Endometrial cancer is the most common gynecological cancer in industrialized nations. According to the International Agency for Research on Cancer registry report, the incidence rate of endometrial cancer has increased significantly in 26 of 43 countries between 2001 and 2010. Endometrial cancer primarily occurs in postmenopausal women (median age 63 years). Compared to women diagnosed with other gynecological cancers, women with endometrial cancer have a higher prevalence of co-existing medical conditions such as hypertension, diabetes mellitus, and arthritis and are less likely to live a healthy lifestyle.[4–6]
Hysterectomy, and bilateral salpingo-oophorectomy with or without lymphadenectomy is the current standard treatment for endometrial cancer. Diagnosis and treatment can cause psychological distress for some women. A recent study from Germany reported that women with gynecological cancer experienced the highest level of distress (63.1%, n = 186/295) compared to any other type of cancer (n = 3724), as indicated by a distress thermometer (≥5). Women with endometrial cancer identified worry, focusing on getting well, and psychological distress including anxiety and depression as the top 3 prioritized problems during the 3-month perioperative period. However, few studies have assessed anxiety and depression before surgery for endometrial cancer and whether its prevalence changes over time.
Anxiety and depression can be examined using the Hospital Anxiety and Depression Scale (HADS), a widely recommended screening instrument.[11–14] In a US cohort study (2003–2004), Kornblith et al (2007) found that the risk of having a HADS total score of ≥15 (indicating elevated distress) was approximately 4 times higher in younger women compared to older women. Rowlands et al (2015) conducted a large population-based case–control study in Australia and found that the proportion of women with at least subclinical level of anxiety (≥8) was 25.6% (n = 160/623) and depression 10.7% (n = 67/623), respectively. Both of these studies included long-term endometrial cancer survivors; however, they did not investigate whether women were already distressed around the time of diagnosis and surgical intervention or if women received treatment for anxiety and depression.
Only 2 studies included women recently diagnosed with endometrial cancer.[13,14] Ferrandina et al (2014) conducted a 2-year prospective, longitudinal study (n = 132) in Italy and found anxiety and depression to be highest pre-surgery. In contrast, a cross-sectional study conducted 2 weeks after diagnosis in Japan (2007–2008) reported that more than half of the patients (55%, n = 36/65) had a HADS score ≥11. However, neither of these studies reported whether or not the women with anxiety and depression received any treatment. Several other studies assessed anxiety and depression using the HADS or other screening tools including patients with all types of gynecological cancer, but it was not possible to separate the anxiety and depression data for those with endometrial cancer from these studies.[15–20] There is also paucity in the literature regarding the extent to which sociodemographic or clinical factors are associated with anxiety and depression.
The primary aim of this study was to determine the point prevalence and cumulative incidence of anxiety and/or depression among patients with stage I endometrial cancer as measured using the HADS from before surgery to 6-month post-surgery, and describe any treatments women received for anxiety and/or depression. The second aim was to examine sociodemographic and clinical factors associated with anxiety and depression in women with endometrial cancer up to 6-month post-surgery.
Data were extracted from an international, multicenter prospective randomized controlled trial (The Laparoscopic Approach to Cancer of the Endometrium (LACE) trial; ClinicalTrials.gov: NCT00096408; Australian New Zealand Clinical Trials Registry: CTRN12606000261516), which tested the equivalence of open versus laparoscopic hysterectomy for stage I endometrial cancer. LACE commenced in October 2005 and recruited to June 2010, then followed patients for 4.5 years. Patients were enrolled from 20 tertiary gynecological oncology centers in Australia, New Zealand, Scotland, and Hong Kong. Data used for this secondary analysis were collected by trained clinical trial nurses before surgery and then 1 week, 3 weeks, 3 months, and 6 months postoperatively.
The details of recruitment have been described elsewhere.
Briefly, patients were included, if they were 18 years or older, had histologically confirmed endometrioid adenocarcinoma of the endometrium of any grade, an Eastern Cooperative Oncology Group score of 0 or 1, and imaging studies (computed tomography, CT) of the abdomen and pelvis and chest radiograph or chest CT suggesting the absence of extrauterine disease. Patients who presented with a histological cell type other than endometrioid on curettage, or clinically advanced disease (stage II–IV), were excluded.
Overall, 760 patients were recruited into the clinical trial and treated either by total abdominal or total laparoscopic hysterectomy. For this secondary analysis, patients were eligible if HADS data were available. Quality of life and HADS data were collected for the first 360 enrolled patients (Fig. 1), which was estimated to provide a sufficient sample size for any research questions associated with quality of life or distress; subsequently enrolled patients then completed questionnaires about other concerns such as pelvic floor issues, and HADS data were no longer collected for these patients.
Sociodemographic and clinical characteristics
The following sociodemographic characteristics were collected: age, height and weight, education, employment, employment location, marital status, insurance, country of birth, and ethnicity. Body mass index (BMI) was calculated and grouped according to World Health Organization (WHO) using weight and height data. BMI was categorized into normal (18.50–24.99), overweight (25.00–29.99), and obesity (≥30.00). Clinical characteristics collected included surgical stage, medical history of comorbidities (hypertension, diabetes, gastroesophageal reflux disease, arthritis, asthma, hyperlipidemia/hypercholesterolemia, past history of anxiety, and/or depression), number of comorbidities, type of surgery, and adjuvant treatment. Antidepressants and anxiolytics were also recorded by the trial nurse at baseline and at each post-surgical follow-up. Any visit to a psychiatrist, psychologist, or other mental health counselor in the 6 months since surgery was considered as evidence for psychological treatment received beside cancer treatment.
Anxiety and depression were determined by the Hospital Anxiety and Depression Scale. This is a 14-item questionnaire categorized into 2 sub-scales, anxiety (Cronbach alpha = 0.875) and depression (Cronbach alpha = 0.817) each measured using 7 items. Each item is rated from 0 to 3, some are reverse coded. The subscale score (0–21) is then divided into normal (0–7), borderline abnormal (8–10), and abnormal (11–21) anxiety and/or depression according to the guidelines by Zigmond and Snaith, (1983). The point prevalence was calculated at 5 different time-points and presented using bar chart and line graphs. The overall cumulative incidence of anxiety or depression was calculated by counting patients who scored ≥8 at any time point from before surgery to 6-month post-surgery. This outcome was used to assess associations with sociodemographic and clinical factors.
Descriptive statistics were used to determine the rate and distribution of dependent and independent variables. Univariate logistic regression models were used to determine socio-demographic or clinical characteristics potentially associated with anxiety and depression (≥8) from before to 6-month post-surgery. Multivariable logistic regression analyses were conducted to determine the independent associations of characteristics found to be associated at P < .2 with anxiety and depression. Linear mixed models were used to determine the association between patients’ mean anxiety and depression value over 5 time-points and sociodemographic and clinical characteristics. Pairwise interactions (characteristics × time) were included, if their P value was <.2. Results were presented as odds ratio (OR) with corresponding 95% confidence intervals (CIs) for all models. All analyses were performed using IBM SPSS software version 25.0 (SPSS Inc, Chicago, IL).
Overall, HADS data were available for 334 patients included in these analyses (Fig. 1). Their sociodemographic and clinical characteristics are presented in Table 1. The mean (standard deviation) age was 62.7 (9.9) ranging from 31 years to 93 years. Most patients were either overweight (22.2%, n = 77/334) or obese (64.0%, n = 213/334). Two-thirds of the patients had completed <12 years of schooling (66.8%, n = 209/313) and two-thirds were retired (65.7%, n = 209/318). The majority of the patients (90.0%, n = 298/331) were diagnosed with surgical stage I disease, indicating that the tumor was limited to the uterus. Hypertension (48.0%, n = 159/331) was the most common coexisting medical condition followed by hyperlipidemia/hypercholesterolemia 23.6% (n = 78/331) and diabetes mellitus 22.1% (n = 73/331). Overall, 285 of 331 patients had ≥ comorbid conditions, whereas 38 of 331 already reported a history of anxiety and/or depression at baseline. Overall, 16.7% (n = 56/334) of patients were prescribed antidepressants and/or anxiolytics at baseline. Only 4.8% (n = 18/334) reported ≥1 visits to a mental health professional between baseline and 6 months post-surgery.
Anxiety and depression at 5 different time points
Figure 1 presents the number of sample completed HADS questionnaire at different time points. Figure 2 and Table 2 present the prevalence of anxiety and depression in patients with endometrial cancer at 5 time-points. The change of anxiety and depression mean score with 95% CI over time is presented in the graphs (Supplementary materials 1, http://links.lww.com/OR9/A3). The prevalence of anxiety was highest before surgery (≥11, 16%, n = 51/318; 8–10, 19%, n = 59/318) and then decreased over time until 6-month post-surgery (≥11, 4%, n = 12/289; 8–10, 10%, n = 28/289) (Fig. 2). The mean anxiety score was 6.6 (95% CI: 6.17–7.12) at baseline and then gradually reduced to 3.6 (95% CI: 3.2–4.0) at 6-month post-surgery. For depression, there was a peak at 1-week post-surgery (3.6, 95% CI; 3.2–4.0) at which time point the prevalence of depression ≥11 was 6% (n = 18/314) and then decreased to 6-month post-surgery (2.1, 95% CI: 1.8–2.4) (Fig. 2; Table 2; Supplementary materials 1, http://links.lww.com/OR9/A3).
Treatments received for cumulative incidence of anxiety and depression
Table 3 presents the cumulative incidence of anxiety and depression (≥8) in patients with endometrial cancer, and treatments received. Overall, from before surgery until 6-month post-surgery, 149/334 (44.6%) and 73/334 (21.8%) patients recorded an anxiety or depression score ≥8 at least once, respectively (Table 3). When anxiety and depression data were assessed individually, the proportion of abnormal level of anxiety and depression only (≥11) was 15.5% (n = 52/334) and 1.8% (n = 6/334), respectively (Table 3), whereas 7.2% (n = 24/334) of patients had both anxiety and depression (≥11). Only 6 of 52 and 1 of 6 patient with anxiety or depression (≥11) visited mental health professionals, respectively. Overall, 4 of 52 patients were prescribed with antidepressants and anxiolytics for the treatment of anxiety, whereas no patient received antidepressant or anxiolytics for depression (≥11) during the study period. Half of the patients (n = 12/24) who were diagnosed with both abnormal level of anxiety and depression (≥11) were prescribed antidepressants, anxiolytics or both. Only 2 of these patients reported visiting a mental health care professional (Table 3).
Association of sociodemographic and clinical characteristics with anxiety and depression between baseline and 6-month post-surgery
Sociodemographic and clinical characteristics associated with HADS anxiety and depression scores ≥8 are presented in Tables 4 and 5. In multivariable analyses, marital status (other than married or living together) and non-European heritage remained significantly associated (P < .05) with anxiety in patients with endometrial cancer. Non-European heritage, comorbidities, and being prescribed with antidepressants and/or anxiolytics were significantly associated (P < .05) with depression (Table 5).
In this cohort of early-stage endometrial cancer patients, the prevalence of anxiety and depression was low from before surgery to 6 months post-surgery. The proportion of endometrial cancer patients with anxiety and/or depression was lower than in a previous Italian study, which recorded the prevalence of around 20% for anxiety and 8% for depression. Both studies examined anxiety and depression at similar time-points relative to the patient's journey, but Ferrandina et al (2014) included 21% of patients with stage II and III disease. The point prevalence of anxiety in this study was highest before surgery, whereas depression rate was highest 1 week after surgery. Similar findings were also identified by Gil et al, (2012) which included patients with a range of cancer types. Gil et al's (2012) study concluded that “anxiety is the symptom that characterizes diagnosis” where existential threat is greatest, “whereas depression is more common after medical treatment” where sadness about loss and illness becomes more dominant (p. 362).
In our analysis, only a small number of patients who had elevated anxiety and/or depression scores on HADS actually received psychological treatment or medication (Table 3). These results are consistent with previously conducted studies on patients with gynecological cancer or patients with any types of cancer,[25–29] which also reported under-treatment of psychological distress. Several factors may be responsible for patients not getting treatment for anxiety and/or depression even after screening for distress was introduced as the sixth vital sign. Health care professionals involved in cancer treatment may find it difficult to differentiate between psychological symptoms and cancer-treatment related symptoms, may consider the symptoms as normal response to a cancer diagnosis, or both health care professionals and patients may prioritize the treatment of physical symptoms over psychological treatment. Recently, Manne et al (2018) proposed a multiple mediator model and showed that 3 mediators including acceptance coping, acceptance of emotion and social support may reduce depression in cancer patients, and proved this theory in patients with gynecological cancer. Acceptance of the diagnosis of cancer, early stage, and well treatable disease, may have result in the comparatively low prevalence of anxiety and depression in our study. Routine collection of patient-reported outcomes, and clear pathways for responding to those outcomes may be another way to improve the situation for patients in the future.[34,35]
Several factors such as marital status, ethnicity, multiple comorbid conditions, and having a prescription for antidepressants of anxiolytics at baseline were associated with elevated anxiety or depression at subsequent time points. Among these characteristics, patients not living with a partner reported lower odds of anxiety (0.59) compared to patients living with a partners. This is similar to previous research using HADS as a screening tool, where married patients reported a higher rate of anxiety in Australia (31%), and in China (79.9%), and may reflect greater worry on how the partner may cope impacting on women's own well-being. Patients with ≥1 comorbidities had lower odds of depression (1–2, OR: 0.43; 3–4, OR: 0.34). Although previous study found that depression is a risk factor for chronic diseases including heart disease, diabetes, the treatments received for these chronic diseases may reduce depression in patients. Patients who already used antidepressants and/or anxiolytics at baseline were more likely to also report distress after endometrial cancer surgery. This result matches with our previously conducted study which found that comorbidities of anxiety and depression were associated with 26 times higher odds of antidepressant and/or anxiolytic prescriptions.
A strength of this research was that the prospective collection of anxiety and depression data from the time of diagnosis and before the surgical procedure up until 6 months after surgery. Anxiety and depression were analyzed separately to determine differences in distress at different time points, received treatment according to severity of symptoms, and the association with sociodemographic and clinical characteristics. The study included a relatively homogenous cancer population thus provides useful information for future targeted psycho-oncology health care interventions.
This surgical study focused on patients with early-stage disease, and cannot be generalized to patients with late-stage cancer, who may be expected to display greater distress. As this study used secondary data from the LACE trial, only 1 screening tool (HADS) was available to determine anxiety and depression, and there was absence of data about the reasons for prescriptions of antidepressants and anxiolytics, reasons for the visits to the mental health care professionals, and details on who provided the psychological treatment. Another limitation of this study was that data on psychological treatments were derived by the research nurses from interviews in the follow-up clinics, and not from medical record data. It is possible that patients may have underreported psychological treatments received from external health professionals. Furthermore, the exact ethnic background of patients who selected the category “Non-European” was not queried. Reasons for the high level of distress observed among non-European women are unknown and need to be explored further in the future. Using data from a surgical clinical trial means that the study includes a relatively homogenous population of patients with good performance status, and the generalizability to other patients may be limited; however, about 80% of endometrial cancer patients usually present with stage I disease.
The prevalence of anxiety and depression was relatively low in this study compared to those reported from studies with patients with other type of cancer.[41,42] This suggests that surgical treatment of early-stage endometrial cancer is psychologically well tolerated by most patients. The majority of patients who had high anxiety or depression scores in this study already reported distress at baseline, and many did not receive psychological or pharmaceutical treatment. Future research should explore in depth reasons for this mismatch to better understand the reasons for lack of treatment. Qualitative data could be used in future research to explore in greater depth the psychological conditions and life impacts during long-term survival.
Conflicts of interest statement
The authors declare no conflicts of interest.
SS was funded by Advance Queensland Scholarship. MJ was funded by NHMRC Translating Research into Practice fellowship APP1151021. SMM was funded by an NHMRC Fellowship (APP1090440). This project was the part of LACE Trialwhich was funded by the Cancer Council Queensland, the Cancer Council New South Wales, the Cancer Council Victoria, and the Cancer Council Western Australia; by project grant 456110 from the National Health and Medical Research Council, project grants 631523 and 1098905 from Cancer Australia, and a Smart health research grant from QLD Health; and funding from the Women and Infants Research Foundation, Royal Brisbane and Women's Hospital Foundation, Wesley Research Institute, Gallipoli Research Foundation, Gynetech, Tyco Healthcare, Johnson & Johnson Medical, Hunter New England Centre for Gynecological Cancer, Genesis Oncology Trust, and the Cherish Foundation.
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