Challenges in determining the global burden of non-malignant central nervous system tumors: an analysis of international incidence and mortality data sources

Challenges in determining the global burden of non-malignant central nervous system tumors: an analysis of international incidence and mortality data sources Authors: Ms. Frances Dean, MA. University of California, San Francisco: Computational Precision Health. University of California, Berkeley: Computational Precision Health. University of Washington: Institute for Health Metrics and Evaluation. Population Health Building/Hans Rosling Center, 3980 15th Ave. NE, Seattle, WA 98195 USA, UW Campus Box #351615. [email protected], 412-996-0279. Ms. Hannah Henrikson, MPH. Boston University: School of Public Health. 715 Albany St, Boston, MA, 02118 USA. [email protected] Ms. Rixing Xu. University of Washington: Institute for Health Metrics and Evaluation. Population Health Building/Hans Rosling Center, 3980 15th Ave. NE, Seattle, WA 98195 USA, UW Campus Box #351615. [email protected] Ms. Hodo Farah. 2 University of Washington: Institute for Health Metrics and Evaluation. Population Health Building/Hans Rosling Center, 3980 15th Ave. NE, Seattle, WA 98195 USA, UW Campus Box #351615. [email protected] Ms. Dan Lu. University of Washington: Institute for Health Metrics and Evaluation. Population Health Building/Hans Rosling Center, 3980 15th Ave. NE, Seattle, WA 98195 USA, UW Campus Box #351615. [email protected] Mr. James Harvey. University of Washington: Institute for Health Metrics and Evaluation. Population Health Building/Hans Rosling Center, 3980 15th Ave. NE, Seattle, WA 98195 USA, UW Campus Box #351615. [email protected] Ms. Weijia Fu, MS. University of Washington: Institute for Health Metrics and Evaluation. Population Health Building/Hans Rosling Center, 3980 15th Ave. NE, Seattle, WA 98195 USA, UW Campus Box #351615. [email protected] Dr. Natalie Pritchett, DRPH. University of Washington: Institute for Health Metrics and Evaluation. 3 Population Health Building/Hans Rosling Center, 3980 15th Ave. NE, Seattle, WA 98195 USA, UW Campus Box #351615. [email protected] Dr. Nickhill Bhakta, MD. St. Jude Children’s Research Hospital: Department of Global Pediatric Medicine. 262 Danny Thomas Pl, Memphis, TN 38105 USA. [email protected] Dr. Daniel C. Moreira, MD. St. Jude Children’s Research Hospital: Department of Global Pediatric Medicine. 262 Danny Thomas Pl, Memphis, TN 38105 USA. [email protected] Dr. Ibrahim Qaddoumi, MD. St. Jude Children’s Research Hospital: Department of Global Pediatric Medicine. 262 Danny Thomas Pl, Memphis, TN 38105 USA. [email protected] Dr. Fabio Girardi, MD, PhD. Cancer Survival Group, Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine. Keppel Street, London, WC1E 7HT, UK. Division of Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS Via Gattamelata 64, Padua, 35128, Italy. 4 [email protected] Dr. Theo Vos, MD. University of Washington: Department of Health Metrics Sciences. University of Washington: Institute for Health Metrics and Evaluation. Population Health Building/Hans Rosling Center, 3980 15th Ave. NE, Seattle, WA 98195 USA, UW Campus Box #351615. [email protected] Dr. Mohsen Naghavi, MD, PhD, MPH. University of Washington: Department of Health Metrics Sciences. University of Washington: Institute for Health Metrics and Evaluation. Population Health Building/Hans Rosling Center, 3980 15th Ave. NE, Seattle, WA 98195 USA, UW Campus Box #351615. [email protected] Dr. Jonathan L. Finlay, MB ChB, FRCP (Lond.), FRCPCH. Division of Hematology, Oncology and Marrow Transplantation, Neuro-oncology Program, Nationwide Children’s Hospital, and the Departments of Pediatrics and Radiation Oncology The Ohio State University College of Medicine, Columbus, Ohio. 110 S Mary Avenue, Suite 2-291, Nipomo, CA 93444 [email protected] Dr. Lisa M. Force, MD. University of Washington: Department of Pediatrics, Division of Pediatric Hematology-Oncology. 5 University of Washington: Department of Health Metrics Sciences. University of Washington: Institute for Health Metrics and Evaluation. Population Health Building/Hans Rosling Center, 3980 15th Ave. NE, Seattle, WA 98195 USA, UW Campus Box #351615. [email protected]u 6 Abstract Background Non-malignant tumors of the CNS contribute substantially to the morbidity and mortality from CNS tumors. It is critical to understand the epidemiology of non-malignant CNS tumors separately from CNS malignancies to inform resource allocation and policy since treatment and prognosis can differ. High quality international data on nonmalignant CNS tumor burden are needed to accomplish this goal. Methods We assessed cancer registry and vital registration data available to the Global Burden of Disease study by its inclusion of non-malignant CNS tumors, reporting on the availability of data over time and by World Bank income group. We analyzed preliminary age-standardized incidence rates (ASIRs), age-standardized mortality rates (ASMRs), and proportions of CNS tumors by behavior for adults, children, and all ages. Results Non-malignant CNS tumors were reported separately in 17·2% (N=66) of registry reports and in aggregate with malignant CNS tumors in 18·0% (N=69) of reports. Only seven lowand middle-income countries (LMICs) had data reporting CNS tumors separately by behavior. Across all ages combined, the median ASIR of non-malignant CNS tumor data was 0·31 (interquartile range: 0·15-0·50) and ASMR was 0·24 (0·10-0·44) per 100,000 in LMICs compared to median ASIR of 3·62 (2·62-4·97) and ASMR of 0·32 (0·16-0·65) in high-income countries (HICs). A larger proportion of incident CNS tumors were reported as non-malignant in HIC data than LMIC data (p<0.0001). Conclusions Our study alludes to current challenges in understanding global non-malignant CNS tumor burden and a need for increased international data collection. Further research is needed to comprehensively investigate opportunities for future data inclusion. Keywords non-malignant CNS tumors, population-based cancer registries, vital registration systems, incidence, mortality Key points 7 • Global reporting of non-malignant CNS tumors by population-based cancer registries and vital registration systems shows variation and challenges. • Less data and lower rates from lowand middle-income countries suggests a need for further research. Importance of the Study Few prior studies of international CNS tumor burden have focused on non-malignant tumors. Most previous research has focused on incidence, typically within a single nation. Complicating research in this space, it has been suggested by prior studies that these tumors are underreported in many settings. To our knowledge, this study is the first to describe reporting patterns and data availability of non-malignant CNS tumors by cancer registries internationally over time and to present data on non-malignant CNS tumor mortality. We observed greater reporting and higher incidence and mortality rates in data from high-income countries, for all ages combined, as well as for children and adults separately. Our data, together with previous studies, suggest that fewer non-malignant CNS tumors are reported in lowand middleincome countries. The precise drivers behind these differences are unclear and more research is needed to comprehensively describe potential biologic versus health systems or other contributors. 8 Introduction Non-malignant tumors of the central nervous system (CNS) cause substantial morbidity and premature mortality despite often being referred to as “benign” tumors.1–4 Therefore, understanding the epidemiology of non-malignant CNS tumors is important to comprehensively estimate global cancer burden. As treatment may include neurosurgical resection, chemotherapy, and radiotherapy for CNS tumors of any behavior, information on trends in non-malignant CNS tumors are critical clinically, for resource allocation decisions, and for policy development.5–7 The WHO Global Initiative for Childhood Cancer recently identified low-grade gliomas as one of six key indicator cancers for measuring progress in childhood cancer survival, further underscoring the need for reliable estimates of the global and local burden of non-malignant CNS tumors.8 Global age, sex, and geographic patterns of individuals with non-malignant CNS tumors are thought to differ from those of malignant CNS tumors.2,3 Non-malignant meningiomas occur in higher rates in females than in males in adults, and this difference by sex varies across countries.3,4,9–12 Non-malignant CNS tumors compose a varying proportion of CNS tumors by age with high-income countries (HICs), such as the United States, describing that approximately one-third of childhood CNS tumors are non-malignant tumors compared to over two-thirds of CNS tumors being non-malignant in adults.3 Less is known about the epidemiologic patterns of childhood non-malignant CNS tumors in many countries around the world, particularly in countries with limited resources.1,2,13,14 The proportion of brain tumors classified as low-grade astrocytomas in children varied from less than 10% to more than 30% across 60 countries in a recent study from CONCORD-3.2 The proportion of pediatric CNS tumors classified as non-malignant also varied across European countries in a study from EUROCARE-5.15 Together these prior studies suggest a need for more granular and robust data on non-malignant CNS tumors to discern true epidemiology. Neglecting non-malignant CNS tumor estimates would be expected to significantly underestimate the burden and impact of CNS tumors worldwide. To accurately estimate the epidemiologic patterns of non-malignant CNS tumors, high quality international data on their burden are necessary. While malignant CNS tumors are registered by most population-based cancer registries, the registration of non-malignant CNS tumors varies greatly.2,16 The Global Burden of Disease (GBD) study iteratively estimates the burden of over 300 diseases and injuries, including CNS cancers, worldwide, but non-malignant CNS tumor burden is not estimated separately.17 Data sources for the GBD study include population-based cancer registry reports and data from vital registration systems. In this manuscript, 9 we perform a preliminary analysis of the international malignant and non-malignant CNS tumor incidence and mortality data available to the GBD study, analyzing variation in population-based cancer registry and vital registration system reporting patterns and unprocessed non-malignant CNS tumor incidence and mortality data. Materials and Methods Our study defined non-malignant CNS tumors as grade I or II in the WHO grading scheme and included tumors classified as of low-grade or uncertain behavior.18 We use the term non-malignant rather than ‘benign’ or ‘lowgrade’ due to our inclusion of tumors of uncertain behavior, as well as to acknowledge that the impact of these tumors is not benign. Disease codes considered to represent non-malignant tumors of the CNS included ICD-10 codes D32-D33, D35.2-D35.4,19 ICD-9 code 225,20 and ICD-O-3 topography codes C70-72, and C75.1-C75.3 when combined with behavior code 0 for both incidence and mortality.21 ICD-10 codes D42-D43, D44.3-D44.5, D49.6, ICD-9 codes 237, 239.6, and the above ICD-O-3 topography codes combined with behavior code 1 were considered CNS tumors of uncertain behavior and included in this analysis as non-malignant tumors for both incidence and mortality. International Classification of Childhood Cancer, third edition (ICCC-3) codes IIIa-f and Xa were considered to include incidence of all CNS tumor behaviors unless stated otherwise.22 Cancer registry data review We performed a review of the cancer registry (CR) sources available to the GBD study to estimate cancer burden. The GBD study has historically modeled malignant CNS cancers by using data on all CNS tumors reported under an invasive disease code or label by any available vital registration (VR) and population-based CR data source from the years 1980 through the current GBD study year. CR sources considered suitable for use in the GBD study must report comprehensively on commonly reported cancers and ideally separate data by sex, in at least five-year age groups, and in singular year bins, although exceptions are made such as for childhood CRs, which often present data aggregated over several years. Data availability results in this analysis are presented by dataset. A single dataset in the GBD study may contain incidence from more than one CR and may represent several years. In some cases, datasets represent tumors in a single country. In other cases, the GBD study incorporates data from large reporting publications, such as the International Incidence of Childhood Cancer (IICC) series or Cancer Incidence in Five Continents (CI5) series, in which a GBD ‘dataset’ may represent data from many CRs around the world. Data considered unusable by the GBD study were considered unusable for this preliminary analysis as well. In addition, 16 found a greater proportion of non-malignant tumor cases in addition to higher ASIRs of CNS tumors overall in the higher income setting (Switzerland).25 Our results also corroborate prior findings across multiple countries and income settings that females may have higher proportions of non-malignant CNS tumors when assessed across all ages combined, which has previously been attributed to a greater incidence of meningiomas.3,4,11,12,26 These prior analyses laid critical groundwork in assessing differences in CNS tumor incidence by behavior internationally, with our study adding a preliminary assessment of incidence data availability and limitations across World Bank income groupings over time as well as an informal analysis of mortality data. Together, this literature suggests possible differences in epidemiological trends of non-malignant CNS tumors with higher ASIRs, ASMRs, and proportions of non-malignant CNS tumors occurring in HICs, as similar trends have been observed by previous studies.9,27,28 These data should be interpreted thoughtfully and continued investigation to understand the root differences in trends is necessary due to the potential for incomplete capture of both nonmalignant and malignant CNS tumors in some disease surveillance systems. The potential for underreporting may be greater in LMICs given data sparsity, lower reported ASIRs of CNS tumors of all behaviors, and lower reported proportions of non-malignant CNS tumor cases and deaths.3,4,11,13,29 It is also possible that genetic factors could contribute to variations in burden of CNS tumors internationally.9,28,30 The potential contribution of low case ascertainment to lower ASIRs and ASMRs alludes to possible benefit of future statistical modeling to account for underestimation. Longer term, addressing the reasons for less data availability and potentially lower non-malignant CNS tumor case ascertainment in LMICs will be important. These reasons are likely multifaceted; individuals may not seek medical care in lower resource settings, access to care may be suboptimal, and efficient referral streams to specialty care may not exist. The diagnosis of non-malignant CNS tumors may also be challenging due to lack of clinical providers, diagnostic imaging, or quality pathology review, leading to potential for misdiagnosis as a malignant CNS tumor or other intracranial process.31 Even if diagnosed, reporting of non-malignant CNS tumors by CRs has barriers. Over the past several decades, there have been many changes in CNS tumor classification and reporting practices across and within countries, and CRs often operate with limited funding and staffing.28,32,33 As has been previously raised,2 the current ICCC disease classification scheme makes it challenging to distinguish CNS tumors of different behaviors, and there is work ongoing to improve the reporting of CNS tumors in children.34 International reporting is also hindered by non-malignant CNS tumors no longer being included in the Cancer Incidence in Five Continents series following version VI in 1997.33 17 Further research and targeted implementation strategies, in close collaboration with CRs around the world, are needed to comprehensively investigate the barriers to reporting non-malignant CNS tumor burden and potential enablers for their future inclusion in reports. Our study alludes to the need for clarity in CR practices and reporting of non-malignant CNS tumors, which would benefit knowledge of global CNS tumor burden. When tumors are not registered, either due to systematic or operational barriers, the disease category remains invisible from a public health perspective. Thus, these data highlight that standard reporting across geographic boundaries are critical to ultimately improve diagnostics, treatment access and quality of care for individuals with CNS tumors worldwide. Previous research showed that the implementation of Public Law 107-260 requiring benign CNS tumor registration in the United States contributed to an increase in non-malignant CNS tumor incidence reported, which stabilized a few years following the statute.35 However, it is unlikely that registry mandates alone would be sufficient to completely capture non-malignant CNS tumor burden, and adequate CR support in addition to improvements in access to care and diagnosis across geographies will be critical to an accurate understanding of, and improved outcomes for, CNS tumor burden globally. This study is an important analysis of international non-malignant CNS tumor data availability. We contribute a comprehensive analysis of CR reporting of non-malignant CNS tumor data, highlighting the need for standardized inclusion of non-malignant CNS tumors and more data from low resource settings. We also report preliminary analyses of non-malignant CNS tumor incidence and mortality data, contributing to literature that can inform public health policy. Still, our study has several limitations. Data sources available for use in the GBD study as of August 2020 were analyzed, and given the time required for registries to report data, data were available through 2018 for evaluation. Moreover, there are data on non-malignant CNS tumors that were not acquired by the GBD prior to this date and are thus excluded from this study. VR and CR data sources were analyzed in as raw of forms as possible given that the primary aim of this analysis was to assess data availability and challenges with data available for this cancer type internationally. Thus, data were not processed for optimal harmonization and adjustments as would typically be the case in the GBD study, and analysis would be anticipated to change as processing steps are applied to the current data and as new data sources are added. Further, data use requirements limited the use of some data at optimal granularity, and some registries may collect non-malignant CNS tumor data that were not available for this analysis. The contribution of unspecified tumors, which were included in our analyses as non-malignant, may also impact our results. Finally, not all countries have CR or VR systems, which limits the generalizability of our 18 exploratory summaries of incidence and mortality results and further underscores the need for continued development and support of sustainable cancer surveillance systems capable of capturing and reporting nonmalignant CNS tumors. Our study illustrates a need for increased international data on non-malignant CNS tumor burden, particularly in LMICs, as well as a need for collaborative development of standardized reporting recommendations, referral pathways, and policies that allow for characterization of non-malignant CNS tumor burden separately from malignant to improve our understanding of overall CNS tumor burden. Our informal exploratory analysis of the available data suggests increasing ASIRs, ASMRs, and proportions of total CNS tumors that are non-malignant with increasing World Bank income status and can provide a starting point for further research into the best strategies for improvement of data capture and reporting practices. Data Availability Data used in this study will be made available upon request unless prohibited by data use agreements. Funding Bill and Melinda Gates Foundation, St. Jude Children’s Research Hospital Comprehensive Cancer Center [P30CA021765]; American Lebanese Syrian Associated Charities (ALSAC) Acknowledgements We are grateful to the cancer registries and vital registration systems that make data available for analysis and to all who are working to improve the lives of individuals with CNS tumors around the world. Conflict of Interest All authors declare no conflict of interest. 19 Author Contributions Conception of the work: Frances Dean, Nickhill Bhakta, Lisa M. Force. Data analysis: Frances Dean, Hannah Henrikson, Rixing Xu, Hodo Farah, Dan Lu, James Harvey, Weijia Fu, Natalie Pritchett. Data acquisition and interpretation: Frances Dean, Nickhill Bhakta, Daniel C. Moreira, Ibrahim Qaddoumi, Fabio Girardi, Mohsen Naghavi, Theo Vos, Jonathan L. Finlay, Lisa M. Force. Draft of the manuscript: Frances Dean, Lisa M. Force. Critical revision of the manuscript: all authors. Final approval of the manuscript: all authors. Agreement to be accountable for all aspects of the work: all authors. References 1 Girardi F, Allemani C, Coleman MP. Worldwide Trends in Survival From Common Childhood Brain Tumors: A Systematic Review. J Glob Oncol 2019; 5: 1–25. 2 Girardi F, Rous B, Stiller CA, et al. The histology of brain tumors for 67 331 children and 671 085 adults diagnosed in 60 countries during 2000-2014: a global, population-based study (CONCORD-3). Neuro-Oncol 2021; 23: 1765–76. 3 Ostrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014–2018. Neuro-Oncol 2021; 23: iii1– 105. 4 Fuentes-Raspall R, Solans M, Roca-Barceló A, et al. Descriptive epidemiology of primary malignant and nonmalignant central nervous tumors in Spain: Results from the Girona Cancer Registry (1994–2013). Cancer Epidemiol 2017; 50: 1–8. 5 Aldape K, Brindle KM, Chesler L, et al. Challenges to curing primary brain tumours. Nat Rev Clin Oncol 2019; 16: 509–20. 6 Lukas, RV; Mrugala, MM. Nonmalignant Brain Tumors. Continuum (Minneap Minn) 2020; 26: 1495–522. 20 7 McCarthy BJ, Schellinger KA, Propp JM, Kruchko C, Malmer B. A Case for the Worldwide Collection of Primary Benign Brain Tumors. Neuroepidemiology 2009; 33: 268–75. 8 WHO | Global Initiative for Childhood Cancer. WHO. http://www.who.int/cancer/childhood-cancer/en/ (accessed March 31, 2021). 9 Bondy ML, Scheurer ME, Malmer B, et al. Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium. Cancer 2008; 113: 1953–68. 10 Tamimi AF, Tamimi I, Abdelaziz M, et al. Epidemiology of Malignant and Non-Malignant Primary Brain Tumors in Jordan. Neuroepidemiology 2015; 45: 100–8. 11 Lee CH, Jung KW, Yoo H, Park S, Lee SH. Epidemiology of Primary Brain and Central Nervous System Tumors in Korea. J Korean Neurosurg Soc 2010; 48: 145–52. 12 Nilsson J, Holgersson G, Carlsson T, Henriksson R, Bergstrom S, Bergqvist M. Incidence Rates in LowGrade Primary Brain Tumors: Are There Differences Between Men and Women? A Systematic Review. World J Oncol Vol 7 No 4 Aug 2016 2016. https://www.wjon.org/index.php/wjon/article/view/976. 13 Ward ZJ, Yeh JM, Bhakta N, Frazier AL, Atun R. Estimating the total incidence of global childhood cancer: a simulation-based analysis. Lancet Oncol 2019; 20: 483–93. 14 Magrath I, Steliarova-Foucher E, Epelman S, et al. Paediatric cancer in low-income and middle-income countries. Lancet Oncol 2013; 14: e104-116. 15 Gatta G, Peris-Bonet R, Visser O, et al. Geographical variability in survival of European children with central nervous system tumours. Eur J Cancer 2017; 82: 137–48. 16 Chirlaque MD, Peris-Bonet R, Sánchez A, et al. Childhood and Adolescent Central Nervous System Tumours in Spain: Incidence and Survival over 20 Years: A Historical Baseline for Current Assessment. Cancers 2023; 15. DOI:10.3390/cancers15245889. 21 17 GBD 2021 Causes of Death Collaborators. Global burden of 288 causes of death in 204 countries and territories, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet 2024; published online April 3. 18 Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO Classification of Tumours of the Central Nervous System. Acta Neuropathol (Berl) 2007; 114: 97–109. 19 ICD-10: International statistical classification of diseases and related health problems. Geneva: World Health Organization, 2011. 20 World Health Organization. International classification of diseases : [9th] ninth revision, basic tabulation list with alphabetic index. ICD-9 Basic Tabul List Alph Index 1978. https://apps.who.int/iris/handle/10665/39473. 21 International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3). https://www.who.int/standards/classifications/other-classifications/international-classification-of-diseases-foroncology (accessed March 31, 2021). 22 Steliarova-Foucher E, Stiller C, Lacour B, Kaatsch P. International Classification of Childhood Cancer, third edition. Cancer 2005; 103: 1457–67. 23 The World Bank Group. World Bank Country and Lending Groups. 2022; published online April. https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-world-bank-country-and-lending-groups. 24 J. Ferlay, C. Burkhard, S. Whelan, D.M. Parkin. Check and Conversion Programs for Cancer Registries (IARC/IACR Tools for Cancer Registries). 2005. 25 Wanner M, Rohrmann S, Korol D, Shenglia N, Gigineishvili T, Gigineishvili D. Geographical variation in malignant and benign/borderline brain and CNS tumor incidence: a comparison between a high-income and a middle-income country. J Neurooncol 2020; 149: 273–82. 26 de Robles P, Fiest KM, Frolkis AD, et al. The worldwide incidence and prevalence of primary brain tumors: a systematic review and meta-analysis. Neuro-Oncol 2015; 17: 776–83. 22 27 Vos T, Lim SS, Abbafati C, et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. The Lancet 2020; 396: 1204–22. 28 Miranda-Filho A, Piñeros M, Soerjomataram I, Deltour I, Bray F. Cancers of the brain and CNS: global patterns and trends in incidence. Neuro-Oncol 2017; 19: 270–80. 29 Bhakta N, Force LM, Allemani C, et al. Childhood cancer burden: a review of global estimates. Lancet Oncol 2019; 20: e42–53. 30 Ostrom QT, Francis SS, Barnholtz-Sloan JS. Epidemiology of Brain and Other CNS Tumors. Curr Neurol Neurosci Rep 2021; 21: 68. 31 Mukhopadhyay S, Punchak M, Rattani A, et al. The global neurosurgical workforce: a mixed-methods assessment of density and growth. J Neurosurg 2019; 130: 1142–8. 32 Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-Oncol 2021; published online June 29. DOI:10.1093/neuonc/noab106. 33 Ferlay J, Kraywinkel K, Brian Rous, Ariana Znaor. Chapter 3: Classification and coding. In: Cancer Incidence in Five Continents. Lyon: International Agency for Research on Cancer, 2017. https://ci5.iarc.fr/CI5XI/PDF/Chapter%203.pdf (accessed May 30, 2022). 34 Moreira D, Chen Y, Qaddoumi I, et al. EPID-05. A novel, clinically-relevant classification of pediatric CNS tumors for cancer registries using a clustering analysis. Neuro-Oncol 2022; 24: i47–i47. 35 McCarthy BJ, Kruchko C, Dolecek TA. The impact of the Benign Brain Tumor Cancer Registries Amendment Act (Public Law 107-260) on non-malignant brain and central nervous system tumor incidence trends. J Regist Manag 2013; 40: 32–5. 23 Figures Category Description % of Incidence Data (N=383 Datasets) % of Mortality Data (N=132 Datasets) I Non-malignant CNS tumors reported separately from malignant 17.2% (N = 66) 27.3% (N = 36) II All behaviors of CNS tumors reported in aggregate 18.0% (N = 69) 11.4% (N = 15) III Malignant CNS tumors only reported and specifies to exclude nonmalignant 22.5% (N = 86) 11.4% (N = 15) IV Malignant CNS tumors reported and specifies to include in situ or uncertain 3.1% (N = 12) 3.0% (N = 4) V Malignant CNS tumors only reported without specifying to exclude nonmalignant 39.0% (N = 150) 47.0% (N = 62) Table 1. Global Burden of Disease (GBD) study cancer registry incidence and mortality data availability, categorized by how CNS tumor data were reported. 24 Figure 1. Countries with at least one population-based cancer registry report of non-malignant CNS tumors (a) prior to 2000 and (b) from 2000 onward in the GBD study. Country colors are based on the existence of any national or subnational cancer registry data on CNS tumors from 1980 to 2018 in the GBD database as of August 8, 2020. If a country had any data in that time frame from category I, it was colored dark blue. If a country did not have any data in category I but had data in category II, it was colored light blue unless the data was pediatric only or coded in ICCC and did not specify inclusion of non-malignant CNS tumors in which case it was colored yellow or orange, respectively. Countries with data in categories III, IV, V or no usable GBD data are colored red to indicate the absense of non-malignant CNS tumor data available to the GBD study. Data on non-malignant CNS tumors not yet used for the GBD study may exist but are not represented in this figure. Abbreviations: ICCC=International Classification of Childhood Cancer, GBD=Global Burden of Disease Study. 25 Figure 2. Median sex-specific ASIRs of CNS tumors from unprocessed cancer registry data sources by behavior and age group across World Bank income grouping from 1980-2018. Black bars represent interquartile range. Abbreviations: ASIRs=age-standardized incidence rates, HICs=High-income countries, LMICs=Lowand middle-income countries. 5 Appendix Figure 4. Age-standardized cancer registry unprocessed incidence data rates across all ages and both sexes combined against SDI by dataset categorization. Data from Algeria and Hungary were omitted due to a lack of reliable population estimates from the registry or by the GBD study for the region of geographic coverage. Data from Japan was omitted because it was presented in an all-ages aggregated form. Data from the following countries were omitted due to data use agreements: United States, China, Belarus, and Turkey. Abbreviations: ASIRs=age-standardized incidence rates, CNS=Central Nervous System, SDI=Socio-demographic Index. Appendix Figure 5. Pediatric CNS tumor ASIRs by behavior. Appendix Figure 5. Combined sex, pediatric (0-14 years) ASIRs of CNS tumors from unprocessed cancer registry data sources by behavior across SDI. Each point represents an annual ASIR from a cancer registry source between 1980 and 2018. Data from Algeria and Hungary were omitted due to a lack of reliable population estimates from the registry or by the GBD study for the region of geographic coverage. Data from Japan was omitted because it was presented in an all-ages aggregated form. Data from the following countries were omitted due to data use agreements: United States, China, Belarus, Turkey. Abbreviations: ASIRs=age-standardized incidence rates, CNS=Central Nervous System, SDI=Socio-demographic Index. 6 Appendix Figure 6. All ages CNS tumor ASMRs by behavior. Appendix Figure 6. Combined sex, all ages ASMRs of CNS tumors from unprocessed cancer registry and vital registration data sources by behavior across SDI. Each point represents an annual ASMR from a data source for a location (national or sub-national) between 1980 and 2018. Abbreviations: ASMRs=age-standardized mortality rates, CNS=Central Nervous System, SDI=Socio-demographic Index. Appendix Figure 7. Pediatric CNS tumor ASMRs by behavior. Appendix Figure 7. Combined sex, pediatric (0-14 years) ASMRs of CNS tumors from unprocessed cancer registry and vital registration data sources by behavior across SDI. Each point represents an annual ASMR from a data source for a location (national or sub-national) between 1980 and 2018. Abbreviations: ASMRs=agestandardized mortality rates, CNS=Central Nervous System, SDI=Socio-demographic Index. 7 Appendix Figure 8. Proportions of pediatric CNS tumor cases by behavior. Appendix Figure 8. Proportion of CNS tumor cases in children (0-14 years) that are malignant and nonmalignant in unprocessed cancer registry data, presented by sex and World Bank income status. Abbreviations: CNS=Central Nervous System, HIC= High income countries, LMIC=Lowand middle-income countries. Appendix Figure 9. Proportions of pediatric CNS tumor deaths by behavior. Appendix Figure 9. Proportion of CNS tumor deaths in children (0-14 years) that are malignant and nonmalignant in unprocessed cancer registry and vital registration data, presented by sex and World Bank income status. Abbreviations: CNS=Central Nervous System, HIC= High income countries, LMIC=Lowand middle-income countries. 8 Appendix Figure 10a. Countries with vital registration data for non-malignant CNS tumors prior to 2000. Appendix Figure 10a. Countries with at least one vital registration death reported for non-malignant CNS tumors prior to 2000. Countries are colored based on the availability of any nonzero data on non-malignant CNS tumors from 1980 to 1999. Abbreviations: CNS=Central Nervous System. Appendix Figure 10b. Countries with vital registration data for non-malignant CNS tumors from 2000 to 2018. Appendix Figure 10b. Countries with at least one vital registration death reported for non-malignant CNS tumors from 2000 to 2018. Countries are colored based on the availability of any nonzero data on non-malignant CNS tumors from 2000 to 2018. Abbreviations: CNS=Central Nervous System. Additional information on data represented in figures. No vital registration system data with nonmalignant CNS tumors available No vital registration system data with nonmalignant CNS tumors available Vital registration system data with nonmalignant CNS tumors Vital registration system data with nonmalignant CNS tumors 9 Maintext Figure 3. Data from Algeria and Hungary were omitted due to a lack of reliable population estimates for the region of geographic coverage. Data from Japan was omitted because it was presented in an all-ages aggregated form. Data from the following countries were omitted due to data use agreements: United States, China, Belarus, and Turkey. Maintext Figure 5a. High income countries included in analysis: Canada, Croatia, Hungary, Slovenia, Lithuania, Japan, Israel, Italy, United Kingdom, Ireland, Estonia, and France. Lowand middle-income countries included: Argentina, Algeria, and Ethiopia. Appendix Figure 8. Data from Japan was omitted because it was presented in an all-ages aggregated form. Data from the following countries were omitted due to data use agreements: United States, China, Belarus, Turkey. High-income countries included: Croatia, Hungary, Slovenia, Lithuania, Japan, Israel, Italy, United Kingdom, Malta, and Estonia. Upper middle income: Argentina. Lower middle income: Algeria. Low income: Ethiopia. Maintext Figure 5b and Appendix Figure 9. Data from the following countries were included. High-income countries: United Arab Emirates, Antigua and Barbuda, Australia, Austria, Belgium, Bahrain, Bahamas, Bermuda, Barbados, Brunei Darussalam, Canada, Switzerland, Chile, Cyprus, Czechia, Germany, Denmark, Spain, Estonia, Finland, France, United Kingdom, Greece, Greenland, Guam, Croatia, Hungary, Ireland, Iceland, Israel, Italy, Japan, Saint Kitts and Nevis, Republic of Korea, Kuwait, Lithuania, Luxembourg, Latvia, Monaco, Malta, Northern Mariana Islands, Netherlands, Norway, New Zealand, Oman, Poland, Puerto Rico, Portugal, Qatar, Saudi Arabia, Slovakia, Slovenia, Sweden, Trinidad and Tobago, Taiwan (Province of China), Uruguay, United States of America, and United States Virgin Islands. Upper middle-income countries: Albania, Argentina, Armenia, American Samoa, Azerbaijan, Bulgaria, Bosnia and Herzegovina, Belarus, China, Costa Rica, Cuba, Dominica, Dominican Republic, Ecuador, Georgia, Grenada, Guatemala, Guyana, Iraq, Jordan, Kazakhstan, Lebanon, Libya, Saint Lucia, Republic of Moldova, Maldives, Mexico, North Macedonia, Mauritius, Malaysia, Panama, Romania, Russian Federation, Serbia, Suriname, Thailand, Türkiye , Saint Vincent and the Grenadines, South Africa. Lower middle-income countries: Belize, Bolivia (Plurinational State of), Cabo Verde, Egypt, Ghana, Honduras, Haiti, India, Iran (Islamic Republic of), Kyrgyzstan, Solomon Islands, El Salvador, Tunisia, Ukraine, Uzbekistan.