Psychological and pharmacological
treatment of anxiety and depression in
patients with endometrial cancer
Saira Sanjida
Bachelor of Pharmacy (Hons), Master of Pharmacy, Master of Applied
Science (Research)
Submitted in fulfilment of the requirements for the degree of
Doctor of Philosophy
School of Public Health & Social Work
Faculty of Health
Queensland University of Technology
2020
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer i
Keywords
Antidepressant, Anxiety, Anxiolytic, Cancer, Depression, Endometrial cancer,
Hospital Anxiety and Depression Scale, Hysterectomy, Intervention, Meta‐analysis,
Pharmacological treatment, Prescription, Psychology, Psychological treatment,
Psychotropic, Randomised Controlled Trials, Survivorship, Systematic Review
ii
Abstract
Background
A cancer diagnosis imposes considerable psychological challenges on patients.
Despite this, many patients cope well due to the help of family and friends. However,
some may become overwhelmed, leading to psychological distress, of which anxiety
and depression are common symptoms. Psychological and pharmacological
treatments alone or in combination can be used for the treatment of anxiety and
depression in cancer patients. Once diagnosed, it is important to treat symptoms of
anxiety or depression in patients with cancer early to prevent chronicity or an
increase in symptom severity.
Clinical practice guidelines for the management of anxiety and depression in cancer
patients recommend psychological treatment as the first line of approach in patients
with cancer, according to their symptoms and severity. The literature demonstrates
the effectiveness of such treatment in some cancer populations. However, the
effectiveness of psychological treatment for anxiety and depression in patients with
endometrial cancer specifically is unknown, as is the influence of patient
characteristics on the effectiveness of this treatment.
Psychotropic medications such as anxiolytics and antidepressants are used in the
pharmacological treatment of anxiety and depression in patients with cancer, but
there are variations in prescription practices, such as type, dose and medication
provider. A previous meta‐analysis by this team of researchers found that the
prevalence of antidepressant use was high in female patients with cancer. However,
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer iii
the majority of data was derived from patients treated for breast cancer, with
insufficient data for other types of female cancers such as endometrial cancer.
The survival rate of early‐stage endometrial cancer is high due to its early symptoms
(abnormal bleeding) and surgical treatment. Hysterectomy and bilateral
oophorectomy is the first line of treatment for endometrial cancer, with some
women also requiring chemo‐, radio‐ or hormonal therapy. Little research has been
conducted into the prevalence and factors associated with anxiety and depression in
patients with endometrial cancer in general, and in particular around the time of
initial diagnosis and surgery. This represents a considerable knowledge gap in the
literature.
The little extant research on anxiety and depression in endometrial cancer commonly
only includes patients 3–5 years post‐diagnosis. In contrast, patients’ psychological
wellbeing around the time of diagnosis, and throughout long‐term survivorship are
understudied. There is also a lack of data on whether women received treatment for
anxiety and depression (if indicated), the type of treatment used and whether it was
beneficial.
Aims
This PhD research program consisted of four studies, which aimed to:
Study 1—a) determine the overall effect size of psychological interventions to
improve anxiety in patients with cancer from randomised controlled trials;
and b) estimate the sample or intervention characteristics associated with the
iv
increased effectiveness of psychological interventions on anxiety in patients
with cancer.
Study 2—a) determine the prevalence and characteristics of psychotropic
medications (i.e., anxiolytics and antidepressants) prescribed to patients with
endometrial cancer; and b) evaluate the sociodemographic and clinical
characteristics associated with receiving a psychotropic medication
prescription.
Study 3—a) determine the prevalence of anxiety and depression in women
with endometrial cancer, using the Hospital Anxiety and Depression Scale
(HADS) measure from before surgery to six months post‐surgery and describe
the treatment that women with anxiety or depression received; and b)
evaluate the sociodemographic and clinical factors associated with anxiety
and depression in women with endometrial cancer from before surgery to six
months post‐surgery.
Study 4—a) understand the psychological wellbeing of women with
endometrial cancer from before surgery to long‐term survivorship; and b)
identify the self‐described range of psychological treatments received for
anxiety and depression during long‐term survivorship.
Methods
The four studies comprising this PhD research program employed three different
research approaches: a systematic review and meta‐analysis; longitudinal cohort
study data analysis; and cross‐sectional qualitative data collection and thematic
analysis.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer v
In Study 1, the systematic review and meta‐analysis followed Preferred Reporting
Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines to determine
the effectiveness of psychological interventions on anxiety in patients with cancer.
Random effects modelling of standardised mean difference (RevMan version 5.3)
was used to estimate intervention effect sizes. Subgroup analyses were conducted
according to sample and intervention characteristics.
Secondary data analyses of longitudinal data were undertaken in Studies 2 and 3.
Data were extracted from the Laparoscopic Approach to Cancer of the Endometrium
(LACE) trial, a large randomised clinical trial including 760 patients. The eligibility
criteria were age 18 years or older, stage I endometrial cancer, Eastern Cooperative
Oncology Group (ECOG) performance status lower than two, and signed written
informed consent. Data were extracted from the perioperative period to six‐month
post‐surgery. Multivariate logistic regression analyses were used in Study 2 to
evaluate the factors associated with patients being prescribed anxiolytic and
antidepressant medications. The HADS‐21 was used to determine anxiety and
depression in patients with endometrial cancer in Study 3. Regression models were
fitted to estimate the association between anxiety and depression, and patients’
sociodemographic and clinical characteristics. The odds ratio (OR), 95% confidence
interval (CI) and p‐value were reported for each covariate.
In Study 4, a qualitative study based on semi‐structured interviews focused on long‐
term endometrial cancer survivors. Patients completed a self‐reported questionnaire
4.5 years after the end of enrolment into the LACE trial. They were asked whether
they would also be interested in a semi‐structured telephone interview. Interviews
vi
were transcribed verbatim and analysed using the framework approach. Two
researchers independently coded responses into meaningful themes that were
finalised into overall themes for inclusion in the results.
Results
In Study 1, 71 studies were eligible for inclusion in the systematic review; of these,
51 were included in the meta‐analysis. The review found that most studies (n =
55/71) included patients newly diagnosed with cancer (n = 19/55) or undergoing
cancer treatments (n = 36/55). Thirty‐six reported on psychological interventions to
women with breast cancer and only three studies on gynaecological cancers,
respectively. Cognitive behavioural therapy (n = 14/71) and psychologist (n = 33/71)
were the most common psychological intervention and providers, respectively. The
HADS (n = 38/71) was the most commonly used screening tool to determine anxiety
in patients with cancer. Nine studies used formal screening to assess anxiety or
distress symptoms, as part of the enrolment procedures for patients with cancer, to
deliver guideline‐driven care treatment.
The meta‐analysis found that the overall effect size of psychological interventions on
anxiety in patients with cancer was –0.21 (95% CI: –0.30 to –0.13), favouring the
intervention. From subgroup analyses, the intervention was more successful with
moderate effect sizes ranging from –0.40 to –0.55 in studies conducted in Asia,
enrolling inpatients, focusing on relaxation, < 6‐week intervention duration, < 30‐
minute intervention dose per session and < 4 hours of total time of intervention. Only
two studies restricted enrolment to patients with clinically elevated levels of anxiety;
these studies showed an effect size of –0.58, representing a moderate to large effect.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer vii
In Study 2, data from 719 patients were included. The overall prevalence of patients
with endometrial cancer who were prescribed one or more psychotropic medications
from before surgery to the six‐month follow‐up was 16.8% (n = 121/719), comprising
antidepressants (12.6%, n = 91/719) and anxiolytics (5.8%, n = 42/719). Most
patients (78.1%, n = 71/91) were already receiving antidepressants before their
cancer diagnosis. The remaining medications (21.9%, n = 20/91) were newly
prescribed perioperatively. Younger patients (18–50 years, OR: 2.61), those who had
hypertension (OR: 0.61), a history of a previous cancer (OR: 1.96) or ≥ 2 comorbidities
(2–3, OR: 2.97; 4–5, OR: 7.85; ≥ 6, OR: 9.13) were significantly (p < .05) more likely to
receive a prescription of psychotropic medications.
Data from 334 patients who had completed the HADS longitudinally were included
in Study 3. The proportion of patients with anxiety and depression (≥ 11) was 16%
(n = 51/318) before surgery, and 6% (n = 18/314) one‐week post‐surgery. This rate
continued to decrease over time. The overall cumulative proportion of anxiety,
depression and both in patients was 22.7% (n = 76/334), 9.0% (n = 30/334) and 7.2%
(n = 24/334), respectively, from before surgery to six months post‐surgery. Only 6/76
patients with a HADS score of ≥ 11 for anxiety and 1/30 patients for depression
reported they had visited mental health professionals. Further, 4/76 patients were
prescribed with antidepressants and anxiolytics for anxiety (HADS ≥ 11). No patient
received medication for depression (HADS ≥ 11). More than half of the patients
(n = 14/24) diagnosed with both anxiety and depression received both psychological
and pharmacological treatments. Patients without a partner (OR 0.59, 95% CI: 0.35–
1.00), those of non‐European ethnicity (OR 1.85, 95% CI: 1.01–3.39) were more likely
viii
to report elevated anxiety according to the HADS score. Comorbid conditions (1–2,
OR 0.43, 95% CI: 0.18–1.02; 3–4, OR 0.34, 95% CI: 0.12–0.98), anxiolytic and
antidepressant prescriptions (OR 2.21, 95% CI: 1.08–4.50) and non‐European
ethnicity (other, OR 2.80, 95% CI: 1.46–5.38) were associated with depression.
Seventeen long‐term endometrial cancer survivors were interviewed in Study 4. Four
themes were identified: i) psychological wellbeing during diagnosis and survivorship;
ii) pharmacological treatment of distress; iii) psychological treatment and support;
and iv) strategies for psychological wellbeing. Women reported they psychologically
tolerated the surgery well; however, some faced persistent, occasional or newly
developed distress symptoms during survivorship. Few women preferred
psychological treatment over medications. Besides a positive attitude towards life
and cancer, a combination of complementary and alternative treatments—including
exercise, medication and walking—was a common approach women adopted to
maintain their psychological wellbeing.
Conclusion
The overall findings of this PhD program contribute to the limited literature on the
psychological outcomes of women diagnosed with endometrial cancer and over the
following years of survivorship. Using the published literature, our study found that
low psychological distress at baseline and interventions provided to people without
first screening them for distress were the main reasons for low effectiveness of
psychological interventions on anxiety in patients with cancer. We also found that
none of the studies reviewed reported on psychological interventions in women with
endometrial cancer. In terms of pharmacological treatment for anxiety and
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer ix
depression in patients, most women who required medication, were already
prescribed with psychotropic medications before diagnosis of endometrial cancer,
few received new psychotropic medication after cancer treatment, and for those
who did, this often did not match with the comorbidities of anxiety and depression.
One reason for this finding may be that the prevalence of anxiety and depression
seems to be lower in women with endometrial cancer compared to other cancer
populations, and therefore may not be readily picked up by health professionals
when it occurs. Noticeably, of the women with elevated level of anxiety or depression
according to the HADS, most did not receive treatment. The interviews with long‐
term survivors shed some light on other potential reasons for this finding, with many
women reporting a wish to live without medication, and many preferring to use
lifestyle complementary and alternative treatments for their psychological
wellbeing. Although major notable findings, these research results stemmed from
secondary data analyses of participants in a clinical trial, who may be healthier and
more highly educated than the average patient. Further qualitative and quantitative
research on the broader population of women with endometrial cancer including
those diagnosed with higher stage disease are required to confirm the results.
PhD research contribution
This PhD research highlighted the current treatment patterns of anxiety and
depression in patients with endometrial cancer, which was under‐researched in
Australia and internationally. Screening and assessment of psychological status of
patients with endometrial cancer could improve the precision with which supportive
care is given. The outcomes of this research can be used to design interventions that
x
will contribute to a greater understanding of how to best overcome psychological
distress in this cancer patient group and can inform psychological and
pharmaceutical treatment approaches according to best treatment guidelines.
Healthcare professionals should also be aware that many women prefer to take as
little medication as possible and prefer lifestyle advice on how to return to optimal
psychological health after a cancer scare.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer xi
List of Publications
1. Sanjida S, McPhail SM, Shaw J, Couper J, Kissane D, Price MA, Janda M. Are
psychological interventions effective on anxiety in cancer patients? A systematic
review and meta‐analyses. Psychooncology. 2018 Sep;27(9):2063‐2076. doi:
10.1002/pon.4794. Epub 2018 Jul 16.
2. Sanjida S, Janda M, McPhail SM, Kissane D, Couper J, Scott J, Obermair A. How
many patients enter endometrial cancer surgery with psychotropic medication
prescriptions, and how many receive a new prescription perioperatively? Gynecol
Oncol. 2019 Feb;152(2):339‐345. doi: 10.1016/j.ygyno.2018.11.018. Epub 2018 Nov
19.
3. Saira Sanjida, David Kissane, Steven M. McPhail, Andreas Obermair, Monika Janda.
Anxiety and depression in patients with early stage endometrial cancer: A
longitudinal analysis from before surgery to 6‐month post‐surgery. Journal of
Psychosocial Oncology Research and Practice. Journal of Psychosocial Oncology
Research and Practice. 2019 Dec 1(3): e13. doi: 10.1097/OR9.0000000000000013.
4. Saira Sanjida, Steven M. McPhail, Andreas Obermair, Monika Janda. Psychological
wellbeing of long‐term endometrial cancer survivors: A qualitative study. Manuscript
in preparation.
xii
List of Conference Oral Presentation
1. Sanjida, Saira; McPhail, Steven M. and Janda, Monika. Prescription practice of
psychotropic medications to the patients with endometrial cancer. In: Hong Kong,
20th World Congress of Psycho‐Oncology, (118‐118). 29 October‐2 November 2018.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer xiii
List of Conference Poster Presentations
1. Sanjida S, Janda M. Psychological well‐being of more than seven years’
endometrial cancer survivors. Clinical Oncology Society of Australia 2019, Asia‐Pacific
Journal of Clinical Oncology, 15 (9), (129), 12‐14 November, Adelaide, Australia.
2. Sanjida, Saira; McPhail, Steven M. and Janda, Monika. Prevalence of anxiety and
depression in patients with endometrial cancer: Before surgery to 6‐month post‐
surgery. Australasian Epidemiological Association Annual Scientific Meeting,
Brisbane, 23‐25 October, 2019.
3. Sanjida, Saira; Obermair, Andreas and Janda, Monika. Anxiety and depression in
patients with endometrial cancer according to the hospital anxiety and depression
scale: A longitudinal analysis. An e‐Poster was presented at Herston Healthcare
Symposium 2019 in Brisbane.
4. Sanjida, Saira; McPhail, Steven M. and Janda, Monika. How many endometrial
cancer patients diagnosed with clinical level of anxiety and depression, and how
many received psychological treatment during survivorship? Cancer Survivorship
conference 2019 organized by Clinical Oncology Society Australia in Sydney. 28‐29
March, 2019.
5. Sanjida, Saira; McPhail, Steven M. and Janda, Monika. Factors influencing
prescription of antidepressants and anxiolytics in patients with endometrial cancer.
Institute Health and Biomedical Innovations Inspires Conference 2018. 16‐17 August,
2018.
6. Sanjida, Saira; McPhail, Steven M. and Janda, Monika. The effect of psychological
interventions on anxiety in cancer patients: Meta‐analyses of randomized controlled
xiv
trials. A poster was presented at the Joint International Society for Clinical
Biostatistics and Australian Statistical Conference 2018 in Melbourne.
7. Sanjida S and Janda M. Factors influencing prescription of antidepressants and
anxiolytics in patients with endometrial cancer. A poster was presented at the RBWH
Healthcare Symposium 2018.
8. Sanjida S, Janda M, Mulvogue, K. The effect of psychological interventions on
anxiety in cancer patients: Meta‐analyses of randomized controlled trials. IHBI
Inspires Conference 2017, Brisbane, Australia, (71), 23‐24 August, 2017.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer xv
List of Abbreviations
AD Antidepressant
AIHW Australian Institute of Healthcare Welfare
ATC Anatomical Therapeutic Chemical
AX Anxiolytics
BAC Beck Anxiety Inventory
BD Twice a day for one patient only
BMI Body mass index
BSI Brief Symptom Inventory
CAM Complementary and alternative medicines
CBT Cognitive behavioural therapy
CI confidence interval
CIDI Composite International Diagnostic Interview
CSAQ Cognitive‐somatic trait anxiety
CT Computed tomography
DASS Depression Anxiety Stress Scales
DSM Diagnostic and Statistical Manual of Mental Disorders
ECOG Eastern Cooperative Oncology Group
ePRO Electronic Patient Reported Outcomes
ES Effect size
GAD Generalized anxiety disorder
GLOBOCAN Global cancer observatory
HAM‐A Hamilton Anxiety Rating Scale
HRA Hamilton rating scale
IES‐R Impact of Events Scale‐Revised
IPOS International Psycho‐Oncology Society
LACE Laparoscopic Approach to Cancer of the Endometrium
MAACL Multiple Affect Adjective Checklist
xvi
MAC Mental Adjustment to Cancer Scale
MeSH Medical Subject Heading
OR Odds ratio
PM Psychotropic medication
PMR Progressive muscle relaxation
PoCoG Psycho‐Oncology Cooperative Research Group
POMS Profile of Mood States
PRISMA Preferred Reporting Items for Systematic Reviews and Meta‐
Analyses
PROSPERO International Prospective Register of Systematic Reviews
PTSD Post‐traumatic stress disorders
SAS Self‐rating anxiety score, Smith Anxiety Scale
SCI Stepped care intervention
SD Standard deviation
SMD Standardised mean difference
SSRIs Selective serotonin reuptake inhibitors
STAI State‐Trait Anxiety Inventory
TAH Total Abdominal Hysterectomy
TDD Three times a day for one patient only
TLH Total Laparoscopic Hysterectomy
UK United Kingdom
USA United States of America
WHO World Health Organisation
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer xvii
Statement of Original Authorship
The work contained in this thesis has not been previously submitted to meet
requirements for an award at this or any other higher education institution. To the
best of my knowledge and belief, the thesis contains no material previously published
or written by another person except where due reference is made.
Signature:
QUT Verified Signature
Date: 18.02.2020
xviii
Acknowledgements
First, I would like to thank my Principal Supervisor, Professor Monika Janda for her
regular supervision, guidelines, and encouragements in every step of this PhD
research project. Thank you so much, Monika for giving me lots of feedback on my
research. I would like to thank my Associate Supervisor, Professor Steven M McPhail
for regular advice and comments on thesis.
Advance Queensland has supported this PhD research program. I would like to thank
this Queensland government initiative for supporting the PhD research scholarship.
I also would like to thank Australian Government Research Training Program
scholarship to support this PhD program. I would like to thank Royal Brisbane
Women’s Hospital as my Industry Partner to support this research and delivery of
data, research support and regular feedback on projects.
I would like to thank researchers from the Psycho‐oncology Co‐operative Research
Group (PoCoG) including Professor David Kissane, Dr Jeremy Couper, Dr Joanne Shaw
for giving me the opportunity to work with them and their valuable comments and
help to conduct the research at national level.
I would to thank all the member of QUT Improving Health Outcomes for People group
within the School of Public Health and Social Work and Institute of Health and
Biomedical Innovation for delivering regular feedback on presentation at various
stage of this course. I would also like to thank Lee Jones, QUT Research Method
Group for helping me with statistical analysis questions.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer xix
I also would like to acknowledge Capstone Editing for editing some of the chapters
of this thesis.
The completion of this thesis would not been possible without the unconditional
support of my family throughout this PhD journey. I want to thank my parents—A. K.
M. Shofiullah and Gulshan Akhter, mother‐in‐law—Momotaz Mahal Begum, brother
and sisters‐ Zahid, Rehana, Shoyeba and Sifat. Finally, thanks to my husband, Saiful
and son, Safir who were always with me and encouraged me at every moment of this
journey.
xx
Table of Contents
Keywords ................................................................................................................................... i
Abstract .................................................................................................................................... ii
Aims .................................................................................................................................... iii
Methods .............................................................................................................................. iv
Results ................................................................................................................................. vi
Conclusion ......................................................................................................................... viii
PhD research contribution .................................................................................................. ix
List of Publications .................................................................................................................. xi
List of Conference Oral Presentation ..................................................................................... xii
List of Conference Poster Presentations ............................................................................... xiii
List of Abbreviations .............................................................................................................. xv
Statement of Original Authorship ......................................................................................... xvii
Acknowledgements .............................................................................................................. xviii
List of Figures ........................................................................................................................ xxv
List of Tables ....................................................................................................................... xxvii
Introduction ........................................................................................................... 1
1.1. Background ................................................................................................................... 1
1.1.1. Epidemiology of cancer .......................................................................................... 1
1.1.2. Anxiety and depression in patients with cancer .................................................... 3
1.1.3. Prevalence of anxiety and depression in patients with cancer ............................. 6
1.1.4. Factors influencing anxiety and depression in cancer patients ............................. 9
1.1.5. Guidelines for the treatment of anxiety and depression in cancer patients ....... 16
1.2. Research gaps identified in research leading to the proposed PhD ........................... 26
1.3. Research aims ............................................................................................................. 28
1.4. Significance ................................................................................................................. 29
1.5. Thesis outline .............................................................................................................. 30
1.6. Reference List .............................................................................................................. 33
Scoping literature reviews .................................................................................... 51
2.1. Introduction ................................................................................................................ 51
2.2. Endometrial cancer ..................................................................................................... 52
2.2.1. Incidence .............................................................................................................. 52
2.2.2. Risk and prevention of endometrial cancer ......................................................... 53
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer xxi
2.2.3. Guidelines for treatment for endometrial cancer ............................................... 55
2.3. Scoping of the literature on anxiety and depression in patients with endometrial
cancer ................................................................................................................................. 56
2.4. Scoping of the literature on treatments for anxiety and depression in patients with
endometrial cancer ............................................................................................................ 60
2.4.1. Pharmacological treatment received by patients with endometrial cancer ....... 60
2.4.2. Psychological treatment received by patients with endometrial cancer ............ 63
2.5. Conclusions ................................................................................................................. 65
2.6. References .................................................................................................................. 66
Psychological interventions on anxiety in cancer patients .................................. 75
3.1. A systematic review and meta‐analyses—are psychological interventions effective
on anxiety in cancer patients? ........................................................................................... 75
3.2. Abstract ....................................................................................................................... 79
3.3. Background ................................................................................................................. 80
3.4. Methods ...................................................................................................................... 82
3.4.1. Search strategy .................................................................................................... 82
3.4.2. Study inclusion and exclusion criteria .................................................................. 82
3.4.3. Study design ......................................................................................................... 84
3.4.4. Study selection ..................................................................................................... 84
3.4.5. Data extraction .................................................................................................... 85
3.4.6. Data synthesis ...................................................................................................... 85
3.4.7. Meta‐analysis modelling ...................................................................................... 86
3.4.8. Risk of bias ........................................................................................................... 86
3.5. Results ......................................................................................................................... 87
3.5.1. Study selection ..................................................................................................... 87
3.5.2. Characteristics of included studies ...................................................................... 88
3.5.3. Overall effect size ................................................................................................. 96
3.5.4. Subgroup analyses ............................................................................................... 99
3.5.5. Is treatment for anxiety more beneficial for patients with clinical level of
anxiety? ........................................................................................................................ 103
3.5.6. RoB assessment ................................................................................................. 105
3.5.7. Publication bias .................................................................................................. 108
3.6. Discussion .................................................................................................................. 109
3.6.1. Overall effectiveness of psychological interventions ........................................ 109
3.7. Conclusions ............................................................................................................... 113
3.7.1. Study strengths .................................................................................................. 113
3.7.2. Study limitations ................................................................................................ 113
xxii
3.7.3. Clinical implications ........................................................................................... 114
3.9. References ................................................................................................................ 114
Chapter 4: Methods ............................................................................................................. 132
4.1. Introduction .............................................................................................................. 132
4.2. The Laparoscopic Approach to Cancer of the Endometrium trial ............................ 133
4.2.1. Sample enrolment .............................................................................................. 133
4.2.2. Study visits ......................................................................................................... 134
4.2.3. Data collection from preoperative to 4.5 years follow–up interview ............... 136
4.3. Sample data available for inclusion in PhD research program ................................. 137
4.4. Data extraction for quantitative analyses ................................................................. 138
4.4.1. Medications of interest ...................................................................................... 140
4.4.2. Hospital Anxiety and Depression Scale .............................................................. 140
4.4.3. Sociodemographic records ................................................................................ 141
4.4.4. Clinical records ................................................................................................... 141
4.5. Follow–up (4.5 years) ................................................................................................ 142
4.5.1. Qualitative data collection ................................................................................. 142
4.5.2. Other supporting data extracted from baseline and 4.5 years follow–up ........ 142
4.6. Definition of data collection time points, variables and exposures ......................... 143
4.7. Data analysis ............................................................................................................. 145
4.7.1. Chapter 5: Secondary analysis 1 ........................................................................ 145
4.7.2. Chapter 6: Secondary analysis 2 ........................................................................ 146
4.7.3. Chapter 7: Qualitative study .............................................................................. 147
4.8. Ethical considerations ............................................................................................... 148
4.9. References ................................................................................................................ 148
Chapter 5: Use of psychotropic medications by endometrial cancer patients ................... 151
5.1. How many patients enter endometrial cancer surgery with psychotropic medication
prescriptions and how many receive a new prescription perioperatively? .................... 151
5.2. Abstract ..................................................................................................................... 155
5.3. Background ............................................................................................................... 156
5.4. Methods .................................................................................................................... 158
5.4.1. Site and timeline ................................................................................................ 158
5.4.2. Patient recruitment ............................................................................................ 158
5.4.3. Sociodemographic and clinical characteristics .................................................. 159
5.4.4. Details of medication data collection ................................................................ 160
5.4.5. Statistical analysis .............................................................................................. 160
5.5. Results ....................................................................................................................... 161
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer xxiii
5.5.1. Patients characteristics ...................................................................................... 161
5.5.2. Prescription characteristics of psychotropic medications ................................. 164
5.5.3. Characteristics associated with the prescription of psychotropic medications 169
5.6. Discussion .................................................................................................................. 172
5.6.1. Study strengths and limitations ......................................................................... 176
5.6.2. Future research .................................................................................................. 176
5.7 References ................................................................................................................. 178
Chapter 6: Anxiety and depression in endometrial cancer patients ................................... 184
6.1. Anxiety and depression in women with early stage endometrial cancer: A
longitudinal analysis from perioperative to 6–month post–surgery ............................... 184
6.2. Abstract ..................................................................................................................... 188
6.3. Introduction .............................................................................................................. 189
6.4. Methods .................................................................................................................... 191
6.4.1. Sample recruitment ........................................................................................... 192
6.4.2. Sociodemographic and clinical characteristics .................................................. 192
6.4.3. Hospital Anxiety and Depression Scale (HADS) ................................................. 193
6.4.4. Statistical analysis .............................................................................................. 193
6.5. Results ....................................................................................................................... 194
6.5.1. Sample characteristics ....................................................................................... 194
6.5.2. Anxiety and depression at five different time points ........................................ 196
6.5.3. Treatments received for cumulative incidence of anxiety and depression ....... 200
6.5.4. Association of sociodemographic and clinical characteristics with anxiety and
depression between baseline and 6–month post–surgery ......................................... 202
6.6. Discussion .................................................................................................................. 205
6.6.1. Main findings ..................................................................................................... 205
6.6.2. Study strengths .................................................................................................. 207
6.6.3. Study limitations ................................................................................................ 207
6.6.4. Future research .................................................................................................. 208
6.7 References ................................................................................................................. 209
Chapter 7: Psychological wellbeing in long‐term endometrial cancer survivors ................. 219
7.1. Psychological wellbeing of long–term endometrial cancer survivors: A qualitative
study ................................................................................................................................. 219
7.2. Abstract ..................................................................................................................... 224
7.3. Introduction .............................................................................................................. 225
7.4. Methods .................................................................................................................... 228
7.4.1. Sample recruitment ........................................................................................... 228
xxiv
7.4.2. Data collection ................................................................................................... 228
7.4.3. Data analysis ...................................................................................................... 230
7.5. Results ....................................................................................................................... 230
7.5.1. Participant characteristics .................................................................................. 230
7.5.2. Profiles of patients who received psychological treatments, antidepressants
and/or anxiolytics during long–term survivorship ....................................................... 233
7.5.3. Qualitative findings ............................................................................................ 234
7.6. Discussion .................................................................................................................. 245
7.7. References ................................................................................................................ 248
Chapter 8: Conclusions ........................................................................................................ 254
8.1. Introduction .............................................................................................................. 254
8.2. Strengths and implementation ................................................................................. 254
8.3. Limitations ................................................................................................................. 261
8.3.1. Unavailability of data in published sources and research dataset .................... 261
8.3.2. Sample inclusion ................................................................................................ 261
8.3.3. Guideline‐driven pharmacological treatment for anxiety and depression ....... 261
8.3.4. Psychological symptoms other than anxiety and depression ............................ 262
8.3.5. Data entered by nurses ...................................................................................... 263
8.3.6. Secondary data from surgical clinical trial ......................................................... 263
8.4. Conclusions ............................................................................................................... 264
8.5. References ................................................................................................................ 265
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer xxv
List of Figures
Figure 1.1.1: Global cancer incidence 2018 (Source: WHO, 2018) [2] …………… 2
Figure 1.1.2: Symptoms of anxiety and depression (Source: American
Psychiatric Association (1994), Diagnostic and Statistical Manual of Mental
Disorders. 4th ed. Washington) [31] …………………………………………………………...
6
Figure 1.1.4a: Trajectories of the psychological health of patients after a
diagnosis of cancer (Source: Andrykowski et al., 2008) [51] ………………………… 10
Figure 1.1.4b: Factors influencing the development of anxiety in patients
with cancer (Source: Traeger et al. 2012) [53] ……………………………………………… 11
Figure 1.1.4c: Interaction of multiple factors influencing depression in cancer
patients (Source: Li et al., 2012) [52] …………………………………………………………… 11
Figure 1.1.4.3: Association of sociodemographic and clinical factors with
increased somatic and psychological symptoms (Source: Thomas et al., 2014)
[65] ……………………………………………………………………………………………………………..
15
Figure 1.1.5.1: Screening tool specifically recommended for use with caution
by ≥3 more reviews (*), 2 reviews (†) and 1 review (‡) (Wakefield et al., 2015)
[76] ………………………………………………………………………………………………………………
21
Figure 1.5: Structure of PhD research project ……………………………………………… 31
Figure 2.1: PhD project structure: Scoping literature reviews ……………………… 51
Figure 3.1: PhD project structure: Chapter 3—Psychological interventions on
anxiety in cancer patients ..…………………………………………………………………………. 74
Figure 3.5.1: PRISMA flow diagram of systematic review and meta‐analysis … 87
Figure 3.5.3: Forest plot of the effects of psychological interventions on
anxiety in cancer patients (negative values favour the intervention—
representing greater reduction in anxiety) …………………………………………………..
96
xxvi
Figure 3.5.7: Funnel plot assessment of publication bias in the studies on
effectiveness of psychological intervention of anxiety in patients with cancer 107
Figure 4.1: PhD project structure: Methods …………………………………………………. 130
Figure 4.2.2: Flow diagram of participants throughout the LACE trial ………….. 132
Figure 4.3: Overall sample data included in each chapter of PhD research
program ……………………………………………………………………………………………………… 135
Figure 5.1: PhD project structure: Chapter 5—Use of psychotropic
medications by endometrial cancer patients ………………………………..……………… 149
Figure 6.1: PhD project structure: Chapter 6–Anxiety and depression in
endometrial cancer patients ………………………………………………………..……………… 182
Figure 6.5.2a: Sample completed HADS questionnaire at different time
points ………………………………………………………………………………………………………….. 195
Figure 6.5.2B: Prevalence of anxiety and depression from before surgery to
6‐month post‐surgery …………………………………………………………………………………. 197
Figure 6.5.2C: Change of HADS score: Before surgery to 6–month post–
surgery………………………………………………………………………………………………………… 197
Figure 7.1: PhD project structure: Chapter 6–Psychological wellbeing of long‐
term endometrial cancer survivors ………………………………………..…………………… 218
Figure 7.5.1: Flow diagram of participant numbers throughout the LACE trial 228
Figure 7.5.3: Themes and groups derived from semi–structured interviews of
psychological wellbeing of long–term endometrial cancer survivor ……………… 232
Figure 8.1: PhD project structure: Conclusions …………………………………………….. 250
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer xxvii
List of Tables
Table 1.1.2: Anxiety disorders and their codes (Source: American Psychiatric
Association, Diagnostic and Statistical Manual of Mental Disorders‐5) [24] …. 4
Table 1.1.5.1: Summary of reviews of depression measures in patients with
cancer [76–85] ……………………………………………………………………………………………. 18
Table 1.1.5.3: Stepped care for anxiety and depression in cancer patients
[75] …………………………………………………………………………………………………………….. 23
Table 2.2.2: Details of the evidence for risk factors for endometrial cancer
incidence or mortality (Raglan et al., 2018) [10] ….………………………………………. 53
Table 3.5.2: Study sample characteristics, intervention methods and
outcome tools……………………………………………………………………………………………… 88
Table 3.5.4: Sub‐group analysis (Negative values represent greater reduction
in anxiety symptoms)† ………………………………………………………………………………… 98
Table 3.5.5: Anxiety screening, assessment tools, intervention type and dose
delivered in patients with cancer ………………………………………………………………… 102
Table 3.5.6: Risk of bias………………………………………………………………………………… 104
Table 4.2.3: Details of data collection by nurses and others ………………………… 134
Table 4.4a: Extraction of data at different time points ………………………………… 137
Table 4.4b: Variables used in each chapter of PhD research program ………… 137
Table 4.6: Definitions of data collection time points, variables and exposures 141
Table 5.5.1: Sociodemographic and clinical characteristics of the 719
patients diagnosed with endometrial cancer ……………………………………………… 159
Table 5.5.2: Prescription characteristics of psychotropic medications (n =
719)† ………………………………………………………………………………………………………….. 162
xxviii
Table 5.5.2S: Type and dose of psychotropic medications prescribed to
patients with endometrial cancer ……………………………………………………………….. 164
Table 5.5.3: Univariate analysis of characteristics associated with the
prescription of psychotropic medications …………………………………………………… 167
Table 5.5.4: Multivariable logistic regression of variables associated with the
prescrip on of psychotropic medica ons† …………………………………………………. 170
Table 6.5.1: Patients characteristics (n = 334) ……………………………………………… 192
Table 6.5.2: Borderline abnormal (8–10) and abnormal (≥11) anxiety and
depression with their change score at different time point ……………………….. 198
Table 6.5.3: Anxiety and depression of patients from before surgery to 6‐
month post‐surgery and their received treatments ……………………………………… 199
Table 6.5.4a: Factors associated with experiencing anxiety or depression
(HADS score ≥8) from before surgery to 6‐month post‐surgery …………………… 200
Table 6.5.4b: Multivariable logistic regression model …………………………………. 202
Table 7.5.1: Participant characteristics (n = 17) …………………………………………… 229
Table 7.5.2: Profiles of women who received psychological treatments,
antidepressants and anxiolytics during long‐term survivorship …………………… 231
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 1
Introduction
This chapter introduces the epidemiology of cancer and the comorbidities of anxiety
and depression, common factors associated with anxiety and depression in patients
with cancer, and guidelines for their treatment (see Section 1.1). It also summarises
key gaps identified in previous research (see Section 1.2), which will be addressed in
Chapters 3 and 5–7. Sections 1.3 and 1.4 describe the research aims and significance
of this thesis, respectively. Finally, Section 1.5 concludes with an outline of
subsequent chapters of the thesis.
1.1. Background
1.1.1. Epidemiology of cancer
Cancer is a leading cause of death worldwide and the most significant barrier to
increasing life expectancy in many countries around the world [1]. According to the
latest global cancer observatory (GLOBOCAN) database, 18.1 million new cancer
cases were diagnosed worldwide in 2018 (see Figure 1.1.1), of which 9.5 million were
diagnosed in male and 6.6 million in female patients, respectively [2]. In the same
year, there were 9.6 million cancer deaths [3]. It is estimated that the number of
cancer cases will increase to 29.5 million by 2040 [2,3].
2
Figure 1.1.1: Global cancer incidence 2018 (Source: WHO, 2018) [2]
The incidence rate of cancer is two times higher in developed regions, such as the
United States (US), Europe and Australia/New Zealand than in less‐developed regions
[2]. According to gender‐based cases, lung and breast cancers were the most
commonly diagnosed cancers in males and females, respectively, and also the leading
causes of cancer deaths in these gender groups [2,4]. Economic status and lifestyle
risk factors, such as tobacco smoking, physical inactivity, excess body weight and
reproductive procedures, are believed to be mainly responsible for the increasing
prevalence of cancer [1,5].
In Australia, cancer comprises one‐fifth of the total burden of disease [6]. Compared
to less‐developed regions like West Africa and South Central Asia, the incidence of
cancer in Australia and New Zealand for both genders is 4–6‐fold higher. The
availability and use of screening services and diagnostic imaging may account for
these large differences in incidence rates [1]. In 2012, there were 143,400 newly
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 3
diagnosed cases of cancer in Australia. By 2020, this figure may increase to 150,000
[7,8], with prostate and breast cancers the most commonly diagnosed cancers in
males and females, respectively [6]. The five‐year relative survival of all cases of
cancer has increased from 48% in 1984–1988 to 68% in 2009–2013 at diagnosis, and
for those who have already survived five years after a diagnosis, the chance of
survival is 91.5% (2009–2013) [6]. However, cancer patients with chronic
comorbidities have poorer survival rates than those without chronic conditions [9].
The presence of comorbidities such as psychiatric disorders may be associated with
delayed cancer diagnosis as well as increased postoperative complications and
mortality [9]. Other risk factors for cancer in Australia include diet, obesity, sunlight
and reproductive hormones [7].
1.1.2. Anxiety and depression in patients with cancer
After a diagnosis of cancer, many patients experience psychological distress.
Symptoms of psychological distress may arise before or at the time of diagnosis and
continue throughout the survival period [10]. In some instances, cancer patients can
cope well without further support [11]. However, often patients become
overwhelmed and require supportive care or treatment. Due to the overlapping
nature of the physical symptoms and side effects of cancer treatment, as well as
psychological distress and its symptoms, it can be difficult for health professionals to
correctly recognise the symptoms or be confident about the type of psychological
distress [12–14]. Under‐recognition and under‐treatment of psychological distress
may threaten cancer patients’ quality of life and have been associated with an
4
increased risk of missing some doses of cancer chemotherapy, non‐adherence to
treatments and increased risk of death [15–19].
Anxiety is a common psychological side effect in patients with cancer [20,21]. After a
cancer diagnosis, anxiety begins with stress, worry, fear or restless nights [21,22].
These psychological symptoms of anxiety can be associated with physiological
symptoms, such as increased heart and respiratory rate, sweating and muscle
tension [23]. The Diagnostic and Statistical Manual of Mental Disorders I (DSM),
published in 1952 by the American Psychiatric Association, stated that anxiety ‘may
be directly felt and expressed or ... may be unconsciously and automatically
controlled by the utilization of various psychological defence mechanisms’ [24 p124,
25]. Psychological responses in patients with cancer may progress into more clinical
manifestations characterised as anxiety disorders [26]. In these early diagnostic test
criteria, several ‘reactions’ including ‘anxiety reaction’ and ‘phobic reaction’ were
recognised as an anxiety disorder. Later, additional diagnostic classes for anxiety
disorders were included in the current DSM‐5 (see Table 1.1.2 for codes).
Table 1.1.2: Anxiety disorders and their codes (Source: American Psychiatric
Association, Diagnostic and Statistical Manual of Mental Disorders‐5) [24]
Codes Anxiety disorders
309.21 (F93.0) Separation Anxiety Disorder 313.23 (F94.0) Selective Mutism 300.29 (_._) Specific phobia 300.23 (F40.10) Social Anxiety Disorder (Social Phobia) 300.01 (F41.0) Panic Disorder 300.22 (F40.0) Agoraphobia 300.02 (F41.0) Generalized Anxiety Disorder 293.84 (F06.4) Anxiety Disorder Due to Another Medical Condition 300.09 (F41.8) Other Specified Anxiety Disorder 300.00 (F41.9) Unspecified Anxiety Disorder
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 5
Often symptoms of anxiety can be associated with depression, a hidden symptom
that is especially common in advanced‐stage cancer patients [22,27–29]. The most
common symptoms of depression include loss of interest, persistent low mood,
feeling worthless, low appetite and suicidal ideation [29,30]. According to DSM‐5,
major depressive disorders [296.99 (F34.8)] present in patients if five or more (of
nine) symptoms persist over a two‐week period [24]. The symptoms are depressed
mood, decreased interest or pleasure, significant weight loss, insomnia, change in
activity, fatigue or loss of energy, feelings of worthlessness or guilt, reduced ability
to concentration and thoughts of death or suicide ideation [24].
In some instances, the symptoms of both anxiety and depression overlap, causing
sleep disturbance, agitation, fatigue and difficulty concentrating (see Figure 1.1.2)
[31]. The most widely recommended method to separate the overlapping symptoms
of anxiety and depression was developed by Roth et al. (1972) and included ‘clinical
symptoms, personality, treatment and treatment response, course and outcome,
prognosis and rating scale’ [32,33 p9]. Later, two important factors—i) choice of scale
to measure symptoms and ii) selection of participants—were considered to
differentiate between the symptoms of anxiety and depression [34]. Scales to
measure anxiety and depression should have good psychometric properties,
especially reliability (which is related to the number of items). Positive affect towards
environment and life, and physiological hyperarousal can help to differentiate
between anxiety and depression [35,36], as anxiety and depression are characterised
by the absence of physiological hyperarousal and positive affect, respectively [36,37].
6
Anxiety
Both anxiety and
depression Depression
Figure 1.1.2: Symptoms of anxiety and/or depression (Source: American Psychiatric
Association (1994), Diagnostic and Statistical Manual of Mental Disorders, 4th ed.
Washington) [31]
Overall, anxiety and depression are common symptoms of psychological distress in
patients with cancer. Their early diagnosis and treatment may reduce the negative
psychological impact on cancer patients’ lives, as well as may prevent development
of other comorbidities. It is important to determine the prevalence and the factors
influencing anxiety and depression in patients with cancer, so that the optimal
treatment can be selected and delivered.
1.1.3. Prevalence of anxiety and depression in patients with cancer
The overall prevalence of anxiety and depression appears to be higher in patients
with cancer compared to the general population. A systematic review and meta‐
analysis of 94 interview‐based studies (until 2010) found that in patients with cancer
the prevalence of anxiety was 10% and depression 20%, respectively (as determined
by the DSM‐4). For the general population (1980–2013 across 63 countries), the
Stress
Worry
Fear
Restless nights
Dry mouth
Nausea
Sweating
Low mood
Loss of interest
Low appetite
Panic
Suicidal ideation
Feeling worthlessness
Difficulty
concentrating
Sleep disturbance
Agitation
Irritability
Fatigue
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 7
prevalence was 7% for anxiety and 5% for depression [38–40]. However, estimates
vary widely depending on the survivorship phase and the type of measurement used.
In a population‐based study (1997–2001) conducted among long‐term cancer
survivors (diagnosed more than five years ago) in New South Wales, Australia,
participants had lower rates of anxiety and depression compared to the general
Australian adult population [41]. Using the HADS, 9% (n = 76/846) and 4% (n
= 34/847) of patients with cancer were diagnosed with clinically elevated levels of
anxiety and depression (≥ 11), respectively [41]. The National Survey of Mental
Health and Wellbeing of Adults (1997) reported that at five years post‐diagnosis,
patients may have recovered well from diagnostic and treatment procedures,
resulting in a similar prevalence of anxiety (9.7%) and depression (5.1%) as in the
general population [42]. Later, Boyes et al. (2011) conducted another large
population‐based study in New South Wales and Victoria in Australia and included
patients at six months post‐diagnosis of cancer (n = 1,360) using the HADS [43]. The
prevalence of anxiety (28%, 95% CI: 23%–33%), depression (24%, 95% CI: 19%–29%),
and both anxiety and depression (14%, 95% CI: 9%–19%) was much higher in this
study, compared to the previously conducted study of long term cancer survivors
[41,43]. This prevalence rate around the time of a cancer diagnosis and treatment
was two times higher than in the general Australian population [44]. Comorbidities,
low levels of social interaction and age were the main factors associated with anxiety
and depression in patients with cancer [43]. Limitations of this study included
selection of samples from only two states, rather than from all over Australia, use of
8
self‐reported questionnaires linked to registry, low response rates (41%,
n = 1360/3315) and selection bias of sample (age and cancer type).
High rates of anxiety and depression in patients newly diagnosed with cancer were
also evident in recently conducted studies in Germany, Canada and the United
Kingdom (UK). Kuhnt et al. (2016) conducted a nationwide population‐based study in
Germany to establish the 12‐month prevalence of mental disorders as determined
by the Composite International Diagnostic Interview (CIDI). They found that around
39.4% (n = 843/2141) of cancer patients were diagnosed with any mental disorders.
Among them, 15.8% (n = 33/843) had an anxiety disorder and 12.5% (n = 105/685)
had a mood disorder [45]. When assessing the four‐week prevalence of mental
health disorders (31.8%, n = 685/2141), the prevalence of any anxiety disorder or a
mood disorder was 11.5% (n = 78/685) and 6.5% (n = 44/685), respectively [46].
Faller et al. (2017) in Germany compared the emotional distress of women diagnosed
with breast (n = 897) and gynaecological cancers (n = 317) using the Patient Health
Questionnaire (PHQ‐9) for depression and Generalized Anxiety Disorder Scale (GAD‐
7) for anxiety [47]. Women with gynaecological cancer (mean, M = 7.48; standard
deviation, SD = 4.76) were found to have higher mean depressive symptom scores
compared to women with breast cancer (M = 6.70, SD = 4.19), while mean anxiety
scores were similar in the two patient groups (M = 5.97, SD = 4.19 vs M = 5.57,
SD = 4.11). The main reasons for the high depression scores in patients with
gynaecological cancer were reported to be lower satisfaction with care and a lack of
psychosocial support and information received.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 9
Using the Psychosocial Screen for Cancer questionnaire in Canada prior to the
beginning of treatment (2004–2009), 19% (n = 1928/10,153) and 12.9%
(n = 1204/9357) of cancer patients were diagnosed with clinical levels of anxiety and
depression (≥ 11), respectively [48]. Further, patients with gynaecological cancer
were diagnosed with the highest rate of anxiety (28.4%, n = 249/878) among any
cancer type and the third‐highest rate of depression (16.5%, n = 144/871) after
haematological and lung cancers [48]. A cross‐sectional study (n = 21,151) was
conducted by Walker et al. (2014) from 2008–2011 in the UK using the HADS and a
structured clinical interview from the DSM‐4 to determine anxiety and depression.
Patients with lung cancer (n = 4316, 13.1%, 95% CI: 11.9–14.2%), followed by those
with gynaecological cancers (n = 3010, 10.9%, 95% CI: 9.8–12.1) were identified as
having the highest rates of major depression [49].
From these population‐based studies, it has been identified that patients with newly
diagnosed cancer and those with gynaecological cancers are at a high risk of anxiety
and depression. It is clear that a cancer diagnosis and its treatment procedures can
be detrimental to patients’ psychological status. However, it is also important to
consider other factors that affect whether a patient may experience anxiety and
depression after a cancer diagnosis.
1.1.4. Factors influencing anxiety and depression in cancer patients
After a diagnosis of cancer, most patients recover over time and return to a normal
life, depending on their coping capacity and treatment intensity. Some patients even
report that while the diagnosis was a challenge initially, they experienced growth and
an increased sense of purpose once they coped with the initial shock. However, in
10
many instances, a person’s psychological health may deteriorate; it has been
proposed that the pathway a person may take could be influenced by factors other
than the cancer diagnosis and subsequent treatment [50]. Andrykowski et al. (2008)
presented trajectories of the psychological health of patients after a diagnosis of
cancer and how these are influenced by physical, psychological or social impairments
(see Figure 1.1.4a) [51].
Figure 1.1.4a: Trajectories of the psychological health of patients after a diagnosis
of cancer (Source: Andrykowski et al., 2008) [51]
Some researchers have reviewed other factors that, individually or in combination,
influence the development of anxiety and depression in patients with cancer [52,53].
Traeger et al. (2011) suggested four different factors that contribute towards anxiety
development in patients with cancer: predisposing factors, cancer‐related factors,
disease and treatment factors and comorbid symptom burden (see Figure 1.1.4b)
[53].
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 11
Figure 1.1.4b: Factors influencing the development of anxiety in patients with
cancer (Source: Traeger et al., 2011) [53]
In terms of depression, Li et al. (2012) suggested that multiple factors—medical,
demographic, disease‐related and psychosocial—may interact and cause depression
in cancer patients (see Figure 1.1.4c) [52].
Figure 1.1.4c: Interaction of multiple factors influencing depression in cancer
patients (Source: Li et al., 2012) [52]
12
In summary, three main factors—sociodemographic, clinical and psychological—
have been identified by Li et al. (2012) and Traeger et al. (2012) as influencing anxiety
and depression in patients with cancer [52,53]. A number of reviews and research
studies have been conducted to determine the exact contribution that each of these
factors make in influencing anxiety and depression in patients with cancer (as
summarised below).
1.1.4.1. Sociodemographic factors
Sociodemographic factors, such as age, gender, education, employment, income,
insurance, ethnicity, marital status, living status and body mass index (BMI) were
studied widely in the psycho‐oncology literature to determine their influence on
anxiety and depression in patients with cancer. Recently, Wen et al. (2019)
conducted a systematic review of 43 studies on the factors associated with
depression in patients with cancer. They found that three sociodemographic
factors—age, level of education and gender—stood out in their contribution as risk
factors for depression in these patients [50]. Older age, higher education and being
female were associated with a higher risk of depressive symptoms. The possible
reasons for risk of depression in elderly patients with cancer may be due to loss of
health status after a cancer diagnosis, functional impairment, family problems, poor
network of social support and loss of interest in activities. They may also suffer from
cognitive impairment, such as poor memory or concentration difficulties, which
cause the actual symptoms of depression [54]. Low education level has been
identified as commonly associated with higher depression in patients, but the reverse
has also been reported [50,55]. Family responsibilities, sexuality issues and change
in appearance may be other possible reasons for risk of depression in females with
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 13
cancer [56,57]. However, this study was limited, as it reviewed studies of patients
undergoing chemotherapy only [50].
Another systematic review and meta‐analysis found that being an ethnic minority
patient with cancer (Hispanic in the USA) was associated with significantly worse
depression (number of studies = 4, effect size: –0.18; 95%CI: –0.35 to –0.01)
compared to an ethnic majority. Lower socioeconomic status was the main reason
for depression in Hispanic patients with cancer [58]. The limitation of this study was
that most studies (n = 18/21) included in the review were conducted in the USA.
Anxiety and depression in patients with migrant cancer is quite high in Australia. Sze
et al, (2015) found that the prevalence of anxiety and depression (using HADS) in
Arabic (n = 145, 25.5% and 20.0%, respectively), Chinese (n = 248, 25.5% and 21.4%,
respectively) and Greek (n = 178, 21.9% and 18.0, respectively) was higher within 12
months of cancer diagnosis compared to Anglo‐Australians (n = 274, 10.9% and 6.9%,
respectively). The main factors associated with anxiety and depression were
understanding of English and the health care system [59].
1.1.4.2. Clinical factors
Common clinical factors considered in review studies on the association between a
cancer diagnosis and anxiety or depression included the type of cancer, time since
diagnosis, pain and type of treatment. In Cook et al. (2017), no evidence was found
for clinical factors associated with anxiety and depression [60]. However, these
authors reported that developing anxiety or depression within three months of
cancer diagnosis was more commonly associated with persistent longer‐term
distress (12 months) compared to anxiety and depression before cancer diagnosis.
14
Importantly, this study highlights the importance of screening and assessment of
anxiety and depression at the time of cancer diagnosis [60]. A number of other
reviews found that anxiety and depression increased when patients with breast
cancer underwent chemotherapy treatment, which causes physical side effects like
vomiting, hair loss, mucositis and peripheral neuropathy [50,61–63]. Surgery is one
of the most common procedures to treat cancer, and depression has been identified
as common following postoperative complications such as pain [50,64].
Although these review studies explored the clinical factors associated with anxiety
and depression, there are other factors, including comorbid chronic conditions (e.g.,
cardiovascular diseases, diabetes, arthritis, etc.) that influence anxiety and
depression in patients with cancer (see Section 1.1.4) [52,53]. A clear research gap in
review studies was found in relation to whether comorbid chronic conditions were
considered in their influence on anxiety and depression in cancer patients.
1.1.4.3. Psychosocial factors
In some instances, sociodemographic and clinical factors are mutually associated,
causing a cluster of burden for patients with cancer and increased somatic and
psychological symptoms. Thomas et al. (2014) provided an example of the
interrelationship of these factors (see Figure 1.1.4.3) [65].
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 15
Figure 1.1.4.3: Association of sociodemographic and clinical factors with increased
somatic and psychological symptoms (Source: Thomas et al. 2014) [65]
Common psychological factors influencing the risk of anxiety and depression in
patients with cancer are a previous history of trauma, life events or distress [50,66].
Sometimes, these symptoms may also originate from the physical symptoms of
cancer or be side effects of the treatment, making it difficult to differentiate between
physical and psychological symptoms [12,14]. Even healthcare professionals highly
experienced in cancer treatment—like cancer care nurses or oncologists—have been
found to not accurately detect depression symptoms [13,67]. Another important
factor, social support, is strongly associated with depression in patients with cancer
[50]. Social support from family members, friends or caregivers can act as buffer at
times of stress, while lack of support has been found to be strongly associated with
depression in cancer patients [50].
Jacob et al. (2016) researched the prevalence of anxiety, depression and the
associated risk factors in patients with breast cancer (n = 44,555) diagnosed between
16
2009 and 2013 in Germany [68]. This research showed that patients with previous
episodes of depression and anxiety were at higher risk (1.97; 95% CI: 1.85–2.09) of
again developing anxiety and depression after a cancer diagnosis. More extensive
cancer symptoms or advanced clinical diagnosis may also make it more likely that
symptoms of anxiety and depression will evolve and continue after cancer treatment.
Interestingly, research by Pearson et al. (2015) in Australia suggest that symptoms of
depression may also be symptom of cancer developing, as these researchers found
that the peak period of antidepressant initiation was three months prior to, and up
to four months after, a cancer diagnosis [69]. This indicates that anxiety or depression
may be caused by the cancer itself, other comorbid conditions or be a side effect of
as yet unexplained symptoms during the diagnostic investigations rather than solely
a result of the diagnosis itself. Further studies are needed to identify the relative
contribution of factors influencing the development of anxiety or depression and
determine the best pathway to diagnosis and treatment of cancer‐related anxiety
and depression.
1.1.5. Guidelines for the treatment of anxiety and depression in cancer patients
A number of guidelines have been developed nationally and internationally and are
recommended to improve the supportive care for patients with cancer [52,70–74].
Most of the guidelines inform the delivery of interventions or treatment according
to the symptoms and severity of the psychological condition. To improve the
psychological treatment of cancer patients with psychological distress, Butow et al.
(2015) developed a clinical guideline for anxiety and depression in adult cancer
patients within the Australian context, suggesting a screening, assessment and
stepped‐care approach [75]. This guideline was based on a review of other existing
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 17
guidelines, systematic reviews, meta‐analyses, stakeholder interviews and input
from a multidisciplinary advisory panel.
1.1.5.1. Screening
According to this guideline, healthcare professionals, including general practitioners,
specialists involved in cancer treatment, nurses and social workers, are
recommended to screen patients with cancer for anxiety and depression. They
should consider using validated screening tools to measure signs of anxiety or
depression in these patients at key points in their journey, such as at diagnosis or the
start of treatment procedures [75]. For example, the HADS (14‐item measure, seven
items each for anxiety and depression) is a detailed and reliable screening tool to
measure anxiety and depression in patients under investigation or treatment [30]. A
HADS score of ≥ 11 on either subscale should be considered an indicator for possible
moderate‐to‐severe anxiety and depression [30].
The International Psycho‐Oncology Society (IPOS) conducted a meta‐review to
determine gold‐standard depression measures for adults with cancer and compare
of positive and negative features of the available best practice screening tools [76].
This meta‐review included the review studies published between 1999 and 2014.
Seven narrative reviews and 12 systematic reviews were included in the meta‐
review. Among these, only four narrative reviews and five systematic reviews
compared the various screening tools with their positive and negative features. A
short comparative summary of various screening tools and their positive and
negative features from the Wakefield et al. (2015) study is presented in Table 1.1.5.1.
18
Table 1.1.5.1: Summary of reviews of depression measures in patients with cancer
[76–85]
Population
Screening tools
Positive features Negative features
Narrative reviews
Carlson and Bultz, 2003 (USA) [77]
All patients with cancer
BDI Recommended for screening
Described as not highly responsive to change
CES‐D Recommended for screening
Not reported
ZSDS Described as “good” Not reported
King et al, 2005
(USA) [78]
Terminally ill older cancer patients
BDI Recommended for older, terminally ill patients
Not reported
CES‐D Recommended for older, terminally ill patients
Not reported
EDS
Described as having “some usefulness” Recommended for older, terminally ill patients
Not reported
HADS
Described as having “some usefulness”, Recommended for older, terminally ill patients
Not reported
Pirl, 2010 (USA) [79]
Mixed diagnoses: all individuals with cancer
CES D
Recommended for screening, Freely available and quick to complete
Not reported
BDI
Recommended for screening, Easy to use and quick to complete
Contains some somatic symptoms
HADS Not reported Less focus on somatic symptoms than other measures
Wilson et al, 2000
(USA) [80]
Advanced cancer/
palliative care, mixed
diagnoses
BDI Described as more accurate
Not reported
HADS Not reported
Most commonly used cut point (8 points) not well supported in validation studies
Systematic reviews
Luckett et al, 2010
(Australia) [81]
Patients receiving treatment, mixed
diagnoses
CES‐D Recommended for screening
Not reported
HADS
Allowing cross‐study comparison Highest scoring measure
Criticised for emphasis on anhedonia Less suitable for advanced cancer Less suitable for detecting minor depression
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 19
PHQ‐9 Not reported
Multiple items problematic for those undergoing active treatment for cancer of any type and stage
POMS‐37 High scoring measure
Not reported
BDI Not reported Not recommended because of low property scores
Nelson et al, 2010
(USA) [82]
Elderly (geriatric)
patients with cancer, mixed diagnoses
BDI Well tested in geriatric patients
Recall period may be too long for geriatric patients
CES‐D Well tested in geriatric patients
Symptoms assessed not as well suited to geriatric patients
PHQ‐9 Not reported Length of recall (2 weeks) is quite burdensome for geriatric population
ZSDS One of the most tested in geriatric patients
Not reported
Thekkumpurath, 2008
(UK) [83]
Advanced cancer and palliative
populations, mixed
diagnoses
BEDS; Recommended for palliative care
Not reported
BDI Recommended for screening
Not reported
EDS
Described as “fairing well” compared with other measures in palliative care
Not reported
Vodermaier et al, 2009
(Canada) [84]
Cancer and palliative
populations, mixed
diagnoses
CES‐D Recommended for screening
Not reported
HADS One of the most widely used scales, Judged as “good”
Most commonly used cut point (8 points) not well supported in validation studies Less suitable for advanced cancer
GHQ‐28 Judged as” excellent”
Longer than other measures
PHQ‐9 Not reported
Judged as “poor” because of low reliability, Low criterion measure Low validity
Ziegler et al, 2011
(UK) [85]
Cancer populations across before, during, and
after treatment, palliative)
BDI Recommended at diagnosis
Not reported
BEDS Recommended for palliative care
Not reported
BDI Recommended at diagnosis
Long, sensitivity seemed to decrease after treatment and during palliative care
HADS Recommended at diagnosis, and post treatment
Most commonly used cut point (8 points) not well supported in validation studies,
20
Less suitable for palliative care, performs less well during active treatment (unless combined with the MHI‐5), Cost may be a barrier
ZSDS Judged as having good specificity at diagnosis
Judged as having poor sensitivity at diagnosis in one study
BEDS=Brief Edinburgh Depression Scale. BDI=Beck Depression Inventory. CES‐D=Center for Epidemiologic Studies‐Depression Scale. EDS=Edinburgh Depression Scale. GHQ‐28=General Health Questionnaire‐28 items. HADS=Hospital Anxiety and Depression Scale. MHI‐5=Mental Health Inventory‐5 items. PHQ‐9=Patient Health Questionnaire‐9 items. POMS‐37=Profile of Mood States‐37 items. ZSDS=Zung Self‐Rating Depression Scale
In summary, the meta‐review and short summary of depression measures (see Table
1.1.5) seem to indicate a consensus that the HADS is one of the most reliable and
widely used screening tool for patients with cancer [76]. Reasons for this include:
i. The HADS was the most evaluated measure to determine depression in patients
with cancer. Therefore, ample evidence for its reliability, sensitivity to change and
validity compared to clinical interviews are available.
ii. It is valuable for comparison of groups of patients in cross‐sectional studies,
providing evidence for its ability to differentiate between the burden of depression
across cancer types.
iii. This screening tool has been used successfully across the cancer trajectory,
indicating that it captures relevant information during treatment and into
survivorship.
iv. Therefore, reviewers recommended use of the HADS at the time of cancer
diagnosis, during treatment and post‐treatment except for geriatric populations (see
Figure 1.1.5.1).
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 21
Figure 1.1.5.1: Screening tool specifically recommended for use by ≥3 more reviews
(*), 2 reviews (†) and 1 review (‡) (Source: Wakefield et al., 2015) [76]
This meta‐review considered extracted data from systematic and narrative reviews.
However, this meta‐review only analysed studies that were concerned with
depression in patients with cancer, but did not extract details of anxiety‐focused
studies. Despite these limitations, there seems to be a consensus that the HADS is a
useful screening tool for the assessment of distress in cancer patients, and can be
used to identify patients who require support or further treatment.
1.1.5.2. Assessment of the severity of symptoms
The guidelines recommend that after screening identifies the likely presence of
anxiety and depression in cancer patients, it is important to assess the severity of
these symptoms. This may require referral to a psychologist or psychiatrist, in
addition to other healthcare professionals that conduct the screening process [75].
A suitably trained healthcare professional should carry out the entire process of
screening, assessment and referral. The symptoms of anxiety and depression are
22
related and sometimes it is difficult for healthcare professionals to differentiate
between them [13,14,27–29]. A standard semi‐structured clinical interview building
on the DSM‐5 or International Classification of Diseases (version 10) can be used to
identify the nature of anxiety or depression, their possible causes and the severity of
relevant symptoms. Clinicians also need to check whether any medical conditions,
treatments or other factors have contributed to the development of anxiety and/or
depression. Any suicidal ideation or self‐harm should be assessed in addition to the
anxiety and depression diagnostic test [75].
1.1.5.3. Stepped care
According to Butow et al. (2015), stepped care is defined as ‘self‐correcting in that
the outcomes of interventions are monitored systematically, and care is stepped up
if current interventions are not achieving significant health gain’ [75 p992]. It is an
effective and proven method in the treatment of anxiety and depression in
healthcare systems [86–88]. Recently, Krebber et al. (2016) examined the effect of
stepped‐care treatment (i.e., watchful waiting, guided self‐help, problem‐solving
therapy and psychotherapy or psychotropic medication) on the psychological
distress of patients with head, neck and lung cancer in the Netherlands [89]. They
found that patients who received stepped care had a faster recovery (55%, n = 75)
from anxiety and depression (screened by HADS) compared to patients in the care‐
as‐usual group (29%, n = 81). To date only few other protocols and clinical trials have
been published that used stepped‐care treatment to reduce anxiety and depression
in patients with cancer [19,90–93].
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 23
The stepped‐care approach has been divided into five steps according to the severity
of anxiety and depression: (i) usual care, (ii) supportive care, (iii) extended care, and
(iv and v) specialist care. Stepped care for anxiety and depression in cancer patients
has been described by Butow et al. (2015) as a clinical practice pathway (summarised
in Table 1.1.5.3.
Table 1.1.5.3: Stepped care for anxiety and/or depression in cancer patients [75]
Stepped care
Step 1 Step 2 Step 3* Steps 4 and 5* Universal care Supportive care Extended care Specialist care
Minimal to mild Mild to moderate Moderate Moderate to
severe
Type of intervention
‐ Patient education (face‐to‐face) ‐ Brief emotional support
‐ Psycho education ‐ Tele‐based cancer helpline ‐ Peer support groups/ group therapy
‐ Face‐to‐face/ online training in coping skills/ psychological therapy ‐ Mindfulness ‐ Pharmacotherapy
‐ Face‐to‐face/ online psychological therapy ‐ Pharmacotherapy
Professional recommended to deliver and review treatment
‐ Treating clinician ‐ General practitioner ‐ Trained staff
‐ General practitioner ‐ Cancer care nurse ‐ Social worker ‐ Psychologist ‐ Non‐government organisation/ community services
‐ General practitioner ‐ Social worker ‐ Psychologist ‐ Psychiatrist ‐ Trained staff
‐ Psychologist ‐ Psychiatrist with the general practitioner
Progress review
‐ 2–4 weeks ‐ No intervention, if improved or remitted ‐ Clinically significant time points or as required for long‐term review
‐ 6–8 weeks ‐ Another intervention, if improved but not remitted ‐ If remitted, clinically significant time points or as required for long‐term review
‐10–12 weeks ‐ Another intervention, if improved but not remitted ‐ If remitted, every 2 months for 12 months or as required and 6–12 months for long‐term review
‐ 12–24 weeks ‐ Another intervention, if improved but not remitted ‐ If remitted, every month for 12 months or as required and 6–12 months for long‐term review
If not improved
Follow Step 2
Follow Step 3
Follow Steps 4 and 5
* Cancer‐related anxiety and depression only
Each step provides detailed information regarding the best intervention method and
duration, review periods, maintenance and continuation phase and involvement of
24
healthcare professionals. For normal to mildly anxious or depressed patients,
education and emotional support is the initial treatment and patients can be
monitored systematically while undergoing the intervention. Care will be increased
step‐by‐step, moving to more intensive interventions and referral to mental health
professionals according to the severity or lack of improvement in symptoms [75].
The benefit of treatment for anxiety and depression in patients with cancer has been
demonstrated and integrated into the available clinical practice guidelines. Review
studies have been published regarding the delivery of psychological treatment for
anxiety and depression in patients with cancer, showing beneficial outcomes [94–
105]. However, it is unknown whether the clinical trials delivered guideline‐driven
care treatments using a screening, assessment and stepped‐care approach and
whether this increased their effectiveness.
1.1.5.4. The role of medication
Besides psychological treatment, anxiolytics and antidepressants are commonly used
for the pharmacological treatment of both anxiety and depression due to the
overlapping nature of their symptoms [106,107]. However, antidepressants are the
preferred medications and are administered worldwide for anxiety and depression
more commonly than are anxiolytics, depending on symptom and severity [75]. In
the stepped care approach, pharmacological treatment combined with psychological
treatment is suggested to treat moderate or severe anxiety and depression [73,75].
Conversely, psychological treatment alone should be considered for the preliminary
treatment of minimal‐to‐mild or mild‐to‐moderate anxiety and depression. Besides
being prescribed for psychological problems, antidepressants and anxiolytics are also
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 25
prescribed for the relief of other health issues common in cancer patients, such as
anger, pain, insomnia, nausea, vomiting panic, fatigue or low energy [108–114].
Many of these symptoms are originating from the physical side effects of cancer
treatment or medical procedures. A 4‐year prospective cohort study (n = 42,075)
showed that higher adherence to antidepressant is associated with a decrease of
mortality in cancer [115].
Large variations in healthcare providers’ practices of prescribing antidepressants and
anxiolytics in patients with cancer have been identified, including by provider type,
dose and prevalence. For example, as identified in the UK General Practice Research
Database, patients with breast and prostate cancer more commonly received
antidepressants than they did anxiolytics (n = 26,213) [116]. Non‐psychiatrist medical
professionals, including general practitioners, have been identified as the most
common health professionals to prescribe medications to cancer patients [117,118].
However, psychiatrists tend to prescribe higher doses of antidepressants compared
to general practitioners [118,119]. These medications can have side effects or drug–
drug interaction with other medicines that may affect patients with cancer [120–
123]. For example, selective serotonin reuptake inhibitors (SSRIs) decrease the
efficacy of a common anti‐cancer drug (i.e., tamoxifen) that is used in the treatment
breast cancer [121]. Therefore, precautions should be taken when prescribing
medications to cancer patients with anxiety and depression.
Concern has been raised by some studies that some patients may receive
antidepressants unnecessarily, while antidepressants may not be received by
patients who do require them. Further, those cancer patients receiving such
26
prescriptions may not receive optimal follow‐up compared to when antidepressants
are prescribed for other reasons [123–125]. According clinical practice guidelines,
antidepressants should be continued for at least six months for the treatment of
depression [74]. However, Lu and Roughead (2012) found in a cohort study (2005–
2008) of antidepressant initiation in the Australian veteran population (n = 28,585)
that there was a high risk of antidepressant discontinuation in patients with cancer
[126]. Later, Pearson et al. (2015) found that comorbid chronic conditions such
cardiovascular disease, disease burden (i.e., anxiety, tension and pain) and the
recommencement of cancer treatment were associated with discontinuation of
antidepressant therapy [69].
There is a dearth of Australian research investigating the types of pharmacological
treatments for anxiety and depression that are provided to patients with cancer,
whether healthcare professionals follow screening and assessment protocols before
delivering pharmacological treatment, and how effective these treatments were
according to severity [75]. While anxiolytics and antidepressants are used in the
treatment of both anxiety and depression in cancer patients, there remains a lack of
research into how well this treatment is targeted towards the patients’ symptom
burden and whether it works for patients in Australia and globally.
1.2. Research gaps identified in research leading to the proposed PhD
This proposed PhD research project builds on research gaps identified in two
previous studies conducted during a Master of Applied Science project. This work
was conducted within the realms of a large national consortium and supported by
the Psycho‐Oncology Cooperative Research Group (PoCoG). First, a systematic
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 27
review and meta‐analysis on antidepressants in cancer patients was conducted [127].
It found only a limited number of research studies on the pharmacological treatment
of depression in cancer patients were available in Australia. Lack of screening and
assessment to determine the presence of depression in patients with cancer
treatments was another limitation of previously conducted studies [127,128]. It is a
priority for future research to screen newly diagnosed cancer patients, especially
females with gynaecological cancer, for anxiety and depression due to the reported
high prevalence of such symptoms in these under‐researched patient groups
[49,124,129,130]. The review also observed that the prescription of antidepressants
was more common for female cancer patients [127]. More research is needed to
identify the type and timing of pharmacological treatment for anxiety and depression
that female cancer patients receive following their cancer diagnosis and throughout
their survival period.
Besides pharmacological treatment, and according to the stepped‐care model, it is
essential to assess the effectiveness of psychological treatments for anxiety and
depression. As described above, there is concern that some cancer patients may
receive antidepressants unnecessarily, that some who require antidepressants may
not receive them and that those receiving such prescriptions may not receive optimal
follow‐up [129]. Even in this researcher’s previous retrospective study, only a small
number of patients with anxiety or depression (n = 7/75) treated in a major tertiary
hospital received services from mental health professionals [128]. To address these
research gaps, this PhD was designed to further investigate both the psychological
and pharmacological treatment of anxiety and depression in female cancer patients.
28
This program was conducted in national collaboration with the PoCoG team and a
team of investigators leading the LACE trial. The LACE trial is a long‐term international
longitudinal study that enrolled 760 patients with endometrial cancer from Australia,
New Zealand, Scotland and Hong Kong. The details of the LACE trial will be discussed
in Chapter 4.
1.3. Research aims
This program of research aimed to:
Study 1—determine the effectiveness of psychological interventions that can
alleviate anxiety in cancer patients as reported in randomised controlled trials. Two
objectives were developed to meet this aim:
o 1a—to determine the overall effect size (ES) of psychological
interventions to improve anxiety in patients with cancer.
o 1b—to estimate the sample or intervention characteristics associated
with greater effectiveness of psychological interventions.
Study 2—determine the prescription characteristics of psychotropic treatments (i.e.,
anxiolytics and antidepressant) in newly diagnosed patients with endometrial cancer.
Two objectives were developed to meet this aim:
o 2a—to determine the prevalence, type, dose, frequency and timing of
psychotropic medications prescribed to endometrial cancer patients at
the time of diagnosis and initial treatment.
o 2b—to study the sociodemographic and clinical characteristics associated
with receiving a psychotropic medication prescription.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 29
Study 3—determine anxiety and depression in newly diagnosed patients with
endometrial cancer using the HADS around the time of diagnosis, during surgery and
up to six months post‐surgery. Two objectives were developed to meet this aim:
o 3a—to determine the rate of anxiety and depression in women with early‐
stage endometrial cancer starting treatment and over the first six month
after surgery.
o 3b—to evaluate the sociodemographic and clinical factors associated
with anxiety and depression in women with endometrial cancer from
before surgery to six months post‐surgery.
Study 4—understand the psychological wellbeing of long‐term endometrial cancer
survivorship. Two objectives were developed to meet this aim:
o 4a—to understand the psychological wellbeing of women from diagnosis
of endometrial cancer to long‐term survivorship.
o 4b—to identify the support, psychological or pharmaceutical treatment
women received and whether it was helpful for their recovery from
anxiety and depression.
1.4. Significance
This program of research was designed building on a national collaboration between
PoCoG and the international LACE clinical trial. The findings of this PhD research are
critical to the field of psycho‐oncology, addressing a significant gap in the literature
which has rarely studied endometrial cancer patients’ psychological wellbeing, or
whether those in need received psychological or pharmaceutical care according to
best practice guidelines. This research mainly used data derived from a large,
30
international trial, which included a relatively homogenous sample of women
diagnosed with early staged endometrial cancer. Using the extensive data collected
within the clinical trial allowed a detailed description of patients’ psychological
profile from just before surgery into long‐time survivorship. Future patients
diagnosed with endometrial cancer in both Australia and worldwide may benefit
from this research, as it provides evidence suggesting who may be at risk of
developing anxiety or depression and how treatment for psychological health
besides cancer treatment can be improved. These findings will likely prompt further
research and service evaluation activities that have the potential to improve patient
health outcomes.
Improved data on risk factors for anxiety or depression may allow healthcare
professionals involved in cancer treatment to focus more closely on patients deemed
high risk, which will likely make any interventions more efficient and effective. The
data may also allow the multidisciplinary team to deliver guideline‐driven
interventions or psychological care to cancer patients at risk, rather than patients
who likely will cope well themselves. This will help to reduce the cost of clinical care
and the expenses of hospital treatment facilities.
1.5. Thesis outline
The overall structure of the thesis is outlined in Figure 1.5. The studies conducted in
this PhD program originated from knowledge gaps identified in previous research
(see Section 1.2) and current literature reviews (see Chapter 2). Building on this data,
the PhD program included a systematic review and meta‐analysis (see Chapter 3),
two chapters building on quantitative analyses of secondary data derived from the
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 31
LACE trial (see Chapters 4 and 6), and a qualitative research study and analysis (see
Chapter 7).
Figure 1.5: Structure of PhD research project
Chapter 1 briefly introduced this thesis, followed by the knowledge gaps of previous
interlinked projects and the aims and significance of this thesis. Chapter 2
summarised the literature review of the psychological and pharmacological
treatment of anxiety and depression in patients with endometrial cancer.
Chapter 3 contains a systematic review and meta‐analysis. The protocol of this
study— ‘What benefit does the provision of psychological interventions have on
anxiety in cancer patients? Protocol for a systematic review and meta‐analysis of
randomised controlled trials’—was registered with the International Prospective
Register of Systematic Reviews (PROSPERO: CRD42017056132). The manuscript of
32
this study— ‘Are psychological interventions effective on anxiety in cancer patients?
A systematic review and meta‐analyses’—was published in the peer‐reviewed Q1
journal Psychooncology in 2018.
Chapter 4 describes the methods of the study, including the LACE clinical trial, data
extraction methods and ethical considerations. Chapters 5–7 describe the research
in this PhD program that originated from the knowledge gaps and existing literature.
These chapters present the research on the longitudinal data of LACE study, in which
women with endometrial cancer participated prior to surgery all the way up to 4.5
years follow‐up. Both quantitative (Chapters 5 and 6) and qualitative analyses were
conducted in this PhD thesis.
Chapter 5 is the first chapter of this PhD thesis that uses data from the LACE trial.
This study examines the prescription practices of psychotropic medications (i.e.,
antidepressants and anxiolytics) in patients with endometrial cancer. It also
determines the sociodemographic and clinical characteristics associated with the
prescription of psychotropic medications in patients with endometrial cancer. The
manuscript of this study— ‘How many patients enter endometrial cancer surgery
with psychotropic medication prescriptions, and how many receive a new
prescription perioperatively?’— was published in the peer‐reviewed Q1 journal
Gynecologic Oncology in 2019.
Chapter 6 provides another analysis of secondary data. Two aims are described in
this chapter. In this study, the prevalence of anxiety and depression in patients with
endometrial cancer was determined, as was the type of treatment received by
patients who were diagnosed with clinically elevated levels of anxiety and
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 33
depression. Sociodemographic and clinical factors associated with clinical levels of
anxiety and depression in patients with endometrial cancer were also evaluated. The
findings of this study was published in the peer‐reviewed Journal of Psychosocial
Oncology Research & Practice in 2019.
Chapter 7 is the qualitative study of patients with long‐term endometrial cancer
survivors, conducted more than 4.5 years after initial treatment. Patients from the
LACE trial participated in a semi‐structured interview to understand how they coped
with the initial diagnosis, and throughout the survivorship phase, and the role of
psychological or pharmaceutical treatment. The findings of this study are also
presented in manuscript format and will be submitted to a peer‐reviewed journal for
publication.
Chapter 8 of the thesis provides a summary of findings and presents the conclusions
from this thesis. The summary links the findings of this research with the literature
and highlights the clinical implications. It also presents the limitations of this program
of research and recommendations for future research.
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Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 51
Scoping literature reviews
2.1. Introduction
In Chapter 1 (see Section 1.2), it was asserted that this PhD research program forms
part of the LACE trial that investigated patients with endometrial cancer. The
research aims were developed according to key knowledge gaps identified in the
literature (see Section 1.2), including lack of research on prescription practices of
antidepressants and anxiolytics, using screening tools to determine anxiety and
depression in patients with cancer. Further research gaps were discovered
conducting scoping and systematic reviews and are described in Chapter 2 (see
Figure 2.1). These gaps include a lack of knowledge of the prevalence of anxiety and
depression and their treatments in patients with endometrial cancer, strongly
supporting the need for this PhD research program (see Sections 2.3 and 2.4).
52
Figure 2.1: PhD project structure: Scoping literature reviews
Chapter 2 contains a literature review, beginning with an overview of the
epidemiology and risks factors for endometrial cancer and guidelines for treatment
(see Section 2.2). Sections 2.3 and 2.4 describe what is known about the prevalence
and treatment of anxiety and depression in patients with endometrial cancer, and
shows that the evidence on which to base psychological or pharmacological
treatment decisions of anxiety and depression in this gynaecological cancer is limited.
2.2. Endometrial cancer
Endometrial cancer is the fifth most common cancer in women and the most
common gynaecological cancer in women of postmenopausal age [1,2]. It originates
from the cells of the epithelial lining (endometrium) of the uterine corpus [3]. Most
cases of endometrial cancer can be diagnosed at an early stage due to visible
symptoms of abnormal uterine bleeding [4]. In terms of histological subtype, there
are two main types of endometrial cancer. Type I (endometrioid adenocarcinoma)
occurs frequently in 80% of cases and can be treated more effectively because of the
presence of early symptoms, unlike type II (serous carcinomas), which resemble
more ovarian cancers and have a much worse prognosis [4,5]. The survival rate of
type I endometrial cancer is 85% at five years, while patients with type II cancers have
lower average 5 years’ survival of only 55% [4,6].
2.2.1. Incidence
According to GLOBOCAN (2018), there were an estimated 382,069 cases of corpus
uteri, including the most common endometrial cancer, in 2018. It is estimated this
figure will rise to 583,560 by 2040. The rate of endometrial cancer was higher
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 53
(13.0/100,000) in developed regions of the world such as the US and Europe and
lower (5.9/100,000) in least developed regions like Africa [7]. Australia and New
Zealand (11.5/100,000) had the fourth‐highest incidence rate of endometrial cancer,
following the US (16.4/100,000), Central and Eastern Europe (14.6/100,000) and
Northern Europe (13.8/100,000) [7]. Incidence rates differ so widely because of the
high prevalence of overweight and obesity— a key risk factor, which rose from 29.8%
to 38.0%, between 1980 and 2013 in high income countries [8,9].
2.2.2. Risk and prevention of endometrial cancer
Raglan et al. (2018) conducted an umbrella review (included systematic review with
or without meta‐analyses of observational epidemiological studies) of the risk factors
associated with endometrial cancer incidence and mortality [10]. A total of 61
systematic reviews have been published up to April 2018 that included 171 meta‐
analyses.
Table 2.2.2: Details of the evidence for risk factors for endometrial cancer incidence
or mortality (Source: Raglan et al., 2018) [10]
Type of evidence Risk factors
Strong evidence Anthropometric indices
Body mass index
Waist‐to‐hip ratio
Past gynaecological history
Highly suggestive evidence
Anthropometric indices
Body mass index
Waist circumference
Height, Weight
History of medical conditions and interventions
Diabetes mellitus
Suggestive evidence
Dietary intake Coffee intake
History of medical conditions and interventions
Diabetes mellitus
Hypertension
Physical activity and sedentary behaviour
Use of medical/hormonal therapy Metformin
Oral contraceptive
54
Past gynaecological history
Smoking
This review summarised the evidence for endometrial cancer risk factors (see Table
2.1), with the overall evidence suggesting that overweight, obesity, and central
distribution of body fat are most strongly related to increased risk.
The current recommendation of the World Cancer Research Fund and the American
Institute for Cancer Research (2007) is that optimally an adult’s BMI should be 21–
23. BMI is defined as a ‘person’s weight in kilograms divided by the square of the
person’s height in metres (kg/m2)’ (WHO, 2018). According to the World Health
Organization, a BMI of 25.0–29.9 is considered overweight while a BMI of ≥ 30 is
considered obese [11]. It has been reported that weight, weight gain and obesity
cause one‐fifth of all cancer cases [12]. Weight gain and the distribution of adipose
tissue during adulthood have both been directly related to the risk of endometrial
cancer [13]. Further, obesity is associated with survival and mortality in patients with
endometrial cancer [14]. Several reviews have been conducted on obesity and the
associated risk of endometrial cancer death. Most of these concluded that obesity is
the main risk factor for endometrial cancer and also strongly is associated with
endometrial cancer mortality [10,14–23].
There were a number of preventive measures identified by MacKintosh and Crosbie
(2018) in their review study to reduce the risk of endometrial cancer (factors include
weight and physical activity, bariatric surgery, diabetes and insulin resistance,
hormonal treatment, dietary approaches) [24]. Among these, bariatric surgery
reduces the risk of endometrial cancer in obese women most; maintaining a normal
weight was also identified as a risk reducing factor [25]. MacKintosh et al. (2018)
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 55
conducted a clinical trial on bariatric surgery on endometrial cancer risk and found
significant changes in endometrial cancer biomarkers—such as insulin resistance,
reproductive function and inflammation, and most importantly, endometrial
morphology—that caused endometrial cancer [26]. However, further long term
studies on the use of bariatric surgery to prevent endometrial cancer are required to
appropriately weigh up the benefits and risks of such procedure for women, given
that bariatric surgery leads to multiple metabolic changes, suicidal ideation and
reports of nutritional deficiencies following surgery have also been published [27—
30].
2.2.3. Guidelines for treatment for endometrial cancer
In 2014, the Cancer Council Australia developed clinical practice guidelines for the
treatment, management and follow‐up of patients with endometrial cancer [31].
Multidisciplinary health care professionals were involved in describing optimal
treatment and management approaches for endometrial cancer. Surgery (see
Section 2.2.3.1) and adjuvant treatments (see Section 2.2.3.2) are the main
approaches used. Similarly, clinical practice guidelines have been developed in other
countries such as the UK, USA and Spain [4,5,31–34].
2.2.3.1. Surgical treatment
Hysterectomy and bilateral salpingo‐oophorectomy with or without
lymphadenectomy are the most common approaches to treat early‐stage
endometrial cancer [6,33]. Total abdominal and laparoscopic hysterectomy are two
widely delivered surgical methods and both show similar results in terms of disease‐
free survival [4,33,35]. A total laparoscopic hysterectomy has a lower risk of
56
complication compared to a total abdominal hysterectomy [33]. This method also
results in a shorter hospital stay, reduced use of pain medication, and improved
quality of life [4].
2.2.3.2. Adjuvant treatment
Adjuvant treatments are delivered to patients with high risk endometrial cancer
subtypes, or cases found to be already advanced at the time of surgery.
Consideration is given to patients’ cancer stage; radiotherapy and chemotherapy
alone or in combination are used as adjuvant treatments [4,33].
While these clinical practice guidelines recommended treatments for patients with
endometrial cancer according to cancer stage, there was a lack of recommendations
in terms of psychological support at any stage of cancer (including diagnosis,
treatment or follow‐up). The high prevalence of depression in patients with newly
diagnosed cancer and women with gynaecological cancer has already been identified
(see Section 1.1.3). It is important to explore the prevalence rate of anxiety and
depression in women with newly diagnosed endometrial cancer and establish the
type of supportive care best suited to treat these symptoms.
2.3. Scoping of the literature on anxiety and depression in patients with
endometrial cancer
In Chapter 1 (see Section 1.1.3), it was summarised that in previous population‐based
studies, women with gynaecological cancer (10.9%) had the second highest
prevalence rate of depression after patients with lung cancer (13.1%). The extant
literature contained a lack of detail on the prevalence of depression in women with
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 57
endometrial cancer [36]. Therefore, a search of the literature was conducted to
determine more details on the prevalence of anxiety and depression in patients with
endometrial cancer and study characteristics including what screening tool was used
to determine anxiety or depression and whether studies reported on factors
influencing anxiety and depression in patients with endometrial cancer. The
keywords used to search the existing literature were ‘cancer’, ‘anxiety’, ‘depression’,
‘endometrial’ and ‘prevalence’. The PubMed and PsycINFO databases were
searched; 42 studies were found using keywords and a manual search.
42 studies were found after using the keywords and database search. Only five
studies were found that specifically focused on anxiety and depression in patients
with endometrial cancer after screening title, abstract followed by full‐text of studies
[37–41]. Four studies used the HADS, a widely recommended assessment tool to
screen for anxiety and depression, except Hoe at al. (2019) [41,42]. In a US‐based
cohort study (2003–2004), Kornblith et al. (2007) found that a total HADS score of
≥ 15 was four more common in younger women (≤ 55 years, 25.0%, n = 15/60)
compared to older women (6.25%, n = 4/64)—who were an average 3.7 years after
completion of endometrial cancer treatment [38]. Rowlands et al. (2015) conducted
a large population‐based case‐control study in Australia on women with endometrial
cancer diagnosed between 2005 and 2007 [39]. These authors contacted the women
3–5 years later to assess their psychological wellbeing. They discovered that the
proportion of women with at least subclinical levels of anxiety and depression (HADS
subscale ≥ 8) was 25.6% (n = 160/623) and 10.7% (n = 67/623), respectively. Both
these studies included long‐term endometrial cancer survivors but did not report
58
whether these women were already distressed around the time of diagnosis and
surgical intervention.
Two studies included women recently diagnosed with endometrial cancer [37,39]. A
two‐year prospective, longitudinal study conducted in Italy (n = 132) between
February 2007 and July 2010 identified that patients’ anxiety scores were highest at
baseline (mean ± standard error: 7.1±1.1) and improved at three months (4.7±1.1)
and six months (2.8±0.7) post‐surgery [37]. Depression scores were low at baseline
for most women (3.5±0.7) compared to the anxiety score and decreased further at
three months (3.1±0.6) and six months (2.8±0.7) post‐surgery. The proportion of
women who reported clinical levels of anxiety (≥11) before surgery was double
(19.5%, n = 25/132) the proportion of women who reported clinical levels of
depression [37]. In contrast, a cross‐sectional study conducted in Japan (2007–2008)
reported that more than half of women had an overall HADS score of ≥11 (55%,
n = 36/65) two weeks after diagnosis [39]. However, the latter study did not report
the separate HADS anxiety and depression subscales, and used an unusual overall
cut‐off of score of 11.
Hoe at al. (2019) conducted a nationwide retrospective cohort study (2010–2014) in
South Korea to analyse the prevalence of mental disorder in endometrial cancer
survivors (n = 8,155) according to age and time of diagnosis [41]. Seven per cent of
women (n = 567/8,155) were diagnosed with a mental disorder; among them, 43.9%
(n = 249/567) and 43.7% (n = 248/567) were diagnosed with depression and anxiety,
respectively. The important finding was that the peak incidence of mental disorders
was within two months of hysterectomy. However, no formal screening tool was
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 59
used to determine anxiety and depression. The first diagnosis of a mental disorder
was identified using Health Insurance Review and Assessment Service claims data
from patients’ hospital visit. No further studies focussing on anxiety and depression
in women during endometrial cancer diagnosis or surgical procedure were found.
Summary of knowledge gaps
No research study was found that reported on anxiety and depression around
the time of diagnosis and initial surgical treatment in Australia, likely the most
stressful time for patients with endometrial cancer.
Several studies assessed anxiety and depression using the HADS or other
screening tools among women with gynaecological cancer, including some
diagnosed with endometrial cancer [43–47] but it was not possible to
separate anxiety and depression data for women with endometrial cancer.
Very few studies reported on risk factors associated with anxiety and
depression in patients with endometrial cancer.
There was no information about treatments received by patients who were
diagnosed with anxiety and depression.
While 5‐year survival rates of women with endometrial cancer are quite high,
the latest time period at which anxiety and depression prevalence rate were
reported was 3─5 years after diagnosis. It is important to explore
psychological status during long‐term survivorship, and there is a lack of data
on the women’s perspective of their psychological wellbeing related to
endometrial cancer.
60
2.4. Scoping of the literature on treatments for anxiety and depression in patients
with endometrial cancer
According to clinical practice guidelines, psychological and pharmacological
treatments are recommended in sequence and in combination for anxiety and
depression in patients with cancer depending on symptoms and severity [49]. It is
recommended that psychological treatment as universal supportive care should be
the initial approach to treat anxiety and depression (see Table 1.1.5), with the
increasing involvement of highly skilled mental health professionals and specialised
pharmacological treatment as necessary. However, it is currently unknown whether
patients with endometrial cancer receive such treatments, whether it is delivered in
accordance with the guidelines and whether such treatment is effective. Therefore,
a scoping review of the literature into the types of psychological and pharmacological
treatments delivered to patients with endometrial cancer who were diagnosed with
anxiety and depression was conducted.
2.4.1. Pharmacological treatment received by patients with endometrial cancer
Psychotropic medications such as anxiolytics and antidepressants are used in the
treatment of moderate‐to‐severe anxiety or depression due to the overlapping
nature of symptoms [49,50]. Worldwide, the current prevalence rate of
antidepressants prescribed to patients with cancer is 15.6%, with a higher
prescription prevalence in female patients and patients with breast cancer (22.0%)
[51].
This scoping review was conducted to determine the pharmacological treatments
provided to patients with endometrial cancer and anxiety and depression. The
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 61
keywords used to search the existing literature were ‘cancer’, ‘anxiety’, ‘depression’,
‘endometrial’, ‘antidepressant’ and ‘anxiolytic’. PubMed and PsycINFO were the
databases used.
No study reported on the use of psychotropic medications for the treatment of
anxiety or depression in endometrial cancer. A few studies aimed to determine
whether the risk of patients to develop endometrial cancer was increased when they
were prescribed antidepressants [52,53]. However, these studies did not provide any
data about prescription practices after the diagnosis of endometrial cancer or during
treatment and post‐treatment follow‐up.
In summary this scoping review identified a distinct lack of research into the
pharmacological treatment for anxiety and depression in women with endometrial
cancer. This supports the importance to further study on this topic as part of this PhD
program.
Summary of knowledge gaps in pharmacological treatment patterns
1. No study was found that reported on the prescription characteristics of
psychotropic medications (i.e., antidepressants or anxiolytics) in patients with
endometrial cancer. The few studies on risk assessment did not provide any
information on the purpose of the antidepressants prescriptions, whereas it
is well known that antidepressants are commonly prescribed for multiple
purposes such as hot flushes, pain, sleep, and so on [51]. It is important to
identify whether cancer patients received pharmacological treatments for
anxiety and depression, as treatment is common after a diagnosis of cancer,
62
specifically in female cancer patients; under‐recognition of psychological
distress may reduce cancer patients’ quality of life and treatment adherence
(see Section 1.1.2).
2. There is also absence of data on other details about prescription
characteristics, such as type or timing of prescriptions relative to the
endometrial cancer diagnosis. Given the high prevalence of psychological
distress in patients with endometrial cancer reported in the epidemiological
studies reviewed in Section 2.3, additional data on the patterns of
psychotropic medication prescription is needed. The timing of medication
initiation is important to differentiate whether treatment was for cancer‐
related or other distress. It is also vital to explore the continuation of
psychotropic medications in women with endometrial cancer. We reported
previously that the discontinuation of antidepressants is high in patients with
cancer in Australia (see Section 1.1.5.4). According to clinical practice
guidelines, pharmacological treatments for moderate and moderate‐to‐
severe anxiety and depression should continue for at least six months for
therapeutic effect (see Table 1.1.5.3). Considering the dose of
antidepressants, the World Psychiatric Association (2008) recommended that
the initial dose should be low and increased according to depression status
[54]. Very few studies (n = 2) provided the details of antidepressant dose
adjustments in patients with cancer; none of these was conducted in women
with endometrial cancer [51].
3. Total laparoscopic hysterectomy and total abdominal hysterectomy is the
common approach of surgical treatment for early stage endometrial cancer.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 63
It is unknown whether these two different treatment approaches or adjuvant
treatments associate with the initiation of prescription of psychotropic
medications. It is also important to explore how long patients continue
psychotropic medications after post‐surgery follow‐up or throughout the
survivorship.
4. There is also a dearth of research into the factors associated with the
prescription of psychotropic medications in patients with endometrial cancer.
Antidepressants are often already initiated three months prior to diagnosis of
a cancer in Australia (see Section 1.1.4.3). It is essential to explore whether
any other factors (such sociodemographic or clinical) are associated with
prescription of psychotropic medications.
2.4.2. Psychological treatment received by patients with endometrial cancer
A literature search was conducted to determine the psychological treatments
delivered to patients with endometrial cancer who had anxiety and/or depression.
The keywords used to search the existing literature were ‘cancer’, ‘anxiety’,
‘depression’, ‘endometrial’, ‘psychological’ and ‘treatment’. PubMed and PsycINFO
were the databases used. No study was found on patients with endometrial cancer.
The searches were then conducted using the broader search term ‘gynaecological
cancer’.
Very few studies (n = 3) aimed to determine whether patients with gynaecological
cancer received psychological treatments [43,55,56]. Among them, Kimmel et al.
(2014) conducted a cross‐sectional study in the US, using the Patient Health
Questionnaire 9 to determine anxiety and depression in patients with gynaecological
64
cancer (45 of the 187 participants included in this study had uterine cancer) [55]. The
study found that of women who screened positive (≥ 10 cut‐off, n = 22), only one‐
third had met with a psychiatrist. However, it was not possible to determine how
many patients with endometrial cancer received psychological treatment. Mattsson
et al. (2018) identified that around half of patients with gynaecological cancer in
Sweden (47%, n = 160/337) sought support for cancer‐related distress, including
speaking with a counsellor (61%, n = 61/160), psychologist or psychotherapist (41%,
n = 61/160) [56]. However, this study was based on self‐reported cancer‐related
prevalence of anxiety (53%, n = 153/337) and depressive symptoms (51%,
n = 141/337), and no screening tool or definitive clinical interview was used to
determine anxiety or depression. Moreover, only a small number of patients (7%,
n = 24/337) with endometrial cancer were included in this study. A study conducted
in the US by Cassedy et al. (2018) used the HADS to screen for anxiety or depression.
In this study, over half of the patients with gynaecological cancer were diagnosed
with anxiety, depression or both (51%, n = 48/94), yet less than one‐fifth of patients
(19%, n = 18/94) received psychological treatment. Only a small number of patients
included in this study were diagnosed with endometrial cancer (n = 11/94) [43].
Knowledge gaps in psychological treatment pattern
1. The search results clearly identified a lack of research on psychological
treatment benefit and symptoms in women with endometrial cancer and
anxiety and depression.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 65
2. Similar to knowledge gaps listed in Section 2.4.1.1, there is also an absence of
data on optimal psychological treatment, starting time of counselling or other
treatment, provider details and so on.
3. According to clinical practice guidelines for the treatment of anxiety and
depression in cancer, psychological treatment should be the first‐line
approach for mild‐to‐moderate anxiety and depression (see Section 1.1.5.3)
[45]. Several literature reviews and meta‐analyses also showed moderate
effectiveness of psychological interventions on anxiety and depression in
patients with cancer [57–60]. However, it is unknown whether such
guidelines are being followed or raised with distressed women with
endometrial cancer.
4. The 5 years’ survivorship of endometrial cancer is 85%. It is important to
explore the type of psychological and pharmacological treatment for anxiety
and/or depression, or support from family, friends or others for psychological
well‐being received during survivorship.
2.5. Conclusions
Based on the reported scoping reviews and the lack of research on psychological and
pharmacological treatment of anxiety and depression in women with endometrial
cancer, a systematic review and meta‐analysis was required to determine the
effectiveness of psychological treatment in women with cancer. Due to limited
research on women with endometrial cancer, this review and meta‐analysis included
people with all types of cancer. Anxiety is often the earliest symptoms of
66
psychological distress and when existential threat is greatest (see Section 1.1.2).
Diagnosis and treatment of this initial symptom of anxiety may reduce progression
of psychological conditions. Therefore, we narrowed the review reported in the
following Chapter 3 to focus on anxiety in patients with cancer to better understand
the benefit of psychological interventions.
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Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 75
Psychological interventions on
anxiety in cancer patients
3.1. A systematic review and meta‐analyses—are psychological interventions
effective on anxiety in cancer patients?
The previous chapter reviewed and found a lack of published data on psychological
treatment of anxiety and depression in women with cancer (see Section 2.4.2.1). The
systematic review reported in this chapter (Study 1, see Figure 3.1) was developed in
collaboration with the national Psycho‐Oncology Collaborative Research Group
(PoCoG).
Figure 3.1: PhD project structure: Chapter 3—Psychological interventions on
anxiety in cancer patients
76
The collaboration aimed to increase the understanding of anxiety and depression in
patients with cancer. This systematic review and meta‐analysis focussed on anxiety
in patients with cancer contributing to PoCoG’s anxiety working group. It aimed to
determine the effectiveness of psychological interventions on anxiety in patients
with cancer. This research expanded on a review and meta‐analysis conducted by
Sheard et al. in 1999. This review included a large number of research articles and
analysed aspects of anxiety only, including the overall effectiveness of psychological
interventions on anxiety, then conducted subgroup analyses, aiming to understand
factors contributing to effectiveness. This chapter has been published in a peer‐
reviewed journal, and the accepted version of the published article is provided.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 77
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78
Are psychological interventions effective on anxiety in cancer patients? A
systematic review and meta‐analyses
Author Names: Saira Sanjida1, Steven M. McPhail1,2, Joanne Shaw3, Jeremy
Couper4,5, David Kissane6, Melanie A. Price3, Monika Janda1,7*
Authors' information:
1School of Public Health and Social Work, Institute for Health and Biomedical
Innovation, Queensland University of Technology, Brisbane, Australia.
2Centre for Functioning and Health Research, Metro South Health, Brisbane,
Australia.
3Psycho‐oncology Co‐operative Research Group, School of Psychology, The
University of Sydney, Sydney, Australia.
4Mental Health, Justice Health, Alcohol and Drug Services, Canberra, Australia.
5Academic Unit of Psychiatry & Addiction Medicine, Australian National University
Medical School, The Canberra Hospital, Canberra, Australia
6Department of Psychiatry, Monash University, Melbourne, Australia.
7Centre for Health Services Research, The University of Queensland, Brisbane,
Australia
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 79
3.2. Abstract
Objective
The aim of this meta‐analysis was to estimate the overall effect size (ES) of
psychological interventions on anxiety in patients with cancer; and extract sample
and intervention characteristics that influence effectiveness.
Methods
PubMed, Scopus, PsycINFO, Embase, Medline and CINAHL were searched using
Medical Subject Heading keywords‐ ‘cancer’ AND ‘anxiety’ AND ‘psychological
intervention’ AND ‘counselling’ AND ‘psycho*’ AND ‘psychotherapy’ AND
‘psychosocial’ AND ‘therapy’ between January 1993‐ June 2017.
Results
Seventy‐one studies were eligible for the systematic review; among them 51 studies
were included in the meta‐analysis calculations. The overall ES was –0.21 (95%
confidence interval; –0.30 to –0.13) in favour the intervention. From sub‐group
analyses, studies conducted in Asia; enrolling inpatients; focussing on relaxation; of
<6‐week intervention duration; <30‐minute intervention dose per session; and <4‐
hour of total time of intervention showed moderate ESs ranging from –0.40 to –0.55.
Only two studies restricted enrolment to pre‐screened patients with clinically
elevated level of anxiety and showed moderate ES of –0.58.
Conclusions
Low psychological distress at baseline and non‐evidence based interventions were
the main factors identified for low effectiveness. Screening and assessment to
80
determine clinical levels of anxiety in patients with cancer should be considered in
future trials as an inclusion criterion before providing psychological interventions.
Systematic review registration: PROSPERO: International prospective register of
systematic reviews: CRD42017056132
3.3. Background
People face many challenges to their psychological wellbeing after a diagnosis of
cancer [1]. Despite this, many people with cancer cope well themselves without
further support, while the coping capacity of some may be overwhelmed requiring
supportive care and treatment [2,3]. Anxiety is a common psychological problem in
patients with cancer, often an early sign of distress originating from being
overwhelmed by the diagnosis, diagnostic tests, treatments or side effects [4–8].
Common symptoms of anxiety are excessive worry, restlessness, and insomnia [9].
Phobia, generalized anxiety disorders, panic, fear of recurrence, post‐traumatic
stress disorder and obsessive–compulsive disorders are all considered part of anxiety
disorders [7,10,11]. Taken together, anxiety disorders are highly prevalent among
cancer patients. Kuhnt et al. (2016) reported a 12‐month and lifetime prevalence of
any anxiety disorder of 15.8% and 24.1%, respectively [12]. This was higher than the
four‐week prevalence (11.5%) reported earlier from the same cohort [13].
Psychological interventions can reduce anxiety in patients with cancer and provide
benefits for both psychological and physical health outcomes such as improved
quality of life [14–16], health behaviour [17,18] and emotional function [14,16,18],
and decreased insomnia [16] and cancer treatment side‐effects [15,19,20] e.g.
fatigue, pain, nausea, vomiting. Evidence for their effectiveness was summarised in
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 81
one early meta‐analysis by Sheard and Maguire (1999) which found that they had a
moderate effect compared to standard care control (number of study, n = 19, sample
size, N = 1023, ES: 0.42; 95% CI: 0.08 to 0.74) [21]. The ES was larger when the analysis
was restricted to interventions providing group psycho‐education (n = 3, ES = 1.59),
of at least 8+ hours duration (n = 4, ES = 1.01), or when patients were only included
after fulfilling predetermined criteria for significant distress (n = 3, ES = 0.85). The
overall ES estimated was lower when two extreme outliers were removed (n = 17, ES
= 0.27) [14]. Later, Faller et al (2013) showed similar benefit of psychologic
interventions in alleviating anxiety (n = 74, ES: 0.38, 95% CI: 0.29 to 0.46) and the ES
was increased for psychotherapy interventions delivered to screen‐selected patients
(n = 8, ES: 0.56) [22]. Two meta‐analyses conducted in China reported large ESs (ES:
>0.8) in reducing symptoms of anxiety, however, these studies may not be
representative of the patient experience elsewhere [23,24]. Other meta‐analyses
focused on differences in effectiveness according to cancer stage, type or
intervention methods (psychoeducation, psychosocial, behavioural) and reported
widely ranging ESs [25–32]. Previous analyses did not apply strict inclusion criteria
which may have contributed to the large differences in ESs. It is therefore important
to consider the real benefits of psychological interventions for anxiety in patients
diagnosed with cancer; and patient and intervention treatment characteristics
associated with better success to guide future psychological interventions.
This study aimed to determine from randomised controlled trials the overall ES of
psychological interventions to improve anxiety in patients with cancer. Sub group
analyses were used to estimate sample or intervention characteristics associated
82
with greater effectiveness. Lastly, we assessed whether or not treatment for anxiety
was beneficial for patients with clinical level of anxiety. We considered for inclusion
studies published after January 1993, since Sheard and Maguire’s review (1999)
already summarised reports before that time [21].
3.4. Methods
3.4.1. Search strategy
This systematic literature review followed the Preferred Reporting Items for
Systematic Reviews and Meta‐Analyses (PRISMA) methods [33]. Six databases
(PubMed, Scopus, PsycINFO, Embase, Medline and CINAHL) were searched by SS and
MJ to identify studies testing interventions for anxiety in patients with cancer. The
Medical Subject Heading (MeSH) terms used were ‘cancer’ AND ‘anxiety’ AND
‘psychological intervention’ AND ‘counselling’ AND ‘psycho*’ AND ‘psychotherapy’
AND ‘psychosocial’ AND ‘therapy’. Searches were limited for publication dates
between January 1993 (to exclude those studies already reviewed by Sheard and
Maguire) to June 2017. In addition to using MeSH Heading searches as detailed
above, any reports that cited Sheard and Maguire’s (1999) study as well as the
bibliographical references of retrieved articles, reviews, meta‐analyses were
screened manually and assessed whether they contained the relevant keywords for
inclusion [21]. The protocol was registered with PROSPERO (CRD42017056132) [34].
The search strategy is presented in Figure 3.5.1.
3.4.2. Study inclusion and exclusion criteria
3.4.2.1. Participants
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 83
Studies were eligible for inclusion if they enrolled patients 18 years or older
diagnosed with any type or stage of cancer; delivered a psychological intervention to
ameliorate anxiety; focused on cancer patients. Studies that aimed to provide
interventions to other participants besides cancer patients such as family members,
friends, caregivers or couples were excluded.
3.4.2.1. Interventions
Stand‐alone or combination interventions were eligible for inclusion: individual or
group counselling described using terms such as psychological or psycho‐social
treatment, relaxation, cognitive behavioural therapy (CBT), psycho‐education,
psychotherapy, counselling or any supportive therapy aimed to improve
psychological or emotional distress or mood specifically mentioning anxiety.
Interventions that solely focused on mindfulness, imagery, visualisation or
meditation were excluded. There were no restrictions as to who provided the
intervention (e.g. oncologist, psychologist, psychiatrist, general practitioner, social
worker, nurse, volunteer or other), mode of intervention (e.g. face‐to‐face,
telephone, online or other), length of intervention or length of follow‐up.
3.4.2.3. Comparator
The presence of a control group that either received a minimal or alternative
intervention, usual care or wait‐list was another main inclusion criterion of this
review. Single group pre‐post comparisons were excluded.
3.4.2.4. Outcome
84
Eligible outcomes were the effects of psychological interventions on anxiety or
emotional or psychological distress. Anxiety or distress could be determined by any
standardised screening or diagnostic measure but to be included the studies needed
to provide a separate score for anxiety outcomes. Studies that only present
composite results of anxiety and depression or overall distress where anxiety
symptoms could not be separated were excluded. Studies that used psychological
interventions with the aim of reducing physical symptoms, prolonging survival, or
impacting on biomarkers rather than ameliorating anxiety were also excluded.
3.4.3. Study design
Random allocation of treatment was another main criterion of this systematic
review. Studies published in English were included. Studies with a sample size of less
than 40 participants were excluded to reduce the potential influence of publication
bias and inflated ES common in small studies [21,35]. Non‐full text sources such as
abstracts, editorial materials, letters, case reports, unpublished materials or
unpublished theses were excluded.
3.4.4. Study selection
All articles were retrieved by one reviewer (SS) using electronic and manual searches.
After removing duplicate articles, titles and abstracts were screened for fulfilling the
study inclusion and exclusion criteria (SS). All potential full‐text articles were
retrieved and evaluated against the eligibility criteria. Two reviewers (SS, MJ) then
independently assessed the eligibility of full text articles to be included in the
qualitative and quantitative synthesis. Any disagreements were resolved by
discussion.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 85
3.4.5. Data extraction
Data were extracted from the final included studies following the pre‐determined
criteria of this systematic review [34]. Initially five studies were used as a pilot set to
formulate the final data extraction criteria. The following major characteristics were
extracted: study characteristics, patient characteristics, eligibility criteria of
participants in the study, intervention characteristics and main outcomes measures.
This included total sample size, average age (range), gender, type and stage of
cancer, eligibility criteria, type and method of intervention received by control and
intervention groups, delivery mode (group or single), provider type, total
intervention time, follow‐up, types of screening tools to measure anxiety, and
outcomes. Outcomes of anxiety (increased, no change or reduced) were determined
from the change in mean score before and after the intervention period for
quantitative analysis. If the mean score was unavailable in the study, outcomes were
determined from mean differences, reductions in proportion diagnosed with anxiety
from baseline to post‐intervention from graphical presentations. e.g. box‐and‐
whisker or line plots.
3.4.6. Data synthesis
For the quantitative analysis, post‐intervention average mean and standard
deviation values of anxiety determined by screening tools were extracted. If standard
error or confidence intervals were reported, these were converted to standard
deviation using the formula provided in the Cochrane Handbook of Systematic
Review using RevMan 5.3 [36]. Median values were used as means in the meta‐
86
analysis [37]. If studies used more than one screening tool to measure anxiety, data
from the tool most commonly used across the reviewed studies were extracted.
3.4.7. Meta‐analysis modelling
Random effect modelling was used to calculate the overall and subgroup ESs using
RevMan 5.3 as a standardised mean difference (SMD) (Cohen’s d) [36,37]. The
interpretation of the ES was <0.2 (small), 0.21 to 0.5 (medium) and >0.8 (large) (two‐
tailed p value of <0.05) [38]. Heterogeneity was denoted by Q and I2 values which
were categorised into low (25%), moderate (50%) or high (75%) [37]. Forest plots
were used to display the number of participants, mean and standard deviation
anxiety score values for intervention and control groups after completion of the
intervention phase, and weight in %, which indicated the influence of the study on
the overall pooled ES. Sub‐group analyses were conducted to determine which
sample or intervention characteristics influenced the ES. Sensitivity analyses were
conducted by excluding the studies with the highest ES observed for the intervention
and control groups, respectively, and in addition by excluding the study with the
smallest sample size at post‐intervention.
3.4.8. Risk of bias
RoB analysis was conducted by two reviewers independently (MJ and SS). The RoB
2.0 tool to assess RoB in randomised trial was used [39]. Five domains were assessed‐
1. Bias arising from the randomisation process including allocation of random
sequence and concealment until recruitment, baseline imbalances of sample group
size;
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 87
2. Bias due to deviations from intended interventions including awareness of
assigned intervention by participants, carers or trial personnel and approach of
‘intention‐to‐treat’ analysis;
3. Bias due to missing outcome data including not using analysis of ‘intention‐to‐
treat’ for all data or excluding missing data;
4. Bias in measurement of the outcome including whether outcome assessors were
blinded to treatment allocation; and
5. Bias in selection of the reported result including whether it followed the protocol
or statistical analysis plan.
For each domain, the RoB was categorised into– ‘yes’, ‘probably yes’, ‘no’, ‘probably
no’ or ‘no information’. Based on the summary score, each individual domain was
then denoted as ‘low risk’, ‘some concerns’ or ‘high risk’. Summarising across
domains resulted in an overall rating of low risk (across all domains), some concerns
(in at least one domain) or high risk (high risk in least one domain). Ratings of each
study by the two reviewers were compared and any disagreement was resolved by
discussion.
3.5. Results
3.5.1. Study selection
Study screening and extraction outcomes are presented in Figure 1. Overall, 1,539
studies were retrieved from electronic (n = 1,203) and other sources (n = 336). Of
these, 177 studies were considered in full‐text after excluding duplicates (n = 344)
and studies not matching inclusion criteria (n = 1,021), and 71 studies were selected
88
for the systematic review. The main reasons for exclusion of studies at full‐text stage
were not reporting anxiety outcomes (n = 40), non‐randomized studies or no control
group (n = 16), no psychological intervention (n = 14), or small (N = <40) sample size
(n = 8).
Figure 3.5.1: PRISMA flow diagram of systematic review and meta‐analysis
3.5.2. Characteristics of included studies
Characteristics of each study are presented in Table 3.5.2 [5,14–20,40–102]. More
than half of the included studies (n = 38/71) were published after 2010. The majority
of studies were conducted in Europe (n = 29/71) or North America (n = 19/71). A total
of 13,098 patients with cancer were enrolled in the clinical trials with a median of
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 89
155 per study (minimum, N = 40 and maximum, N = 803). Around three‐quarters of
participants were female (N = 9,773/13,098). The mean age of participants was 55
years. The majority of the studies (n = 55/71) included patients newly diagnosed with
cancer (n = 19/71) or undergoing active treatment (n = 36/71). Only three studies
included patients with <6‐month life expectancy. More than half of the studies (n =
39/71) provided interventions for female patients diagnosed with breast (n = 36/39)
or gynaecological cancer (n = 3/39). Only two studies (n = 2/71) delivered
interventions to male patients diagnosed with prostate or testicular cancer, the
remaining 29 studies included mixed gender samples.
Table 3.5.2: Study sample characteristics, intervention methods and outcome tools
Sample size Average age (range) Gender
Cancer type Cancer stage
Inclusion criteria of cancer
Type Group/Single intervention
Providers Intervention dose and timeline (T) Follow‐up (F)
Screening tool Outcomes of anxiety
Andersen et al 2004 (USA)
‐N = 227 ‐50.82 (20‐85) ‐Female
‐Breast ‐II/III
Surgically treated, awaiting adjuvant therapy
‐Psychosocial ‐Group (N=8‐12)
Clinical Psychologist
T: 1.5‐hour session/ week, 4‐month (18 session) F: No
‐POMS ‐Reduced
Antoni et al 2006 (USA)
‐N = 199 ‐50.20 ‐Female
‐Breast ‐0‐III
Surgery within past 8 weeks
‐Cognitive behaviour stress management ‐Group (N=8)
Clinical psychologist
T: 2 hr/week for 10‐week F: 3‐month, 6‐month, 1 year
‐HRA ‐Reduced
Arakawa et al 1997 (Japan)
‐N = 60 ‐57(22‐74) ‐Both
‐Mixed ‐
Chemotherapy patient
‐ PMR ‐Group
Psychologist
T: Cancer treatment period F: No
‐STAI ‐Reduced
Arving et al 2007 (Sweden)
‐N = 179 ‐55.2(23‐87) ‐Female
‐Breast ‐I‐IV
About to start adjuvant therapy
‐Psychosocial ‐Single
Psychologist, Clinical oncology nurse
T: 45‐60 min/session. 16 sessions for one group and 23 sessions for another group F: No
‐HADS, STAI ‐Reduced
Beatty et al 2010 (Australia)
‐N = 49 ‐55.2(32‐86) ‐Female
‐Breast ‐0‐II
After cancer diagnosis
‐Self‐help workbook ‐Single
‐ T: 15 min/week for 3‐month F: 6‐month
‐DASS ‐Increased
Bjorneklett et al 2012 (Sweden)
‐N = 382 ‐61.5(30‐84)
‐Breast ‐
First year after
‐Psychosocial support
Oncologist, social worker, art
T: 7 days ‐HADS ‐Reduced
90
‐Female
diagnosis/ Newly diagnosed
‐Group therapist, massage therapist, dietician, person trained in Qi‐gong and mental visualisation
F: 2‐month, 6‐month, 1‐year
Boesen et al 2011 (Denmark)
‐N = 186 ‐(30‐70) ‐Female
‐Breast ‐I‐IIIA
1‐2 weeks after surgery
‐Existential cognitive therapy ‐Group (N = 8)
Breast cancer specialist, nurse, psychologist, or social worker, dietician
T: 2 weekly 6‐hr session, 8 weekly 2‐hr session F: 6‐month, 12‐month
‐POMS ‐Reduced
Braamse et al 2016 (Netherland)
‐N = 95 ‐54.4 ‐Both
‐Haematological ‐
Life expectations >3 months
‐Stepped care intervention ‐Single
Psychiatrist, nurse
T: 2‐hr per module for 6‐week F: 13‐week, 30‐week, 42‐week
‐STAI, HADS ‐No change
Bredal et al 2014 (Norway)
‐N = 367 ‐54.7(18‐70) ‐Female
‐Breast ‐Early
Undergone for surgery
‐Psychoeducation ‐Group (N = 4‐10)
Nurse
T: 8 weeks F: 2‐month, 6‐month, 12‐month
‐HADS ‐Reduced
Breitbart et al 2010 (USA)
‐N = 90 ‐60.1(27‐91) ‐Both
‐Mixed ‐III/IV
Advanced cancer/solid tumor
‐Meaning‐centered psychotherapy ‐Group (N = 8‐10)
Psychiatrist, clinical psychologist, Social worker
T: 3‐hr for 8‐week F: 2‐month after treatment
‐HADS ‐No change
Breitbart et al 2015 (USA)
‐N = 253 ‐58.2(27‐91) ‐Both
‐Mixed ‐III/IV
Advanced/ terminal
‐Meaning‐centered psychotherapy ‐Group (N = 8‐10)
Psychiatrist, clinical psychologist, Social worker
T: 8‐week F: 2‐month after treatment
‐HADS ‐Reduced
Burton et al 1995 (UK)
‐N = 244 ‐62.3(28‐37) ‐Female
‐Breast ‐I‐IV
Before surgery
‐Psychotherapy ‐Single
Clinical psychologist, Surgeon
T: 45‐60min/session for 4 days F: 3 months, 1 year after surgery
‐HADS ‐Reduced
Chan et al 2005 (Hong Kong)
‐N = 155 ‐44.7(18‐70) ‐Female
‐Mixed (Gynaecological) ‐I‐IV
Newly diagnosed
‐Psychotherapy ‐Single
Clinical psychologist
Timeline: 3 months Follow‐up: Every 3 months for 18 months
‐BAC ‐Increased
Chan et al 2011 (Hong Kong)
‐N = 140 ‐ ‐Both
‐Lung ‐III/IV
During radiotherapy
‐Psycho‐education ‐Group
Registered nurse
T: 40 min/day for 12 weeks F: No
‐STAI ‐Reduced
Chan et al 2016 (Singapore)
‐N = 72 ‐53 ‐Female
‐Breast ‐I‐III
Completed chemotherapy
‐Psycho‐education ‐Group
Neuropsychologist, dietician, social worker, nurse, breast cancer survivor psychotherapist
T: 4.5‐hr/week for 3 weeks F: 2‐month
‐BAI ‐Reduced
Charalambous et al 2015 (Cyprus)
‐N = 208 ‐(31‐>60) ‐Both
‐Breast, prostate ‐0‐III
Receiving chemotherapy
‐PMR ‐Single
Research assistant
T: 27‐min for 4 weeks F: No
‐SAS ‐Reduced
Chen et al 2015 (Taiwan)
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 91
‐N = 65 ‐50.77 ‐Female
‐Breast ‐
Received chemotherapy
‐Relaxation, guided imagery ‐Single
‐ T: 1‐day training, 20‐minute for 7‐day F: No
‐HADS ‐Reduced
Cheung et al 2003 (USA)
‐N = 59 ‐56.4 ‐Both
‐Colorectal ‐
Life after stoma surgery
‐PMR ‐Group
Nurse
T: 2‐3 times/ week for 10‐week F: No
‐STAI ‐Reduced
Chochinov et al 2011 (USA, Australia, Canada)
‐N = 326 ‐65 ‐Both
‐Mixed ‐
Terminally ill (<6 months)
‐Psychotherapy ‐Group
Psychologist, psychiatrist or experienced palliative care nurse
T: 6‐8 weeks F: No
‐HADS ‐Increased
Classen et al 2001 (USA)
‐N = 125 ‐53.4(33‐80) ‐Female
‐Breast ‐
Time from initial diagnosis to first metastasis/ recurrence
‐Supportive expressive therapy ‐Group (N = 3‐10)
Psychiatrist, psychologists, and social workers
T: 90‐min for 1 year F: 1 year
‐POMS ‐No change
Classen et al 2008 (USA)
‐N = 357 ‐49.7 ‐Female
‐Breast I‐IIIA
Primary, one year of diagnosis
‐Supportive expressive therapy ‐Group (N = 10)
Nurse, Social Worker, Psychologist
T: 90‐min for 12‐week F: 2‐year
‐HADS ‐No change
Dieng et al 2016 (Australia)
‐N = 151 ‐58.5 ‐Both
‐Melanoma ‐0‐II
Previously diagnosed melanoma
‐Psycho‐education ‐Single
Psychologist
T: 4 weeks F: I years
‐DASS ‐Reduced
Dirksen & Epstein‐2007 (USA)
‐N = 81 ‐58 (29‐86) ‐Female
‐Breast ‐I‐III
3‐month post completion of cancer treatment
‐CBT ‐Single
Nurse
T: 1‐2 hr for 10‐week F: No
‐STAI ‐Reduced
Dolbeault et al 2009 (France)
‐N = 203 ‐53 ‐Female
‐Breast ‐
Early stage ‐Psycho‐educational ‐Group (N = 8‐10)
Psychiatrist, Psychologist
T: 2‐hour for 8‐week F: No
‐STAI, POMS ‐Reduced
Edelman et al 1999 (Australia)
‐N = 124 ‐50(29‐65) ‐Female
‐Breast ‐
During therapy
‐CBT ‐Group
Psychologist
T: 2‐hr for 8‐week F: 3‐month, 6‐month
‐POMS ‐Reduced
Edmonds et al 1999 (Canada)
‐N = 66 ‐50.7 ‐Female
‐Breast ‐
Newly diagnosed
‐Psychotherapy ‐Group (N=8)
Psychologist, Social worker
T: 2‐hour for 35‐week, 12‐week, 14‐hour for first 2‐4 month F: 4‐month, 8‐month, 14‐month
‐MAC ‐Increased
Fukui et al 2000 (Japan)
‐N = 50 ‐53 ‐Female
‐Breast ‐I‐III
Primary surgery within 4‐18 month
‐Psychosocial ‐Group (N = 6‐10)
Psychologist, Psychiatrist
T: 1.5 hour for 6‐week F: 6‐month
‐HADS, POMS ‐Reduced
Garssen et al 2013 (Netherland)
‐N = 70 ‐53 ‐Female
‐Breast ‐I‐III
Pre‐surgical ‐Stress management training ‐Single
Clinical psychologist
T: 5‐days and 1‐day pre‐surgery and on 2‐day and 1‐month post‐surgery
‐STAI ‐Reduced
92
F: 3‐month
Gaston‐ Johansson et al 2000 (USA)
‐N = 110 ‐(22‐ >51) ‐Female
‐Breast ‐II‐IV
Undergoing autologous bone marrow transplant
‐Coping strategy program ‐Single
Clinical social worker
T: 7 days F: No
‐STAI ‐Reduced
Geerse et al 2017 (Netherlands)
‐N = 223 ‐61.45 ‐Both
‐Lung ‐Ib‐IV
Starting therapy
‐Psychosocial ‐Single
Psychosocial Nurse
T: 25‐week F: No
‐HADS ‐Reduced
Goerling et al 2011 (Germany)
‐N = 131 ‐57.2(18‐79) ‐Both
‐Mixed ‐
Malignant tumor, surgical treatment
‐Psychological ‐Single
Psychologist
T: Follow‐up: 12 months
‐HADS ‐Reduced
Goodwin et al 2001 (Ireland)
‐N = 355 ‐50.2 ‐Female
‐Breast ‐
Prolonged survival, metastatic, <3‐month survival
‐Supportive expressive therapy ‐Group (N = 8‐12)
Psychiatrist, psychologist, social worker, nurse, clinicians
T: 90 min/week F: 1‐year
‐POMS ‐Reduced
Greer et al 2012 (USA)
‐N = 40 ‐55.9(31‐81) ‐Both
‐Mixed ‐
Terminal cancer, 4‐week after cancer diagnosis
‐CBT ‐Single
Clinical psychologist
T: 6 therapies for 8‐week F: No
‐HADS ‐Reduced
Groarke et al 2013 (Ireland)
‐N = 355 ‐53.7 ‐Female
‐Breast ‐All
First diagnosis of cancer, undergone for surgery
‐Cognitive behavioural stress management‐relaxation ‐Group (N = 8‐10)
Clinical Psychologist, oncology nurse
T: 3‐hour for 5‐week F: 12‐month
‐HADS ‐Reduced
Guo et al 2013 (China)
‐N = 178 ‐(20‐79) ‐Both
‐Mixed ‐All
Undergone for radiotherapy
‐Psychosocial ‐Group (N = 5‐8)
Clinician, nurse, radiation therapist
T: 8‐12 therapies F:>2 years
‐SAS ‐Reduced
Heiney et al 2003 (USA)
‐N = 66 ‐50.4(31‐65) ‐Female
‐Breast ‐I‐II
Diagnosed within the past 6 months
‐Psychosocial ‐Group (N = 8‐15)
Experienced group therapists
T: 90‐min/week for 6‐session F: 3‐month
‐POMS ‐Reduced
Ho et al 2016 (Hong Kong)
‐N = 157 ‐47.7(18‐65) ‐Female
‐Breast ‐I‐III
Completed treatment
‐Supportive expressive therapy, body‐mind‐spirit ‐Group (N=8‐12)
Psychologist, social worker
T: 2‐hr/week for 8‐week F: 4‐month, 8‐month, 1‐year.
‐HADS ‐Increased
Høybye et al 2010 (Denmark)
‐N = 803 ‐ ‐Both
‐Any ‐
Cancer survivor
‐Psychosocial ‐Group
Multi‐disciplinary professional team
T: 13‐month F: 1, 6, 12‐month
‐POMS ‐Reduced
Johansson et al 2008 (Sweden)
‐N = 481 ‐63.95 ‐Both
‐Breast, prostate gastrointestinal
Newly diagnosed (<3‐month)
‐CBT ‐Both
Psychologist, oncology nurse, dietician, general practitioner, physiotherapist
T: 3‐month F: 3, 6, 12, 24‐month
‐HADS ‐Reduced
Kissane et al 2003 (Australia)
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 93
‐N = 303 ‐46.3(36‐65) ‐Female
‐Breast ‐I‐II
Early stage ‐Relaxation ‐Group (N=6‐8)
Psychologist, psychiatrist, social worker, occupational therapist, oncology nurse
T: Maximum 50‐90 min for 20‐week F: 12‐month
‐HADS Reduced
Krebber et al 2016 (Netherlands)
‐N = 156 ‐62.25 ‐Both
‐Mixed ‐I‐IV
Treated with curative intent at least 1 month earlier
‐Stepped care intervention ‐Single
Psychologist, nurse, psychiatrist, social worker
T: 10‐15minute for 10‐week, 45‐60‐minute for 6‐week F: 3‐month, 6‐month, 9‐month, 12‐‐month
‐HADS ‐Reduced
Leo´n‐Pizarro et al 2010 (Spain)
‐N = 66 ‐53.8(24‐83) ‐Female
‐Mixed ‐I‐IV
Before brachytherapy
‐Psychological Relaxation, imagery ‐Single
Nurse
T: 1/2‐week prior to hospitalisation to 2‐3 weeks after intervention F: No
‐HADS ‐Reduced
Livingston‐2010 (Australia)
‐N = 571 ‐64 ‐Male
‐Mixed ‐I‐III
Newly diagnosed
‐Counselling ‐Single
Oncology nurse
T: 6‐month F: 12‐month
‐HADS ‐Reduced
McArdle et al 1996 (UK)
‐N = 272 ‐56.75 ‐Female
‐Breast ‐
Undergoing for surgery
‐Psychological ‐Group
Specialist breast care nurse, voluntary organisation
T: 20‐30 min F: 3‐month, 6‐month, 12‐month
‐HADS ‐Reduced
Merckaert et al 2016 (Belgium)
‐N = 170 ‐50.6(30‐81) ‐Female
‐Breast ‐I‐III
Surgically treated, approached during radiotherapy
‐ CBT & hypnosis ‐Group (6)
Psychologist
Timeline: 6‐month Follow‐up: No
‐HADS ‐Reduced
Moorey et al 1998 (UK)
‐N = 57 ‐51(18‐74) ‐Both
‐Mixed ‐
‐ ‐Adjuvant Psychological Therapy ‐Single
Psychiatrist
T: 8‐week F: 4‐month, 1‐year
‐HADS ‐Reduced
Moorey et al 2009 (UK)
‐N = 80 ‐63.65 ‐Both
‐Mixed ‐
Palliative care with advanced cancer
‐CBT ‐Single
Nurse
T: 16‐week F: No
‐HADS ‐Reduced
Moynihan et al 1998 (UK)
‐N = 73 ‐(18‐65) ‐Male
‐Testicle ‐
Agreed to treatment plan
‐CBT ‐Single
Mental health nurse
T: 8‐week F: 12‐month
‐HADS ‐Reduced
Owen et al 2017 (USA)
‐N = 347 ‐53.1 ‐Both
‐Mixed ‐
‐ ‐Psychological ‐Single
Clinical psychology student
T: 12‐week F: No
‐IES‐R ‐Reduced
Pelekasis et al 2016 (Greece)
‐N = 61 ‐55.9 ‐Female
‐Breast ‐I‐IV
Undergoing chemotherapy
‐Psychological ‐Single
‐Psychologist, health visitor
T: 8‐week F: No
‐DASS ‐Reduced
Periasamy et al 2017 (Malaysia)
‐N = 162 ‐65.49 ‐Both
‐Any ‐I‐IV
Undergoing chemotherapy
‐Counselling ‐Single
Pharmacist
T: 3‐5‐month F: 3‐6‐week interval for three times
‐GAD ‐Reduced
94
Petersen & Quinlivan‐2002 (Australia)
‐N = 53 ‐62 ‐Female
‐Mixed ‐I‐IV
Newly diagnosed, postoperative
‐Counselling and relaxation ‐Single
Doctor
T: One hour within 24‐hour operation for 6‐week F: No
‐HADS ‐Reduced
Rissanen et al 2015 (Sweden)
‐N = 155 ‐57.5 ‐Female
‐Breast ‐I‐III
Newly diagnosed, adjuvant treatment
‐CBT ‐Both
Nurse
T: 3 Months F: 12‐month
‐HADS ‐Reduced
Ross et al 2005 (Denmark)
‐N = 249 ‐68.4 ‐Both
‐Mixed ‐I‐IV
Treated with abdominal surgery in primary cancer
‐Psychological ‐Single
Nurse, doctor
T: 1 hr/10 home visit each for 2‐3 months F: 3‐month, 6‐month, 12‐month, 24‐month
‐HADS ‐No change
Sandgren & McCaul 2003 (USA)
‐N = 222 ‐54.5(30‐84) ‐Female
‐Breast ‐I‐III
1‐3 months after diagnosis
‐Telephone therapy ‐Single
Oncology nurse, Psychologist
T: 30‐min for 5‐week F: 3‐month
‐POMS ‐Reduced
Savard et al 2005 (Canada)
‐N = 57 ‐54.1 ‐Female
‐Breast ‐I‐III
1 month prior to chemotherapy
‐CBT ‐Group (N=4‐6)
Psychologist
T: 90 min for 8‐week F: 3‐month, 6‐month, 12‐month
‐HADS ‐Reduced
Schofield et al 2016 (Australia)
‐N = 331 ‐67.4 ‐Male
‐Prostate ‐
Commenced radiotherapy
‐Psychological ‐Group
Nurse
T: 1‐hr for 4‐session for 13 weeks F: 6‐month
‐HADS ‐Reduced
Simpson et al 2001 (Canada)
‐N = 89 ‐49.5 ‐Female
‐Breast ‐0‐II
Primary ‐Psychotherapy ‐Group (N = 7‐10)
Psychiatrist
T: 90‐min for 6‐week F: 2‐year
‐MAC ‐Reduced
Trask et al 2003 (USA)
‐N = 48 ‐53.6(22‐92) ‐Both
‐Mixed ‐0‐III
Stage IV melanoma
‐CBT ‐Group
‐Psychotherapist Timeline: 50‐min for 4‐week Follow‐up: 6‐month
‐STAI ‐Reduced
van der Spek et al 2017 (Netherlands)
‐N = 170 ‐57.1 ‐Both
‐Mixed ‐
5‐year of diagnosis
‐Meaning‐centered psychotherapy ‐Group (N = 7‐10)
‐ T: 2‐hour for 8‐week F: 3‐month, 6‐month
‐HADS ‐Reduced
Walker et al 1999 (UK)
‐N = 111 ‐49.7 ‐Female
‐Breast ‐
Newly diagnosed, Primary chemotherapy
‐Relaxation training & guided imagery ‐Group
Psychologist
T: 5 training for 18‐week F: No
‐HADS ‐Reduced
Watson et al 2017 (UK)
‐N = 118 ‐50.45(18‐79) ‐Both
‐Any ‐
Post diagnosis
‐CBT ‐Single
Psychologist
T: 8 sessions for 12‐week F: No
‐HADS ‐Reduced
Wenzel et al 2015 (USA)
‐N = 204 ‐44.5 ‐Female
‐Cervices ‐I‐IVA
≥9 and less than 30 months from diagnosis
‐Psychosocial telephone counselling ‐Single
‐ T: 20‐60 min for 5 week F: 9‐month
‐BSI ‐Reduced
White et al 2012 (Australia)
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 95
‐N = 647 ‐64.5 ‐Both
‐Colorectal ‐I‐IIIB
<3 months of cancer diagnosis
‐Psychological ‐Single
Volunteer
T: 3‐week F: 3‐month
‐HADS ‐Reduced
Willems et al 2016 (Netherlands)
‐N = 409 ‐56.27 ‐Both
‐Mixed ‐All
Completed cancer treatment
‐Psychosocial ‐Single
‐ T: 9‐month F: 3‐month, 6‐month, 9‐month
‐HADS ‐Reduced
Winzelberg et al 2002 (USA)
‐N = 72 ‐49.5(30‐69) ‐Female
‐Breast ‐
32‐month of diagnosis
‐Supportive expressive therapy ‐Group (N = 10‐15)
Mental health professionals
T: 3‐month F: No
‐STAI ‐Increased
Wu et al 2016 (China)
‐N = 60 ‐51.6(18‐70) ‐Both
‐Thyroid ‐
Undergoing for thyroid treatment
‐Psychological ‐Single
Nurse
T: Before treatment F: 1 year after treatment
‐SAS ‐Reduced
Ye et al 2016 (China)
‐N = 204 ‐(18‐60) ‐Female
‐Breast ‐0‐II
On active treatment
‐Psycho‐education ‐Group (N = 3‐5)
Psychologist, Nurse, Oncologist, dietitians, physicians, physical therapist, breast cancer survivors
T: 3hr/17 session for 12 months F: 2‐month, 6‐month and 12‐month
‐HADS ‐Reduced
Yekta et al 2017 (Iran)
‐N = 90 ‐(30‐50) ‐Female
‐Breast ‐
Mastectomy ‐Relaxation ‐Single
‐ T: 20‐minute twice, three times before surgery
‐CSAQ ‐Reduced
Yoo‐2005 (South Korea)
‐N = 60 ‐4.35 ‐Female
‐Breast ‐II‐III
During chemotherapy
‐ Relaxation training & guided imagery ‐Single
Therapist T: 3 days F: 6‐month
‐MAACL Reduced
Yorke‐2015 (UK)
‐N = 101 ‐67.7 ‐Both
‐Lung ‐
Received radiotherapy to the chest or chemotherapy
‐ Psycho‐educational counselling ‐Group
Specialist nurses, physiotherapists, therapists
T: 1‐hour for 4‐week F: 12‐week
‐HADS ‐Reduced
N‐ Sample size, POMS‐ Profile of Mood States, HRA‐ Hamilton rating scale, STAI‐ State‐Trait Anxiety Inventory,
DASS‐ Depression Anxiety Stress Scales, HADS‐ Hospital Anxiety and Depression Scale, BAC‐ Beck Anxiety
Inventory, SAS‐ Smith Anxiety Scale, BSI‐ Brief Symptom Inventory, SAS‐ Self‐rating anxiety score, MAC‐ Mental
Adjustment to Cancer Scale, PMR‐ Progressive muscle relaxation, IES‐R‐ Impact of Events Scale‐Revised, MAACL‐
Multiple Affect Adjective Checklist, GAD‐ Generalized anxiety disorder, CSAQ‐ Cognitive‐somatic trait anxiety,
UK‐ United Kingdom, USA‐ United States of America, CBT‐ Cognitive behavioural therapy, PMR‐ Progressive
muscle relaxation
Cognitive behavioural therapy (CBT) (n = 14/71), relaxation (n = 12/71) and
psychosocial therapy (n = 9/71) were the most commonly delivered interventions.
Thirteen studies delivered supportive care interventions. Only three studies
delivered stepped‐care interventions. Interventions were delivered in group (n =
35/71) or individual settings (n = 34/71) using face‐to‐face, telephone, online, self‐
96
delivery or combination delivery modes. Most common delivery was by psychologists
(n = 33/71), nurses (n = 23/71), psychiatrists (n = 11/71), or social workers (n = 11/71),
by one (n = 31/71) or multiple (n = 27/71) providers. Involvement of pharmacists (n
= 2/71) was common in recently conducted studies to provide education about side
effects of chemotherapeutic agents to the patients. Besides health care
professionals, trained cancer survivors were involved in 2/71 studies in the delivery
of psycho‐educational interventions. The duration of the interventions ranged widely
from just 4 days to 1 year. Fifty studies monitored patients at fixed time intervals,
with a minimal follow‐up of 3‐month to more than 2 years, while the remaining the
studies reported immediate post intervention outcomes.
Different outcome assessment tools were used to measure anxiety, most commonly
the Hospital Anxiety and Depression Scale (HADS) (n = 38/71), State‐Trait Anxiety
Inventory (n = 10/71), or Profile of Mood States (n = 8/71). Overall, 87% (n = 61/71)
studies reported a reduction in anxiety scores from baseline to after the intervention.
The remaining studies showed either no change (n = 2/71) or an increase (n = 7/71)
in mean anxiety scores.
3.5.3. Overall effect size
Of the 71 studies, 51 studies (N = 8,283) were included in the meta‐analysis. The
remaining studies (n = 20) were excluded due to reporting insufficient details on
anxiety outcomes (Figure 3.5.1). The proportion of participants lost to post‐
intervention was 10.5% and the final sample size included in the meta‐analysis was
7,491.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 97
The overall ES for reduction in anxiety was small (–0.21; 95%CI; –0.30 to –0.13)
(Figure 3.5.3). The meta‐analysis showed moderate heterogeneity among the studies
(Q = 155.16, P< 0.00001; I² = 68%). Only five studies showed a large ES ranging
between –0.80 to –1.43, while seven studies reported medium ESs ranging between
–0.53 to –0.75. Factors which characterised studies with moderate to large ES were
recruiting patients with high level of anxiety symptoms [19,67], intervention method
well‐matched to patients’ needs [41], recruiting patients who were undergoing highly
stressful cancer treatments [14,16,76], and specifically targeting anxiety treatments
[18,60,64,76,85,101].
98
Figure 3.5.3: Forest plot of the effects of psychological interventions on anxiety in
cancer patients (negative values favour the intervention— representing greater
reduction in anxiety).
For sensitivity analyses, studies with the highest ES favouring the intervention (ES: –
1.43) [64] or control groups (ES: 0.47) [70] were excluded, but this resulted in minimal
(ES of –0.19 and ES of –0.22, respectively) change in overall ES. After excluding the
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 99
two studies with the smallest sample size at post‐intervention, the overall ES
remained unchanged [43,92].
3.5.4. Subgroup analyses
Sub‐group analyses are presented in Table 3.5.4. Studies conducted in Asia (n = 11;
ES: –0.46), those including patients with mixed types of cancer (n = 16; ES: –0.30) and
intervening on inpatients (n = 20; ES: –0.40) showed higher than average ES. A
moderate ES (n = 2; ES: –0.58) was also identified in two studies which screened
participants for anxiety before including them into the study [67,72].
Sub‐group analysis stratified by intervention characteristics showed that studies that
provided relaxation training (n = 12; ES: –0.53), individual delivery (n = 24; ES: –0.32),
face‐to‐face with self‐delivery mode (n = 7; ES: –0.35), or deliver by multiple
providers (psychologist and psychiatrist, n = 2; ES: –0.40) resulted in higher ESs.
Interventions of short duration (1‐7 days, n = 7; ES: –0.55 and <6 weeks, n = 7; ES: –
0.48) showed moderate ES. Higher ESs were identified for interventions that were
provided at lower dose per session (<30 minutes, n = 8; ES: –0.42 & 30‐60 minutes; n
= 14; ES: –0.35). Short programs with smaller number of session (<4 hours, n = 12;
ES: –0.44 and 1‐3 sessions, n = 9; ES: –0.43) had higher ESs more intense or long
programs.
Table 3.5.4: Sub‐group analysis (Negative values represent greater reduction in
anxiety symptoms)†
100
Number of studies
Effect size [95% CI]
Heterogeneity (I2) (%)
Overall effect size 51 –0.21 [–0.30, –0.13] 68
Sample characteristics
1. Origin of participants Asia 11 –0.46 [–0.65, –0.26] 58 Europe 21 –0.25 [–0.38, –0.11] 75 Australia 6 –0.10 [–0.23, 0.03] 0 North America 12 –0.02 [–0.16, 0.12] 34 International 1 0.1 [–0.13, 0.32] –
2. Gender Male and female 20 –0.25 [–0.40, –0.10] 76 Female only 30 –0.19 [–0.31, –0.08] 62 Male only 1 –0.13 [–0.34, 0.09] –
3. Type of cancer Mixed1 16 –0.30 [–0.48, –0.13] 80 Melanoma 2 –0.22 [–0.51, 0.06] 0 Breast 28 –0.17 [–0.29, –0.06] 63 Other2 3 –0.15 [–0.50, 0.21] 65 Lung 2 –0.12 [–0.37, 0.13] 0
4. Inclusion criteria to participate in the study Inpatient treatment 20 –0.40[–0.57, –0.23] 78 After treatment 10 –0.19 [–0.31, –0.06] 28 Any cancer patients 6 –0.07 [–0.21, 0.06] 0 Newly diagnosed 11 –0.06 [–0.21, 0.09] 47 Palliative treatment 3 0.04 [–0.17, 0.24] 21 Advanced stage 1 0.16 [–0.19, 0.51] –
5. Screening to measure anxiety and other Measure anxiety and depression using HADS3
2 –0.58 [–1.01, –0.15] 63
Provider reported distress without using screening tool
2 –0.40 [–1.26, 0.46] 91
No/Not reported 41 –0.21 [–0.30, –0.12] 63 Patient self–reported distress 1 –0.09 [–0.41, 0.22] – Measure anxiety symptom– insomnia using DSM III3
2 –0.05 [–0.78, 0.68] 78
Measure psychiatric disorder using DSM III4
2 –0.00 [–0.21, 0.20] 0
Measure distress using distress thermometer3
1 0.08 [–0.13–0.29] –
Intervention characteristics
1. Type of intervention Relaxation 12 –0.53 [–0.79, –0.26] 78 Counselling & other 2 –0.25 [–0.65, 0.14] 43 Psychological 6 –0.24 [–0.51, 0.03] 77 Psychosocial 6 –0.20 [–0.50, 0.10] 78
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 101
Psycho–education 5 –0.18 [–0.36, –0.01] 42 Supportive expressive therapy 4 –0.16 [–0.35, 0.03] 0 Stepped care 3 –0.08 [–0.40, 0.25] 61 Cognitive behavioural therapy 9 –0.08 [–0.20, 0.05] 14 Psychotherapy 4 0.07 [–0.09, 0.23] 0
2. Group/individual Individual 24 –0.32 [–0.47, –0.18] 75 Group 25 –0.13 [–0.24, –0.03] 58 Both 2 –0.07 [–0.25, 0.11] 0
3. Delivery mode Face–to–face & self–delivery 7 –0.35 [–0.61, –0.08] 73 Face–to–face 25 –0.27 [–0.40, –0.14] 71 Face–to–face & telephone 9 –0.21 [–0.41, –0.00] 65 Face–to–face & online 2 –0.11 [–0.67, 0.46] 79 Online 3 –0.00 [–0.14, 0.13] 0 Telephone 4 0.05 [–0.17, 0.28] 29 Individual 1 0.07 [–0.52, 0.65] –
4. Change of anxiety score No change 1 –0.30 [–0.72, 0.11] – Reduced 45 –0.24 [–0.33, –0.14] 70 Increased 5 0.04 [–0.12, 0.20] 0
5. Follow–up No 17 –0.24 [–0.40, –0.09] 68 Yes 34 –0.20 [–0.30, –0.09] 68
6. Type of provider Not reported 7 –0.41 [–0.68, –0.14] 62 Psychologist & psychiatrist 2 –0.40 [–0.78, –0.02] 37 Other5 5 –0.33 [–0.66, –0.01] 76 Only psychologist 11 –0.24 [–0.50, 0.01] 80 Psychologist & nurse 3 –0.21 [–0.45, 0.04] 52 Only nurse 8 –0.20 [–0.34, –0.06] 29 Group6 10 –0.10 [–0.28, 0.08] 73 Psychologist & social worker 2 –0.01 [–0.28, 0.26] 0 Dual professional7 3 0.03 [–0.26, 0.31] 41
7. Duration 1–7 days 7 –0.55 [–0.75, –0.35] 16 Less than 6 weeks 7 –0.48 [–0.82, –0.15] 83 Not reported 2 –0.34 [–1.25, 0.57] 93 6–11 weeks 16 –0.13 [–0.29, 0.03] 69 More than 12 weeks 19 –0.08 [–0.15, –0.01] 0
8 Dose/session Less than 30 min 8 –0.42 [–0.75, –0.09] 81 30–60 min 14 –0.35 [–0.53, –0.17] 70 Not reported 10 –0.10 [–0.23, 0.03] 28 More than 60 min 19 –0.10 [–0.22, 0.02] 60
9. Number of sessions
102
1–3 9 –0.43 [–0.69, –0.16] 76 Not reported 6 –0.21 [–0.51, 0.09] 71 More than 8 15 –0.18 [–0.33, –0.03] 69 4–8 21 –0.17 [–0.30, –0.04] 64
10. Total hours Less than 4 hours 12 –0.44 [–0.64, –0.25] 55 4–7 hours 7 –0.26 [–0.56, 0.05] 84 More than 8 hours 20 –0.15 [–0.28, –0.02] 70 Not reported 12 –0.10 [–0.21, 0.02] 25
11. Experience of provider Not reported 7 –0.41 [–0.68, –0.14] 62 Not specified8 24 –0.29 [–0.42, –0.16] 70 Yes 19 –0.08 [–0.21, 0.04] 63 No 1 0.06 [–0.39, 0.51] –
12. Training of provider No 4 –0.28 [–0.65, 0.08] 62 Not reported 25 –0.23 [–0.36, –0.09] 66 Yes 22 –0.19 [–0.32, –0.07] 73
13. Manual used in intervention No 1 –0.82 [–1.22, –0.41] – Other9 13 –0.31 [–0.53, –0.09] 72 Not reported 13 –0.28 [–0.48, –0.09] 73 Yes 24 –0.12 [–0.22, –0.02] 55
14. Control condition Standard care 30 –0.28 [–0.41, –0.16] 74 Minimal/Alternate intervention10
15 –0.12 [–0.24, 0.00] 40
Waitlist 6 –0.08 [–0.30, 0.14] 62 †Sample and intervention characteristics were presented according to the highest negative effect size for intervention favour to the highest positive effect size of control favour. CI– Confidence Interval, DSM– Diagnostic and Statistical Manual of Mental Disorders, HADS– Hospital Anxiety and Depression Scale. 1Included two or more different types of cancer. 2Included prostate, thyroid and blood cancer. 3Formally screened patients for the presence of anxiety and anxiety symptoms using standard tools 4Did not screen for anxiety, but assessed anxiety using structured clinical interview as a part of baseline data collection procedure. 5Included doctor, therapist, research assistant, psychotherapist, pharmacist individually. 6Included three or more health care professionals. 7Included nurse and volunteer, psychiatrist and nurse, psychologist and health visitor. 8Not informed the experience of provider. 9Written instruction, workbook, booklet, leaflet, handouts, reading materials or audiotape. 10Minimal or alternate intervention means that the patients in the control group received only a component of the full intervention or received a different intervention (for example exercise) from the intervention group.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 103
3.5.5. Is treatment for anxiety more beneficial for patients with clinical level of
anxiety?
Nine studies used formal screening for presence of anxiety or distress symptoms
more broadly as part of the enrolment procedures (see Table 3.5.5). Only one pilot
study used a minimal cut–off score specifically for anxiety (Hamilton Anxiety Rating
Scale, HAM–A; ≥14 score) as a formal inclusion criterion. This study delivered CBT, an
appropriate evidence–based treatment for anxiety symptoms, and showed a large ES
of 0.80 [15].
Five other studies (n = 5/9) (see Table 3.5.5) screened participants using the overall
HADS score (such as ≥8, ≥11, ≥12 and ≥14), but not specifically their anxiety score
[67,75,79,80,97]. Among them Moorey et al (1998 and 2009) delivered CBT for
patients with HADS scores ≥8 [79,80]. Two studies used psychological interventions
for elevated level of anxiety and/or depression (HADS score, ≥11) [67,97]. Only one
study (n = 1/9) delivered a stepped–care treatment following clinical practice
guidelines to patients with head, neck and lung cancer and diagnosed with anxiety
and/or depression symptoms (HADS–A > 7, or HADS–total > 14) and resulted in an ES
of –0.38 [79]. In two studies (n = 2/9), the structured clinical interview (Diagnostic
and Statistical Manual of Mental Disorders, DSM III) was used to determine
evidence–based anxiety symptoms (insomnia) in patients with cancer before
delivering CBT, but not as an inclusion criterion [59,89]. Owen et al (2017) delivered
online psychological interventions to patients diagnosed with distress determined by
the distress thermometer (minimum score of 4 to 10) [82].
104
Table 3.5.5: Anxiety screening, assessment tools, intervention type and dose
delivered in patients with cancer
Screening Variables Tool Study Intervention
type Intervention
dose Effect size†
Studies that formally screened patients for presence of anxiety using standard tool
Screening (n = 9)
Anxiety HAM–A Greer et al 2012
[64] CBT
6 therapies for 8–week
††
Anxiety & depression
HADS, CIDI Krebber et al 2016 [72]
SCI
10–15–minutes for 10–week, 45–60 min for 6–week
–0.38
HADS
Goerling et al 2011 [62]
Psychological – –0.82
White et al 2012 [95]
Psychological 3–week †††
Moorey et al 1998 [77]
Psychological therapy
8–week †††
Moorey et al 2009 [78]
CBT 16–week †††
Anxiety symptoms– insomnia
DSM–III
Dirksen & Epstein 2007 [54]
CBT 1–2 hour for 10–week
–0.41
Savard eta al 2005 [87]
CBT 90–minute for 8–week
0.34
Distress Distress
thermometer Owen et al 2017
[80] Psychological 12–week 0.08
Studies that screened for distress according to patient and provider report
Patient self–
reported (n = 2)
Anxiety symptoms
(Cough/fatigue/ breathlessness)
Yes, No
Yorke et al 2015 [102]
Psycho–education, counselling
12–week †††
Psychological complaint, e.g.
anxiety
van der Spek et al 2017 [91]
Psychotherapy 2–hour for 8–week
–0.09
Provider reported (n = 2)
Anxiety & depression
Charalambous et al 2015 [47]
PMR 27–minute for 4–week
–0.82
Psychological needs
Watson et al 2017 [93]
CBT 8–session
for 12–week 0.06
Studies that did not screened for anxiety, but assessed anxiety disorder using structured clinical interview as a part of baseline data collection procedure after enrolling patients into the study
Structured interview (n = 4)
Anxiety disorder DSM–III
Burton et al 1995 [43]
Psychotherapy 45–60–
minute for 3–week
†††
Kissane et al 2003 [71]
Relaxation 50–90–
minute for 20–week
0.03
Walker et al 1999 [92]
Relaxation 18–week –0.10
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 105
Simpson et al 2001 [89]
Psychotherapy 90–minute foe 6–week
†††
CIDI– Composite international diagnostic interview, HADS– Hospital Anxiety and Depression Scale, DSM– Diagnostic and Statistical Manual of Mental Disorders, HAM–A– Hamilton Anxiety Rating Scale, CBT– Cognitive behavioural therapy, SCI– Stepped care intervention †ES originated from forest plot (Figure 3.5.3). ††Greer et al, (2012) study showed large effect size for intervention (ES: 0.84). †††Did not include in the meta–analysis.
Four studies screened for distress using patient or provider self–report. Patients who
self–reported respiratory distress symptoms (breathlessness, cough, or fatigue) or
psychological complaint (such as anxiety) were included in two studies [93,102].
Another two studies considered provider–reported anxiety and depression as well as
psychological needs as reliable sources of sample inclusion criteria and delivered
progressive muscle relaxation and CBT, respectively (n = 2, ES: –0.40) (see Table
3.5.4) [19,95]. However, these four studies did not use a standard screening tool to
determine anxiety symptoms.
None of the studies used a diagnostic interview to determine anxiety disorder before
sample enrolment. Four studies assessed clinical anxiety disorder using structured
interview such as DSM III as part of the baseline data collection procedure after
enrolling patients into the study [50,74,91,94], but patients with or without anxiety
disorder were included in these interventions.
3.5.6. RoB assessment
Overall, around one–third of the trials (n = 22/71) were judged to have high RoB on
at least one criterion (see Table 3.5.6). The remaining trials (n = 49/71) presented
only some concerns. The highest RoB was identified in the randomization process (n
= 17/71), with concealment of allocation sequence often not reported. Most studies
had low risk of selective reporting of result (n = 68/71), or missing outcome data (n =
106
63/71). Most clinical trials were not blinded for intervention or outcome
measurement. A high proportion of trials therefore scored high due to awareness of
assigned intervention by participants as well trial personnel (n = 66/71) and outcome
assessors (n = 64/71).
Table 3.5.6: Risk of bias
Study
Bias Domain
Overall risk of bias
Bias arising from the
randomization process
Bias due to deviations
from intended
interventions
Bias due to missing outcome data
Bias in measurement of the outcome
Bias in selection of the reported
result
Andersen–2004
Some concerns
Some concerns
Low risk Low risk Low risk Some
concerns
Antoni–2006 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Arakawa–1997 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Arving–2007 Low risk Some
concerns Low risk
Some concerns
Low risk Some
concerns
Beatty–2010 Low risk High risk Low risk Some
concerns Low risk High risk
Bjorneklett– 2012
Some concerns
Some concerns
High risk Some
concerns Low risk High risk
Boesen–2011 Low risk Some
concerns Low risk
Some concerns
Low risk Some
concerns
Braamse–2016 Low risk Some
concerns Low risk Low risk Low risk
Some concerns
Bredal–2014 Low risk Some
concerns Low risk
Some concerns
Low risk Some
concerns
Breitbart–2010 High risk High risk Some
concerns Some
concerns Low risk High risk
Breitbart–2015 High risk Some
concerns Low risk
Some concerns
Low risk High risk
Burton–1995 Low risk Some
concerns Low risk
Some concerns
Low risk Some
concerns
Chan–2005 Low risk Some
concerns Some
concerns Some
concerns Low risk
Some concerns
Chan–2011 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Chan–2016 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Charalambous–2015
High risk Some
concerns Low risk Low risk Low risk High risk
Chen–2015 High risk Some
concerns Low risk
Some concerns
Low risk High risk
Cheung–2003 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Chochinov–2011
Some concerns
Some concerns
Low risk Some
concerns High risk High risk
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 107
Classen–2001 High risk Some
concerns Low risk
Some concerns
Low risk High risk
Classen–2008 Some
concerns Some
concerns High risk
Some concerns
Low risk High risk
Dieng–2016 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Dirksen & Epstein–2007
Some concerns
Some concerns
High risk Some
concerns Low risk High risk
Dolbeault–2009
Some concerns
Some concerns
Low risk Some
concerns Low risk
Some concerns
Edelman–1999 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Edmonds–1999
High risk Some
concerns High risk
Some concerns
Low risk High risk
Fukui–2000 Some
concerns Some
concerns Some
concerns Some
concerns Low risk
Some concerns
Garssen–2013 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Gaston– Johansson–
2000 High risk
Some concerns
Some concerns
Some concerns
High risk High risk
Geerse–2017 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Goerling–2011 Some
concerns Some
concerns Some
concerns Some
concerns Low risk
Some concerns
Goodwin–2001 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Greer–2012 Some
concerns Some
concerns Low risk Low risk Low risk
Some concerns
Groarke–2013 Low risk Low risk Low risk Some
concerns Low risk
Some concerns
Guo–2013 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Heiney–2003 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Ho–2016 Low risk Some
concerns Low risk
Some concerns
Low risk Some
concerns
Høybye–2010 Low risk Some
concerns Low risk
Some concerns
Low risk Some
concerns
Johansson–2008
Some concerns
Some concerns
Low risk Some
concerns Low risk
Some concerns
Kissane–2003 High risk Some
concerns Low risk
Some concerns
Low risk High risk
Krebber–2016 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Leo´n–Pizarro–2010
Some concerns
Some concerns
Low risk Some
concerns Low risk
Some concerns
Livingston–2010
High risk Some
concerns Low risk
Some concerns
Low risk High risk
McArdle–1996 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Merckaert–2016
High risk Some
concerns Low risk
Some concerns
Low risk High risk
Moorey–1998 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Moorey–2009† High risk, Low risk
Some concerns
Low risk Some
concerns Low risk High risk
108
Moynihan–1998
Some concerns
Some concerns
Low risk Low risk Low risk Some
concerns
Owen–2017 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Pelekasis–2016 Low risk Some
concerns Low risk
Some concerns
Low risk Some
concerns
Periasamy–2017
High risk Some
concerns Low risk Low risk Low risk High risk
Petersen & Quinlivan–
2002
Some concerns
Some concerns
Low risk Some
concerns Low risk
Some concerns
Rissanen–2015 Low risk Low risk Low risk Some
concerns Low risk
Some concerns
Ross–2005 Low risk Some
concerns Low risk
Some concerns
Low risk Some
concerns
Sandgren & McCaul–2003
High risk Some
concerns Low risk
Some concerns
High risk High risk
Savard–2005 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Schofield–2016†
Some concerns, Low risk
Some concerns
Low risk Some
concerns Low risk
Some concerns
Simpson–2001 Low risk Some
concerns Low risk
Some concerns
Low risk Some
concerns
Trask–2003 Low risk Some
concerns Low risk
Some concerns
Low risk Some
concerns
Van der Spek–2017
High risk Some
concerns Low risk Low risk Low risk High risk
Walker–1999 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Watson–2017 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Wenzel–2015 High risk Some
concerns Low risk
Some concerns
Low risk High risk
White–2012 High risk Some
concerns Low risk
Some concerns
Low risk High risk
Willems–2016 High risk Some
concerns Low risk
Some concerns
Low risk High risk
Winzelberg–2002
Some concerns
Some concerns
Low risk Some
concerns Low risk
Some concerns
Wu–2016 Some
concerns High risk Low risk
Some concerns
Low risk High risk
Ye–2016 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Yekta–2017 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns
Yoo–2005 Low risk Some
concerns Low risk
Some concerns
Low risk Some
concerns
Yorke–2015 Some
concerns Some
concerns Low risk
Some concerns
Low risk Some
concerns †Followed cluster randomised controlled trial
3.5.7. Publication bias
Publication bias was assessed using a funnel plot of standard error against
standardised mean difference generated by RevMan 5.3. The funnel plot (Figure
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 109
3.5.7) showed asymmetry, making it likely that publication bias was present in the
studies included in the meta–analysis.
Figure 3.5.7: Funnel plot assessment of publication bias in the studies on
effectiveness of psychological intervention of anxiety in patients with cancer
3.6. Discussion
3.6.1. Overall effectiveness of psychological interventions
This large review and meta–analysis systematically identified the sample and
intervention characteristics associated with effective psychological interventions to
improve anxiety in patients with cancer. Overall the interventions achieved only a
low ES of –0.21 (95%CI; –0.30 to –0.13), lower compared to previously conducted
meta–analyses [21–25,27,31,32]. In contrast to these previous reports, our study
applied much stricter inclusion criteria only extracting data from large and high
quality studies. Our study further closely examined moderators of effectiveness.
110
Lack of distress or anxiety already at baseline was one common reason identified by
study authors for low effectiveness of psychological interventions
[46,48,49,51,53,55,57]. Inclusion of an unscreened sample was another reason
[42,51,58]. These issues have been raised previously with recommendations that
evidence–based care should only be offered to patients for whom intervening in
clinically indicated [7,21,22,27,32,103]. A review of 14 meta–analyses looking at
distress reduction more broadly, not specifically for anxiety, showed that the
treatment benefit of psychological interventions was three times higher when
screening was done compared to no screening [104]. Despite this, the majority of the
clinical trials in this review included patients based on their status as a cancer patient
receiving treatment, having symptoms from their cancer treatment or for the
prevention of distress. In a recent study, Braamse et al (2013) reported that patients
(18.7%, N = 9/48) who dropped out of interventions did so stating that they felt they
can cope well themselves [46].
Furthermore, studies reported that many patients from both intervention and
control groups [42] or only control groups [56,69], already received routine mental
health support, psychological treatment [45,81,93] or psychotropic medications
[45,50,59,67,80]. In some instances, patients even received both psychological and
pharmacological treatment before being enrolled in the intervention studies. For
example, 25% [15] and 10.3% [46] of patients received support from a mental health
professional and antidepressants, making it difficult to disentangle any independent
intervention benefit. In an another study, the proportion of participants taking
antidepressants increased over time – from 29% at the baseline to 37% at 10 weeks
of psychological intervention [80]. In that context, several studies deliberately
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 111
excluded patients with severe distress (HADS score ≥20 followed by DSM IV
interview) [63], high anxiety [78], past depression [58], regular psychotropic
medication prescription [19,83,89], mood disorder, psychiatric disorder or major
depressive disorder [18,40,60,68,83,90], or psychiatric comorbidity diagnosed by
psychiatrist [66], limiting the findings of many studies to patients with mild distress.
Besides receiving active off–trial treatment, control group participants may show
improvements in their anxiety due to the Hawthorne effect. This was observed in the
study of Dolbeault et al (2009) which used a wait–list control group design [60] as
well in a study by Cheung et al (2003) who provided a minimal intervention to the
control group [14]. Randomisation may be a factor associated with non–uptake of
potentially eligible patients [95]. Patients who have an expressed need to receive
psychological interventions may decline to participate in a study where they may be
assigned to a no–intervention control group [81,95].
Our subgroup analyses aimed to determine factors associated with low ES and found
that patients assigned to group interventions, certain intervention methods, patients
diagnosed with breast cancer or female patients, newly diagnosed patients, and
intervention characteristics including high duration, large dose of intervention per
session, number of session and total hours seemed to result in less benefit than
others. One reason for why low dose interventions may have been more effective
was that such interventions were commonly provided to inpatients or in crisis
response settings. For example, Arakawas et al (1997) study provided relaxation
training within 3–4 sessions which resulted in large ES and reduced anxiety symptoms
during chemotherapy [41].
112
Previous studies found that group therapy has similarly effective compared to
individual therapy and more cost–effective [21]. It is therefore not surprising that
more than half of the studies reviewed used group setting, although many of these
were designed to provide psychological support and not primarily to treat anxiety.
However, the ES of group interventions was much smaller (n = 25, ES: –0.13) than
that of individual interventions (n = 24, ES: –0.32). Given the infectious nature of
anxiety, an individual treatment mode may be most desirable for anxiety disorders.
Observing that others become unwell or die, feeling uncomfortable in presence of
others, and less flexible scheduling were previously identified as other possible
barriers to group therapy [49,60–62,74,76,86,87]. For example, in the Breitbart et al
(2015) study, around one–third of the sample (N = 81/253) never participated in the
group intervention due to scheduling conflicts or deteriorating health (N = 35/81
each) [49]. In a study by Edmonds et al (1999), patients felt, ‘the group setting too
anxiety provoking’ [62], while some ‘dislike group therapy’ or ‘did not want to meet
other sick women with a poorer prognosis’ [44,59].
According to international clinical practice guidelines from the United States of
America, Australia and Canada for the management of anxiety in patients with
cancer, the type and severity of anxiety should be determined before providing
psychological or pharmacological treatment [105–107]. The Australian Clinical
Pathway recommends a stepped care model whereby patients should receive the
minimum level of psychological treatment that is effective in treating their anxiety,
and more intensive psychological treatment in combination with pharmacological
treatment should be reserved for patients with severe anxiety [106]. Recently, three
studies specifically trialled stepped care treatments [46,75,86]. However, the
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 113
treatment was ineffective for anxiety in two studies. Braamsee et al (2016) attributed
this to low intervention uptake or low psychological distress at baseline (prevalence
of elevated anxiety symptoms at baseline was only 6.5%) [46]. Rissanen et al (2015)
mentioned that the intensity of the initial step intervention (stress management
education) may have been too low or too similar to easily accessible online
information [86]. Moreover, both studies did not screen patients for anxiety or
distress. The stepped care approach was genuinely conducted by Krebber et al (2016)
and resulted in moderate amelioration of anxiety symptoms (ES: –0.38) [75].
3.7. Conclusions
3.7.1. Study strengths
This analysis has several strengths including stringent selection of randomised
controlled trials, exclusion of studies with small sample size, and detailed systematic
review evaluation of the bias of each study using the Cochrane Risk of Bias (RoB) 2.0
form. Our study provided evidence for factors associated with low intervention
effects, which should be considered when planning future clinical trials.
3.7.2. Study limitations
Limitations include difficulties to extracting data on anxiety outcomes specifically
which many studies did not report separately from overall distress. This may have
resulted in some potentially relevant studies being excluded from the review.
Second, studies published in non–English languages and unpublished research were
excluded. Third, we excluded interventions focusing on fear of recurrence, pre–
existing conditions or comorbid conditions such as pain [7]. Fourth, we only
estimated the ES using the immediate post–intervention outcomes and did not
114
estimate the ES at different time intervals during follow–up. Therefore, we could not
determine whether the benefit of psychological interventions was sustained or not.
3.7.3. Clinical implications
In conclusion, this review has highlighted that many clinical trials have provided
psychological interventions to patients who presented with minimal level of anxiety
symptoms rather than following evidence–based treatment guidelines or focussing
on patients with clinically elevated anxiety. Although the meta–analyses indicated
that these interventions were effective, the absence of screening in the design of
most trials, alongside a relative paucity of evaluations of stepped–care intervention
models are likely to have contributed to smaller benefits than may have otherwise
been achieved. Given that most health systems operate in the context of constrained
resource environments, future studies should follow appropriate screening and
assignment procedures, and test interventions including stepped–care models that
are likely to be both effective and cost–effective.
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132
Chapter 4: Methods
4.1. Introduction
The previous chapters reviewed and identified a lack of research on the psychological
wellbeing and treatment of women with endometrial cancer with anxiety and/or
depression. Considering the research gaps identified in Chapters 1–3, this PhD
research program used a mixed‐methods approach. Quantitative analyses (Chapters
5 and 6) used secondary data from a large, international, longitudinal clinical trial of
endometrial cancer. Chapter 5 used that data to determine the prescription practice
of psychotropic medications. Chapter 6 used data from the trial to determine the
prevalence of anxiety and depression in women with endometrial cancer. The final
study employed semi‐structured interviews to understand how women maintained
their psychological wellbeing during long‐term survivorship (Chapter 7).
Figure 4.1: PhD project structure: Methods
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 133
Chapter 4 outlines key aspects of the methodology used in this PhD research program
to achieve the aims and objectives stated in Section 1.3 (Figure 4.1). Section 4.2 starts
with a short introduction about the LACE trial, sample recruitment process and data
collected at each of the study visits. Sections 4.3–4.7 describe the sample data
available for the PhD research, data extraction for quantitative and qualitative
interviews, definition of each variable and data analysis methods. Finally, Section 4.8
concludes the chapter with the ethical considerations of this research.
4.2. The Laparoscopic Approach to Cancer of the Endometrium trial
The LACE trial was a long–term, international, longitudinal study that enrolled
patients from 20 tertiary gynaecological oncology centres in Australia, New Zealand,
Scotland and Hong Kong between October 2005–June 2010. This large, randomised
clinical trial assessed disease–free survival at 4.5 years and evaluated the equivalence
of total laparoscopic hysterectomy (TLH) compared with total abdominal
hysterectomy (TAH) for patients diagnosed with endometrial cancer [1,2]. The study
also assessed quality of life, psychological health and lifestyle outcomes following
treatment for endometrial cancer [3].
4.2.1. Sample enrolment
4.2.1.1. Inclusion criteria
Inclusion criteria for the LACE study were: females, aged 18 years or older,
histologically confirmed stage I endometrial cancer and a performance status of
Eastern Cooperative Oncology Group, ECOG (0–1). Patients did not receive any
remuneration to participate in LACE trial.
4.2.1.2. Exclusion criteria
134
The exclusion criteria were histologic types other than endometrioid
adenocarcinoma of the endometrium, clinically advanced disease (stages II–IV),
uterine size larger than 10–week gestation, less than six months estimated life
expectancy, and enlarged aortic lymph nodes. Serious concomitant systemic
disorders incompatible with surgery and fitness to complete quality of life
measurements were also considered.
4.2.2. Study visits
Written consent was obtained before any study specific procedures were
undertaken. The overall visit plan and time–line procedures in the LACE trial is
presented in Figure 4.2.2.
Figure 4.2.2: Flow diagram of participants throughout the LACE trial
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 135
4.2.2.1. Pre–operative (Visit 1)
Patients were screened for eligibility and required to sign an informed consent form
within 28 days before surgery. Demographic data, medical history and concomitant
illnesses were collected in case report forms. All medication records (including
prescription, over‐the‐counter remedies, vaccination, vitamin, or herbal
preparations) used before surgery and within the past 12 weeks were collected. The
HADS and the ECOG were used to assess psychological function and performance
status, respectively, using self–administered questionnaire. Weight (kg) and height
(cm) were also obtained by the study nurse to determine BMI.
4.2.2.2. Surgery
The following procedures were performed at this visit:
• conduct surgery as per randomisation result: TLH or TAH
• record intra–operative and postoperative information (including operation
details, histological findings, intra–operative complications, transfusion details and
any other special conditions around the operation).
4.2.2.3. Postoperative (Visit 2 to 6)
Postoperative data collection was performed at one‐week, four‐week, three‐month
and six‐month visits after surgery (±3 days). HADS data, concomitant medication
records and illness were collected at each visit. Health services data were collected
at visit 6.
4.2.2.4. Follow–up questionnaire and interview (4.5 years)
Long–term endometrial cancer survivors who participated in the LACE trial who were
known to be alive and did not withdraw from the study were contacted for long‐term
136
follow–up once they were at least 4.5 years after surgery. Most patients were
between 5.5 and 10 years after surgery at the time of the follow–up when they
received the self–administered questionnaire. Patients signed the consent form
again to participate in the long‐term follow–up questionnaire and interview. Initially,
patients reported on their health, lifestyle, anxiety and depression, and quality of life
in the self–reported questionnaire. Participants from Queensland were also asked to
participate in semi–structured interviews when they received the long–term follow–
up questionnaire. This interview allowed for an exploration of changes in patients’
lifestyle, medication used and psychological conditions after the treatment of
endometrial cancer and whether these were successful and helpful for their
wellbeing.
4.2.3. Data collection from preoperative to 4.5 years follow–up interview
Multidisciplinary health care professionals including experienced gynaecologist,
behavioural psychologist, nurses, biostatistician, epidemiologist were involved to
develop the questionnaires at baseline and 4.5 years of follow‐up of LACE clinical
trials. Patients and nurses were involved in the data collection from preoperative
stage to the six‐month postoperative period. The details of the data collection by
nurses and others throughout the timeline are presented in Table 4.2.3‐
Table 4.2.3: Details of data collection by nurses and others
Time points Methods of
data collection Variables Who involved
Preoperative to 6 months postoperative
Case report form Clinical characteristics Completed by nurses
Self–administered questionnaire
Sociodemographic, HADS, quality of life, etc.
Completed by patients
Case report form Medical and medication record
Completed by nurses
4.5 years follow–up
Self–administered questionnaire
Lifestyle, HADS, quality of life, etc.
Completed by patients
Interview Lifestyle, medication use, psychological wellbeing,
Interviewed by an experienced psychologist
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 137
support by health care professionals
4.3. Sample data available for inclusion in PhD research program
Overall, 760 women were recruited into the LACE trial at baseline. The number of
participants reduced over time due to loss of follow–up, relocation, death, inability
or unwillingness to return and so on. The number of participants involved in each of
the components of this PhD research program is presented in Figure 4.3.
Figure 4.3: Overall sample data included in each chapter of PhD research program
The data available for each part of this PhD program (see Section 1.3) differ and are
presented below:
1. Chapter 5: For this study, participant data were used if medications, and
sociodemographic and clinical data were available (n = 719).
2. Chapter 6: The availability of HADS data was the main criterion for inclusion
in this study. Only the first 360 women enrolled in the LACE trial were asked
to complete the HADS, after which time the self‐administered questionnaire
LACE trial
(n= 760)
Study 2
(Chapter 5)
(n = 719)
Study 3
(Chapter 6)
(n = 334)
Study 4
(Chapter 7)
(n = 17)
Sample participated in baseline clinical
trial,
n = 760
Availability of sociodemographic,
clinical and medication data
Availability of final sample data
included in study 1,
n = 719
138
was switched to other topics (e.g. pelvic floor wellbeing). Overall, 334 women
had HADS data from baseline to six months’ post–surgery and were eligible
for this analysis.
3. Chapter 7: 259 women participated in 4.5 years of follow–up study and were
eligible to participate in a telephone interview. Overall, 17 patients with long–
term endometrial cancer survivor participated in the interviews. Recruitment
for further interviews was then discontinued as saturation of data (no new
data were found) was achieved. [4].
4.4. Data extraction for quantitative analyses
Different data at different time points were used in the quantitative analysis of
Studies 2–4 according to the aims of study (see Section 1.3). Data extracted from the
pre–operative visit to the 4.5 years follow–up are presented in Table 4.4a.
Demographic data and a complete medical history were collected at visit 1
(preoperative visit). A complete physical examination was conducted at visits 1─5.
Sample participated in baseline clinical trial,
n = 760
360 patients received HADS
questionnaire
Availability of HADS data
Final sample data included in study 2,
n = 334
Sample participated in
4.5 years follow‐up
questionnaire,
n = 259
Patients received further
consent form to participate in interview
Sample participated in interview in Study 3,
n = 17
Extract 17 patients sociodemographic,
clinical & medications data from baseline and 4.5 years follow‐
up
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 139
Table 4.4a: Extraction of data at different time points
Evaluation / Examination
Pre–Operative
Post–operative 4.5–year follow–
up
1 week 4 weeks 3 months 6 months
Visit 1 Visit 2 Visit 3 Visit 4 Visit 5
Informed Consent X X
Inclusion/Exclusion criteria
X
Medical History X
Height, Weight X X X X X X
ECOG PS X X X X X
Endometrial Biopsy / D&C
X
Personal status X
Concomitant illness X X X X X X
Concomitant medications
X X X X X X
Hospital Anxiety and Depression Scale (HADS)
X X X X X X
Patient’s Disease Status
X
Performance status was assessed using ECOG performance score assessed at visits
1─5. Anxiety and depression were assessed using the HADS. For consistency, all
efforts were taken to have the physical examination performed by the same qualified
study staff at screening, follow‐up and final visits. Variables used in each chapter (5–
6) of the PhD research program are presented in Table 4.4b.
Table 4.4b: Variables used in each chapter of the PhD research program
Variables Study 2 (Chapter 5)
Study 3 (Chapter 6)
Study 4 (Chapter 7)
Sociodemographic X X X
Clinical X X X
Antidepressants and anxiolytics
X X X
HADS X X
Qualitative interview data X
140
4.4.1. Medications of interest
Details of anxiolytic and antidepressant medication including medication name,
dose, frequency, unit, start date, and end date of prescription were recorded for each
patient and extracted for each study (Chapters 5─7) to determine the
pharmacological treatment of anxiety and depression in women with endometrial
cancer. Antidepressants (NP6A) and anxiolytics (NO5B) were categorised using the
Anatomical Therapeutic Chemical (ATC) Classification System [5]. The recommended
dose of antidepressant was determined from the defined daily dose in the ATC
Classification System.
4.4.2. Hospital Anxiety and Depression Scale
Overall, 334 sample data were available and mainly used in Chapters 6 and 7 (see
Table 4.4b). Anxiety and depression were determined by the HADS–21 and extracted
at five different time points (see Table 4.4a) [6,7]. It was specifically developed to
measure anxiety and depression in physically ill patients through the omission of
items measuring common physical symptoms, such as fatigue or dizziness. It is a 14‐
item questionnaire in two sub‐scales—anxiety and depression—each consisting of
seven items scored from 0–3, some of which are reverse coded. The total score for
each subscale (0–21) is divided into three parts—normal (0–7), borderline elevated
(8–10) and elevated (11–21) anxiety or depression—according to the guidelines of
Zigmond and Snaith (1983) [7]. HADS data were extracted from pre‐surgery to 6
months post‐surgery and used in Study 3 (see Chapter 6). For Study 4 (see Chapter
7), HADS data were extracted from the 4.5 years follow‐up questionnaire.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 141
4.4.3. Sociodemographic records
The sociodemographic records of cancer participants were collected at the baseline
of the LACE trial only. The following data were extracted to determine the
sociodemographic status of women with endometrial cancer and used in each
chapter (5–7): age (average), education (did not complete school or have no formal
school, completed primary or junior or senior high school, trade or technical
certificate or diploma, university or college degree and other, employment (full time,
part time or casual, home duties, student, unemployed or seeking work, retired,
disabled and other), marital status (married or living together, divorced or separated,
widowed, single or never married, other), private insurance (yes with hospital cover
only, yes with extras cover only, yes with hospital and extras cover, yes with other
and no), income, birth place (Australia, New Zealand, England, Scotland or Ireland or
Wales, Northern Europe [e.g., Norway, Sweden, the Netherlands, Germany],
Southern Europe [e.g., Greece, Italy, Spain], Eastern Europe [e.g., Russia, Poland,
Estonia], Asia, Middle East, other—specify), ethnicity (British/Scottish/Welsh/Irish,
Southern European, Central/Eastern European, Northern/Western European,
Indigenous Australian, North‐East Asian, South Asia, South‐East Asian, Middle
Eastern, Other), weight and height.
4.4.4. Clinical records
Clinical records of participants were collected at each visit and 4.5 years follow‐up.
Chapters 5 and 6 used the clinical records from baseline to six months follow‐up.
Chapter 7 used the both baseline and 4.5 years follow‐up to determine the change
in comorbid conditions. Medical history and the presence of any chronic condition
142
after diagnosis of cancer were extracted. The date of the hysteroscopy diagnostic
test was extracted to use as proxy for the date of endometrial cancer diagnosis.
Surgical stage, history of previous cancer (including type and number), type of
surgery (TAH or TLH), adjuvant treatment (chemotherapy, radiotherapy) were
extracted from visit 1 records. Comorbidities of anxiety and depression data were
extracted from each visit to identify the previous history of patients and new cases.
Visits to a psychiatrist, psychologist or other mental health counsellor in the six
months since surgery were used to identify the psychological treatment received for
anxiety and depression besides anti‐cancer treatment.
4.5. Follow–up (4.5 years)
4.5.1. Qualitative data collection
Seventeen long–term cancer survivors participated in semi–structured telephone
interview to explore their survivorship experiences, lifestyle and psychological status.
A health psychologist with extensive experience supporting cancer patients
interviewed the women in July–December 2017. The mean interview duration was
30 minutes. All interviews were professionally transcribed verbatim. Two researchers
analysed the transcribed data individually and coded them into meaningful themes
and sub–themes. Themes related to psychological well–being were extracted and
used for the qualitative study in Chapter 7.
4.5.2. Other supporting data extracted from baseline and 4.5 years follow–up
Patients’ BMI, comorbid chronic disease and concomitant medication details
(including antidepressants and anxiolytics) were extracted from the baseline and
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 143
follow–up questionnaire. HADS data were extracted to determine anxiety and
depression in patients 4.5 years after an endometrial cancer diagnosis.
4.6. Definition of data collection time points, variables and exposures
Table 4.6 provides definitions of all study measures, including data collection time
point, methods of data collection at different time points, and clinical and
prescription characteristics.
Table 4.6: Definitions of data collection time points, variables and exposures
Variables Definition
Data collection time points
Timeline of study Perioperative to six months post–surgery (October
2005–June 2010)
Perioperative Time between diagnosis of endometrial cancer and
surgery
Post–surgery period Time between the surgery to six months post‐surgery
and follow‐up at four different time points—one‐week,
four weeks, three months and six months
Follow–up 4.5 years of study followed by qualitative interview
Methods of data collection at different time points
Self–administered
questionnaire
Screening tools completed by patients at baseline and
4.5 years follow–up
Case report form Completed by nurse at baseline
Interview Conducted after 4.5 years of follow–up study
Clinical characteristics
Proxy for the date of
endometrial cancer
diagnosis
Date of hysteroscopy diagnostic test
144
Medical history of
comorbid conditions
Presence of comorbidities (such as hypertension,
diabetes, anxiety, depression, etc.) before diagnosis of
endometrial cancer.
New cases of anxiety
and depression
Presence of anxiety, depression after diagnosis of
endometrial cancer and post–surgery period
Clinical level of anxiety
and depression Assessed by patients on HADS questionnaire
Prescription characteristics of psychotropic medication (PM) including
antidepressants (ADs) and anxiolytics (AXs)
Pharmacological
treatment
Prescription psychotropic medications (PM) including
antidepressants and anxiolytics
Overall prevalence of
PM
The number of patients prescribed one or two PMs (ADs
and/or AXs, regularly or as needed) from perioperative
to 6–months post–surgery timeline divided by the
number of patients included in this study
Number of PMs
prescribed
Total number of PMs (ADs and/or AXs) including
changes of medications and one or more ADs and/or
AXs.
Time point of initial
prescription
Starting date of PMs recorded by trial nurse from
patients’ clinical records was considered prescription
date of PMs.
Starting date of PMs was overlapped with date of
diagnosis of endometrial cancer at different time points
to determine the initiation of PMs before diagnosis of
endometrial cancer, peri–operative or post–surgery
Continuation of PMs Presence of end date of PMs in the medication record
was considered to determine whether medications were
ongoing or discontinued during the timeline of study
Reasons for PMs Presence of anxiety and/or depression in the medical
history as well as new cases was matched with
prescriptions of PMs. Data also matched with the case
report form.
Change of PMs dose Change of PMs dose from initial PMs dose to next dose
at any point of timeline of study
Psychological
treatment
Visit to a psychiatrist, psychologist or other mental
health counsellor in the past 6 months since surgery was
considered psychological treatment received beside
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 145
anti–cancer treatment. Data were collected after
surgery at every time point. These patients were
assessed for comorbidity with anxiety and/or
depression; and prescription of PMs.
4.7. Data analysis
The quantitative analyses used secondary data collected between 2005 and 2010, as
long‐term longitudinal data collection continuing to 4.5 years follow‐up would have
been impossible within a three‐year PhD timeline. Therefore, using secondary data
was the best possible method considering the timeline, sample size and availability
of high‐quality data. The best statistical approach was used according to the research
question of each study to inform the aims described in Section 1.3.
4.7.1. Chapter 5: Secondary analysis 1
Research questions 1: What is the prevalence, type, dose, frequency and timing of
psychotropic medications prescribed to patients with endometrial cancer?
Statistical analysis 1: Descriptive statistics including means±standard deviation and
frequency±ranges were used to present the prevalence, type, dose, frequency and
timing of psychotropic medications prescribed to the patients with endometrial
cancer.
Research questions 2: Which sociodemographic and clinical characteristics were
associated with receiving a psychotropic medication prescription?
Statistical analysis 2: Logistic regression models were used to determine the
association of any psychotropic medications (antidepressants and/or anxiolytics) as
the dependent variable with sociodemographic and clinical characteristics. This
146
model is popular in epidemiological research and widely used to determine the
association of different characteristics with dichotomous outcomes [8,9].
4.7.2. Chapter 6: Secondary analysis 2
Research questions 1: What is the prevalence of anxiety and depression in women
with early–stage endometrial cancer and treatments received for elevated anxiety
and depression?
Statistical analysis 1: Descriptive statistics were used to present the prevalence of
anxiety and depression. Bar charts and line graphs were used to express the
prevalence rate and mean value with a 95% CI, respectively. Number and percentage
was used to describe the proportion and type of treatment received for elevated
anxiety and depression.
Research questions 2: Which sociodemographic and clinical characteristics were
associated with anxiety and depression in women with endometrial cancer from
before surgery to six months post–surgery?
Statistical analysis 2: Both logistic and linear regression models were used in this
analysis. Similar to Chapter 5, logistic regression models were used to determine
sociodemographic and clinical characteristics associated with the presence of anxiety
and depression in women with endometrial cancer at each time point cross‐
sectionally. Linear mixed models were used for longitudinal analysis to determine the
association between sociodemographic and clinical characteristics with changes in
the mean value of anxiety and depression over five time points. This model is also
widely used in epidemiological research considering continuous variables at different
time points. Most importantly, this model is a reliable method for when there is
missing data at random [8,10].
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 147
4.7.3. Chapter 7: Qualitative study
Research questions 1: What did women experience their psychological well–being
during survivorship of endometrial cancer?
Research questions 2: What support or treatment women did receive including
psychological or pharmacological treatment for anxiety and depression and was it
helpful for their recovery?
Thematic analysis 1 and 2: This study is aimed to address the research gaps identified
in Chapters 5 and 6. Thematic analysis was used to present the qualitative semi‐
structured interview data of women’s experiences of psychological wellbeing during
long‐term survivorship. Thematic analysis was chosen in this study because it is a
widely used research method to present qualitative datasets in a meaningful way
reflecting the intended message as conveyed by the participants. It is a useful
method for social and psychological interpretation of qualitative data due to its
flexible, rich, detailed and complex characteristics [11]. According to Braun and
Clarke (2006), thematic analysis is, ‘a method for identifying, analysing and reporting
patterns (themes) within data … thematic analysis can be a method that works both
to reflect reality and to unpick or unravel the surface of ‘reality’ (p79, 81). Nowell et
al. (2017) described thematic analysis as ‘the process of conducting a rigorous and
trustworthy thematic analysis has been illustrated in a way that helps those in the
process of interpreting and representing textual data’ [12 p11]. This method is useful
to summarise main codes according to each identified theme and allows for easy‐to‐
express, well‐structured analysis [11,12].
148
4.8. Ethical considerations
This clinical trial was a multi–centre research project and site–specific ethics approval
was obtained from each hospital’s human research and ethics committees (HRECs).
The HREC approved the protocol, informed consent, advertisements to be used for
patient recruitment and other written information regarding this study to be
provided to the patient or the patient’s legal guardian. All HREC approvals were
signed by the HREC chairman and identified the HREC name and address, clinical
protocol by title and protocol number and the date the approval was granted. This
trial was registered with ClinicalTrials.gov (NCT00096408) and the Australian New
Zealand Clinical Trials Registry (CTRN12606000261516). Federal, state and local
regulations and the International Conference on Harmonisation (ICH) guidelines
required that approval be obtained from a HREC prior to the participation of human
patients in the research.
The Lace trial was approved by the University of Queensland (Approval No:
2006000368), and all participating hospital ethics committees. This doctoral research
project used de–identified data under the supervision of a chief investigator and
therefore was included into existing ethical approvals, with access to the data only
by the research team and the doctoral student.
4.9. References
1. Janda M, Gebski V, Davies LC, Forder P, Brand A, Hogg R, et al. Effect of Total
Laparoscopic hysterectomy vs total abdominal hysterectomy on disease–free
survival among women with stage i endometrial cancer: A randomized clinical
trial. JAMA. 2017;317(12):1224–1233.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 149
2. Obermair A, Janda M, Baker J, Kondalsamy–Chennakesavan S, Brand A, Hogg R,
et al. Improved surgical safety after laparoscopic compared to open surgery for
apparent early stage endometrial cancer: results from a randomised controlled
trial. Eur J Cancer. 2012;48(8):1147–1153.
3. Janda M, Gebski V, Brand A, Hogg R, Jobling TW, Land R, et al. Quality of life after
total laparoscopic hysterectomy versus total abdominal hysterectomy for stage I
endometrial cancer (LACE): a randomised trial. Lancet Oncol. 2010;11(8):772–
780.
4. Saunders B, Sim J, Kingstone T, Baker S, Waterfield J, Bartlam B, et al. Saturation
in qualitative research: exploring its conceptualization and operationalization.
Qual Quant. 2018;52(4):1893–1907.
5. ATC/DDD Index 2017. (2015) WHO collaborating centre for drug statistics
methodology web site. http://www.whocc.no/atc_ddd_index/. Accessed 15
June, 2017.
6. Snaith RP. The Hospital Anxiety and Depression Scale. Health Qual Life Outcomes.
2003;1;1:29.
7. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr
Scand. 1983;67(6):361–370.
8. Kang H, Appropriate design of research and statistical analyses: observational
versus experimental studies. Korean J Anesthesiol. 2013;65(2):105–107.
9. Sperandei S. Understanding logistic regression analysis. Biochem Med (Zagreb).
2014;24(1):12–18.
150
10. Schneider A, Hommel G, Blettner M. Linear regression analysis part 14 of a series
on evaluation of scientific publications. Dtsch Arztebl Int. 2010;107(44):776–782.
11. Braun V, Clarke V. Using thematic analysis in psychology. Qualitative Research in
Psychology. 2006;3(2):77–101.
12. Nowell LS, Norris JM, White DE, Moules NJ. Thematic analysis: Striving to meet
the trustworthiness criteria. Int J Qual Methods. 2017;16:1–13.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 151
Chapter 5: Use of psychotropic medications by
endometrial cancer patients
5.1. How many patients enter endometrial cancer surgery with psychotropic
medication prescriptions and how many receive a new prescription
perioperatively?
This PhD research program used the extensive longitudinal data collected for the
LACE Trial to undertake an in–depth secondary analysis of research gaps identified in
the literature as described in Section 1.2, as well as the scoping review (see Section
2.4.1, Figure 5.1).
Figure 5.1: PhD project structure: Chapter 5— Use of psychotropic medications by
endometrial cancer patients
152
This chapter aims to provide an overview of the psychotropic medications
prescription practices to women with endometrial cancer from before surgery to six
months follow–up, and establish factors associated with the prescription of
medications. This chapter has been published in a peer–reviewed journal, and the
accepted version is presented here.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 153
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154
How many patients enter endometrial cancer surgery with psychotropic
medication prescriptions, and how many receive a new prescription
perioperatively?
Author Names: Saira Sanjida1, Monika Janda1,2*, Steven M. McPhail1,3, David
Kissane4, Jeremy Couper5, James Scott6, Andreas Obermair7
Authors' information:
1School of Public Health and Social Work, Institute for Health and Biomedical
Innovation, Queensland University of Technology, Brisbane, Australia.
2Centre for Health Services Research, The University of Queensland, Brisbane,
Australia.
3Centre for Functioning and Health Research, Metro South Health, Brisbane,
Australia.
4Department of Psychiatry, Monash University, Melbourne, Australia.
5Adult Mental Health Program, Eastern Health, Melbourne, Australia.
6Queensland Centre for Mental Health Research, The University of Queensland,
Brisbane, Australia.
7Queensland Centre for Gynaecological Cancer, Royal Brisbane and Women’s
Hospital, Brisbane Australia
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 155
5.2. Abstract
Objective: Psychotropic medications including antidepressants and anxiolytics are
used to treat anxiety and depression in cancer patients; however, little is known
about the prescription practices in endometrial cancer. This study aimed to
determine the prevalence, type, dose, frequency and timing of psychotropic
medications prescribed to endometrial cancer patients. A secondary aim was to
study sociodemographic and clinical characteristics associated with receiving a
psychotropic medication prescription.
Methods: Secondary data analysis of an international, multicentre, prospective
randomised controlled trial was conducted. Patients aged >18 years diagnosed with
Stage I endometrial cancer were included. Logistic regression models were fitted to
estimate the association of receiving psychotropic medications with patient’s socio–
demographic and clinical characteristics.
Results: The overall prevalence of patients prescribed one or more psychotropic
medications was 16.8% (n= 121/719) comprising antidepressants (12.6%, n= 91/719)
and anxiolytics (5.8%, n= 42/719). The majority of patients (78.1%, n= 71/91) were
already receiving antidepressants before cancer diagnosis, the remaining
medications were newly prescribed perioperatively (21.9%, n= 20/91). Patients of
younger age (18–50 years, OR (Odds Ratio): 2.61; 95% CI (Confidence Interval): 0.81–
3.20), who had hypertension (OR: 0.61; 95% CI: 0.63–1.39), history of a previous
cancer (OR: 1.96; 95% CI: 0.88–2.94), and ≥2 comorbidities (2–3, OR: 2.97, 95% CI:
1.07–3.44; 4–5, OR: 7.85, 95% CI: 2.44–8.08; ≥6, OR: 9.13, 95% CI: 2.34–9.98) were
156
significantly (p<0.05) more likely to receive a prescription of psychotropic
medications.
Conclusions: While one in eight patients already had psychotropic medications
prescribed before surgery for early stage endometrial cancer, only few women
received a new prescription after surgery. The overall prescription rates were similar
to other patients with cancer, but higher than those observed in the general
population, likely reflecting the comorbidity burden of patients who develop
endometrial cancer. Qualitative data could be used in future research to explore the
psychological and quality of life impacts of endometrial cancer.
5.3. Background
Endometrial cancer is the most commonly diagnosed gynaecological cancer in
developed countries [1]. Globally, the incidence rate of endometrial cancer is higher
in more developed regions (13.0/100,000) such as Northern America, Europe and
Australia compared to less developed regions (5.9/100,000) such as Africa [2]. The
majority of cases (>90%) are diagnosed in women 50 years or older and surgery is the
primary treatment for early stage cancer [3,4]. Overweight or obesity is the main risk
factor for endometrial cancer [5]. Compared with other gynaecological cancers,
women diagnosed with endometrial cancer often present with multiple chronic
comorbid conditions, such as diabetes, hypertension or arthritis [6]. After a diagnosis
of cancer, many patients experience anxiety or depression which may continue
throughout the cancer survival period [7]. Anxiety and depression has been reported
to be the third prioritised problem after worry and focusing on getting well in
patients with endometrial cancer [8]. Using the Hospital Anxiety and Depression
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 157
Anxiety sub–scales, it has been reported that before surgery, patients more
commonly experience symptoms of anxiety (19.5%, n= 25/132) than depression [9].
Symptoms of anxiety and depression continue for many women beyond the period
of primary treatment of endometrial cancer [9,10].
Psychotropic medications such as antidepressants and anxiolytics are recommended
for the treatment of moderate to severe anxiety or depression [11]. Across the world,
the current prescription prevalence rate of antidepressants to patients with cancer
more broadly is 15.6%, with a higher prevalence of prescribing observed in female
patients and patients with breast cancer (22.0%) [12]. Fortuny et al., 2009 [13] found
in the United States of America that within the first year after an endometrial cancer
diagnosis the prevalence of antidepressant prescriptions (Serotonin selective
reuptake inhibitors only) and anxiolytics (Benzodiazepines only) was 10.2% (n=
48/469) and 5.1% (n= 24/469), respectively. Recently, Lin et al., 2016 [14] specifically
focused on antidepressant prescriptions among a nationwide endometrial cancer
population in Taiwan and found that 19.2% (n= 1,612/8,392) of patients were
prescribed an antidepressant. However, these studies aimed to assess if medications
increased the risk of developing endometrial cancer; and provided little information
about the details of the prescription characteristics, such as type or timing of
prescriptions relative to the endometrial cancer diagnosis. Given the reported high
prevalence of psychological distress in patients with endometrial cancer, more
details about the patterns of psychotropic medication prescribing including overall
prevalence, reasons for prescription, time of initiation of medications, and details of
prescription characteristics are needed. There is also a lack of research focusing on
158
sociodemographic and clinical characteristics associated with the prescription of
psychotropic medications. Many prevalence studies combine gynaecological cancers
and remain unfocused on individual tumour types or stage of disease.
To address these gaps, we conducted a secondary analysis of data from a large
prospective clinical trial that enrolled patients diagnosed with stage 1 endometrial
cancer to determine– 1) the prevalence and characteristics of psychotropic
medications prescribed to patients with endometrial cancer; and 2)
sociodemographic and clinical characteristics associated with receiving a
psychotropic medication prescription.
5.4. Methods
5.4.1. Site and timeline
Data were extracted from an international, multicentre prospective randomised
controlled trial (The Laparoscopic Approach to Cancer of the Endometrium (LACE)
trial; ClinicalTrials.gov: NCT00096408; Australian New Zealand Clinical Trials Registry:
CTRN12606000261516). LACE commenced in October 7, 2005 and recruited to June
30, 2010, then followed patients for 4.5 years. Patients diagnosed with endometrial
cancer were enrolled from 20 tertiary gynaecological oncology centres in Australia,
New Zealand, Scotland and Hong Kong [15]. Data used for these secondary analyses
were collected in detail during the pre and perioperative period and then one–week,
four–week, three–month and six–month postoperatively.
5.4.2. Patient recruitment
The details of recruitment were described elsewhere [15,16].
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 159
Briefly, women were eligible to enrol, 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 less than one/two, and imaging studies
(computed tomography, CT) of the abdomen and pelvis and chest radiograph or
chest CT suggesting the absence of extrauterine disease. Patients were excluded if
they had histological cell type other than endometrioid on curettage, clinically
advanced disease (stage II–IV).
Overall 760 women were recruited for the clinical trial and underwent either total
abdominal or total laparoscopic hysterectomy surgery. For this secondary analysis,
patients were eligible if sociodemographic and clinical characteristics as well as
information on psychotropic medication prescriptions were available.
5.4.3. Sociodemographic and clinical characteristics
The following sociodemographic characteristics were collected: age, height and
weight, education, employment, employment location, marital status, insurance,
birth country and ethnicity. Body mass index (BMI) was calculated and grouped
according to World Health Organisation (WHO) using weight and height data [17].
Clinical characteristics included hysteroscopy date (used as a proxy for the date of
endometrial cancer diagnosis), surgical stage of cancer, perioperative medical history
of comorbidities (hypertension, obesity, diabetes, gastro–oesophageal reflux disease
(GORD), arthritis, asthma, hyperlipidaemia/ hypercholesterolemia), number of
comorbidities, previously diagnosed cancer type and number, comorbidity and new
cases of anxiety and depression, types of surgery (total abdominal or total
160
laparoscopic hysterectomy), and adjuvant treatment (radiotherapy and/or
chemotherapy).
5.4.4. Details of medication data collection
Antidepressants and anxiolytics (name, dose, frequency, unit, start date and end date
of prescription) were recorded by the trial nurse at pre, peri, and post–operative
assessments. They were classified using the Anatomical Therapeutic Chemical (ATC)
Classification System [18]. This classification system is the gold standard for
international drug utilisation research and is maintained by the WHO Collaborating
Centre for Drug Statistics Methodology. Anatomical Therapeutic Chemical codes
used were: NO5B (anxiolytics) and N06A (antidepressant) [18].
5.4.5. Statistical analysis
Descriptive statistics were used to determine the prevalence and distribution of
dependent and independent variables. Normality for continuous variables was
tested and accepted when the mean was within ± 10% of the median, skewness and
kurtosis coefficients were within ±2 and the histogram was approximately
symmetrical and bell–shaped. Univariate logistic regression models were used to
determine sociodemographic and clinical characteristics potentially associated with
the use of any psychotropic medications (antidepressants and/or anxiolytics) as the
dependent variable. The set of variables showing statistically significant (p<0.05)
associations with the use of psychotropic medications were then tested in
multivariable logistic regression models using backward model selection for their
independent contribution [19]. Results are presented as odds ratio (OR) with
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 161
corresponding 95% confidence intervals (CIs) for both univariate and multivariable
analyses. All analyses were performed SPSS software version 23.0.
5.5. Results
5.5.1. Patients characteristics
Sociodemographic and clinical characteristics of the 719 patients included in these
analyses are presented in table 5.5.1. The mean age of patients was 62.7 (range from
31 to 93). Only 13.1% (n = 91/696) had a BMI of ≤25 kg/m2 (normal category), the
remaining patients (86.9%, n = 605/696) were overweight or obese. Half of the
patients (49.9%, n = 359/719) completed senior high school or less, over 60% (n =
440/719) were retired. Less than one–third of patients were employed full time or
part–time/casual (27.1%, n = 195/719) and held private health insurance (26.6%, n =
191/719). The majority of patients were born in Australia (65.1%, n = 468/719) and
were of European ancestry (75.2%, n = 541/719).
Table 5.5.1 Sociodemographic and clinical characteristics of the 719 patients
diagnosed with endometrial cancer
Characteristics n (%)
Age at diagnosis (n = 716) (Mean, SD) 62.7, 10.1 18–50 71 (9.9) 51–70 486 (67.9) 71+ 159 (22.2)
BMI (n = 696) Normal (18.50–24.99) 91 (13.1) Overweight (25.00–29.99) 162 (23.3) Obesity class I (30.00–34.99) 155 (22.3) Obesity class II (35.00–39.99) 134 (19.2) Obesity class III (≥40) 154 (22.1)
Education Did not complete primary school 31 (4.3) Completed primary school 112 (15.6) Completed junior/senior high school 359 (49.9)
162
Trade or technical certificate 86 (12.0) University or college degree 77 (10.7) Other1 54 (7.5)
Employment Employed full–Time 97 (13.5) Employed part–time or casual 98 (13.6) Home duties/home–carer 133 (18.5) Retired 304 (42.3) Other2 87 (12.1)
Employment location (n = 698) Indoors 434 (62.2) Outdoors 28 (4.0) Both indoors and outdoors 236 (33.8)
Marital status Married/living together 455 (63.3) Divorced/separated 106 (14.7) Widowed 101 (14.0) Other3 57 (7.9)
Insurance4 Yes, cover hospital/extra/other 72 (10) Yes, cover hospital and extra 119 (16.6) No 528 (73.4)
Income <AUS$40,000 468 (65.1) AUS$40,001+ 165 (22.9) Not reported 86 (12.0)
Birth country Australia 468 (65.1) Other 251 (34.9)
Ethnicity (n = 718) European 541 (75.2) Indigenous Australian 17 (2.4) Other5 160 (22.3)
Surgical Stage (n = 716) I 594 (83.0) II 72 (10.0) III 44 (6.1) IV 6 (0.9)
Comorbidities (n = 701) Hypertension 368 (52.5) Hyperlipidaemia/ Hypercholesterolemia
179 (25.5)
Diabetes 157 (22.4) Arthritis 124 (17.7) Obesity 112 (16) Asthma 94 (13.4) GORD 84 (12.0)
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 163
Number comorbidities (n = 701) Nil 75 (10.4) 1 140 (19.5) 2 147 (20.4) 3 128 (17.8) 4 87 (12.1) 5 62 (8.6) 6 31 (4.3) 7 16 (2.2) ≥8 15 (2.0)
History of previous cancer 66 (9.2) Single 62 (8.9) Two or more 4 (0.6)
Previously diagnosed cancer type Breast 33 (4.6) Skin 27 (3.7) Blood and renal each 6 (0.8) Other6 4 (0.5)
Anxiety & depression 93 (12.9) Before diagnosis of cancer 82 (11.4) Depression 57 Anxiety 18 Anxiety & depression 7 New case after surgery 11 (1.5) Depression 9 Anxiety 2
Surgery7 (n = 718) Abdominal Hysterectomy 327 (45.5) Laparoscopic Hysterectomy 391 (55.5)
Adjuvant treatment Chemotherapy 12 (1.7) Radiotherapy 131 (18.2) Both 42 (5.8) No further treatment 534 (74.3)
SD– Standard deviation, BMI– Body–mass index, GORD– Gastro–oesophageal reflux disease. 1Not stated or informed different education level. 2Student, unemployed or looking for work, permanently ill/unable to work or other. 3Included single/never married or other. 4Public insurance is universally available for all Australian citizen and permanent residence. 5Included Australian, Asian or other. 6Included colorectal, bowel and choriocarcinoma. 7One surgery was abandoned.
Many patients (89.3%, n = 626/701) had one or more comorbidity, for example,
52.5% (n = 368/701) had hypertension. Around 10% (n = 66/701) were previously
diagnosed with another cancer, about half of these (n = 33/66) with breast or skin
164
cancer (n = 27/66). Overall, 12.9% (n = 93/719) patients had either a medical history
(n = 82/93) of anxiety or depression or were new cases diagnosed post–surgery (n =
11/93). Of the 82 patients with a history, most had a diagnosis of depression alone
(n = 57/82) or comorbid depression with anxiety (n = 7/82). One–quarter of the
patients (n = 185/719) received chemotherapy and/or radiotherapy as adjuvant
treatment (see Table 5.5.1).
5.5.2. Prescription characteristics of psychotropic medications
Characteristics of the psychotropic medications are presented in table 5.5.2. The
overall prevalence of patients with endometrial cancer during the six–month study
period of having been prescribed one or more psychotropic medications was 16.8%
(see Table 5.5.2A). A total of 137 prescriptions of psychotropic medications were
recorded for 121 patients (see Tables 5.5.2A and 5.5.2B). Among these, the
prevalence of patients prescribed with antidepressants and anxiolytics was 12.6% (n
= 91/719) and 5.8% (n = 42/719), respectively (see Table 5.5.2A).
Table 5.5.2: Prescription characteristics of psychotropic medications (n = 719)†
A. Overall prevalence of patients prescribed with psychotropic medication from baseline to
6–month post–surgery period
Prevalence of patients with one or more psychotropic medications 121 (16.8%)
Prevalence of AD 91 (12.6%)
Prevalence of AX 42 (5.8%)
B. Number of psychotropic medications prescription
Number of prescriptions (including changed & double prescription) 137
Number of double prescription of AD and/or AX 16
Change of ADs
Double ADs or AXs
2
2
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 165
Both ADs & AXs 12
C. Time–point of initial psychotropic medication prescription
Number of patient Before diagnosis of
endometrial cancer Perioperative
Post–surgery
W1 W4 M3 M6
AXs (n = 42)
ADs (n = 91)
18
71
5
4
14
6
2
4
2
4
1
2
Total 891 9 20 6 6 3
D. Continuation of psychotropic medications from perioperative to six–month post–
surgery††
Prescription Ongoing Discontinued Then recommenced
AD & AX (n = 137) 98 36 3
ADs 78 142,3 2
AXs 20 223 1
E. Reasons for psychotropic medications prescription before diagnosis of endometrial
cancer and new cases
Reason AX4 (n=42) AD4 (n=91) Total (AX & AD) No AD or AX
Depression 7 49 56 15
Anxiety 5 8 13 8
Anxiety and depression 2 5 7 2
Other than anxiety and
depression5 28 29 – –
Total 76 256
F. Psychological treatment (n = 43)
Visited a psychiatrist, psychologist or other mental
health counsellor
Number of visits for treatment
One visit Two visits 3 to 12 visits
(Mean: 6)
Comorbid with anxiety or depression, no AD or AX (n= 2) 1 1 –
Prescribed with ADs and/or AX with anxiety and
depression (n = 6) 1 4 1
Prescribed with ADs and/or AXs (n = 6) 2 1 3
No anxiety or depression or AD/AX (n = 22) 8 9 5
166
Other (n = 7)7 3 1 3
Total (n = 43) 15 16 12
AD– Antidepressant, AX– Anxiolytics, W– Week, M– Month. †Measurement of each characteristic are presented in the Table 4.6. 1Six patients prescribed with both antidepressants and anxiolytics. 2Two patients were discontinued due to change of AD and five patients were discontinued after diagnosis of cancer. 3Limited duration of prescription (1–4 days) was identified in AD (n= 3/14) and AX (n= 19/22). 49/42 of AX and 52/91 of AD were prescribed before diagnosis of cancer to treat anxiety and depression. 5The most commonly prescribed medications were diazepam, lorazepam, citalopram, venlafaxaine, etc. 619/25 patients had long medical history of anxiety and/or depression (mean: 5 years) after considering year of endometrial cancer diagnosis and as well as anxiety and/or depression. 7Included schizophrenia, delusional/bipolar disorder, etc.
Type, dose and change of dose are presented in Table 5.5.2S. Sertraline (n = 20/94)
was the most delivered antidepressant prescription followed by venlafaxine (n =
17/94), paroxetine (n = 16/94) and citalopram (n = 13/94). Oxazepam (n = 17/43) was
the most prescribed anxiolytic followed by diazepam (n = 15/43) and lorazepam (n =
10/43).
Table 5.5.2S: Type and dose of psychotropic medications prescribed to patients
with endometrial cancer
Anxiolytics Prescription (n = 43) Change of dose
Increased Decreased
Bromazepam n = 1 1.5mg 1 10 mg –
Diazepam n = 15 1 1 2mg 4 2.5mg 3 5mg 61 10mg 2
Lorazepam n = 10 0.5 mg 11 1 mg 51 1.5 mg 1 2 mg 3 2.5 mg –
Oxazepam n = 17 2 1 3.8 mg 1 5 mg 1 7.5 mg 4 15 mg 52 30 mg 41 50 mg –
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 167
60 mg 2
Antidepressants Prescription (n = 94) Change of dose
Increased Increased
Amitriptyline n = 1 1 10mg 1 75mg –
Citalopram n = 13 1 10 mg 1 20mg 9 40mg 3
Desvenlafaxine n =1 50mg 1
Dothiepin n =2 25mg 2 75mg –
Doxepine n =1 100mg 1
Escitalopram n =6 10mg 3 20mg 3
Fluoxetine n =9 10mg 1 20mg 8
Imipramine n = 2 50mg 1 100mg 150mg 1
Mirtazapine n =3 15mg 1 30mg 2
Nortriptyline n =2 25mg 2 30mg
Paroxetine n = 16 2 10mg 5 20mg 8 25mg 1 40mg 1 60mg 1
Sertraline n = 20 1 50mg 9 75mg 2 100mg 81 200mg 1
Trimipramine n = 1 75mg 1 150mg
Venlafaxine n = 17 1 37.5mg 41 75mg 9
168
100mg – 150mg 2 225mg 1 300mg 1 1BD– Twice a day for one patient only. 2TDD–Three times a day for one patient only. Italicized entries indicated the recommended dose antidepressants and anxiolytics according to Anatomical Therapeutic Chemical (ATC) Classification System.
Time point of initial psychotropic medications and their continuation in the timeline
of this study are presented in table 2C and 2D, respectively. Majority of the patients
(n = 71/91) patients were already receiving antidepressant prescriptions before
cancer diagnosis, whereas the number (n = 24/42) was higher for anxiolytics during
perioperatively (see Table 5.5.2C). 98/137 of the psychotropic medication
prescriptions were continued by patients until 6–month post–surgery. Anxiolytics
were more commonly initiated in the early post–operative phase than
antidepressants, and half of the anxiolytics prescriptions (n = 22/42) were stopped
within the first 6–month post–surgery (see Table 5.5.2D).
The reasons for the prescription of psychotropic medications and whether or not
psychological treatment was also received, are presented in the tables 5.5.2E and
5.5.2F, respectively. Overall, 62.8% (n = 76/121) of the patients were prescribed one
or more psychotropic medications for the treatment of depression and/or anxiety.
Almost the same proportion of antidepressants (n = 29/121) and anxiolytics (n =
28/121) were prescribed to patients without anxiety or depression. Notably, 25
patients with a long medical history (n = 19/25) of anxiety (n = 6/19), depression (n =
11/19) or both (n = 2/19) did not receive psychotropic medications (Table 5.5.2E).
Only 6% (n = 43/719) of patients visited a psychiatrist, psychologist or other mental
health counsellor during the first six months after surgery. The majority of these
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 169
patients (n = 31/43; 72.1%) only attended one or two sessions with a mental health
professional (see Table 5.5.2F).
5.5.3. Characteristics associated with the prescription of psychotropic medications
Sociodemographic and clinical characteristics associated with the prescription of
psychotropic medications are presented in Table 5.5.3. Univariate analyses showed
that younger age (18–50), having GORD or asthma, ≥2 comorbidities, and having a
medical history or being newly diagnosed with anxiety and/or depression were
associated with the prescription of psychotropic medications (see Table 5.5.3).
Table 5.5.3: Univariate analysis of characteristics associated with the prescription
of psychotropic medications
Characteristics OR (95% CI) p value
Age (n = 716) (years)
18–50 1.61 (0.81–3.20) 0.17
51–70 0.98 (0.60–1.59) 0.93
71+ 1.00
BMI (n = 696) (kg/m2)
Normal (18.50–24.99) 1.00
Overweight (25.00–29.99) 1.65 (0.78–3.48) 0.18
Obesity class I (30.00–34.99) 1.14 (0.52–2.49) 0.74
Obesity class II (35.00–39.99) 1.67 (0.77–3.59) 0.19
Obesity class III (≥40) 1.91 (0.91–4.00) 0.08
Education
Did not complete primary school 1.08 (0.37–3.12) 0.88
Completed primary school 0.98 (0.46–2.08) 0.95
Completed junior or senior high school 0.92 (0.48–1.74) 0.80
Trade or technical certificate 0.80 (0.35–1.83) 0.60
170
University or college degree 1.00
Other 0.67 (0.25–1.79) 0.42
Employment
Employed full–Time 1.00
Employed part–time or casual 0.72 (0.34–1.57) 0.41
Home duties/home–carer 1.14 (0.58–2.25) 0.70
Retired 0.97 (0.53–1.77) 0.92
Other 0.83 (0.37–1.82) 0.63
Employment location (n = 698)
Indoors 1.21 (0.80–1.83) 0.36
Outdoors only or both 1.00
Marital status
Married/living together 1.00
Divorced/ Separated 1.02 (0.59–1.78) 0.93
Widowed 0.63 (0.33–1.21) 0.16
Other 1.00 (0.48–2.06) 0.99
Birth country
Australia 1.00
Other 1.08 (0.72–1.62) 0.71
Surgical stage (n = 716)
1 1.00
≥2 0.91 (0.53–1.55) 0.73
Hypertension
No
Yes
1.00
0.94 (0.63–1.39)
0.76
Obesity
No
Yes
1.00
1.29 (0.78–2.15)
0.32
Diabetes
No
1.00
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 171
Yes 1.17 (0.74–1.86) 0.48
Gastro–oesophageal reflux disease
No
Yes
1.00
2.46 (1.48–4.11)
0.00
Arthritis
No
Yes
1.00
1.26 (0.77–2.06)
0.34
Asthma
No
Yes
1.00
1.68 (1.00–2.82)
0.05
Hyperlipidaemia/Hypercholesterolemia
No
Yes
1.00
1.36 (0.88– 2.09)
0.16
Number of comorbidities (n = 701)
Nil or one 1.00
2–3 1.92 (1.07–3.44) 0.03
4–5 4.44 (2.44–8.08) 0.00
6 or more 4.83 (2.34–9.98) 0.00
History of previous cancer (n = 701)
No
Yes
1.00
1.61 (0.88–2.94)
0.12
Medical history or new cases of anxiety and/or depression (n = 701)
No
Yes
1.00
26.44 (15.53–45.01)
0.00
Surgery (n = 718)
Total abdominal hysterectomy
Total laparoscopic hysterectomy
1.08 (0.73– 1.59)
1.00
0.70
Adjuvant treatment
No 1.00
Yes 0.99 (0.63–1.55) 0.97
172
OR– Odds ratio, CI– Confidence interval
In a mutually adjusted multivariable model (excluding a medical history or new
diagnosis of anxiety and/or depression), younger age (18–50 years, OR 2.61),
hypertension (OR 0.61), history of previous diagnosed cancer (OR 1.96) and ≥2
comorbidities (2–3, OR 2.97; 4–5, 7.85 and ≥6, 9.13) remained significantly
associated (p <0.05) with having a prescription of psychotropic medications (Table
5.5.4).
Table: 5.5.4 Multivariable logistic regression of variables associated with the
prescrip on of psychotropic medica ons†
Characteristics OR (95% CI) p value
Age 18–50 2.61 (1.18–5.76) 0.01 51–70 1.30 (0.77–2.20) 0.32 71+ 1.00
Hypertension No 1.00 Yes 0.61 (0.39–0.98) 0.04
History of previous cancer No 1.00 Yes 1.96 (1.01–3.82) 0.04
Number of comorbidities Nil or one 1.00 2–3 2.97 (1.55–5.68) 0.00 4–5 7.85 (3.93–15.67) 0.00 ≥6 9.13 (3.97–20.98) 0.00
OR– Odds ratio, CI– Confidence interval †Adjusted for all variables in the model excluding medical history or new cases of anxiety and/or
depression.
5.6. Discussion
This large international multicentre study identified that the prevalence of
psychotropic medications was 16.8%, comprised of antidepressants (12.6%) and/or
anxiolytics (5.8%). This prevalence rate of antidepressants (12.6%) was similar to
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 173
those reported by previous studies on female patients 12.5% [20], but higher than
the 10.2% observed in a study in endometrial cancer patients that focused on SSRIs
only [13]. Conversely, the prevalence of antidepressants was a little lower than in a
recent Taiwanese population–based study (19.2%), which collected medication data
from prescriptions filled, including all classes of antidepressants [14]. The observed
rate of anxiolytics was similar to the 5.1% observed by Fortuny et al. (2009) [13]
although that study included benzodiazepines only.
Considering the time of initiation of the psychotropic medication, most prescriptions
(77.6%, n = 73/94) of antidepressants were already provided to patients before the
diagnosis of endometrial cancer, and few new prescriptions were Initiated peri– (n =
5/94) or post–operatively (n = 16/94) (see Table 5.5.2C). This is similar to the original
Psychosocial Collaborative Oncology Group (PSYCOG) study conducted by Derogatis
et al., 1983 [21], which found that only 11% of psychiatric disorders arose after the
cancer, with most mental health morbidity having predated the diagnosis. This
suggests that either the majority of patients are coping well with their endometrial
cancer diagnosis and do not require psychotropic medications, given that the cohort
involves patients with early stage disease whose goal of treatment is cure, or that
there is an under–recognition and under–treatment of psychological problems.
When we assessed the overlap between antidepressant prescriptions with the
patients’ psychological status as comorbidities, we found that 52 patients had a
medical history of anxiety and/or depression (see Table 5.5.2). Pre–existing, long–
term chronic medical health issues and risk factors of endometrial cancer (such as
abnormal uterine bleeding, obesity, menopausal syndrome) may lead to
174
psychological distress and treatment with antidepressants [22–26]. In contrast,
24/42 anxiolytics were newly prescribed after diagnosis of cancer for anxiety and/or
depression (see Table 5.5.2C). This may reflect the fact that anxiolytics are often used
for other purposes such as to overcome insomnia or neuropathic pain [27–32].
After matching the comorbid conditions of anxiety and/or depression with
psychotropic medications, 25 patients did not receive medication despite having a
long–term (2 to 10 years) medical history (n = 19) or being a new case (n = 6) of
depression and/or anxiety (see Table 5.5.2E). This may either reflect a lack of
awareness of the symptoms by health care professionals, or that alternative
management options are being pursued instead of psychotropic medications. Almost
all participants (89.3%, n = 644/719) had one or more comorbidities. Therefore, it is
also possible that treatment was focused of the many physical conditions presented
by the patients rather than their psychological well–being [33]. Use of secondary data
did not allow us to distinguish between the aforementioned potential explanations
regarding non–use of medications for depression and/or anxiety. Only 8 patients
reported they received psychological treatment for anxiety and/or depression (see
Table 5.5.2F). Recent clinical guidelines for management of depression and anxiety
in adult cancer patients [11] emphasise the importance of psychological care for
these conditions.
A very short duration (one to four days) of anxiolytic (n = 19/22) or antidepressant (n
= 3/14) prescriptions was observed for some patients (see Table 5.5.2D). This
indicates that they may have been prescribed for symptom relief including to treat
insomnia [30,31], pain [29–32], nausea or vomiting [27,28] (see Table 5.5.2D), or that
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 175
side–effects emerged. Our data shows that 28 anxiolytics (such as diazepam,
lorazepam) and 29 antidepressant prescriptions (such as citalopram, venlafaxaine)
were received by patients for reasons other than anxiety and depression (see Table
5.5.2E). Possible indications besides anxiety and depression were identified in a
previous study by Stiefel et al., (1990) [34], including to overcome fear of procedure
(anxiolytics), or insomnia (antidepressants). Additionally, venlafaxine is considered
the safest medication for the treatment of hot flashes [35] and also used to reduce
neuropathic pain [36].
Several characteristics were associated with the prescription of psychotropic
medications in the multivariable analyses including– 1) age, 2) history of previous
cancer and 3) number of comorbidities, while hypertension was associated with
lower risk. It is well known that younger patients have more difficulty adjusting to
the existential threat of cancer. Alternatively, they may also be more likely or willing
to seek help for mental health concerns than older patients [37]. As the population
ages, the development of second and third cancers is becoming more common. Our
finding that the need for psychotropic medications seems to increase with the
number of cancer diagnoses is a novel finding of our study. Multiple cancer diagnoses
may increase the complexity of treatment or may overwhelm patients coping ability
more than a first diagnosis of cancer does. A further important outcome of this study
is the recognition of comorbidities increasing the likelihood of psychiatric disorders
occurring. The burden of medical illnesses can take its toll on patients’ capacity to
cope. Ashbury et al., 2003 [38] showed that patients with breast cancer and
comorbid physical disorders had 2.15 higher odds of antidepressant prescriptions.
176
Similar results (≥3 comorbidities, OR: 4.74) were also reported in an international
multicentre study with advanced cancer patients [39], but here we confirm
importance of comorbidities in early stage endometrial cancer. Presence of
hypertension was associated with 0.61 lower odds prescription of psychotropic
medications. Possible explanation may be that the use of beta–blockers and other
anti–hypertensive medications has been found to reduce the incidence of anxiety
[40].
5.6.1. Study strengths and limitations
Strengths of this study are its large sample size and detailed record of medications.
Limitations include lack of data to identify who prescribed psychotropic medications
(i.e. the general practitioner, psychiatrist or oncologist), and what type of
psychological treatment was received. Patient–reported medical history and
comorbid conditions entered by the study nurse were used to identify the
comorbidities of anxiety and depression, rather than through a formal clinical
interview. Using data from a surgical clinical trial means that the study includes a
relatively homogenous patient population of relatively well patients with early stage
cancer and this is a limitation of this study. However, given that over 80% of
endometrial cancers are diagnosed at early stages this should still capture the patient
experience well.
5.6.2. Future research
This research found that the prevalence rate of psychotropic medications was high
before the diagnosis of endometrial cancer and only few patients were initiated on
psychotropic medications after surgery. This suggests that surgical treatment of
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 177
endometrial cancer is well tolerated psychologically by most women although
under–recognition and under–treatment of mental illness post–surgery cannot be
excluded. There was some mismatching between prescriptions and noted diagnosis
of anxiety or depression, and future research should consider patients’ symptom
factors to better explain the prescribing or otherwise of psychotropic medications to
women treated for endometrial cancer. Qualitative data could be used in future
research to explore in greater depth the psychological conditions and life impacts
during long survival.
Acknowledgement
Saira Sanjida was funded by Advance Queensland Scholarship. Monika Janda was
funded by NHMRC Translating Research into Practice fellowship APP1151021. Steven
M. McPhail (#1090440) was funded by NHMRC Fellowships. This project was part of
LACE Trial which 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 Gynaecological Cancer,
Genesis Oncology Trust, and the Cherish Foundation.
Conflict of interests
178
The authors have declared no conflicts of interest.
Author Contribution
Conception and design: Saira Sanjida, Monika Janda
Extraction and assembly of data: Saira Sanjida
Data analysis and interpretation: Saira Sanjida, Steven M. McPhail, Monika Janda
Drafting of manuscript: Saira Sanjida, Monika Janda
Critical revision and final approval of manuscript: All authors.
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184
Chapter 6: Anxiety and depression in
endometrial cancer patients
6.1. Anxiety and depression in women with early stage endometrial cancer: A
longitudinal analysis from perioperative to 6–month post–surgery
This chapter of this PhD research program used the longitudinal data collected for
the LACE Trial to undertake in–depth secondary analysis to address the research gaps
identified in the scoping review (see Section 2.3.1) and previous Chapter 5 (see
Section 5.7, Figure 6.1)‐
Figure 6.1: PhD project structure: Chapter 6—Anxiety and depression in
endometrial cancer patients
1. No research has been conducted in Australia to determine the prevalence of
anxiety and depression at the time of diagnosis and surgical procedure in
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 185
women with endometrial cancer; or established the treatments received for
anxiety and depression.
2. Very few studies assessed factors associated with anxiety and depression in
patients with endometrial cancer.
This chapter aims to determine the prevalence of anxiety and depression in women
with endometrial cancer from before surgery to 6 months post–surgery and
treatments received for these symptoms. It also analyses the factors associated with
the clinical level of anxiety and depression. This chapter is currently under–review in
a peer–reviewed journal, and the submitted version of the manuscript is presented.
186
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2. they take public responsibility for their part of the publication, except for the responsible author who accepts overall responsibility for the publication;
3. there are no other authors of the publication according to these criteria; 4. potential conflicts of interest have been disclosed to (a) granting bodies, (b) the
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Please state the publication title and date of publication or status: Anxiety and depression in patients with early stage endometrial cancer: A longitudinal analysis from before surgery to 6–month post–surgery. Published 2019.
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Saira Sanjida Conception and design, data cleaning, extraction and assembly of data, data analysis and interpretation, drafting of manuscript, critical revision and final approval of manuscript
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Date: 18.02.2020
Professor Monika Janda Conception and design, data analysis and interpretation, drafting of manuscript, critical revision and final approval of manuscript
Professor Steven M McPhail
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Professor David Kissane Critical revision and final approval of manuscript
Professor Andreas Obermair
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Date: 18.02.2020
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 187
Anxiety and depression in patients with early stage endometrial cancer: A
longitudinal analysis from before surgery to 6–month post–surgery
Saira Sanjida1, David Kissane2, Steven M. McPhail1,3, Andreas Obermair4, Monika
Janda1,5*
Authors' information:
1School of Public Health and Social Work, Institute for Health and Biomedical
Innovation, Queensland University of Technology, Brisbane, Australia.
2Department of Psychiatry, Monash University, Melbourne, Australia.
3Centre for Functioning and Health Research, Metro South Health, Brisbane,
Australia.
4Queensland Centre for Gynaecological Cancer, Royal Brisbane and Women’s
Hospital, Brisbane Australia
5Centre for Health Services Research, The University of Queensland, Brisbane,
Australia.
188
6.2. Abstract
Background: The prevalence of anxiety and depression, and psychological treatment
received by patients with endometrial cancer has rarely been studied. The primary
aim of this paper was to determine the point prevalence and cumulative prevalence
of anxiety and depression in patients with endometrial cancer and types of
psychological treatment received. The secondary aim was to evaluate the
sociodemographic and clinical factors associated with anxiety and depression from
before surgery to 6–month post–surgery.
Methods: Secondary data analysis of an international, multicentre, prospective
randomized controlled trial of surgery for stage I endometrial cancer was conducted.
Anxiety and depression was established by the Hospital Anxiety and Depression
Scale–21 (HADS). The subscale score (0–21) was divided into– normal (0–7),
borderline abnormal (8–10), and abnormal (11–21) anxiety and/or depression.
Regression models were fitted to examine the association of sociodemographic and
clinical characteristics of patients with anxiety and depression.
Results: Based on a HADS subscale score of ≥11, the highest prevalence of anxiety
occurred before surgery (n = 51/318; 16%), and the highest prevalence of depression
just after surgery (n = 18/314; 6%), respectively. The cumulative incidence of anxiety
only, depression only or both anxiety and depression in women within a 6–months
timeframe was 15.5% (n = 52/334), 1.8% (n = 6/334), and 7.2% (n = 24/334),
respectively. Very few of these patients received mental health support. Comorbid
conditions, prescriptions of antidepressants or anxiolytics already at baseline, and
non–European ethnicity were associated with depression.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 189
Conclusions: Up to 16% of patients with endometrial cancer experienced anxiety or
depression around the time of diagnosis and treatment, which is lower than reported
in broader gynaecological cancer samples. The majority of distressed patients did not
receive psychological or pharmaceutical treatments. Further research should aim to
identify reasons why patients did not receive support to alleviate anxiety and
depression.
6.3. Introduction
Endometrial cancer is the most common gynecological cancer [1] 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 out
of 43 countries between 2001–2010 [2]. Endometrial cancer primarily occurs in
postmenopausal women (median age 63 years) [3]. 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 [7].
Diagnosis and treatment can cause psychological distress for some women [8]. 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) [9]. Women
with endometrial cancer identified worry, focusing on getting well, and psychological
distress including anxiety and depression as the top three prioritized problems during
190
the 3–month perioperative period [10]. 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 or more (indicating elevated distress) was approximately four 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 two 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 two weeks after diagnosis in Japan (2007–2008)
reported that more than half of the patients (55%, n = 36/65) had a HADS score ≥11
[14]. 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 gynaecological cancer, but it was not possible to separate the anxiety
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 191
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.
6.4. Methods
Data were extracted from an international, multi–center 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 [21]. LACE commenced in October 2005
and recruited to June 2010, then followed patients for 4.5 years. Patients were
enrolled from 20 tertiary gynaecological oncology centers in Australia, New Zealand,
Scotland and Hong Kong. Data used for this secondary analyses were collected by
trained clinical trial nurses before surgery and then one–week, four–week, three–
month and six–month postoperatively.
192
6.4.1. Sample recruitment
The details of recruitment have been described elsewhere [21].
Briefly, patients were included, if they were i) 18 years or older, ii) had histologically
confirmed endometrioid adenocarcinoma of the endometrium of any grade, iii) an
Eastern Cooperative Oncology Group score of 0 or 1, and iv) 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, 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 was no longer collected for these
patients.
6.4.2. 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 [22].
BMI was categorized into normal (18.50–24.99), overweight (25.00–29.99) and
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 193
obesity (≥30.00). Clinical characteristics collected included surgical stage, medical
history of comorbidities (hypertension, diabetes, gastro–oesophageal reflux disease
(GORD), arthritis, asthma, hyperlipidaemia/ 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 counsellor in the 6 months since surgery was considered as
evidence for psychological treatment received beside cancer treatment.
6.4.3. Hospital Anxiety and Depression Scale (HADS)
Anxiety and depression were determined by the HADS [23]. This is a 14–item
questionnaire categorised into two sub–scales, anxiety (Cronbach’s Alpha = 0.875)
and depression (Cronbach’s Alpha = 0.817) each measured using seven 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 five 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.
6.4.4. Statistical analysis
Descriptive statistics were used to determine the rate and distribution of dependent
and independent variables. Univariate logistic regression models were used to
194
determine sociodemographic 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<0.20 with anxiety and
depression. Linear mixed models were used to determine the association between
patients mean anxiety and depression value over five time points and
sociodemographic and clinical characteristics. Pairwise interactions
(characteristics*time) were included, if their p–value was <0.2. 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.
6.5. Results
6.5.1. Sample characteristics
Overall, HADS data were available for 334 patients included in these analyses (Figure
6.5.1). Their sociodemographic and clinical characteristics are presented in Table
6.5.1.
Table 6.5.1: Patients characteristics (n = 334)
Sociodemographic characteristics n (%) Clinical characteristics n (%)
1. Age (Mean±SD) 62.7±9.9 1. Surgical Stage (n = 331)
≤65 200 (59.9) I 298 (90.0)
>65 134 (40.1) ≥II 33 (10.0)
Range 31–93 2. Comorbidities (n = 331)
2. BMI (n = 320) Hypertension 159 (48.0)
Normal (18.50–24.99) 44 (13.8) Hyperlipidaemia/ 78 (23.6)
Overweight (25.00–29.99) 71 (22.2) Hypercholesterolemia
Obesity class I (30.00–34.99) 78 (23.4) Diabetes 73 (22.1)
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 195
Obesity class II (35.00–39.99) 56 (16.8) Arthritis 61 (18.4)
Obesity class III (≥40) 71 (21.3) GORD 48 (14.5)
3. Education (n = 313) Asthma 43 (13.0)
Completed <12 years of school 209 (66.8) Past history of anxiety and/or 38 (11.5)
Completed ≥12 years of school 104 (33.2) depression
4. Employment (n = 318) History of previous cancer5 25 (7.6)
Retired 141 (44.3) 3. No of comorbidities (n = 331)
Full–Time/ Part–time/ Casual 83 (26.1) 0 46 (13.9)
Home duties/carer 65 (20.4) 1–2 131 (39.6)
Other1 29 (9.2) 3–4 99 (29.9)
5. Employment location (n = 310) ≥5 55 (16.6)
Indoors 191 (61.6) 4. Surgery6 (n = 333)
Both indoors and outdoors 103 (33.2) Abdominal Hysterectomy 139 (41.6)
Outdoors 16 (5.2) Laparoscopic Hysterectomy 194 (58.4)
6. Marital status (n = 318) 5. Adjuvant treatment7
Married/living together 213 (67.0) Yes 74 (22.2)
Other2 105 (33.0) No 260 (77.8)
7. Insurance3 (n = 318) 6. Prescription filled
Yes 89 (28.0) Antidepressants and/or anxiolytics 56 (16.7)
No 229 (72.0) No 278 (83.3)
8. Income (n = 318) 7. Visit mental health professionals
Less than AUS$40,000 209 (65.7) Yes 18 (4.8)
AUS$40,001+ 68 (21.4) No 316 (95.2)
Not stated 41 (12.9)
9. Birth country (n = 318)
Australia 221 (69.5)
Other 97 (30.5)
10. Ethnicity (n = 318)
European 251 (78.9)
Non–European4 67 (20.1)
SD– Standard deviation, BMI– Body–mass index, GORD– Gastro–oesophageal reflux disease. 1Student, unemployed or looking for work, self–employed, permanently ill/unable to work/disable, volunteer or other. 2Divorced/ Separated/ Widowed/ Single/ never married or other. 3Public insurance is universally available for all Australian citizen and permanent residence. 4Included Australian, Asian or not stated. 5Included breast (n= 10), skin (n= 8) and other (n= 7). 6One surgery was abandoned. 7Radiotherapy and/or chemotherapy
196
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 less than 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, 285/331 patients had one or more comorbid conditions,
whereas 38/331 already reported a past 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 one or more visits to
a mental health professional between baseline and 6 months post–surgery.
6.5.2. Anxiety and depression at five different time points
Figure 6.5.2a presents the number of sample completed HADS questionnaire at
different time points.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 197
Figure 6.5.2a: Sample completed HADS questionnaire at different time points
Figure 6.5.2b presents the prevalence of anxiety and depression in patients with
endometrial cancer at five time points.
198
Figure 6.5.2b: Prevalence of anxiety and depression from before surgery to 6–
month post–surgery
The change of anxiety and depression mean score with 95% CI over time is presented
the graphs and the data supporting these graphs are summarized in Figure 6.5.2c and
Table 6.5.2. The prevalence of anxiety was highest before surgery (≥11, 16%, n =
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 199
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) (see Figure 6.5.2b). 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.
Figure 6.5.2c: Change of HADS score: Before surgery to 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
200
decreased to 6–month post–surgery (2.1, 95% CI: 1.8–2.4) (see Figures 6.5.2b and
6.5.2c, Table 6.5.2).
Table 6.5.2: Borderline abnormal (8–10) and abnormal (≥11) anxiety and
depression with their change score at different time point
Time point Mean (CI)
Anxiety (n, %) Mean (CI)
Depression (n, %)
Normal Borderline abnormal
Abnormal Normal Borderline abnormal
Abnormal
Before surgery (n = 318)
6.6 (6.2–7.1)
208 (65) 59 (19) 51 (16) 3.2 (2.8–3.5)
286 (90)
21 (7) 11 (3)
Week–1 (n = 314)
5.3 (4.9–5.7)
241 (77) 44 (14) 29 (9) 3.6 (3.2–4.0)
276 (88)
20 (6) 18 (6)
Week–4 (n = 309)
4.0 (3.6–4.4)
264 (85) 30 (10) 15 (5) 2.5 (2.2–2.8)
287 (93)
16 (5) 6 (2)
Month–3 (n = 298)
3.6 (3.2–4.0)
258 (87) 23 (8) 17 (6) 2.1 (1.8–2.4)
281 (94)
13 (4) 4 (2)
Month–6 (n = 289)
3.6 (3.2–4.0)
249 (86) 28 (10) 12 (4) 2.1 (1.8–2.4)
275 (95)
11 (4) 3 (1)
CI: Confidence Interval
6.5.3. Treatments received for cumulative incidence of anxiety and depression
Table 6.5.3 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 (see Table 6.5.3). 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 (see Table 6.5.3), while
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 201
7.2% (n = 24/334) of patients had both anxiety and depression (≥11). Only 6/52 and
1/6 patient with anxiety or depression (≥11) visited mental health professionals,
respectively. Overall, 4/52 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 two of these
patients reported visiting a mental health care professional (see Table 6.5.3).
Table 6.5.3: Anxiety and depression of patients from before surgery to 6–month
post–surgery and their received treatments
Anxiety,
n = 334 (%)
Depression,
n = 334 (%)
Both anxiety and depression, n = 334 (%)
(≥8) (8–10) (>11) (≥8) (8–10) (>11) (≥8) (8–10) (>11)
Overall cumulative incidence*
149 (44.6)
73 (21.8)
76 (22.7)
73 (21.8)
43 (12.8)
30 (9.0)
– – –
Cumulative incidence of anxiety or depression only
91 (27.2)
39 (11.6)
52 (15.5)
15 (4.5)
9 (2.7)
6 (1.8)
58 (17.3)
34 (10.2)
24 (7.2)
Visit mental health professional (n = 14)
11 5/39 6/52 1 – 1/6 2 – 2/24
Antidepressants (n = 18)
6 3/39 3/52 – – – 12 7/34 5/24
Anxiolytics (n = 11) 3 2/39 1/52 1 1/9 – 7 3/34 4/24
Antidepressants & anxiolytics (n = 4)
– – – – – – 4 1/34 3/24
According to scoring instructions by Zigmond and Snaith, 8–10 considered as borderline abnormal
anxiety/depression, ≥11 considered as abnormal anxiety/depression. *Included patients with anxiety/depression only and both anxiety and depression.
202
6.5.4. 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 6.5.4a and 6.5.4b.
Table 6.5.4a: Factors associated with experiencing anxiety or depression (HADS
score ≥8) from before surgery to 6–month post–surgery
Anxiety (n = 334) Depression (n = 334)
Factors Yes
n=149(%)
OR (95% CI) p value Yes
n = 73(%)
OR (95% CI) p value
Sociodemographic characteristics
1. Age
≤65 101(67.8) 1 42(57.5) 1
>65 48(32.2) 0.54(0.35–0.85) 0.01 31(42.5) 1.13(0.67–1.91) 0.64
2. BMI
Normal & overweight (<30)
58(41.4) 1 25(37.3) 1
Obesity (≥30) 82(58.6) 0.65(0.41–1.04) 0.07 42(62.7) 0.93(0.53–1.62) 0.79
3. Education
Completed <12 years of school
88(63.3) 0.75(0.47–1.21) 0.24 46(67.6) 1.05(0.59–1.86) 0.86
Completed ≥12 years of school
51(36.7) 1 22(32.4) 1
4. Marital status
Married/living together
103(73.6) 1 44(63.8) 1
Other 37(26.4) 0.58(0.36–0.94) 0.02 25(36.2) 1.20(0.68–2.10) 0.52
5. Insurance3
Yes 42(30.0) 1 20(29.0) 1
No 98(70.0) 0.83(0.51–1.37) 0.48 49(71.0) 0.94(0.52–1.69) 0.83
6. Household income before tax
Less than AUS$40,000
80(57.1) 1 41(59.4) 1
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 203
AUS$40,001+ 36(25.7) 1.81(1.04–3.15) 0.03 13(18.8) 0.97(0.48–1.94) 0.93
Not stated 24(17.1) 2.27(1.15–4.50) 0.02 15(21.7) 2.36(1.15–4.86) 0.02
7. Birth country
Australia 96(68.6) 1 43(62.3) 1
Other 44(31.4) 1.08(0.67–1.74) 0.75 26(37.7) 1.51(0.86–2.65) 0.14
8. Ethnicity
European 102(72.9) 1 45(65.2) 1
Non–European 38(27.1) 1.91(1.11–3.30) 0.02 24(34.8) 2.55(1.41–4.63) 0.00
Clinical characteristics
1. Surgical Stage
I 131(89.1) 1 59(84.3) 1
≥II 16(10.9) 1.20(0.58–2.46) 0.62 11(15.7) 2.02(0.93–4.41) 0.07
2. Hypertension
No 84(57.1) 1 44(61.1) 1
Yes 63(42.9) 0.69(0.44–1.06) 0.09 28(38.9) 0.62(0.36–1.06) 0.08
3. Hyperlipidaemia/ Hypercholesterolemia
No 117(79.6) 1 57(79.2) 1
Yes 30(20.4) 0.72(0.43–1.22) 0.22 15(20.8) 0.82(0.43–1.54) 0.53
4. Diabetes
No 112(76.2) 1 55(76.4) 1
Yes 35(23.8) 1.20(0.71–2.02) 0.49 17(23.6) 1.12(0.60–2.08) 0.72
5. Arthritis
No 115(78.2) 1 59(81.9) 1
Yes 32(21.8) 1.49(0.85–2.59) 0.16 13(18.1) 0.97(0.49–1.90) 0.92
6. Gastro–oesophageal reflux disease
No 123(83.7) 1 56(77.8) 1
Yes 24(16.3) 1.30(0.70–2.40) 0.40 16(22.2) 2.02(1.04–3.95) 0.04
7. Asthma
No 128(87.1) 1 61(84.7) 1
Yes 19(12.9) 0.99(0.52–1.88) 0.99 11(15.3) 1.28(0.61–2.68) 0.51
8. History of previous cancer
No 137(93.2) 1 65(90.3) 1
Yes 10(6.8) 0.82(0.36–1.89) 0.64 7(9.7) 1.44(0.57–3.60) 0.43
9. No of comorbidities
204
0 24(16.3) 1 14(19.4) 1
1–2 51(34.7) 0.58(0.29–1.15) 0.12 24(33.3) 0.51(0.24–1.10) 0.08
3–4 46(31.3) 0.79(0.39–1.60) 0.52 15(20.8) 0.41(0.17–0.94) 0.03
≥5 26(17.7) 0.82(0.37–1.80) 0.62 19(26.4) 1.20(0.52–2.79) 0.66
10. Surgery
Abdominal Hysterectomy
61(41.2) 1 31(43.1) 1
Laparoscopic Hysterectomy
87(58.8) 1.04(0.67–1.61) 0.86 41(56.9) 0.93(0.55–1.58) 0.80
11. Adjuvant treatment
No 116(77.9) 1 55(75.3) 1
Yes 33(22.1) 1.00(0.59–1.68) 0.99 18(24.7) 1.20(0.65–2.20) 0.56
12. Antidepressants and/or anxiolytics
No 121(81.2) 1 53(72.6) 1
Yes 28(18.8) 1.24(0.70–2.20) 0.45 20(27.4) 2.28(1.23–4.25) 0.01
OR– Odds Ratio, CI– Confidence Interval.
Bold value showed statistically significant (p<0.05) associations with anxiety and depression.
In multivariable analyses, marital status (other than married or living together) and
non–European heritage remained significantly associated (p<0.05) with anxiety in
patients with endometrial cancer. Non–European heritage, comorbidities and being
prescribed with antidepressants and/or anxiolytics were significantly associated
(p<0.05) with depression (see Table 6.5.4b).
Table 6.5.4b: Multivariable logistic regression model
Factors Anxiety Depression
OR (95% CI) p value OR (95% CI) p value
1. Marital status Married/living together 1 – – Other 0.59(0.35–1.00) 0.05 – –
2. Ethnicity European 1 1 – Other 1.85(1.01–3.39) 0.04 2.80(1.46–5.38) 0.00
3. No of comorbidities 0.08 0 – – 1 – 1–2 – – 0.43(0.18–1.02) 0.05 3–4 – – 0.34(0.12–0.98) 0.04 ≥5 – – 0.76(0.25–2.26) 0.62
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 205
4. Antidepressants and/or anxiolytics No – – 1 – Yes – – 2.21(1.08–4.50) 0.03
OR– Odds Ratio, CI– Confidence Interval.
6.6. Discussion
6.6.1. Main findings
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 [13], 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 one
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, (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 [24 p362].
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
(see Table 6.5.3). These results are consistent with previously conducted studies on
patients with gynaecological cancer [18] or patients with any types of cancer [25–
29], which also reported under–treatment of psychological distress. Several factors
206
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 [30]. Health
care professionals involved in cancer treatment may find it difficult to differentiate
between psychological symptoms and cancer–treatment related symptoms [31],
may consider the symptoms as normal response to a cancer diagnosis [32], 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 three mediators including acceptance
coping, acceptance of emotion and social support may reduce depression in cancer
patients, and proved this theory in patients with gynaecological cancer [33].
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 an antidepressants or anxiolytics prescription 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 screening tool, where married patients reported a higher rate of anxiety
in Australia (31%), [36] and in China (79.9%) [37], and may reflect greater worry on
how the partner may cope impacting on women’s own wellbeing. Patients with one
and more comorbidities had lower odds of depression (1–2, OR: 0.43; 3–4, OR: 0.34).
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 207
Although previous study found that depression is a risk factor for chronic diseases
including heart disease, diabetes [38], the treatments received for these chronic
diseases may reduce depression in patients [39]. 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 [40].
6.6.2. Study strengths
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 analysed 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.
6.6.3. Study limitations
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 one
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
208
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 diagnose at early stage
due to abnormal uterine bleeding [40].
6.6.4. Future research
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 [42,43]. 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.
Acknowledgments
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 209
Saira Sanjida was funded by Advance Queensland Scholarship. Monika Janda was
funded by NHMRC Translating Research into Practice fellowship APP1151021. Steven
M. McPhail was funded by an NHMRC Fellowship (APP1090440). This project was the
part of LACE Trial which 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
Gynaecological Cancer, Genesis Oncology Trust, and the Cherish Foundation.
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Supplementary Materials: Parameter estimates, interaction for anxiety and
depression
Table 1: Linear mixed model: Parameter es mates†
Anxiety Depression
Factors Mean (SE)
95% CI P
value Factors
Mean (SE)
95% CI P
value
Main effects
1. Visit number 0.001 1. Visit number 0.001 Before surgery
8.43(0.80) 6.85–10.02
Before surgery
4.88(0.60) 3.69–6.07
Week–1 7.17(0.80) 5.58–8.76 Week–1 5.34(0.60) 4.15–6.53 Week–4 5.94(0.81) 4.35–7.53 Week–4 4.30(0.60) 3.00–5.49 Month–3 5.67(0.81) 4.08–7.26 Month–3 3.96(0.60) 2.76–5.15 Month–6 5.66(0.81) 4.07–7.26 Month–6 4.08(0.60) 2.89–5.27
2. Ethnicity 0.001 European 5.80(0.78) 4.27–7.35 Other 7.34(0.88) 5.60–9.08
OR– Odds Ratio, CI– Confidence Interval, SE– Standard Error. †Income for anxiety and hypertension for depression was interacted with visit number and showed statistically significant association (p<0.05). The parameter of estimates and line graph is presented in the Supplementary material 2.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 217
Table 2: Interaction for anxiety and depression
Factors Mean
(Standard Error) 95% Confidence
Interval P value
Anxiety: Income*Visit number 0.001
≥AUS$40,001*Before surgery 8.71(0.61) 7.51–9.90 Not stated * Before surgery 8.55(0.64) 7.28–9.82 <AUS$40,000*Before surgery 6.91(0.38) 6.17–7.65 ≥AUS$40,001*Week–1 5.60(0.61) 4.40–6.79 Not stated *Week–1 6.64(0.65) 5.36–7.92 <AUS$40,000*Week–1 5.14(0.38) 4.39–5.89 ≥AUS$40,001*Week–4 5.13(0.61) 3.93–6.34 Not stated *Week–4 4.75(0.65) 3.47–6.04 <AUS$40,000*Week–4 4.43(0.38) 3.68–5.18 ≥AUS$40,001*Month–3 4.95(0.62) 3.73–6.17 Not stated *Month–3 4.83(0.67) 3.51–6.16 <AUS$40,000*Month–3 3.84(0.38) 3.08–4.60 ≥AUS$40,001*Month–6 4.49(0.62) 3.27–5.71 Not stated*Month–6 5.41(0.68) 4.06–6.75 <AUS$40,000*Month–6 3.78(0.39) 3.01–4.55
Depression: Hypertension*Visit number 0.03
No*Before surgery 4.83(0.47) 3.89–5.76 Yes*Before surgery 4.09(0.45) 3.20–4.99 No*Week–1 4.94(0.48) 4.00–5.89 Yes*Week–1 3.76(0.46) 2.85–4.67 No*Week–4 3.64(0.48) 2.70–4.58 Yes*Week–4 3.07(0.56) 2.17–3.97 No*Month–3 2.94(0.48) 1.99–3.90 Yes*Month–3 2.48(0.46) 1.57–3.39 No*Month–6 3.23(0.49) 2.25–4.21 Yes*Month–6 2.90(0.47) 1.97–3.83
218
Figure A: Line graph between the interaction of anxiety and income at five
different time point
Figure B: Line graph between the interaction of depression and hypertension
(HTN) at five different time point
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 219
Chapter 7: Psychological wellbeing in long‐term
endometrial cancer survivors
7.1. Psychological wellbeing of long–term endometrial cancer survivors: A
qualitative study
Building on the evidence in the literature, and the quantitative data analyses
reported in Chapters 5 and 6, this final research component of the PhD focussed on
understanding the experience of patients in the areas found to be lacking in previous
research (see Chapters 5 and 6).
Figure 7.1: PhD project structure: Chapter 7—Psychological wellbeing in long‐term
endometrial cancer survivors
220
Data collected in semi–structured interviews were used to better understand the
psychological wellbeing of women with endometrial cancer throughout their
survivorship. Further, it was used to identify the psychological and pharmacological
treatment profiles provided for anxiety and depression to long term survivors, as well
as benefits provided by such treatments from the perspective of the patients. This
chapter has been prepared in manuscript form for submission to a peer–reviewed
journal.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 221
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2. they take public responsibility for their part of the publication, except for the responsible author who accepts overall responsibility for the publication;
3. there are no other authors of the publication according to these criteria; 4. potential conflicts of interest have been disclosed to (a) granting bodies, (b) the
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Please state the publication title and date of publication or status: Psychological wellbeing in long‐term endometrial cancer survivors. Manuscript in preparation.
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Saira Sanjida Conception and design, data cleaning and coding, extraction and assembly of data, data analysis and interpretation, drafting of manuscript, critical revision and final approval of manuscript
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Date: 18.02.2020
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222
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 223
Psychological wellbeing in long‐term endometrial cancer survivors
Saira Sanjida1, Steven M. McPhail1,2, Andreas Obermair3, Monika Janda1,4
Authors' information:
1School of Public Health and Social Work, Institute for Health and Biomedical
Innovation, Queensland University of Technology, Brisbane, Australia.
2Centre for Functioning and Health Research, Metro South Health, Brisbane,
Australia.
3Queensland Centre for Gynaecological Cancer, Royal Brisbane and Women’s
Hospital, Brisbane Australia
4Centre for Health Services Research, The University of Queensland, Brisbane,
Australia.
224
7.2. Abstract
Background
Five‐year survival outcomes of women with early‐stage endometrial cancer are good
at over 86%; however, little is known about patients’ long term psychological
wellbeing, given that anxiety and depression are commonly reported shortly after
diagnosis. There is minimal data on whether wellbeing remains affected throughout
survivorship, whether women receive psychological or pharmacological treatment
when required, or whether this is beneficial. This study aims to understand the
psychological wellbeing of women with endometrial cancer during long‐term
survivorship and to describe support and treatment they received for anxiety and
depression.
Methods
Semi‐structured telephone interviews were conducted with 17 long term
endometrial cancer survivors. Participants were women aged 46–73 years who had
received surgical treatment within the LACE trial 7–10 years earlier. Thematic
analysis was performed by two researchers to extract the most relevant codes
related each theme.
Results
Seventeen women were interviewed. Four major themes were identified, including
how psychological wellbeing changed from diagnosis to survivorship,
pharmacological treatment of distress, psychological treatment and support, and
strategies for psychological wellbeing. Women tolerated surgery well
psychologically; however, some faced persistent or newly developed distress during
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 225
survivorship. Few women actively seek pharmacological or psychological support to
overcome distress. The women were more interested in complementary and
alternative treatments, and many used exercise, meditation and walking to improve
or sustain psychological wellbeing.
Conclusions
Women preferred psychological treatment and complementary and alternative
medicines (CAM) over pharmacological treatments due to their interest in natural
healing or therapies and achieving a healthy lifestyle. Future research should
consider studying in depth the types or and reasons for CAM received by women with
endometrial cancer.
7.3. Introduction
The incidence rate of endometrial cancer continues to increase in developed and
developing countries throughout the world [1,2]. Excessive BMI and chronic
comorbidities are the main risk factors associated with endometrial cancer [3].
Fortunately, four out of five patients may survive for over five years if diagnosed with
stage I endometrial cancer, which is common, as it presents with symptoms such as
irregular or postmenopausal bleeding [4,5]. Surgical procedures, including
hysterectomy and bilateral salpingo‐oophorectomy (with or without
lymphadenectomy), are the main treatment approaches for endometrial cancer [6].
Survivorship wellbeing may be negatively impacted if women feel they cannot cope
well themselves with treatment or the fact that they were diagnosed with cancer [7].
Diagnosis and surgical treatment may be extremely stressful for some women,
226
especially those who suffered from anxiety, depression or other psychological
morbidity already before the cancer diagnosis [8]. However, the trajectory of changes
in women’s psychological wellbeing during long–term survivorship is under‐
researched.
Few quantitative and qualitative research studies have been conducted on
psychosocial recovery in women with endometrial cancer. An Italian study (n = 132)
reported high prevalence of sub‐clinical and clinical anxiety and depression (using
HADS) among women with endometrial cancer at the time of surgery (42% and 15%,
respectively) [9]. In contrast, a much lower sub‐clinical and clinical prevalence was
found in Australian study (n = 629) on 3–5 years after diagnosis (25.4% for anxiety
and 10.6% for depression, respectively) [10]. Very few studies have studied in depth
the lived experiences and psychological wellbeing throughout survivorship. In a
mixed‐methods analysis, women with endometrial cancer (n = 52; 2011–2012) in
Denmark reported major psychological problems such as anxiety and depression
after worrying and focusing on becoming well within the first three months after
surgery. [8] Rowlands et al. (2015) conducted a thematic analysis of open‐ended
comments on a questionnaire by Australian women within 3–5 years of endometrial
cancer survival (n = 237) (diagnosed between 2003 and 2005), who underwent both
surgical and adjuvant treatments [11]. Some women faced ongoing and severe
distress, and reported they needed social support from their families and doctors to
aid in emotional wellbeing. However, neither of these studied followed women
beyond five years into long‐term survivorship.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 227
When we considered studies conducted on women with gynaecological cancers
more broadly—some of which included, but did not report separately, women with
endometrial cancer—only one examined psychological wellbeing while also
considering psychosocial support [12]. Kimmel et al. (2014) used both the Structured
Clinical Interview for Diagnosis (SCI‐D) and a semi‐structured interview to assess
women’s experiences and assess their needs. They discovered that family and social
wellbeing were strongly associated with lower levels of anxiety. Fewer than one–
third of women who were diagnosed with anxiety (≥ 10 using both Generalized
Anxiety Disorder–7 and Patient Health Questionnaire–9) had been seen by a
psychiatrist [12]. Further, the impact of psychological or pharmaceutical treatment if
received, on women’s wellbeing was not been explored in detail.
In our previous quantitative analyses (n = 719), we identified a number of evidence
gaps including mismatches between pharmacological treatments and self–reported
anxiety and depression; furthermore, limited data were available on the types of
psychological treatment received [13]. When anxiety and depression were measured
(n = 334) using the HADS, we found that most women diagnosed with clinically
elevated levels of anxiety and depression (scoring ≥ 11) did not receive psychological
or pharmacological treatment [14]. From this survey data, it could not be determined
whether women used other self–management techniques to improve their anxiety
and depression or received social support, which then influenced them to not
undergo pharmacological or psychological treatment. To address these knowledge
gaps, the present interview–based qualitative study was conducted on women with
stage I endometrial cancer at least 4.5 years after surgery. The primary aim of this
228
study was to understand in depth the psychological wellbeing of women with
endometrial cancer from diagnosis to long–term survivorship. The secondary aim
was to identify what support, psychological or pharmacological treatment women
received and whether it was helpful for their recovery from anxiety and depression.
7.4. Methods
7.4.1. Sample recruitment
This was a qualitative study collecting data via semi–structured interviews of women
who participated in the long–term follow–up of the LACE (The Laparoscopic
Approach to Cancer of the Endometrium) trial (ClinicalTrials.gov: NCT00096408;
Australian New Zealand Clinical Trials Registry: CTRN12606000261516). The LACE
randomised clinical trial was conducted from 2005 to 2010, then followed–up all
participants for 4.5 years. The details of sample recruitment have been described
elsewhere [15]. The flow diagram of sample recruitment throughout the LACE study
is presented in Figure 4.2.2. During the 4.5–year follow–up study, women were asked
to complete a self–report questionnaire about their survivorship experiences,
lifestyle and quality of life. At the end of the questionnaire, they were also asked to
participate in a recorded telephone interview. These interviews were conducted
from July to December 2017.
7.4.2. Data collection
Sociodemographic and clinical characteristics
Sociodemographic and clinical characteristics were collected from the baseline and
4.5–year follow–up questionnaires, including: age, height, weight, education and
birth country. Body mass index (BMI) was calculated and grouped using weight and
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 229
height data, in accordance with the World Health Organization [16]. The clinical
characteristics included date of hysteroscopy (used as a proxy for the date of
endometrial cancer diagnosis), comorbidities (hypertension, diabetes, anxiety,
depression), previously diagnosed cancers, surgery type (total abdominal or total
laparoscopic hysterectomy), adjuvant treatment and visits to a psychiatrist,
psychologist or other mental health counsellor at six–month post–surgery and 4.5
years follow–up.
Data on the anxiety and depression scores using the HADS–21 were collected [17].
This is a 14–item questionnaire divided evenly into two sub–scales: anxiety and
depression. Each item is rated from 0 to 3; some are reverse–coded. A sum score was
computed for both anxiety and depression. The score (which ranges from 0 to 21)
can be considered normal (0–7), borderline abnormal (8–10) or abnormal (11–21) to
indicate anxiety and/or depression.
Interviews
For each telephone interview, separate signed written consent forms were collected
from the participants. Mutually suitable times for telephone interviews were
arranged and women were also informed of the main purpose of the study.
Interviews began with questions on wellbeing around the time of cancer diagnosis,
surgery and survivorship, with a focus on psychological well–being. The interviews
were conducted by MJ, a health psychologist with extensive experience supporting
cancer patients. The interviews were 20–40 minutes long and were professionally
transcribed verbatim.
230
7.4.3. Data analysis
A thematic analysis of the transcripts was conducted according to Braun and Clark
(2006, 2014) [18,19]. Two researchers (SS and LC; backgrounds in pharmacy and
psychology, respectively) analysed all transcribed interviews, utilising the following
methods: (i) each researcher read the transcripts individually to generate initial
codes of the study, (ii) codes were combined with meaningful statements to make
themes, (iii) researchers prepared a thematic map of the analysis, (iv) compared their
codes, to be evaluated and checked by the other researcher, (v) the themes and
coding were discussed in detail in a group meeting to identify the commonalities, (vi)
coded data were separated according to the themes, (vii) and finally, the results were
summarised according to the thematic map. Descriptive statistics were used to
present the participants’ characteristics and psychological treatment received, using
SPSS software, version 25.0.
7.5. Results
7.5.1. Participant characteristics
The characteristics of the 17 women who participated in the study (Figure 7.5.1) are
presented in Table 7.5.1.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 231
Figure 7.5.1: Flow diagram of participant numbers throughout the LACE trial
The mean age at surgery was 58.1 years (range: 46–73 years). The mean weight was
91.5 kg at surgery, which decreased to 87.9 kg at the 4.5 years follow–up. Two
women were found to have a normal BMI; others were overweight (n = 4/17) or
obese (n = 10/17) at interview. The majority of women were born in Australia (n =
14/17).
232
Table 7.5.1: Participant characteristics (n = 17)
Sociodemographic characteristics At surgery 4.5 years follow‐up interview
1. Age (mean, range) 58.1 (46–73)
2. Weight (mean, range) 91.5 (53–132) 87.9 (50–111)1
3. Body mass index (BMI) Normal (18.50–24.99) 2 (11.7) Overweight (25.00–29.99) 4 (23.5) Obesity (30.00–34.99) 10 (58.9) Not stated 1 (5.9)
4. Education Primary school 2 (11.8) High school 8 (47.1) Trade/technical/diploma 3 (17.6) College/university degree 4 (23.5)
5. Birth country Australia 14 (82.4) Scotland, New Zealand, USA. 3 (17.6)
Clinical characteristics
1. Comorbidities Hypertension 4 (40.0) 6 (35.2) Diabetes 3 (30.0) 4 (23.5) Anxiety and/or depression 3 (30.0) 4 (23.5)
2. Time since diagnosis of endometrial cancer (years) ≥ 7 7 (41.1) ≥ 9 10 (58.9)
3. Type of surgery received– Abdominal hysterectomy 8 (47.1) Laparoscopic hysterectomy 9 (52.9)
4. Adjuvant treatment 3 (17.6)
5. Previous history of other cancer2 5 (33.3)
6. Family history of cancer 3 (17.6)
7. Had visited a psychiatrist, psychologist or other mental health counsellor–
1 (5.9)
3 (17.6)
8. Prevalence at 4.5 years’ follow‐up: HADS anxiety Normal (0–7) Borderline abnormal (8–10)
14 (82.4) 3 (17.6)
9. Prevalence at 4.5 years’ follow‐up: HADS Depression Normal (0–7) Borderline abnormal (8–10)
13 (76.5) 4 (23.5)
1n = 16; 2Only 15 data were available. Five of them were diagnosed with breast cancer (n = 3), basal and renal cell carcinoma (n = 2).
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 233
At follow–up, six and four women had comorbid hypertension and diabetes,
respectively. Eight women were diagnosed with endometrial cancer ≥ 10 years prior
to the interview. Three women had visited a psychiatrist, psychologist or mental
health professional during survivorship, whereas only one woman did so at the time
of surgery. At follow–up and according to the HADS results, three and four of the 17
women had high scores in accord with borderline elevated anxiety and depression,
respectively.
7.5.2. Profiles of patients who received psychological treatments, antidepressants
and/or anxiolytics during long–term survivorship
The profiles of eight women who received psychological treatments, antidepressants
and/or anxiolytics are presented the Table 7.5.2. Anxiolytics, such as diazepam and
oxazepam, were prescribed mainly around the time of surgery and were not
continued during the 6–month post–surgery follow–up or survivorship. One
participant was prescribed an antidepressant at the time of surgery. Four different
antidepressants (citalopram, duloxetine, desvenlafaxine and paroxetine) were
prescribed to five women during the 4.5–year follow–up period. The primary reasons
for these prescriptions were depression (n = 2) and panic attacks/anxiety (n = 1). Two
women were prescribed antidepressants for other purposes, such as treating the side
effects of fibromyalgia and to control vertigo.
234
Table 7.5.2: Profiles of women who received psychological treatments,
antidepressants and anxiolytics during long–term survivorship
Anxiolytics (AX, n = 2) Antidepressants (AD, n = 5) No AX or AD
Diazepam Oxazepam Desvenlafaxine Citalopram Duloxetine Paroxetine –
Sample ID S7 S17 S12 S1 S9 S16 S14 S10
At surgery Yes Yes Yes No No No –
Post–surgery
follow–up
No No No – – – – –
At 4.5–year
follow–up
No No No Yes Yes Yes Yes –
Dose 10 mg 3.8 mg – 100 mg 5 mg 60 mg 20 mg –
Previously
prescribed
– – Sertraline – Others, not
stated
Fluoxetine
20 mg
– –
Primary
reason
– – Depression Control
vertigo
Depression Side effect of
fibromyalgia
Panic attack,
anxiety
Stress
Secondary
reason
– – – Anxiety, calm
down
– – – –
Comorbidity
at follow–up
Mental
illness
Anxiety Anxiety – Anxiety – –
Who
prescribe
Case
manager
of mental
health
– – General
practitioner
General
practitioner
– – –
Side effect – – – – Nausea – – –
Consulted a
psychologist
– – Yes – Yes (recently) – – Yes
(Relaxation)
General practitioners (n = 2/5) or mental health case managers (n = 1/5) prescribed
the antidepressants, while the prescribing doctor was unknown for two of the
patients. Besides pharmacological treatment, two women saw psychologists for the
treatment of depression. One woman, who was not prescribed any anxiolytic or
antidepressant, received relaxation treatment for stress from a psychologist.
7.5.3. Qualitative findings
Figure 7.5.3 provides an overview of the thematic map extracted from the interview
transcripts: 1) Psychological well–being during cancer diagnosis and survivorship; 2)
Pharmacological treatment for symptoms of distress; 3) Psychological treatment and
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 235
support; and 4) Strategies to achieve psychological well–being. These themes are
described in more detail accompanied with direct quotes exemplifying related
statements made by the women during the interviews.
Figure 7.5.3: Themes and groups derived from semi–structured interviews of
psychological wellbeing of long–term endometrial cancer survivor
Theme 1: Psychological well–being during cancer diagnosis and survivorship
The interviews began by asking participants to recall how they reacted
psychologically the diagnosis of cancer. Women expressed their reactions to the
cancer diagnosis in the following ways:
•Diagnosis
•Surgery experience
•Symptoms of distress during survivorship
•Factors affecting psychological wellbeing
Psychological wellbeing during
cancer diagnosis and survivorship
•Reason for anxiety or depression
•Improvement of anxiety or depression
•Side effect of medications
•Goal to be drug‐free, despite the fact medication can improve depression
Pharmacological treatment of distress
•Met psychologist
•Preferred psychological treatment over medications
•Engaged social support or community support
•Sought support elsewhere
Psychological support and treatment
•Meditation
•Exercise
•Positive thinking
Strategies to acheive psychological wellbeing
236
When I first was diagnosed with the cancer, I was like ‘oh my God’, and it was
like being hit in the face with a wet fish as they say. I got such a shock. But I
was so shocked. I burst into tears because you think the worst. (S9)
You are always going to have some sort of distress when you’ve been given a
diagnosis but it depends on your own mindset. (S4)
The women were all treated through hysterectomy using either a total abdominal or
total laparoscopic surgical approach. When the women were asked about their
surgery experiences, many had expressed very positive views of the surgical
procedure and healing, including for example: ‘really good’, ‘so quick’, ‘fantastic’,
‘healing time … zero’, ‘extremely happy’, ‘no side/after affects at all’, ‘felt so well’.
However, one woman stated that the long waiting period for surgery was ‘very
distressing’:
I only got distressed when I thought about it. I wanted to get it over and done
with so that the period of waiting, just the 30 days that I had to wait, was just
like ‘I wish it would hurry up, is it growing any quicker, what’s happening’.
And you have all those thoughts going through your head and that was the
distressing time. Very distressing. (S9)
When the interviewer asked about the psychological distress symptoms experienced
during their survivorship, some of the women reported symptoms, including anxiety,
panic attacks, pain and worrying about possible recurrence of cancer. Sometimes,
the side effects of hormonal treatments also caused psychological distress. Among
the participants, two women reported persistent symptoms of distress, while the
others faced recurring, occasional or newly developed symptoms:
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 237
I have a tendency towards anxiety and so forth. I have an anxious kind of
disposition. (S1)
I think I find, too, that the ARIMIDEX tends to—I can get a bit grumpy
sometimes, overtired, and I think that’s all part of the medication, too … And
I suppose just the condition, as well, when you’re in pain and you’re overtired
and that, it’s easy to get a bit grumpy. (S2)
I’ve got anxiety, like panic attacks … I couldn’t do anything, and I’ve had these
panic attacks. I couldn’t go outside and my heart raced, but they put me on a
low dosage [Paroxetine] of that too, and I often have a little one every now
and again. (S15)
I talked myself out of my anxiety attacks, and I haven’t had one for years now.
(S16)
Now I’m worried now I’m going to have cancer; cancer seems to hit me every
10 years. So yeah, so I’m worried that it’s coming up to the 10th year and I’m
going to have another bout of something and I’m hoping—I know that sounds
sort of silly but that’s the way it is and I’m thinking, ‘oh if I can’t get through
this I can get through anything’ but—well just about. (S9)
Anyway, I’m not too worried about having cancer again. I suppose, in the back
of your mind, it’s always there. Every time I get terrible stomach ache or
something: ‘What could it be?’ (S17)
A number of other factors also affected the psychological well–being of participants.
Two women, being a single parent and carer, respectively, stated how the cancer
238
diagnosis caused psychological distress, as they thought about how their families
would cope without them. Another woman mentioned the death of her father and
associated other factors causing panic attacks:
So, I worried about my children. That was the distressing thing more than
anything because they didn’t have anybody else except me … And that was a
big issue because I am a very family–oriented person and that distressed me
quite a bit. (S9)
But it was hard. Like I said, we had these three little girls and I was kind of a
bit depressed in the beginning about what had happened to me. I thought,
‘oh I just’—but I thought, ‘I can’t help it, I’ve got to keep going for these little
kids’. (S10)
I’ve got anxiety, like panic attacks, but that mainly happened after my dad
passed and a couple of other things happened at the same time, and I just
laid on the couch and cried. I couldn’t do anything, and I’ve had these panic
attacks. (S15)
Theme 2: Pharmacological treatment of distress
After discussing psychological distress, the interview considered pharmacological
treatments, such as prescriptions of antidepressants and anxiolytics for depression
and anxiety that were received by the women. Interestingly, participants commonly
stated they were prescribed antidepressants for other reasons besides depression:
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 239
Yes. I’m on an antidepressant, but I’m not on that for depression. The side
effect is a pain blocker for my muscle pain, from the fibromyalgia. And it
seems to be working really well. (S16)
I take Pristiq, 100 mg per day, which was told to me that it was to control my
vertigo. (S1)
A woman who was initially reluctant to take antidepressants for depression later
began a course of treatment and stated that it improved her depression:
I feel I’m being undermined or lied to. And the doctor asked me to go on
tablets years ago and I didn’t do it. I probably should have then, but I am—I
have been on them for [three] years now. They’ve helped. (S9)
Another woman, who was prescribed different antidepressants due to the side
effects experienced, did not continue treatment:
I mean, I was on an antidepressant years ago, and it was an old one, really old
one. But he tried a couple new ones first, just sick. Made me nauseous. (S12)
Two women expressed strong initial reluctance to take medications for depression
and hoped to be drug–free, despite the fact that medication improved their
symptoms. One woman, who claimed to be physically and psychologically healthy,
shared a strong opinion about medicines. She stated that she did not wish to take
medications for psychological distress:
I don’t know. I’m pretty casual. I don’t like stress. I hate stress. I hate
confrontation. I like my peace and quiet … I think I got in a bad habit. I just
240
don’t know. Honestly, because he says to me—he’s [psychologist] trying to
work on what stresses I have, ‘what are the things in your life that you can’t
deal with?’ Yeah so anyway, at least I’m proactive and I went to the doctor
because I don’t want to take drugs [for psychological distress] or anything.
(S10)
Another woman reported a desire to be avoid medications after becoming interested
in natural therapies:
Participant: I’m hoping to be drug–free by the end of this year.
Interviewer: But still, you notice when you don’t take those at the moment,
it’s not that good…
Participant: Oh yes, it’s not good, no. (S1)
Theme 3: Psychological treatment and support
Beyond antidepressant prescriptions, two women stated they had recently met with
a psychologist and had begun psychological treatment for ongoing depression:
Yeah, I have been seeing a psychologist recently because I was having some
issues again and I wasn’t coping and I was on the antidepressants. So, and just
talking through things with her and things like that. (S9)
I still am [concerned the cancer will spread]. I’m still going through that sort
of thing. I have seen the psychologist on a couple of occasions—lots of
sessions, different people, and I’m actually going again next year. (S12)
One participant (S10) who was reluctant to take antidepressants preferred to receive
psychological treatment:
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 241
And I actually am seeing a psychologist at the moment. I’m doing 10 sessions
with him to try and help me to relax, to learn to switch off and be able to relax
at night to try and get to sleep because it’s really—I said to him, I said, ‘Most
times, I can just get to sleep but then I wake up about midnight and there’s
no way I can get back to sleep’. So, he’s helping me at the moment to try and,
yeah, to relax more and to help my mind switch off. (S10)
Participants reported that social or community support from family, friends, pets and
colleagues helped their psychological well–being during surgery and recovery:
Well I got a puppy when I had the surgery and he helped me through the
recovery time because I got him not long after I had the surgery so that was
really good … But the hospital were—it’s not there all the time. It’s not
somebody you can call all the time. It’s not someone you can lean on all the
time. You’ve got to lean on your family, you’ve got to have your family
support. You’ve got to start to think positive. (S9)
And as long as you’ve got good support in family and friends and work
colleagues, which I’ve always had. (S4)
I’m very grateful for my beautiful family. (S1)
Besides psychological treatments received from psychologists, some participants
preferred to seek support elsewhere, for example, a cancer support group,
homeopathy or a chiropractor:
It was relaxation and basically connecting to your own inner knowing and
strength. So, yeah, so it would always start off with breathing and relaxing or
242
relaxing all your muscles. I actually started a—I know whether you’ve heard
of CanSurvive, which is a cancer support group up in Nambour and I was living
at Gympie at the time, and I started a branch of that at Gympie. I started a
cancer support group there, so I used to do a healing meditation and take
people in and let them go into the site that they were having trouble with and
take their breath into it and breathe it away, and that sort of thing. That would
help, visualise their body healed and well, and that sort of thing. (S2)
Because I’m also seeing a homeopathic lady, we were talking about all these
things—this is only just recently, so I only found this out recently; that’s how
my body handles it. Even in my head, I don’t feel the stress. My body is
actually taking it on, and it’s coming out through my body, and not in my head.
If that makes sense? (S6)
I have a fantastic chiropractor. I’ve been going to him for 20 years, and he is
a holistic believer as well. Every now and then, when I get a bit jaded, or I get
a bit down, or I’ve done something silly like I did a couple of weeks ago, and
ripped my shoulders out, he’s philosophic. He knows my history; he knows
my body type and so forth, and he is just so—he’s brilliant. I really have great
faith in him. (S1)
Theme 4: Strategies for psychological wellbeing
When asked about their strategies for psychological wellbeing during survivorship,
the participants reported that positive thinking was one of the best strategies to
reduce stress:
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 243
I think on the whole that I’m pretty well adjusted and I have a philosophical
outlook that I feel is pretty positive, and I’m very grateful for my beautiful
family. I know I’m one of the people who has been extremely lucky in my
journey, so I don’t really have any complaints of any sort. I have my own
problems, but I cope with them. I am grateful for my life, so I don’t have any
negatives to report, I don’t think. (S1)
I’m very aware [that] this is going to be a continuing thing for the rest of my
life so you have to accept that. You just have to accept that fact and then live
your life as you normally would, otherwise it’s not much, just sitting at home
feeling sorry for yourself. (S4)
I know to just go outside and breathe and get control. But, they’re the only
two things I do have … But, it’s no good thinking that way because that’s not
going to help you, so you’re better off being positive, and I think that’s a big
thing in getting through those times. Be positive and be grateful for what
you’ve got and what time you’ve got with your family and friends. (S14)
The women reported using a combination of techniques, which improved
psychological well–being during survivorship. These included multiple exercises,
meditation, Qi Gong and Pilates:
I have tried a variety of different sorts of exercises, and I find it’s just better
to do everything myself. Like, I still clean my own house, whereas I’ve got
friends who don’t even sweep their floors. When I go shopping, if it’s less than
three floors I go up the stairs. I don’t park my car very close to where—and, I
244
think that sort of exercise, and doing everything around the house like taking
out the garbage, hanging out the washing—all of that I do myself. I don’t have
structured exercises sessions. (S13)
No, I never took any antidepressants or anything like that, no. I guess that’s
where I use the meditation and that sort of thing, too. I think if I’m feeling
overwrought or getting stressed, then one of the best things for me to do is
quiet time and being able to sit down and meditate and just go into a quiet
space and just connect with that inner knowing that you have inside and find
peace, basically … I think so. I think they do strengthen—I think exercise is
really good for you in lots of ways, not only physically but I think it’s mentally
good for you, too, because I think it does help you feel better and I think it
helps with your breathing … But we do at least a half an hour’s walk every
morning. We get up early and do that walk … now if I get too much pain and
just the only thing that will relieve it is if I lay down. So, I lay down and then
get up and go and do more or if it’s still painful, then I just lay for a bit longer.
So, I guess I’ve learnt to manage things and learnt to live with it, I guess. (S2)
Yes, and for the mind as well, try and relax your mind. It’s so gentle and it’s
beautiful because I live here near the beach and I walk first of all and then I
do the Qi Gong and we’re on the grass just up from the beach with the sun
rising and it’s just absolutely beautiful … Also for 10 years I’ve done Pilates.
Yes, I do that and my strength has improved so much from doing Pilates. (S5)
See, this is the funny thing. I reckon I don’t feel stressed, but it comes out
through my body. Maybe, in my head I didn’t feel like I was stressed, but my
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 245
body was telling me other things. So, I started to exercise a lot more, because
I was starting to put weight on, even after I had the operation and I could
move around a lot better. I tried to keep it up but at this moment in time, I’ve
turned back into a little fat slug…But I am doing Pilates now, which is helping
me a lot. (S6)
7.6. Discussion
This study used data from women reflecting on the past 7‐10 years living with
endometrial cancer to better understand their experience with psychological and
pharmacological treatments of anxiety and depression, and how they returned to or
maintained their emotional wellbeing.
The first theme of this analysis, psychological wellbeing during cancer diagnosis and
survivorship, showed that several women experienced significant psychological
distress, but in their description of this distress as either persistent, occasional
recurring or newly developed. Similar findings were noted in women up to 18 years
post‐breast cancer diagnoses (n = 13) by Rosedale and Fu (2010). They reported that
‘Distress intensified when women expected symptoms to disappear but symptoms
persisted instead’ [22 pE28]. In other studies, in the breast cancer setting, distress
was more common among women with children (compared to women without
children) [23,24], and the experience of worrying about children or people they cared
for was shared by women in the interview.
Although several women had taken or were still taken psychotropic medications,
many spoke about the value of psychotropic medications being hampered by side
246
effects or fear of side effects, and several women reported wanting to discontinue
medication, or not taking the medication even if it was prescribed instead opting for
psychological or lifestyle support. Other reasons for not taking psychotropic
medications included stigma and the hope of living a life without the need to take
any medication. Several women were deeply interested in natural living or therapies.
Previous qualitative research in other settings showed similar reasons for reluctance
to use antidepressants. Some people (n = 80, UK) stated a desire to avoid lifelong use
of antidepressants and others worried about the dangers of long–term drug use for
their physical or mental health [25]. Another study was conducted in Canada with
women who were prescribed antidepressants, but had decided not to begin the
treatment [26]. Six women participated in that study and cited different reasons for
discontinuing antidepressants: ‘potential side effects of antidepressants, positioning
lay knowledge as superior to expert knowledge and denigrating medical authorities’
[26, p1569]. The potential for side effects was also given as a reason to discontinue
antidepressants by patients with anxiety and/or depression in studies conducted by
Bosman et al. (2016) and Schofield et al. (2011) [27,28]. Clinically structured
interviews or structured questionnaires should be considered in future research to
quantify how common each of the potential reasons for not taking antidepressants
is among long‐term cancer survivors.
Several of the interviewed women sought support besides psychological treatments,
family and social support, including cancer support groups and CAM health
professionals (e.g. homeopath and chiropractor). Cancer support groups are
commonly attended by cancer survivors and have been shown to be important
facilitators of recovery in psycho–oncology, with many delivering relaxation, art or
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 247
meditation therapy to reduce psychological distress, and offering the opportunity to
exchange with others similar circumstances [29]. Samuels et al. (2018) found that 35
of 124 cancer patients received homeopathic treatment for emotional symptoms; 20
of 35 felt this was beneficial [30].
Women reported using multiple self‐management techniques such as exercise,
meditation, Pilates and Qi Gong to maintain their health and psychological wellbeing
throughout the long‐term cancer survivorship. These techniques also improved
women’s weight management and quality of life [31,32] and were described by them
as a good alternative to traditional psychological treatments.
Limitations
Patients who consented to participate in the interview were relatively more
physically and psychologically active. As participants were asked to recall their
psychological wellbeing around the time of surgery and throughout the subsequent
years in a 20–40‐minute interview, there was a chance of only selected memories or
events being reported. Interviews were conducted via telephone, potentially limiting
the participants’ chances of recalling some memories within a period of time.
Future research
A number of important findings from these qualitative interviews warrant future
research. Such work should consider why some women started pharmacological
treatment rather than psychological treatment, whether they were screened for
distress before prescription or whether their symptoms were sufficiently obvious for
healthcare professionals to prescribe without screening. The reasons for
248
discontinuation of, or reluctance to start, pharmacological treatment in patients with
cancer is another area for future research. Although women reported that CAM
improved their psychological wellbeing, future research should consider an in‐depth
CAM strategies women used during survivorship and if and how CAM benefited
recovery.
Acknowledgement
Saira Sanjida was funded by Advance Queensland Scholarship. Monika Janda was
funded by NHMRC Translating Research into Practice fellowship APP1151021. Steven
M. McPhail (#1090440) was funded by NHMRC Fellowships. This project was part of
LACE Trial which 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 Gynaecological Cancer,
Genesis Oncology Trust, and the Cherish Foundation.
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Chapter 8: Conclusions
8.1. Introduction
This chapter provides strengths and limitations discussed in Sections 8.2, 8.3 and 8.4,
followed by final concluding statements and outlook for future research. It reflects
back on the research program corresponding to the research aims reported in
Chapter 1 (see Section 1.3, Figure 8.1), and the knowledge gaps identified in the
available evidence (see Sections 1.2, 2.3 and 2.4).
Figure 8.1: PhD project structure: Conclusions
8.2. Strengths and implementation
This thesis advanced previous knowledge, by addressing the evidence gaps identified
in sections 1.2, 2.3 and 2.4 and studying in detail the psychosocial wellbeing
outcomes of long–term endometrial cancer patients, a previously under‐researched
population. The work formed part of work undertaking in collaboration with a larger
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 255
research group ‐ the national PoCoG. At the time when this program of research
commenced, PoCoG had formed working groups devoted to advancing the science
on how to best address depression, anxiety, fear of recurrence and adjustment
disorders in cancer patients, respectively. In each of these working groups, based on
current evidence, research programs were devised to improve on the psycho‐
oncological care that patients currently receive, and address areas of need identified
as not supporting patients optimally in their current form.
This thesis’s review and meta‐analyses described in Chapter 3 provided data for the
anxiety working group planning more broadly, while the analyses of data from the
LACE trial informed the group’s insights into the long‐term psychosocial wellbeing of
patients, and their use of psychotropic medications. The qualitative interview study
(Chapter 7) was conducted to triangulate some of the findings obtained from the
quantitative survey data, and allowed to understand women’s motivation to use or
not use psychotropic medications. It was interesting to note a reluctance by many of
the interviewed women to use psychotropic medication, and medications in general,
with many preferring to manage their wellbeing otherwise. A number of the women
interviewed were sceptical about the benefit of medications, and highlighted their
potential for unwanted side effects. The interviews provided evidence that women
searched for sources of support and often found these outside the traditional
medical system, including social support groups (both physical and online), cancer
support groups, and CAM practices and practitioners. Guideline‐driven psychosocial
care as suggested in the stepped care model by Butow et al. (2015) [1], appeared to
have been rarely received by women in the present study (Chapter 7). If it had been
256
received, it may have eased their path to optimal psychosocial and pharmacological
care, rather than women having to search for support widely. The interviews also
highlighted that as the cancer experience was becoming a more distant past, other
health issues became important, but thoughts about the possibility of another cancer
scare were never far from women’s mind.
The overall outcomes of this PhD thesis showed that many women with endometrial
cancer could have benefited from guideline‐driven psychological and
pharmacological treatment for their psychosocial wellbeing throughout their
survivorship. In 2006, Institute of Medicine and National Research Council
Committee (USA) reported on cancer survivorship and stated that psychological
wellbeing including anxiety and depression is one of the most four important
recovery domains for cancer survivors in addition to physical, social and spiritual
wellbeing [2]. More than a decade later, the National Cancer Policy Forum of the
National Academies of Sciences, Engineering, and Medicine (USA) proceeded with a
workshop on long‐term survivorship care after cancer treatment and reported that
‘integrating psychosocial services into cancer care …’ is one of the main goals to
accelerate progress in cancer survivorship [3,4]. Similar to the findings of our
research—that guideline driven treatment of anxiety and depression by following
screening and assessment would be beneficial for many women—the workshop
forum also reported that routine assessment of survivors needs was as main pathway
by which to achieve better cancer survivorship care. Workshop members
recommended that screening and assessment of psychological wellbeing should be
implemented in every phase of survivorship care, including ‘soon after diagnosis and
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 257
repeatedly throughout treatment and into posttreatment survivorship or end‐of‐life
care’ [4 p40].
Electronic patient reported outcome (ePRO) were considered in the workshop to
facilitate such assessment, with many collecting a comprehensive list of physical and
psychosocial symptoms and functional impairments of relevance to cancer survivor.
Additionally, workshop outcomes revealed that steps should be taken to breaking
the silence of survivors [5]. Since the research reported in this thesis has started,
several national and international clinical practice guidelines adopted the workshop
recommendations and emphasised the importance of delivering guideline‐driven
psychological treatments [6–11]. In 2017, Cancer Australia developed an optimal
care pathway for women with endometrial cancer with a key focus on screening and
assessment of psychological distress during survivorship [12]. The care pathway
suggests appropriate referral for women identified to require psychological care,
which depending on the severity of symptoms include online self‐help, GP services,
mental health professionals, or outpatient and inpatients services in hospitals.
This thesis started with research on the prescription characteristics of psychotropic
medications during the initial phases (including diagnosis and surgical treatment) of
endometrial cancer survivorship (Chapter 5). The notable finding was that the
majority of patients with prescriptions already received antidepressants before the
diagnosis of endometrial cancer, which indicated cancer diagnosis and treatment was
not the only reason for taking antidepressants. Pre‐existing medical conditions,
stressful life events, or cancer related symptoms, may be other possible reasons for
taking antidepressants before the cancer diagnosis. Further analysis showed that
258
having multiple medical conditions was associated with greater likelihood of
prescription of antidepressants indicating that multi‐morbidity was taking a toll on
women’s psychosocial wellbeing. Due to using secondary data the study could not
identify, however, the exact reason for the prescription, or whether the delivery of
medications for anxiety and depression was guideline‐driven.
The studies reported in Chapters 5 and 6 seemed to indicate that there was a lack of
concordance between symptoms of anxiety and depression and the receipt of
psychological or psychotropic treatments. Previously others studied found similar
results, and provided some possible reasons for this finding. For example, Holch et
al. (2011) reported on oncology professionals’ views on the use of antidepressants in
cancer patients: ‘Oncologists and surgeons may be reluctant to prescribe
antidepressants to cancer patients’. These authors further stated that: ‘This may be
due to lack of knowledge of current prescribing practice, inability to monitor patients
in tertiary care and negative attitudes about the use of antidepressants’ [13 p301].
This study also reported that GPs were the most common professionals to prescribe
antidepressants. Interestingly, McFarland et al. (2016) survey results showed that
more than 3 out of 4 women with breast cancer preferred to receive antidepressants
from their oncologists [14]. It would be interesting to further study oncologists’, GPs’
and other health professionals’ opinion on how the assessment and referral of cancer
patients to psychosocial care could be improved. A lack of clear referral pathways
may still be one of the reasons that may play a role in the findings of the studies
reported here.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 259
Pharmacists could play an increasing role working along with the multidisciplinary
oncology team given the complex and overlapping symptoms of cancer, treatment
side effects, anxiety and depression. In 2001, researchers from Canada showed that
involvement of a pharmacist in the multi‐disciplinary team improved long‐term
effectiveness of anxiety and depression treatment in advanced cancer patients [15].
Further research on the involvement of pharmacists to identify and recommend
major depressive disorder in patients undergoing chemotherapy was conducted in
Japan by Ito et al. (2011) [16]. This study tested the early introduction of psychiatric
treatment of cancer patients compared to usual care, with promising results.
Recently, researchers from Malaysia reported that involvement of pharmacist for
counselling during chemotherapeutic treatment improved quality of life, anxiety and
depression in patients with cancer [17—19]. Given these positive findings greater
involvement of pharmacists in the psycho‐oncological care should be considered.
However, as reported in Chapter 7 women’s attitudes and beliefs with regards to
psychotropic medication appear to play a significant part in the results. The
interviews found that some women were unwilling to discuss anxiety and depression
face‐to‐face with others, or to take antidepressants or anxiolytics due to fear of side
effects. These data indicate that health care professionals need to have an in depth
discussions about the risks and benefits of medication, and clearly explain to women
why they require medication as otherwise adherence may be low [20]. Three
systematic reviews showed that pharmacists played in important role in
improvement of adherence to antidepressants in general patients with depression
by providing education, counselling, and explaining the side effects of
260
antidepressants [21—23]. Pharmacists who have knowledge of medications
pharmacologically and pharmaceutically, can play an important role to deliver such
psycho‐oncological care on risk and benefit of medications, their side effects,
screening of psychological conditions, psychiatric referral etc. [16,24]. They can also
contribute to accurate CAM advice for cancer patients who are interested in use of
such options in conjunction with oncological treatment [24]. The basic psychological
training required for pharmacist who are interested in working in the cancer field and
their benefit in psycho‐oncological care should be explore in future research [24].
In this research, the journey of women from endometrial cancer diagnosis to more
than 10 years past diagnosis was described in more detail than had previously been
reported, and allowed new insights into long‐term survivorship issues. Many of the
women were living with more than one cancer and more than one chronic health
condition, with the endometrial cancer a less severe concern for some compared to
other ailments. Similar to women’s reported preference of using their own favoured
approaches to recover, women with breast and gynaecological cancer in another
study demanded eHealth‐based psychological care such as web‐based information,
websites, blogs, that provided them with content on how to cope with anxiety, or
depression, regain their self‐esteem, or adjustment to a new life situation [25]. Both
of these research outcomes provided some insights into women’s preferred methods
of supportive care delivery. Health care professionals should consider women’s
preference to improve the psychological wellbeing of patients. It is important that
they will feel their treating team is interested in their preferences and supports their
preferred way of getting and staying well during survivorship.
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 261
8.3. Limitations
Despite several notable findings and strengths, some limitations of this PhD research
program are discussed in Sections 8.3.1–8.3.6.
8.3.1. Unavailability of data in published sources and research dataset
The review and meta‐analysis reported in Chapter 3 was hampered by the fact that
many studies did not report separate data for anxiety outcomes from overall distress,
resulting in the exclusion of several potentially relevant studies.
8.3.2. Sample inclusion
Chapters 5 and 6 used secondary data from a surgical clinical trial. While this
provided detailed and prospectively collected data, with few missing forms, the study
included a relatively homogenous patient population with early stage cancer, low risk
cancer cell type, and high performance status only. Therefore, study findings are
likely not applicable to patients diagnosed with more advanced disease or high risk
cell type. Patients in Chapter 7 who consented to participate in the telephone
interviews may have had relatively better physical and psychological wellbeing
compared to women who declined, although we purposefully aimed to reach out to
women with as diverse health profile as possible. Despite this, it is likely that these
interviews do not reflect the full burden of anxiety and depression in patients
diagnosed with advanced‐stage endometrial cancer.
8.3.3. Guideline‐driven pharmacological treatment for anxiety and depression
Using secondary data in Chapter 5 (Study 2), there was no information regarding
whether the delivery of pharmacological treatment for anxiety and depression to the
262
women with endometrial cancer followed guideline‐driven recommendations. In
particular, no information was available in terms of whether patients received the
medication after they had been appropriately screened and assessed for anxiety and
depression. When further secondary analysis was conducted on women with a high
score of HADS and prescription of medications, most patients with a high HADS score
did not receive medication, and also did not report receiving psychological care.
Some of this apparent lack of psychological care may have been due to
underreporting if women may not have felt it necessary to provide information in the
structured questionnaire during follow up.
8.3.4. Psychological symptoms other than anxiety and depression
The main aim of this PhD research program was to understand the prevalence and
burden of anxiety and depression and their treatments, specifically antidepressants
and anxiolytics. In some instances, other symptoms of psychological distress such as
fatigue, low mood, sleep disturbances may occur more frequently than the classical
symptoms of anxiety or depression. Alternatively, they may develop as a direct
response to treatment procedures such as chemotherapy or radiotherapy which
were uncommonly received by the patients included in our study [26]. It has been
reported that one of the most bothersome symptoms for patients is dealing with the
uncertainty of cancer as a life‐threatening condition. This uncertainty results in
expression of key symptoms such as worry, which is also a primary symptom of
anxiety [27,28], making the distinction between normal response to the diagnosis of
cancer and psychological distress requiring treatment challenging. These symptoms
also commonly overlap with those indicating anxiety and/or depression, making the
distinction particularly hard for health professionals [29,30]. In addition, in cancer
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 263
care antidepressants and anxiolytics are used for the treatments of physical
symptoms other than anxiety or depression. The use of secondary data in this PhD
did not allow to completely disentangle these relationships, and should be
considered in greater detail in future research.
8.3.5. Data entered by nurses
During the baseline data collection, clinical trial nurses collected data such as
medications, reasons for their use and psychological treatment. While the data were
audited by the clinical trial team, some data may have been missed or inconsistently
entered by the trial nurses across the 20 centres that participated in the LACE trial
[31]. Nurses may not have noted some of the reasons why patients were taking the
medications, and future studies should take advantage of electronic medical records
to be certain that a complete record of all medications and reasons for their
prescription is obtained.
8.3.6. Secondary data from surgical clinical trial
Data used in this PhD research originated from the clinical trial which had the primary
purpose to determine the equivalence of two different surgical approaches, in early
stage endometrial cancer, considered to have a good prognosis. Health care
professionals involved in this clinical trial may have overlooked psychological
symptoms as cancer–treatment related symptoms, may consider the psychological
symptoms as a normal response to a cancer diagnosis, or both health care
professionals and patients may prioritise the treatment of cancer over psychological
treatment [32,33], all of which may have led to lower than usual referral for
264
psychological care. Care may have been received outside the hospital setting and
could have been missed if not self‐reported by the participant in the questionnaire.
8.4. Conclusions
Despite the availability of treatment guidelines, many patients who experience
anxiety and/or depression may not receive treatment for these symptoms, and on
the other hand, the delivery of treatments for anxiety and depression without
screening and assessment still appears to be common. This thesis found that some
patients who scored highly on the HADS, a validated screening instrument for
psychological distress, did not receive referral for psychological or pharmacological
treatment. Given the recent publication of optimal stepped care pathways, more
work is needed to identify how such approach can best be implemented in clinical
practice. It has been suggested that to make screening and referral for psychosocial
care a reality in hospitals, “team ownership, endorsement by leaders, education and
training modules designed for health professionals and patients and identify ways to
integrate the pathway into existing cancer service” are five essential elements that
are required for successful translation into practice [34,35 p1]. On the other hand,
patients interviewed during long–term survivorship reported that they would like to
be as independent from prescribed medications and sometimes also psychological
treatment as possible. They often incorporated alternative methods, including CAM,
exercise and lifestyle changes, to maintain their psychological wellbeing. While we
determined these factors as important to women in the interviews, the LACE long‐
term follow‐up questionnaire did not cover such wellbeing methods sufficiently;
future studies should consider asking patients about the range of methods they use
to maintain their psychological wellbeing, and should quantify their preferred
Psychological and pharmacological treatment of anxiety and depression in patients with endometrial cancer 265
supportive care products and providers. This would allow to streamline the
supportive care services optimally towards women’s preferences and allow
comorbidities such as anxiety and depression to be resolved in the medium to long
term.
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