The mortality burden of hematological malignancies in Ecuador

Background The Hematological neoplasms (HN) are a heterogeneous group of cancers that originated in the hematopoietic or lymphoid tissues. There is reduced information published regarding HN mortality in Ecuador. This study aims to present the crude and age-specific mortality rates for HN in the Ecuadorian population. Methods We performed a cross-sectional study through the national database of defunctions published by the Ecuadorian National Institute of Statistics and Census, 2019. We used the ICD-10 codes to classify the HN. Results During 2019, 1462 deaths were reported, 53.83% were males, 87.96% of mestizo ethnicity, and 78.32% residents in urban areas. The median age was 62 years, with an interquartile range of 34. The crude mortality rate obtained was 8.49 per 100000 inhabitants, and the higher age-specific mortality rates was 43.29 per 100000 inhabitants aged ≥ 60 years, contrasting with the 2.63 per 100000 inhabitants in people aged < 20 years. Considering each ICD-10 group, we found the following rates by 100000 inhabitants; C85 2.04, C91 1.92, C92 1.46, C90 1.11, C83 0.70, C95 0.48, C81 0.38, C84 0.16, C82 0.10, C96 0.05, C93 0.04, C86 and C94 0.02, and C88 0.01. Conclusion In Ecuador, during 2019, approximately eight people died due to HN by 100000 inhabitants, affecting mainly people aged ≥ 60 years. The most frequent neoplasms were Non-Hodgkin lymphomas, similar to other reports globally. These results should be analyzed considering some deficiencies in the Ecuadorian health system and the national registry. Therefore, we suggest conducting more studies regarding HN.


Introduction
The term "Hematological malignancies" (HM) defines a diverse group of neoplastic diseases originated in the hematopoietic and lymphoid tissues, with a particular cytogenetic profile and clinical presentation depending each case and cell lineage [1]. In 2016 the World Health Organization published an updated version of the classification of tumors of the hematopoietic and lymphoid tissues, including more than 100 clinical entities [2]. HN represents 6.5% of all cancers globally, and particularly in Latin America, it has been observed that 57.7% of HN are represented by Non-Hodgkin Lymphoma (NHL), 29.5% Multiple Myeloma (MM), and 12.7% Chronic Lymphocytic Leukemia (CLL) [3,4]. There is limited information regarding the mortality by HN in the Ecuadorian population. Therefore, this study aims to present the mortality analysis for these pathologies through the national registry of deaths corresponding to 2019.

Methodology
We performed an observational and cross-sectional study, reporting the crude and age-specific death rates by HN in the Ecuadorian population in 2019.

Location
Ecuador is a country located in the northwest of South America and borders Colombia to the North, the Pacific Ocean to the West, and Peru to the South and East. The country crosses the Equatorial line and has approximately 17 million inhabitants living in 283 560 km2. It is administratively divided into 24 provinces, distributed in four regions, Andean (Sierra), Coastal (Costa), Amazon (Oriente), and Insular (Galapagos) (Figure 1). Data collection Data were obtained from the governmental database published in 2019 [last year published] by the Ecuadorian National Institute of Statistics and Census (INEC), the last published by the institution. The information is presented by INEC in SPSS format and is freely available on their website. The datasets analyzed during the current study are entitled "Anuario de Nacimientos y Defunciones" (https://www.ecuadorencifras.gob.ec/anuario-de-nacimientosy-defunciones/). As the SPSS report has data on all the deaths reported in the country during 2019, we used the ICD-10 codification to find the patients affected by hematological neoplasms. The ICD-10 codes, which correspond to hematological neoplasms, range from C81 to C96.
For this study, we included the following information: the total number of deaths reported by hematological neoplasms each year, the total number of inhabitants each year by province, and demographic characteristics, including age, sex, and province of residence.

Calculation
We performed the statistical analysis using the software SPSS V.25 and Excel 2013. Qualitative variables were presented as percentages and quantitative variables as median values with interquartile interval. To calculate the crude mortality rate, we used the equation: Crude mortality rate = Total number of deaths in a calendar year by HN Estimated mid − year population that year × 10 5 To calculate the age adjusted mortality rate, we used the equation: Age specific mortality rate = HN deaths in a calendar year for a particular age group Estimated mid − year population of the same year for the same age group × 10 5 Years of life lost (YLL) due to premature mortality (YLLs) were calculated using the following equation: [5] YLL=Number of deaths by a specific HN ×Life expectancy at the age of death Because the database provided by INEC does not present the date of diagnosis, we cannot include the calculation of disability-adjusted life years (DALY) and years lived with disability (YLDs). As described by INEC in the document "MUJERES Y HOMBRES del Ecuador en Cifras III", we considered life expectancy of 74.3 years for the male population and 80.2 for females. To compare the mortality rates between regions, we used the mean differences (MD), which was presented along with confidence intervals (CI) and significance level through pvalue.

Results
According to the data published by the National Institute of Statistics and Censuses (INEC), during 2019, 1462 deaths were associated with hematological neoplasms. From them, 787 (53.83%) were males, 1286 (87.96%) consider themselves to be of mestizo ethnicity, 1145 (78.32%) lived in the urban area. Additionally, the median age was 62 years, with an interquartile range (IQR) of 34. For male patients, the median age was 63 years (IQR 35), and for females, the median age was 62 years (IQR 33).

Discussion
As estimated by GLOBOCAN 2018, there were 18.1 million new cases and 9.6 million cancer deaths worldwide, from which 248,724 (2.6%), 309,006 (3.2%), 106,105 (1.1%), and 26,167 (0.3%) deaths corresponds to NHL, Leukemia, MM, and Hodgkin lymphoma (HL), respectively [6]. In our study, we found that the crude mortality rate for HN was 8.49 per 100000 inhabitants, with the highest number of deceased patients corresponding to NHL, leukemia, and MM. This results are similar whit other reports presented in the region. In Central and South America, regarding NHL, the reported age-standardized mortality rates per 100,000 varied from 1.3 to 9.2 in female patients and 1.4 to 10.9 among males [7]. In an analysis conducted through data corresponding to 17 countries from the World Health Organization, for the period 1995-2013, mortality rates were higher in male population, the highest MM mortality rates were registered in Chile (15.1/100,000 in men and 11.9/100,000 in women), and the majority of countries presented increasing trends with the highest increments in Guatemala, Ecuador, Paraguay, and Brazil [8]. In Latin America from 1990 to 2017, for AML, it has been reported that El Salvador and Ecuador had the most rapid increase in Age-Standardized Death Rate (ASDR), with estimated annual percentage changes of 3.62 (95% CI 2.93 to 4.31) and 3.53 (95% CI 3.13 to 3.93), respectively [9]. Similarly, for ALL, Andean Latin America had the fastest increase in ASDR from 1990 to 2017 (EAPC=1.59, 95% CI 1.46 to 1.72) [10]. Another relevant aspect is the small number of hematologists nationwide. According to what was presented in the 2018 Yearbook of Health Activities and Resources, 130 hematologists where registered in Ecuador for that year. In the 24 provinces, 11 did not have this specialist, and 84.62% were centralized in Pichincha (30%), Guayas (32.31%), and Manabí (22.31%). This information may explain why the Amazon region has the lowest number of deaths reported, along with the lack of availability to relevant tools such as cytogenetics, molecular biology, immunohistochemistry, PET-TC, among others. In this context, health authorities must take action to overcome the reduced access to hematology services in the majority of the provinces. Besides, there is reduced availability of bone marrow transplant (BMT) centers in Ecuador, as only one institution in Guayaquil offers this service [11]. This last aspect is preoccupying, especially when many deceased patients have HN in which BMT is the first line of treatment. Additionally, the lack of access to hematology in provinces with higher poverty rates concerns us as poverty by itself is related to increased mortality in cancer in both adults and pediatric patients [12,13]. Similarly, some ethnic groups can be affected by this unequal distribution of access, such as indigenous communities in Coastal, Andean and Amazonic regions and the afro-descendant population located north of the Coastal region. In line with this suggestion, the association between ethnicity and poverty could also negatively impact the survival of children with acute lymphoblastic leukemia and other types of adult cancers [14,15].

Conclusion
In Ecuador, during 2019, approximately eight people died due to HN by 100000 inhabitants, which increases to 43 defunctions by 100000 inhabitants in the population aged 60 years or more. The neoplasms with the highest number of patients deceased corresponds to Non-Hodgkin lymphomas, similar to other reports globally. These results should be analyzed considering some deficiencies in the Ecuadorian health system as well as in the national registry, such as the reduced number of hematologists and the insufficient access to more specific diagnostic tools. Therefore, we suggest conducting more studies to understand better, how HN affects the Ecuadorian population. Acknowledgement None Authors' affiliations: 1 (2) drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted

Competing interests
There is no conflict of interest for any author of this manuscript.

Source of Support:
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.