ample scope for further research and exploration of the reasons behind these epidemiological trends.

Supplementary Material

Supplementary material is available online at Neuro-Oncology (http://neuro-oncology.oxfordjournals.org/).

Funding

This study has no funding.

Conflict of Interest

We declare no conflict of interest.

Ethics

This study was approved by the Survey and Behavioural Research Ethics Committee, The Chinese University of Hong Kong (No. SBRE-20-332).

Authorship Statement

J.H., S.Z.C., M.C.W: substantial contributions to the conception and design of the work; acquisition, analysis, and interpretation of data for the work; drafting the work and revising it critically for important intellectual content; V.L., L.Z., X.L., D.E.L.P., W.X., Z.Z., E.E., M.W.: revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work.