Factors Affecting the Occurrence of Mental Health Problems in Female Cancer Survivors: A Nationwide Cohort Study.

The purpose of this study is to determine the effect of cancer survivorship stage and health-related behaviors on the risk of developing mental health problems (depressive and anxiety disorders) in women who have experienced cancers that affect women (breast cancer, cervical cancer, ovarian cancer, endometrial cancer). Using the healthcare utilization and medical checkup data from 2010 to 2020 provided by the National Health Insurance Service, the occurrence of mental health problems since 2020 was tracked for 36,801 women diagnosed with cancer. The occurrence of mental health problems was defined as the cases in which the disease code was assigned to anxiety disorders (F40~F44, F48) and depressive disorders (F32~34, F41.2, F92) as presented in ICD-10. To evaluate the effect of cancer survivorship stage and health-related behaviors on the development of mental health problems, the hazard ratio (HR) and 95% confidence intervals (CI) were calculated using the Cox proportional hazard model. During the follow-up period of 5.6 years, anxiety disorder occurred in 14,698 (39.9%), and by cancer type, breast cancer survivors accounted for the most at 1.02 per 1000 person-years. The risk of anxiety disorders increased in those who experienced cervical cancer (AHR, 1.08, 95% CI, 1.03-1.13) and those in the acute survivorship stage (AHR, 1.38, 95% CI, 1.22-1.55). In terms of health-related behaviors, the risk of developing anxiety disorder was shown to be reduced in drinkers (AHR, 0.91, 95% CI, 0.87-0.96), former smokers (AHR, 0.86, 95% CI, 0.77-0.97), and current smokers (AHR, 0.80, 95% CI, 0.71-0.90). During the follow-up period of 5.6 years, depressive disorder occurred in 6168(16.8%), and by cancer type, ovarian cancer survivors accounted for the most at 1.30 per 1000 person-years. The risk of developing depressive disorders was highest in those who experienced ovarian cancer (AHR, 1.40, 95% CI, 1.27-1.53) and those in the acute survivorship stage (AHR, 2.99, 95% CI, 2.60-3.42). For health-related behaviors, the risk of developing depressive disorders was increased in former smokers (AHR, 1.32, 95% CI, 1.14-1.54), current smokers (AHR, 1.21, 95% CI, 1.04-1.41), and those with insufficient physical activity (AHR, 1.09, 95% CI, 1.02-1.15). It has been confirmed that cancer type, cancer survivorship stage, and health-related behaviors, such as smoking, drinking, and physical activity, are significantly related to the risk of mental health problems. Thus, it is necessary to develop strategies to cope with mental health problems at the individual and national levels and to develop interventions to promote a more active lifestyle.

1. Introduction

According to the 2020 National Cancer Registration Statistics in Korea, the 5-year relative survival rate for people who have experienced cancer in the past five years is 66.5%, and females have a higher survival rate (71.5%) than males (62.4%). The increase in the relative survival rate leads to an increase in the number of long-term cancer survivors. The number of survivors of long-term cancer over a duration of 5 years or more is approximately 1.3 million, accounting for about 60% of the total cancer survivors. In addition, the proportion of female cancer survivors who have experienced cancers that affect women, including breast cancer, accounts for more than 30% of all cancer survivors [1]. Thus, the importance of health management for the increasing number of female cancer survivors is being emphasized.

Those who have experienced cancer encounter physical and psychological pain resulting from the side effects of surgery, radiation, and chemotherapy from the time of diagnosis. Even after the end of treatment, they experience feelings of helplessness, depression, and anxiety in the process of adjusting to life at home and work due to recurrence, secondary cancer, and altered physical functioning [2]. When women are diagnosed with gynecological cancer in particular, they can experience more mental health problems than men because of their femininity-associated factors [3]. Previous studies have also shown that gynecological cancer survivors had the highest level of anxiety compared to survivors of other cancers [4], and breast cancer survivors had the highest depression score compared to those who experienced other cancers [5]. Psychological pain such as depression and anxiety in female cancer survivors can lead to reduced quality of life [2], lower treatment compliance [6], and lower survival rates [7,8]; therefore, it must be monitored and managed promptly.

Mullan (1895) described the stages of cancer survivorship by applying the experience of cancer survivors to the traditional concept of cancer survivorship, which defines survivors as those who survive for more than 5 years without evidence of recurrence or metastasis after treatment. Mullan classified the stage at which the patients receive various treatments for less than 2 years since diagnosis as the acute stage, the period between 2 to 5 years after diagnosis in which the disease remission or follow-up after active treatment is completed as the extended stage, and the stage in which cancer cell activity almost disappears after more than 5 years after diagnosis as the permanent stage [9]. Previous studies revealed that health-related behaviors differ according to these stages of survivorship [9], and inappropriate health-related behaviors increase as the duration of the disease increases [10,11] Health-related behaviors such as smoking, drinking alcohol, and physical activity are defined by the International Agency for Research on Cancer (IARC) as carcinogenic factors for gynecological cancers such as ovarian and uterine cancers, and breast cancers [12]. Inappropriate health-related behaviors have been reported to affect the occurrence of mental health problems [13,14,15].

A previous study revealed that smokers who experienced cancer reported severe psychological distress more frequently due to depression and anxiety compared to nonsmokers who experienced cancer [16], and the higher the depression score, the higher the risk of drinking in breast cancer survivors [15]. In addition, physical activity promotes the release and synthesis of serotonin as well as improvements of physical symptoms such as fatigue and pain, thereby reducing anxiety and depressive symptoms [17]. The mental health scores of cancer survivors who did not follow the physical activity guidelines were found to be lower than that of those who did [14]. Consequently, it is necessary to examine the relationship between health-related behaviors such as smoking and physical activity and the mental health status of female cancer survivors. Most previous studies on mental health problems of women who have experienced cancer focused on breast cancer [15,18,19], health-related behavior, and quality of life at a certain point in time [2,9,10,17] and identified the relationship over a short-term survival period of fewer than five years [3,20,21]. However, there are insufficient studies on survivors of other female cancers, such as ovarian and endometrial cancers, which have a high incidence rate as well as high survival and recurrence rates. Therefore, by establishing a national population-based female cancer cohort over the past 10 years, this study investigated the hypothesis that cancer type, cancer survivorship stage, and health-related behaviors are related to the risk of mental illness among women who have experienced breast, cervical, ovarian, endometrial, and cervical cancers.

Purpose of Study

The purpose of this study is to investigate the effect of cancer survivorship stage and health-related behaviors on the risk of mental health problems (depressive and anxiety disorders) in women who have experienced cancers that affect women (breast cancer, cervical cancer, ovarian cancer, and endometrial cancer). The specific research objectives are as follows:

Identifying general and clinical characteristics of study participants;

Identifying the incidence and risk of anxiety disorders according to the cancer survivorship stage and health-related behaviors of the study participants;

Identifying the incidence and risk of depressive disorders according to the cancer survivorship stage and health-related behaviors of the study participants.

2. Materials and Methods

2.1. Research Design

This study is a retrospective cohort study with secondary data analysis to determine the relationship between survivorship stage and health-related behaviors and the occurrence of mental health problems in women who have experienced cancer (breast cancer, cervical cancer, ovarian cancer, endometrial cancer) in Korea.

2.2. Data Source

This study utilized the National Health Insurance Service’s insurance qualification, claim and health checkup data from 2009 to 2020. The National Health Insurance Service is the sole insurer in Korea, with 97% of the population enrolled in health insurance and the remaining 3% in medical benefits. A single database with integrated health insurance and medical benefits insurance was constructed in 2006, and a qualification database (age, gender, income, region, qualification type, etc.), a claim database (consultation statements, diagnosis statements defined by the International Classification of Disease 10th revision (ICD-10), prescription statements, outpatient visits, and hospitalization records, etc.), a health checkup database (medical checkup results), death information, and medical institution information, etc., have been established as sub-databases [22]. Furthermore, the National Health Insurance Service carries out standardized health checkups for its members for the purpose of early detection of diseases. All members are required to receive a health checkup every two years at an institution recognized by the National Health Insurance Service, and the checkup includes physical measurements (e.g., height and weight), clinical examinations (e.g., blood pressure, fasting blood sugar, blood lipid tests), and questionnaires (e.g., health-related behaviors such as smoking, drinking, physical activities, and medical history). Physical measurements and clinical examinations are conducted by the staff at the medical institution, and examinees’ self-response is recorded in the questionnaires.

2.3. Study Participants and Data Collection Process

In this study, female cancer survivors, cancer survivorship stage, and mental health problems were defined. A cancer survivor is defined as a case in which one of the codes for breast cancer (C50), cervical cancer (C53), ovarian cancer (C56), and endometrial cancer (C54.1) presented in the International Classification of Disease 10th revision (ICD-10) is assigned in addition to the special code for cancer (V193). The cancer survivorship stage refers to the acute, extended, and permanent stages as defined by Mullan [9]. The acute stage refers to the stage less than two years from diagnosis, the extended stage refers to the period between two to five years after diagnosis, and the permanent stage refers to the stage more than five years after diagnosis. The date of diagnosis was based on the date on which the special code for cancer (V193) in the program implemented by NHIS to enhance the health coverage for severe disease was assigned. Mental health problems were defined as cases in which the codes for anxiety disorders (F40~F44, F48) and depressive disorders (F32~34, F41.2, F92) presented in the International Classification of Disease 10th revision (ICD-10) were assigned.

The participants’ selection process in this study is shown in Figure 1. First, to establish a cohort of women who had experienced cancer, women over the age of 20 whose main disease in the health insurance healthcare utilization history were female cancer, including breast cancer (C50), cervical cancer (C53), ovarian cancer (C56), or endometrial cancer (C54.1), who were also assigned the special code (V193) for health coverage for a severe disease at the time of diagnosis from 1 January 2010, to 31 December 2019, were extracted. Among them, women with a history of medical utilization due to mental health problems were extracted. The period between the date on which the special code (V193) was assigned and one year before the very date was set as the wash-out period. Patients with mental health problems in this wash-out period were excluded; therefore, only those with a history of healthcare utilization for mental health problems after the initial cancer diagnosis were selected. Among them, patients whose main disease in the health insurance healthcare utilization history included anxiety disorders (F40~F44, F48) and depressive disorders (F32~34, F41.2, F92) were extracted. Finally, a total of 36,801 were selected as study participants, excluding those who did not undergo health checkups within 1 year of the occurrence of anxiety or depressive disorders to confirm the effect of health-related behaviors on the occurrence of mental health problems.

Figure 1

Flow chart of study participants.

2.4. Measurement

2.4.1. General Characteristics

Age, insurance premium quartiles from qualification data, cancer type derived from claim data, blood pressure, body mass index from the health checkup data, and blood test results were the participants’ characteristics considered in this study.

Blood pressure was recorded as systolic blood pressure (mmHg) and diastolic blood pressure (mmHg). Body mass index (BMI) was calculated by dividing the measured weight by the square of the height (weight (kg)/height2 (m2)) and classified into the underweight group (BMI < 18.5 kg/m2), normal group (18.5 ≤ BMI < 23.0 kg/m2), overweight group (23.0 ≤ BMI < 25.0 kg/m2), class 1 obesity group (25.0 ≤ BMI < 30.0 kg/m2), and class 2 to severe obesity group (BMI ≥ 30.0 kg/m2) according to the criteria presented in the 2020 Obesity Treatment Guidelines [23].

For blood test results, blood lipids (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides) and fasting blood sugar were considered. According to the 2018 dyslipidemia treatment guidelines [24], total cholesterol (TC) was categorized as normal (TC < 200 mg/dL), borderline (200 ≤ TC < 240 mg/dL), and high (TC ≥ 240 mg/dL). High-density lipoprotein cholesterol (HDL) was categorized as low (HDL < 40 mg/dL) and average (HDL ≥ 40 mg/dL). Low-density lipoprotein cholesterol (LDL) was categorized as normal (LDL < 130 mg/dL), borderline (130 ≤ LDL < 160 mg/dL), and high (LDL ≥ 160 mg/dL). Triglycerides (TG) were categorized as average (TG < 150 mg/dL), borderline (150 ≤ TG < 200 mg/dL), and high (TG ≥ 200 mg/dL). Furthermore, fasting blood sugar (FBS) test results were categorized as average (FBS < 100 mg/dL), fasting blood sugar disorder (100 ≤ FBS < 125 mg/dL), and diabetic (FBS ≥ 126 mg/dL) according to the 7th edition of the 2021 Diabetes Treatment Guidelines [25].

2.4.2. Survivorship Stage

The survivorship stage is defined as acute if it has been less than two years from the date of diagnosis, extended if it has been between two to five years from the date of diagnosis, and permanent if more than five years had elapsed from the date of diagnosis, where the date of diagnosis is based on the date on which the special code for cancer (V193) was assigned.

2.4.3. Health-Related Behaviors

For health-related behaviors, the questionnaire results for smoking status, drinking status, and physical activity surveyed during the health checkup were used.

Based on the answer to the question, “Have you ever smoked more than 100 cigarettes in your life?”, participants were classified as nonsmokers if they answered “No,” as a former smoker if they answered “Yes, but I have quit,” and as current smokers if they answered “Yes, and I am currently smoking.” Drinking status was classified into nondrinkers, moderate-risk drinkers, and high-risk drinkers. Participants were classified as nondrinkers if they answered “0” to the question “How many days per week do you drink on average?” or answered “None,” to the question, “How many times have you drank alcohol in the past year?” According to the amount of alcohol converted into a standard glass, moderate-risk drinkers and high-risk drinkers were classified as drinkers. Alcohol consumption using a standard drink is determined by the number of drinks according to age. Those over the age of 65 are considered moderate-risk drinkers if they drink less than four glasses, and those under the age of 65 are considered moderate-risk drinkers if they drink less than eight glasses. Anyone who exceeds the standards for moderate-risk drinking is considered a high-risk drinker. Lastly, for the physical activity, the physical activity of 150 min in terms of time or 5 or more times a week in terms of frequency from the results of the questionnaire was defined as average or health-promoting, and anything below was defined as insufficient physical activity.

2.4.4. Study Outcome: Mental Health Case Ascertainment

For the selected study participants, they were confirmed to have a diagnosis of mental illness if anxiety disorders (F40~F44, F48) and depressive disorders (F32~34, F41.2, F92) were identified as the main disease in the health insurance healthcare claim data from the time of diagnosis for cancer to the end of the follow-up period.

2.5. Ethical Consideration

This study was approved for IRB review exemption (IRB No, CR321342) by the institutional ethics review committee of Yonsei University Wonju Severance Christian Hospital, and it was analyzed using de-identified data.

2.6. Statistical Analysis

Analysis in this study was performed using SAS v.9.4. (SAS Institute Inc., Cary, NC, USA). Among the general and clinical characteristics of study participants, frequency and percentage were analyzed for categorical variables, and mean and standard deviation were analyzed for continuous variables. The incidence rate of mental health problems was presented as the number of events per 1000 person-years, and the hazard ratio (HR) and 95% confidence intervals (CI) were calculated using the Cox proportional2 hazard model.

3. Results

3.1. General Characteristics of Study Participants

The general characteristics of the study participants are shown in Table 1. The average age of the participants at the time of diagnosis was 56.6 years (SD 10.3 years), and in the age group distribution, the 50~59 group accounted for the most at 37.6%. By cancer survivorship stage, the permanent stage accounted for the most at 77.6%, followed by the extended stage at 19.2%, and the acute stage at 3.3%. Among the diagnosed cancer type, breast cancer was the most common at 74.6%, and endometrial cancer was the least common at 5.8%. As for medical history, hypertension was the most prevalent at 23.3%, followed by diabetes at 8.7%, and heart disease at 2.4%. In terms of health-related behaviors, current smokers accounted for 2.5% and drinkers for 17.4% of the participants, and 73.3% showed insufficient physical activity. In terms of body mass index, the normal group showed the largest distribution at 41.8%, but 55% were overweight, including obesity and severe obesity. The blood lipid test results showed that 46.2% had borderline or high levels of total cholesterol, 33.2% had borderline or high levels of low-density lipoprotein cholesterol, and 23.6% had borderline or high levels of triglycerides. Furthermore, 92.6% had high levels of high-density lipoprotein cholesterol, and 34.7% had a fasting blood sugar level that corresponds to impaired fasting glucose or diabetes.

Table 1

General characteristics of study participants (n = 36,801).

Variable		Category	n	%	Mean ± SD
Age (years) (at cancer diagnosis)					56.6 ± 10.3
		<30	126	0.3
		30~39	1657	4.5
		40~49	10,715	29.1
		50~59	13,826	37.6
		60~69	7615	20.7
		≥70	2862	7.8
Survival stage		Acute SS	1198	3.3
		Extended SS	7052	19.2
		Permanent SS	28,551	77.6
Cancer type		Breast	27,464	74.6
		Cervical	4873	13.2
		Ovarian	2329	6.3
		Endometrial	2135	5.8
History	Diabetes	Yes	3188	8.7
	Hypertension	Yes	8573	23.3
	Heart disease	Yes	868	2.4
Health-related behavior	Smoking	Nonsmoker	35,012	95.1
		Former smoker	886	2.4
		Current smoker	903	2.5
	Drinking	Nondrinker	30,382	82.6
		Drinker	6419	17.4
	Physical activity	Insufficient	26,988	73.3
		Average or health-promoting	9813	26.7
BMI (Kg/m2)		<18.5	1155	3.1	23.8 ± 3.4
		18.5~22.9	15,397	41.8
		23~24.9	8705	23.7
		25~29.9	9899	26.9
		≥30	1645	4.5
Systolic BP (mmHg)					121.4 ± 15.5
Diastolic BP (mmHg)					74.9 ± 9.9
Fasting blood glucose (mg/dL)		<100	24,028	65.3
		100~125	10,211	27.7
		≥126	2562	7.0
Total cholesterol (mg/dL)		<200	19,789	53.8
		200~239	11,96	32.5
		≥240	5048	13.7
High-density lipoprotein (HDL) cholesterol (mg/dL)		<40	2726	7.4
		≥40	34,075	92.6
Low-density lipoprotein (LDL) cholesterol (mg/dL)		<130	24,567	66.8
		130~159	8120	22.1
		≥160	4114	11.2
Triglycerides (mg/dL)		<150	28,128	76.4
		150~199	4769	13.0
		≥200	3904	10.6

SS = survivorship stage.

3.2. Incidence Rate and Risk of Mental Health Problems According to Cancer Survivorship Stage and Health-Related Behavior

3.2.1. Incidence Rate of Mental Health Problems

The median follow-up period for the occurrence of anxiety disorders was 5.6 years. During the follow-up period, anxiety disorders were newly developed in 14,698 (39.9%) patients, and the incidence rate of anxiety disorders was 0.95 cases per 1000 person-years. By cancer type, breast cancer had the highest incidence rate at 1.02 cases, and cervical cancer had the lowest at 0.78 cases. By survivorship stage, the acute stage had the highest incidence rate at 5.53 cases, and the permanent stage had the lowest incidence rate at 0.86 cases .