Global, regional and national burden, incidence, and mortality of cervical cancer

Abstract Aim Among gynecological cancers, cervical cancer is the most common cause of cancer‐related death in developing countries. This study analyzes the incidence, mortality, and burden of cervical cancer using the Global Burden of Disease (GBD) 2019 study. Materials and Methods The GBD (2019) data on cervical cancer was extracted from the Global Health Data Exchange (GHDx) query tool. Age‐standardized rate (ASR) incidence, deaths, lost years of life (YLLs), years of life with disabilities (YLDs), and adjusted years of life with disabilities (DALYs) of cervical cancer in women were extracted. Data were extracted globally for 204 countries and groups based on a socio‐demographic index (SDI), World Health Organization (WHO) regions, continents, World Bank regions, and 22 GBD regions. Results The higher standardized age incidence of cervical cancer is in lower SDI countries, Africa, the African region (According to the WHO), and Sub‐Saharan Africa (According to GBD regions). The highest deaths of ASR is in countries with low SDI, low‐income group, Africa, the African region (According to the World Health Organization), and Sub‐Saharan Africa (According to GBD regions). According to SDI classification, the highest DALYs ASR is in low SDI countries, World Bank Low‐income countries, African and then American continents, African region, Sub‐Saharan Africa, and then Latin America & Caribbean‐WB (Based on GBD regions). Conclusion In 2019, incidence, mortality, and DALYs of cervical cancer mostly affected countries with lower socioeconomic status. Given that cervical cancer is highly preventable, access to screening services and the presence of trained and knowledgeable health care staff can reduce illness, suffering, and death caused by this malignancy. It is recommended to use the national and international potentials to reduce the incidence of this malignancy.


| INTRODUCTION
After heart disease, cancer is the second most common cause of death in the world, which imposes a significant burden on healthcare systems. 1 Among gynecological cancers, cervical cancer is the most common cause of cancer-related death in countries with low and middle Human Development Index (HDI) countries. 2 Cervical cancer has the highest incidence among young women. 3 Adenocarcinoma and squamous cell carcinoma are the two most common histological types of cervical cancer. 4 Infection with human papillomavirus carcinogens is a necessary cause of invasive cervical cancer. The progression of intraepithelial dysplastic lesions following persistent HPV infection leads to cervical cancer. 5 HPV is a sexually transmitted virus, so factors such as young age at marriage, multiple sexual partners, and unprotected sex, which increase the risk of contracting this virus, are linked with cervical cancer. Although HPV is a necessary cause of cervical cancer, not all lesions lead to malignancy. Some cofactors, such as multiparity, young age at marriage, and the use of oral contraceptives, in combination with HPV, cause malignant deformities of cancer cells. 6 Knowing that human papillomavirus carcinogenesis is the leading cause of cervical cancer has opened up new avenues for prevention.
Also, early detection and treatment of precancerous lesions have prevented a significant proportion of morbidity and mortality associated with cervical cancer. 3 Although there has been a gradual decline in cancer-related incidence and mortality, cervical cancer still imposes a significant burden on health systems. Decreased screening coverage, poor screening tests to identify precancerous lesions, and lack or inadequate treatment are responsible for most of the cost of cervical cancer in some societies. 7 Unfortunately, 80% of women in developing countries attend medical centers after the onset of symptoms. 8 These factors along with cultural and socio-economic factors, as well as societies' norms explain some of the geographical differences in the incidence of cervical cancer in different parts of the world. 7 According to statistics, cervical cancer is the most common disease in low-income areas, with more than two-thirds of cases and deaths occurring in developing countries. 9 At present, the development of effective prevention programs requires accurate statistics. Statistics, in addition to showing the current situation, make it necessary to take action to improve the situation, allocate the necessary budget and facilities, make purposeful planning, and finally select the best possible approach. 10 Therefore, the present study has gathered and presented epidemiological data, including incidence cases, age-standardized incidence rate, deaths, age-standardized mortality rate, YLLs, YLDs, and DALYs from the study of GBD in 2019.

| MATERIALS AND METHODS
In summary, the GBD (2019) data on cervical cancer was extracted from the GHDx query tool. GBD (2019) has systematically and comprehensively estimated 286 causes of death, 369 causes of diseases and injuries, and 87 risk factors for 204 countries and regions.
Geographically, the GBD divides the world into 7 main regions and 21 subregions. Detailed information on the data sources used in the present study can be found at GBD 2019 (http://ghdx.healthdata.org/ gbd-2019/data-input-sources).
In this study, the variables obtained from GBD statistics include cervical cancer incidence, mortality rate, years of life lost due to premature mortality (YLLs), years lived with disability (YLDs), disability-adjusted life years (DALYs), age-standardized incidence, and mortality rates per 100 000 people in 2019 based on socio-demographic Index (SDI) indicators. These variables also included World Bank income levels, continents, WHO regions, and GBD regions. The Socio-demographic Index (SDI) is a composite indicator of a country's lag-distributed income per capita, average years of schooling, and the fertility rate in females under the age of 25 years. 11 Overall, SDI = 0 has the lowest level of healthrelated development and SDI = 1 has the highest health-related development. In the GBD study (2019), countries and territories were classified as low, low-medium, medium, medium-high, and high based on the SDI. 12 In this study, a description of the mentioned indicators was done separately for each group by crude and age-standardized rates. Agestandardized mortality rates can be used to compare national mortality rates without being affected by differences in age distribution across countries. Without such standardization, it would be difficult to determine if the different mortality rates are due to age or other factors. 13 For GBD, an internationally standardized form of QALY has been developed, known as the Adjusted Year of Life (DALY). DALY is defined as the years of life lost due to premature death and the years lived with a disability of specified severity and duration. A DALY is therefore a wasted year of healthy living. "Premature" death is defined as a death occurring before the age at which the dying person would have expected to survive if they were part of a standardized population with a life expectancy at birth equal to that of the longest surviving population in the world, Japan. For calculating the total number of DALYs for a given condition in a population, years of life lost (YLLs) and years of disability of known severity and duration (YLDs) for this condition should be estimated and then added together. 14 More details presented in Table 1.

| The global incidence rate of cervical cancer
In 2019, a total of 565 541 new cases of cervical cancer with a confidence level (636435-481 524) were reported in women worldwide, with an incidence of ASR of 13.35 cases per 100 000 people. Statistics show that the lower the SDI index is, the higher age-standardized incidence rates of cervical cancer will be so that the highest standardized age incidence can be found in countries with low SDI and the lowest in countries with high SDI. This rate is equal to 8 YLLs r, K, Years lived with disability (YLDs) One YLD represents the equivalent of one full year of healthy life lost due to disability or ill-health 15 and A measure of years of life without perfect health. 19 YLDs r, K, Age-standardized rate (per 100.000) Comparisons of crude age-specific rates over time and between populations may be very misleading if the underlying age composition differs in the populations being compared. 25 where a i and w i represent the age-specific rates and the number of persons (or weight) in the same age subgroup of the chosen reference standard population (where i denotes the ith age class), respectively. 25 T A B L E 2 Cervical cancer incidence cases, age-standardized incidence rate, deaths, age-standardized mortality rate, DALYs, age-standardized DALY rates, YLLs, age-standardized YLLs rates, YLDs, and age-standardized YLDs rates in 2019 countries and the highest value (30.29) in the low-income countries.
Among the continents, the highest incidence of ASR is in Africa (24.02) and the lowest is in Europe (10.79

| DISCUSSION
Despite recent advances in the diagnosis and treatment of cervical cancer, with 280 479 deaths reported in 2019, this cancer was the fifth leading cause of neoplasm death in women worldwide. 26 Compared to many cancers, the average age of women who develop cervical cancer is low, so the number of years lost due to this disease is significant and can deprive women of survival at the peak of their social and family life. 27 In 2019, this cancer caused 8.9 million DALYs.
In 2019, a total of 565 541 cases of cervical cancer were reported worldwide, of which only 11% were detected in high SDI countries.
The age-standardized incidence of cervical cancer in the world in 2019 was 13.35 per 100 000 women and the age-standardized mortality rate was 6.51 per 100 000 women. This rate also varied significantly in different parts of the world. Among the various cancers, the highest variability in cancer incidence and mortality is seen in this malignancy. 28 According to the results of GBD in 2019, the highest incidence rates of ASR, death ASR, and DALYs ASR are seen in low SDI countries.
Of the 21 GBD regions, the highest age-standardized incidence,

mortality, and DALYs have been reported in Southern and Central
Sub-Saharan Africa, respectively. Numerous factors have changed the rate of cancer in these areas. The high incidence of HPV in the world is also seen in sub-Saharan Africa. 29 Women in this region start having sex at a younger age due to cultural norms, followed by a younger pregnancy and higher parity. In addition, financial, socio-cultural, and governmental barriers have made screening in these areas less effective. 30,31 The cost of Pap smear test, lack of access or difficult access to service providers and long waiting time are some of the system barriers in this region that indicate their socio-economic status. 32 The five-year survival rate for women with cervical cancer in these regions is 33%, which is much lower than the 80% rate in high-income countries. 33  The difference in cervical cancer rate depends on several factors such as the human development index, sexual behaviors, fertility patterns, and the degree of adherence to screening programs. Meanwhile, social differences also play a significant role in the differences in incidence and mortality of cervical cancer. Compared to higher socioeconomic status, lower socioeconomic status increases the risk of cervical cancer by 2-3 times. 36 Cervical cancer is considered a preventable disease. Screening reduces the mortality of this cancer by identifying and treating precancerous lesions at a lower stage. 37 Also, performing a single cervical cancer screening test in a lifetime reduces this cancer by 25-36%. 38 Screening is most effective when women at high risk of precancerous lesions take part in screening programs. Lack of access to quality screening programs is one of the challenges facing many women around the world. On the other hand, in many parts of the world, opportunistic screening is being implemented that does not target high-risk individuals. 7 While, in recent years, screening programs and epidemiologic indicators of cervical cancer have been affected by the COVID-19 crisis. 39 Also, during this period, receiving appropriate treatment by cervical cancer patients was appealed to challenges due to psychological distress (mostly fear of infectiousness). 40 In addition to screening, HPV vaccination is an effective way to prevent cervical cancer, which has been used in some areas. Nevertheless, cervical cancer is still one of the most common cancers in women, leading to high morbidity and mortality in many women. From 2008 to 2012, the incidence of cervical cancer in young women decreased in some countries, which can be attributed to the introduction of vaccination in this group. 41 Although HPV vaccination has been introduced as an approach to reducing the incidence of this disease, its use is insignificant in many areas. The high cost of vaccination is one of the barriers to its widespread use, especially in poor and low-income countries. 42 Not all cases of intraepithelial neoplasia progress to invasive cancer. Progression from CIN to invasive cancer requires HPV and some cofactors, such as smoking, high parity, multiple sexual partners, prolonged use of hormonal contraceptives, and failure to perform regular screening programs. 6 In areas where the prevalence of risk factors is higher, cervical cancer has a higher incidence and case fatality rate. 26 Cervical cancer is a clear example of inequality in health services in a country and between different countries. Differences in exposure to risk factors and injustice in access to screening, diagnostic, and treatment centers can explain some of these significant differences between different regions of the world. 43 Inequality in mortality is wider than inequalities in the incidence of cervical cancer. Patient survival and mortality are affected by the stage of cancer at diagnosis, access to health care, and appropriate treatment. 44 In 2015, cervical cancer was the 18th leading cause of death in high-SDI countries, while it was 2nd in low-SDI countries. Compared to developed countries, the mortality rate of cervical cancer in low and middle-income areas is 18 times higher. 28 High SDI countries account for a smaller share of incidence, mortality, and DALYs of cervical cancer. This rate has been controlled in many areas with early diagnosis and appropriate treatment. 45 Implementing cancer control measures around the world requires appropriate action and concerted effort by the governments of each country and the international agencies in the public and private sectors. Therefore, in May 2018, the World Health Organization called for the elimination of cervical cancer as one of the public health problems to reduce the health, social and economic burden of cervical cancer by removing related barriers. 46 Given that cervical cancer is highly preventable, access to screening services and the presence of trained and knowledgeable health care staff can reduce illness, suffering, and death caused by this malignancy. So, according to the World Health Organization, using a combination of interventions to achieve these goals should be considered. 47 Therefore, it is recommended to use the national and international potentials to reduce the incidence of this malignancy.
This study had some limitations that should be noted. First, although GBD (2019) has collected data from various sources, data from some areas is limited, which can affect the results of this study.
Second, GBD statistics were based on a set of data sources such as cancer registry data and cytological results, while access to these resources is limited in some low-income countries, and estimating statistics may be erroneous. Third, due to several years delay in presentation of cancer data, up to date data not available.