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\begin{document}

\title{Burden of gynecological malignancies in China, 1990-2019: findings from
the Global Burden of Disease Study 2019}



\author[1]{Yuan  Zhang}%
\author[1]{Xiaolei Zhang}%
\author[2]{Ruijie  Wu}%
\author[1]{Tongchao Zhang}%
\author[1]{Xiaoyan  Liu}%
\author[1]{Hao  Chen}%
\author[2]{Zhen  Li}%
\author[2]{Yuan  Fang}%
\author[1]{Xiaorong  Yang}%
\author[1]{Ming Lu}%
\affil[1]{Qilu Hospital of Shandong University}%
\affil[2]{Shandong University}%


\vspace{-1em}



  
  \date{May 29, 2024}


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\selectlanguage{english}
\begin{abstract}
Objective To evaluate the epidemiological trends and patterns of
cervical cancer, uterine cancer and ovarian cancer in China in 1990 and
2019. Design Systematical and updated worldwide epidemiological study.
Setting Global Burden of Disease (GBD) Study 2019. Population or Sample.
Chinese population was obtained from World Health Organization (WHO)
World Standard Population Distribution (2000-2025) and the United
Nations World Population Prospects 2019 Revision. Methods Data were
extracted from the Global Burden of Diseases, Injuries, and Risk Factors
Study 2019. GBD methodology was used to estimate the burden of
gynecological malignancies in China, including cervical cancer, uterine
cancer and ovarian cancer. Main Outcome Measures The incidence,
mortality, disability-adjusted life-years (DALYs), and estimated annual
percentage change (EAPC) were systematically analyzed. We additionally
predicted the incidence and mortality of gynecological malignancies from
2020 to 2030. Results From 1990 to 2019, the numbers of incidence cases,
deaths and DALYs of cervical cancer, uterine cancer and ovarian cancer
all significantly increased. The EAPCs in age-standardized incidence
rate (ASIR) of three cancers were 1.61 (95\% CI: 1.35, 1.88), 1.26 (95\%
CI: 0.58, 1.94) and 1.88 (95\% CI: 1.79, 1.98). From 2020 to 2030, the
predicted numbers of incident cases and deaths of gynecological
malignancies should continue to increase, and the incidences of uterine
cancer would expect to exceed cervical cancer in 2030. Conclusions In
China, the numbers of new cases and deaths of gynecological malignancies
will continue to increase in the next ten years. Reducing the prevalence
of gynecological malignancies should be prioritized in future work.%
\end{abstract}%



\sloppy


\textbf{Burden of gynecological malignancies in China, 1990-2019:
findings from the Global Burden of Disease Study 2019}

Yuan Zhang,\textsuperscript{a,b,c,\textbf{*}} Xiaolei
Zhang,\textsuperscript{d,\textbf{*}} Ruijie
Wu,\textsuperscript{b,\textbf{*}} Tongchao
Zhang,\textsuperscript{a,c}Xiaoyan Liu,\textsuperscript{d} Hao
Chen,\textsuperscript{a,c} Zhen Li,\textsuperscript{b} Yuan
Fang,\textsuperscript{b} Xiaorong Yang,\textsuperscript{a,c} Ming
Lu\textsuperscript{a,b,c}

\textsuperscript{a} Clinical Epidemiology Unit, Qilu Hospital of
Shandong University, Jinan, Shandong 250012, P. R.
China\textsuperscript{b} School of Public Health, Cheeloo College of
Medicine, Shandong University, Jinan, Shandong 250012, P. R.
China\textsuperscript{c} Clinical Research Center, Shandong University,
Jinan, Shandong 250012, P. R. China \textsuperscript{d} Department of
Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan,
Shandong 250012, P. R. China

\textbf{Correspondence}

Xiaorong Yang, Clinical Epidemiology Unit, Qilu Hospital of Shandong
University, No. 107, Wenhua West Road, Jinan, Shandong 250012, P. R.
China.

E-mail: yangxiaorong@sdu.edu.cn

Ming Lu, Clinical Epidemiology Unit, Qilu Hospital of Shandong
University, No. 107, Wenhua West Road, 250012, Jinan, Shandong 250012,
P. R. China.

E-mail: \emph{lvming@sdu.edu.cn}

\textbf{Short Title:}

Gynecological malignancies burden in China.

\textsuperscript{\textbf{*}} Joint first authors and contributed equally
to this paper.

\textbf{Abstract}

\textbf{Objective} To evaluate the epidemiological trends and patterns
of cervical cancer, uterine cancer and ovarian cancer in China in 1990
and 2019.

\textbf{Design} Systematical and updated worldwide epidemiological
study.

\textbf{Setting} Global Burden of Disease (GBD) Study 2019.

\textbf{Population or Sample} . Chinese population was obtained from
World Health Organization (WHO) World Standard Population Distribution
(2000-2025) and the United Nations World Population Prospects 2019
Revision.

\textbf{Methods} Data were extracted from the Global Burden of Diseases,
Injuries, and Risk Factors Study 2019. GBD methodology was used to
estimate the burden of gynecological malignancies in China, including
cervical cancer, uterine cancer and ovarian cancer.

\textbf{Main Outcome Measures} The incidence, mortality,
disability-adjusted life-years (DALYs), and estimated annual percentage
change (EAPC) were systematically analyzed. We additionally predicted
the incidence and mortality of gynecological malignancies from 2020 to
2030.

\textbf{Results} From 1990 to 2019, the numbers of incidence cases,
deaths and DALYs of cervical cancer, uterine cancer and ovarian cancer
all significantly increased. The EAPCs in age-standardized incidence
rate (ASIR) of three cancers were 1.61 (95\% CI: 1.35, 1.88), 1.26 (95\%
CI: 0.58, 1.94) and 1.88 (95\% CI: 1.79, 1.98). From 2020 to 2030, the
predicted numbers of incident cases and deaths of gynecological
malignancies should continue to increase, and the incidences of uterine
cancer would expect to exceed cervical cancer in 2030.

\textbf{Conclusions} In China, the numbers of new cases and deaths of
gynecological malignancies will continue to increase in the next ten
years. Reducing the prevalence of gynecological malignancies should be
prioritized in future work.

\textbf{Funding} The National Key Research and Development Program of
China (No.2021YFF1201101)

\textbf{Keywords} Burden, gynecological malignancies, China, global
burden of disease study

\textbf{Introduction}

Gynaecological malignancies are the leading causes of premature death
and disability for women worldwide, mainly including cervical cancer,
uterine cancer and ovarian cancer. There were approximately 1,309,165
new cases and 609,377 deaths of gynaecological malignancies worldwide in
2018. Cervical cancer is the fourth most frequently diagnosed cancer and
the fourth leading cause of cancer death in women, with an estimated
604,000 new cases and 342,000 deaths worldwide in
2020\textsuperscript{1}. Cervical cancer represents a major global
health challenge. Uterine cancer is the sixth most commonly diagnosed
cancer in women, with 417,000 new cases and 97,000 deaths in
2020.\textsuperscript{1} Uterine cancer mostly affects post-menopausal
women. For patients with advanced disease, with lymph node invasion or
metastasis, the 5-year overall survival is only 50\% and 20\%,
respectively.\textsuperscript{2} Ovarian cancer is the most lethal of
the gynecologic malignancies with highest mortality rate among all
gynecological malignant tumors. Although progress has been made in the
diagnosis, prevention, screening and treatment of these malignancies
over the past decades, many issues remain to be unsolved, such as
chemoresistance, metastasis, recurrence, and family financial
burden.\textsuperscript{3,4}

Gynecological malignancies are the serious public health problem for
women in China. These malignancies put the heavy burden on women, family
and society in China, so there is an urgent need for comprehensive
understanding of the epidemic trends and patterns of gynecological
cancer in China. We conducted this study to investigate and characterize
the temporal trends and patterns in China over 30 years based on Global
Burden of Disease (GBD) 2019, and predict incidence and mortality of
gynecological malignancies from 2020 to 2030. Findings of this study
will provide certain enlightenment for the etiological research of these
cancers in China, measure the progress of specific treatments, help
policymakers allocate resources and formulate relevant medical policies
and opinions in the future.

\textbf{Methods}

\textbf{Overview}

October 2020, GBD 2019 estimates incidence, prevalence, mortality, years
of life lost (YLLs), years lived with disability (YLDs), and
disability-adjusted life-years (DALYs) due to 369 diseases and injuries
for 204 countries and territories from 1990 to
2019.\textsuperscript{2}In this study, we describe the burden and risk
factors of gynecological malignancies, including cervical cancer,
uterine cancer and ovarian cancer in China.

The ethics committee of Qilu Hospital of Shandong University reviewed
and approved this study. Informed consent was waived because no
identifiable information was included in the analyses. This study
complied with the Guidelines for Accurate and Transparent Health
Estimates Reporting statement.\textsuperscript{5}

\textbf{Data sources}

The detail methods of GBD study (2019) have been reported in several
studies.\textsuperscript{2,6,7} The data on incidence, mortality and
DALYs were downloaded from the Institute for Health Metrics and
Evaluation (IHME, http://ghdx.healthdata.org/gbd-results-tool). The
codes used for GBD study analysis can be accessed through the following
address: http://ghdx.healthdata.org/gbd-2019-code. In GBD study, all
estimates were generated with 95\% uncertainty intervals (95\% UIs),
which were determined based on the 2.5th and 9.75th percentiles of 1000
draw of the uncertainty distribution. The inclusion criteria were as
follows: (1) the cause was ``cervical cancer'', ``uterine cancer'', and
``ovarian cancer''; (2) the year was selected from 1990 to 2019 and the
location was ``China''; (3) ``incidence'', ``death'' and ``DALYs'' were
selected for measures.

The age-standardized rates for the incidence, mortality, and DALYs of
gynecological malignancies were estimated using the World Health
Organization (WHO) World Standard Population Distribution (2000-2025).
For the prediction of burden, the predicted Chinese population was
obtained from the United Nations World Population Prospects 2019
Revision, by year, sex and age
(https://population.un.org/wpp/Download/Standard/Population/).

\textbf{Evaluation of burden of gynecological malignancies}

The incidence and mortality of gynecological malignancies in the GBD
dataset were evaluated in the following ways: (1) based on all the data
sources that reported incidence and mortality of cervical cancer,
uterine cancer and ovarian cancer (with international disease
classification codes), the mortality-to-incidence ratio (MIR) was
computed; (2) we calculated mortality estimates by multiplying cancer
register incidence data by the MIR; (3) all these data were used as
input to follow the Cause of Death Ensemble model process to determine
the cancer-specific mortality of cervical cancer, uterine cancer and
ovarian cancer; and (4) we divided the cancer-specific mortality of
cervical cancer, uterine cancer and ovarian cancer estimates by the MIR
to generate incidence. DALYs were computed by adding years of life lost
(YLLs) and years lived with disability (YLDs).

\textbf{Statistical analysis}

Estimated annual percentage change (EAPC) was used to quantify the
trends of age-standardized incidence rate (ASIR), age-standardized
mortality rate (ASMR) and age-standardized DALYs rate (ASDR). The
logarithmic age-standardized indicators could be fitted to a regression
line, i.e., ln(y) = \selectlanguage{greek}α\selectlanguage{english}+\selectlanguage{greek}β\selectlanguage{english}x+\selectlanguage{greek}ε, \selectlanguage{english}where y stands for the respective
age-standardized indicators, x the calendar year. EAPC was calculated as
100 \selectlanguage{ngerman}× (exp (\selectlanguage{greek}β\selectlanguage{english})-1), and its 95\% confidence interval (CI) could also be
calculated from the model 21. The age-standardized indicator was
recognized to be in an increasing trend if the 95\% CI of corresponding
EAPC estimation \textgreater{} 0, to be decreasing trend if the 95\% CI
\textless{} 0, and to be stable if the 95\% CI including 0. Furthermore,
we predicted the numbers of new cases and deaths of gynecological
malignancies from 2020 to 2030 by conducting a Bayesian
age-period-cohort (BAPC) analysis using integrated nested Laplace
approximation (INLA) packages in R. All analyses were conducted using R
program (Version 4.0.2, R core team, Vienna, Austria). A\emph{P}
\textless{}0.05 was considered statistically significant.

\textbf{Results}

\textbf{Incidence, mortality and DALYs of gynecological malignancies in
2019}

In 2019, the number of incidence cases and ASIR of cervical cancer were
109.76 thousand (95\% UI: 58.19, 141.54) and 11.01 per 100,000 (95\% UI:
5.87, 14.22), respectively. Cervical cancer contributed to 53.44
thousand (95\% UI: 30.40, 68.86) deaths, and ASMR was 5.13 per 100,000
(95\% UI: 2.92, 6.60). Cervical cancer caused 1622.24 thousand (95\% UI:
892.58, 2090.86) DALYs, and ASDR was 157.50 per 100,000 (95\% UI: 86.90,
202.91) (Table 1).

The number of incidence cases and ASIR of uterine cancer were 66.74
thousand (95\% UI: 51.38, 92.05) and 6.39 per 100,000 (95\% UI: 4.89,
8.74), respectively in 2019. Uterine cancer contributed to 12.22
thousand (95\% UI: 9.43,17.34) deaths, and ASMR was 1.17 per 100,000
(95\% UI: 0.9, 1.66). Uterine cancer caused 364.28 thousand (95\% UI:
286.56, 503.57) DALYs, and ASDR was 34.93 per 100,000 (95\% UI: 27.27,
47.77) (Table 1).

The number of incidence cases and ASIR of ovarian cancer were 45.48
thousand (95\% UI: 33.11, 57.38) and 4.54 per 100,000 (95\% UI: 3.33,
5.71), respectively. Ovarian cancer contributed to 29.10 thousand (95\%
UI: 20.96, 36.86) deaths, and ASMR was 2.77 per 100,000 (95\% UI:
2.01,3.50). Ovarian cancer caused 835.06 thousand (95\% UI: 612.56,
1063.25) DALYs, and ASDR was 80.52 per 100,000 (95\% UI: 59.44, 102.57)
(Table 1).

In 2019, the numbers of incident cases and DALYs of cervical cancer,
uterine cancer and ovarian cancer reached the peak among the female
population aged 50-54 years (Figure 1A and 1C, Table S1 and S3). The
peak numbers of deaths of cervical cancer, uterine cancer and ovarian
cancer appeared at aged 50-54, 65-69 and 65-69 years, respectively.
(Figure 1B, Table S2). Meanwhile, the numbers of incident cases, deaths
and DALYs of ovarian cancer covered all age groups over 5 years old
(Figure 1).

The incidence rate reached the peak among cervical cancer and uterine
cancer aged 55-59 years, and 70-74 years for ovarian cancer. The
mortality rate reached the peak among cervical cancer and uterine cancer
aged over 95 years, and 90-94 years for ovarian cancer. The peak of DALY
rate of cervical cancer, uterine cancer and ovarian cancer appeared at
aged 55-59, 60-64 and 65-69 years, respectively (Figure 1, Table S1-S3).

\textbf{Trends of incidence, mortality and DALYs of gynecological
malignancies from 1990 2019}

From 1990 to 2019, the numbers of incidence cases, deaths and DALYs of
cervical cancer, uterine cancer and ovarian cancer all significantly
increased. The EAPCs in ASIR of three cancers from 1990 to 2019 were
1.61 (95\% CI: 1.35, 1.88), 1.26 (95\% CI: 0.58, 1.94) and 1.88 (95\%
CI: 1.79, 1.98), respectively. The EAPC of ASMR and ASDR among patients
with cervical cancer in 20 years was not much different with 0.09 (95\%
CI: -0.18, 0.36) and 0.16 (95\%: -0.09, 0.41), respectively. Overall
downward trends in ASMR and ASDR among patients with uterine cancer were
observed with the EAPC of -2.27 (95\% CI: -2.88, -1.66) and -2.21
(95\%CI: -2.81, -1.60). The EAPC of death and DALYs of ovarian cancer
still showed an upward trend with 1.51 (95\% CI: 1.42, 1.61) and 1.15
(95\%CI: 1.04, 1.25) (Table 1, Figure 2).

The incidence rate of cervical cancer aged 35-70 years was increasing
from 1990 to 2019. In recent years, the incidence rate of uterine cancer
has declined in most age-specific groups, but had shown a youth-oriented
tendency. The incidence and death rate of ovarian cancer showed an
upward trend in overall groups. Overall downward trends in mortality and
DALYs rates were observed in cervical cancer and uterine cancer at most
age-specific groups from 1999 to 2019. The DALYs rates of ovarian cancer
increased in most age-specific groups (Figure 2).

\textbf{DALYs rates and proportions attributable to risk factors for
gynecological malignancies from 1990 to 2019}

In all age-specific groups, the DALYs rates of cervical cancer
attributed to unsafe sexual activity were the highest, and fortunately,
the DALYs rates attributable to unsafe sexual activity showed a downward
trend in recent years. The DALYs rates of cervical cancer due to smoking
showed a downward trend in above 60-year-old groups. The DALYs rates of
uterine cancer due to high body-mass index were higher between 50 and 69
years. The DALYs rates of ovarian cancer attributable to high body-mass
index, high fasting plasma glucose and occupational asbestos exposure
had an upward trend from 1990 to 2019.

The DALYs proportion of cervical cancer attributable to unsafe sexual
activity was 100\% continuously, and smoking's contribution descended in
2019 compared to 1990. Proportions of DALYs attributable to high
body-mass index for uterine cancer and ovarian cancer were higher in
2019 than in 1990 in all age-specific groups. The high fasting plasma
glucose was the most significant contribution to ovarian cancer,
accounting for more than 6\% in above 60-year-old women. The proportion
of DALYs attributable to occupational asbestos exposure was slightly
lower in 2019 than in 1990 (Figure 3).

\textbf{Predictions ofincidence and mortality of gynecological
malignancies from 2020 to 2030}

Based on GBD data of gynecological malignancies from 1990 to 2019 in
China, we predicted the incident cases and deaths in the next eleven
years (Figure 4). The numbers of incident cases and deaths of cervical
cancer, uterine cancer and ovarian cancer should continue to increase
from 2020 to 2030. The predicted new cases of uterine cancer have the
steepest rising slope, which is expected to exceed the cases of cervical
cancer in 2030. Meanwhile, the growth of uterine cancer deaths also had
the steepest slope, followed by ovarian cancer and cervical cancer. In
2030, the overall new cases of cervical cancer, uterine cancer and
ovarian cancer should increase to 123,902, 132,118 and 72,488,
respectively (Figure 4A). And the overall deaths of cervical cancer,
uterine cancer and ovarian cancer should increase to 59,145, 18,571 and
45,680, respectively (Figure 4B).

We further predicted the age-standardized incidence rate and death rate
of gynecological malignancies from 2020 to 2030 (Figure 5).
Age-standardized rates of incidence and mortality of cervical cancer
should show a downward trend (Figure 5A and 5B). The age-standardized
incidence rate of uterine cancer should show a slow upward trend and the
death rate of uterine cancer remain stabilized trend (Figure 5C and 5D).
Seriously, the age-standardized rates of incidence and mortality of
ovarian cancer should show an upward trend (Figure 5E and 5F).

\textbf{Discussion}

Cancer is a leading cause of death and disability worldwide, especially
in women.\textsuperscript{8,9}Gynecologic cancers which have negative
effects on the physical and psychological health of patients, seriously
threaten women's life and health. According to GLOBOCAN 2020 Project
data, cervical cancer, uterine cancer, and ovarian cancer are among the
top 10 common cancers in females worldwide.\textsuperscript{1}China is
the world's most populous country with around 685 million women.
Approximately 214,400 new cases of gynecologic cancer occurred in 2015,
and there were about 74,800 deaths from gynecologic cancer in
China.\textsuperscript{10} Therefore, it is of great social significance
to comprehensively understand the epidemic trends and patterns of
gynecological cancers in China. In this study, we not only assessed the
prevalence of gynecologic cancers in China, but also systematically
analyzed trends of incidence, mortality, DALYs and proportions
attributable to risk factors for gynecological malignancies from 1990 to
2019. In addition, we predicted incidence and mortality rates for
gynecologic malignancies from 2020 to 2030. This is one substantial
study to investigate the long-term trends of morbidity and mortality for
gynecologic malignancies in China and to assess DALYs rates and
proportions attributable to risk factors for gynecological malignancies
from 1990 to 2019.

The global costs associated with cancer are significant and are
estimated to comprise 2-4\% of the annual gross domestic product (GDP).
The majority of the world's cancer burden occurs in low- and middle-
income countries (LMICs).\textsuperscript{11}In addition to social and
economic burden on women and their family, gynecologic malignancies play
negative effects on women's self-concept, body image, sense of
femininity and sex life.\textsuperscript{12-16}Most of the people in
China have medical insurance, however cancer costs are only partly
covered by insurance. Medical costs are still problem for patients with
gynecologic malignancies. Due to women's increasingly important roles in
the family and society in China, gynecologic cancer patients are more
likely to suffer from anxiety and depression. China is the most populous
country in the world, so cancer patterns in China is an important focus
of public health. China is undergoing a transition period from being a
developing country to a developed country, with a large number of female
residents, it is of great social significance to summarize and analyze
the epidemiological patterns of gynecologic malignancies in China.

The incidence, mortality, disability-adjusted life-years (DALYs) could
be used to measure disease and economic
burdens.\textsuperscript{7,17-20} The burden of cancer incidence and
mortality is growing rapidly worldwide. Around the world, the total
incidence and mortality of gynecologic cancers increased sharply from
1990 to 2019. From 1990 to 2019, the numbers of incidence cases, deaths
and DALYs of cervical cancer, uterine cancer and ovarian cancer all
significantly increased, which is consistent with the reports in another
paper.\textsuperscript{7} As shown in Table 1, the ASIRs and ASDRs of
these three types of cancers exhibited different epidemiological
patterns. We analyzed numbers and rates of incidence, death and DALYs of
cervical cancer, uterine cancer and ovarian cancer by age in 2019 in
China. Data showed that the numbers of incident cases and DALYs of
cervical cancer, uterine cancer and ovarian cancer reached the peak
among the female population aged 50-54 years. Meanwhile, the peak
numbers of deaths of cervical cancer, uterine cancer and ovarian cancer
appeared at aged 50-54, 65-69 and 65-69 years, respectively. More
screenings and attention should be paid to Chinese women aged 50-69
years. The results showed that the high-risk group of gynecologic cancer
was middle-aged and elderly women in China; The middle-aged and elderly
population is the key population to carry out comprehensive prevention
and control of malignant tumors. It is necessary to strengthen the
health examination, health knowledge education, tumor screening, early
diagnosis, early treatment, tumor registration and follow-up of the
middle-aged and elderly population. The prevention and treatment of
gynecologic cancer is a long-term and arduous task. On the basis of
improving the monitoring of cancer incidence and death, we should fully
analyze the types of high-incidence cancers and high-risk factors in
different age groups, and adopt targeted prevention and treatment
strategies with overall consideration, so as to obtain a good effect of
tumor prevention and treatment.

We explored DALYs rates and proportions attributable to risk factors for
gynecological malignancies from 1990 to 2019, in order to provide
scientific basis for effective prevention and intervention of cervical
cancer, uterine cancer and ovarian cancer. Cervical cancer is one of the
leading causes of cancer-related deaths in women
worldwide,\textsuperscript{21} meanwhile, it is the most common
gynecologic cancer in China. High-risk subtypes of the human
papillomavirus (HPV) cause almost all cervix
cancers.\textsuperscript{22} Persistent infection of the lower genital
tract by one of the high-risk HPV (hrHPV) types is the ``necessary''
cause of cervical cancer. HPV16 and 18 are associated with approximately
71\% of cervical cancer cases, while 31, 33, 45, 52 and 58 are
associated with another 19\% of cases.\textsuperscript{23-25} High
proportion of sexually active women become infected with some human
papillomavirus type by age 25 years, but most infections resolve
spontaneously.\textsuperscript{26} It suggests that the infection is
predominantly transmitted through the sexual activity. Our results
showed that, the DALYs rates of cervical cancer attributed to unsafe
sexual activity were the highest in all age-specific groups, and the
DALYs rates attributable to unsafe sexual activity showed a downward
trend in recent years. However, the DALYs proportion of cervical cancer
attributable to unsafe sexual activity was 100\% continuously. Studies
show that cervical cancer is positively correlated with premature sexual
life, excessive sexual life, multiple sexual partners and unclean sexual
life. The risk of cervical cancer in women with initial sexual behavior
[?] 21 years old is lower than that in women with initial sexual behavior
aged 15\textasciitilde{}16 years old.\textsuperscript{27} It is an
effective measure to improve people's awareness of cervical cancer
related knowledge, HPV vaccine and cervical cancer screening and improve
their awareness of prevention and control in China. Cervical cancer
screening has become one of the most common gynecological screening
programs in China.\textsuperscript{28} This is of great significance in
the early diagnosis of cervical cancer. Studies have shown that smoking
and passive smoking are also related to the occurrence of cervical
cancer and precancerous lesions. The mechanism may be that the
concentration of nicotine in cervical mucus of smoking women increases
significantly, consumes a large number of Langham cells, and leads to
the reduction of cervical immunity. According to relevant statistics,
the risk of cervical cancer increased 11.8 times in patients with
passive smoking time [?]5 h/d.\textsuperscript{29} The results of our
study show that the DALYs rates of cervical cancer due to smoking showed
a downward trend in above 60-year-old groups, and smoking's contribution
descended in 2019 compared to 1990 (shown in Figure 3). This indicates
that health education, lifestyle improvement and anti-smoking laws must
be carried out throughout the comprehensive prevention and control of
cancer. This has important implications for improving women's
reproductive health.

Studies have found that obesity may be an important factor affecting the
occurrence and development of uterine
cancer.\textsuperscript{30-32}Body-mass index (BMI) was positively
correlated with the risk of endometrial cancer, and the risk of
endometrial cancer in overweight and obese people was 2.45 times and 3.5
times higher than that in normal people,
respectively.\textsuperscript{33} In a prospective study of 36 755
women, there was a strongly positive and linear association of BMI with
the risk of uterine cancer.\textsuperscript{32} Our results indicated
that the DALYs rates of uterine cancer due to high body-mass index were
higher between 50 and 69 years. In addition, proportions of DALYs
attributable to high body-mass index for uterine cancer were higher in
2019 than in 1990 in all age-specific groups. Previous data also showed
that compared with normal BMI, 181 genes involved in lipid metabolism,
fatty acid metabolism and metabolic signal transduction pathway were
up-regulated or down-regulated in obese patients with uterine
cancer.\textsuperscript{34} In recent decades, the implementation of
comprehensive staging surgery for uterine cancer, the application of
minimally invasive technology, reasonable adjuvant chemotherapy and
radiotherapy, and comprehensive treatment for advanced patients have
greatly improved the prognosis of patients. However, the pharmacokinetic
changes and metabolic abnormalities caused by obesity will reduce the
chemotherapy effect of uterine cancer and cause poor
prognosis.\textsuperscript{35} Improving the risk awareness of high-risk
groups for uterine cancer, carrying out active and effective screening,
changing adverse lifestyle, and early intervention for metabolic
diseases can reduce the risk of uterine lesions, and effectively reduce
the incidence and mortality of uterine cancer.

The result showed that the incidence and death rate of ovarian cancer
showed an upward trend in overall groups in China from 1990 to 2019. As
one of the deadliest cancers, the early diagnosis of ovarian cancer is
very difficult. When patients are diagnosed, they are often in the
middle and advanced stage, which is not conducive to the treatment and
prognosis of patients. The 5-year survival rate will not exceed
30\%.\textsuperscript{36} Previous studies suggested that the risk
factors for ovarian cancer mainly included family genetic history,
fertility factors, menstrual history, body mass index, obesity,
lifestyle, diet, hormone replacement therapy and so
on.\textsuperscript{37-41} Other studies have shown that organic dust,
asbestos, and talcum powder are also risk factors for ovarian
cancer.\textsuperscript{42,43} We analyzed the DALYs rates and
proportions attributable to risk factors for ovarian cancer in China
from 1990 to 2019. As shown in Figure 3, the DALYs rates of ovarian
cancer attributable to high body-mass index, high fasting plasma glucose
and occupational asbestos exposure had an upward trend from 1990 to
2019. In addition, proportions of DALYs attributable to high body-mass
index for ovarian cancer were higher in 2019 than in 1990 in all
age-specific groups. This seems to suggest that with the increase of
China's GDP and the improvement of people's quality of life, the
malignant tumors caused by metabolic diseases are on the rise. It is
necessary to formulate relevant strategies, including promoting
exercise, healthy diet, regular screening, controlling metabolic
diseases and so on. The proportion of DALYs attributable to occupational
asbestos exposure was slightly lower in 2019 than in 1990. Although most
countries prohibit the use of asbestos, millions of people still work in
factories exposed to asbestos, and at least 90000 people die each year
from asbestos related diseases or cancer
diseases.\textsuperscript{44}Governments should increase efforts to
limit the production and use of asbestos, and find alternatives to
reduce asbestos exposure. Regular occupational disease screening and
physical examination for women at risk of asbestos exposure also
contribute to the prevention of ovarian cancer.

According to the data forecast, there will be 28.4 million new cancer
cases worldwide by 2040, an increase of 47\% compared with 19.3 million
cases in 2020.\textsuperscript{1} The global economic burden on cancer
will be heavy. Based on GBD data of gynecological malignancies from 1990
to 2019 in China, we predicted the incident cases and deaths in the next
eleven years. Results showed that the numbers of incident cases and
deaths of cervical cancer, uterine cancer and ovarian cancer should
continue to increase from 2020 to 2030. This indicates that the economic
burden on gynecological malignancies in China will further increase in
the next decade. We further analyzed the trends of three major
gynecological malignancies, in order to facilitate government
departments to adjust their budgets, better allocate prevention and
research funds, and adjust the total prevention expenditure. The
predicted new cases of uterine cancer have the steepest rising slope,
which is expected to exceed the cases of cervical cancer in 2030.
Meanwhile, the growth of uterine cancer deaths also had the steepest
slope, followed by ovarian cancer and cervical cancer. In recent years,
with the rapid development of China's economy, people's living habits
and diet structure have changed greatly. With the increase of metabolic
diseases, uterine cancer also has an increasing incidence rate and
younger onset trend. Uterine cancer has become a serious problem
endangering the health of Chinese women. It is urgent to establish
effective screening methods to realize the early diagnosis and treatment
of uterine cancer. Screening guidelines for uterine cancer have been
developed in the United States,\textsuperscript{45} the United
Kingdom,\textsuperscript{46} Germany,\textsuperscript{47} and other
countries. In addition to carrying out primary prevention, changing
lifestyle and reducing risk factors, it is also important to carry out
secondary prevention with periodic screening among high-risk groups in
China. According to China's Expert Consensus on Screening and Early
Diagnosis of Endometrial Cancer, screening is recommended for women over
45 years old, especially those with metabolic syndrome such as diabetes
and obesity, history of estrogen use, tamoxifen treatment, and family
history of cancer. Molecular classification was applied to uterine
cancer when the results of the Cancer Genome Atlas (TCGA) project were
published.\textsuperscript{48} This molecular classification is
important for diagnosis, prognosis and treatment of uterine cancer.

There are several limitations of the current study. First, the
predictions were based on the GBD Study, in some cases, primary data was
lacking. The quality of original individual registration data greatly
affects the accuracy and stability of database estimation, and the
missing or false data may lead to bias. This bias was also kept low due
to the GBD study's many measures to reduce this bias, such as correcting
incompleteness, underreporting and misclassification, as well as
reassigning garbage code, and so on. Second, due to the limited
information in the GBD database, the burden of gynecological
malignancies caused by other risk factors cannot be fully evaluated.

\textbf{Conclusion}

From 1990 to 2019, the numbers of incidence cases, deaths and DALYs of
cervical cancer, uterine cancer and ovarian cancer all significantly
increased. Unsafe sex, smoking, high body-mass index, high fasting
plasma glucose, and occupational exposure to asbestos are the leading
risk factors of gynecological malignancies in China From 2020 to 2030,
the predicted numbers of incident cases and deaths of these three major
gynecologic cancers will continue to increase, and the incidences of
uterine cancer would expect to exceed cervical cancer in 2030. Our
results will provide suggestions for the government to take tailored
actions for the future management of gynecological malignancies.
Measures to improve the early diagnosis and new effective treatment
methods should be formulated to reduce the burden of gynecological
malignancies.

\textbf{Acknowledgement}

This work was supported by the National Key Research and Development
Program of China (No.2021YFF1201101).

\textbf{Contribution to authorship}

YZ, XY, and ML contributed to the concept of the manuscript. YZ, XZ, RW
and TZ completed the first draft of the manuscript. YF, ZL, and RW
contributed to the data collection. HC and XY provided critical feedback
on data analysis and results interpretation. YZ, XZ, and XL contributed
to the discussion part of the manuscript. ML revised the manuscript
critically for important intellectual content. All authors contributed
to the framework construction, results interpretation, manuscript
revision, and approved the final version of the manuscript. The
corresponding authors attest that all listed authors meet authorship
criteria and that no others meeting the criteria have been omitted.

\textbf{Data Availability Statement}

All data can be extracted from the online GBD repository, http://
ghdx.healthdata.org/gbd-results-tool.

\textbf{Conflict of interest}

The authors have no conflict of interest to declare.

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\textbf{TABLE 1} Overall incidence, deaths, DALYs and EAPC from 1990 to
2019 by cervical cancer, uterine cancer and ovarian cancer in China\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& Cervical cancer & Uterine cancer & Ovarian cancer\tabularnewline
\midrule
\endhead
Incidence & & &\tabularnewline
1990: No.\selectlanguage{ngerman}×10\textsuperscript{3} & 40.68 (30.92, 73.18) & 24.28 (18.18,
29.96) & 12.68 (9.91, 17.51)\tabularnewline
ASIR per 10\textsuperscript{5} & 8.41 (6.44, 15) & 5.13 (3.89, 6.29) &
2.56 (2, 3.58)\tabularnewline
2019: No.\selectlanguage{ngerman}×10\textsuperscript{3} & 109.76 (58.19,141.54) & 66.74
(51.38,92.05) & 45.48 (33.11,57.38)\tabularnewline
ASIR per 10\textsuperscript{5} & 11.01 (5.87,14.22) & 6.39 (4.89,8.74) &
4.54 (3.33,5.71)\tabularnewline
1990-2019: EAPC & 1.61 (1.35,1.88) & 1.26 (0.58,1.94) & 1.88
(1.79,1.98)\tabularnewline
Deaths & & &\tabularnewline
1990: No.\selectlanguage{ngerman}×10\textsuperscript{3} & 26.42 (20.52, 43.53) & 10.6 (7.95,
13.04) & 8.04 (6.18, 11.67)\tabularnewline
ASMR per 10\textsuperscript{5} & 5.85 (4.59, 9.57) & 2.38 (1.81, 2.9) &
1.76 (1.36, 2.59)\tabularnewline
2019: No.\selectlanguage{ngerman}×10\textsuperscript{3} & 53.44 (30.40,68.86) & 12.22
(9.43,17.34) & 29.10 (20.96,36.86)\tabularnewline
ASMR per 10\textsuperscript{5} & 5.13 (2.92,6.60) & 1.17 (0.9,1.66) &
2.77 (2.01,3.50)\tabularnewline
1990-2019: EAPC & 0.09 (-0.18,0.36) & -2.27 (-2.88,-1.66) & 1.51
(1.42,1.61)\tabularnewline
DALYs & & &\tabularnewline
1990: No.\selectlanguage{ngerman}×10\textsuperscript{3} & 855.36 (654.48, 1432.99) & 332.05
(238.02, 411.58) & 275.06 (212.26, 377.97)\tabularnewline
ASDR per 10\textsuperscript{5} & 176.40 (135.68, 294.69) & 69.61 (50.73,
85.85) & 55.57 (42.86, 77.80)\tabularnewline
2019: No.\selectlanguage{ngerman}×10\textsuperscript{3} & 1622.24 (892.58, 2090.86) & 364.28
(286.56, 503.57) & 835.06 (612.56, 1063.25)\tabularnewline
ASDR per 10\textsuperscript{5} & 157.50 (86.90, 202.91) & 34.93 (27.27,
47.77) & 80.52 (59.44, 102.57)\tabularnewline
1990-2019: EAPC & 0.16 (-0.09,0.41) & -2.21 (-2.81,-1.60) & 1.15
(1.04,1.25)\tabularnewline
\bottomrule
\end{longtable}

Data in parentheses are 95\% uncertainty intervals (UI).
ASIR=age-standardized incidence rate. ASMR=age-standardized mortality
rate. DALYs=disability-adjusted life years. ASDR=age-standardized DALY
rates. EAPC=estimated annual percentage change.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4/Figure-4}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-5/Figure-5}

\end{center}
\end{figure}

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