Psychological and pharmacological of anxiety and ... · Saira Sanjida Bachelor of Pharmacy (Hons), Master of Pharmacy, Master of Applied Science (Research) Submitted in fulfilment

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


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


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


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.


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].


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


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].


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


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


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


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


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).


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].


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


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


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.


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


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


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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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


(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)


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


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


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


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.


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



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 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.


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of any thesis chapter which includes a co‐authored publication.

The authors listed below have certified that:

1. they meet the criteria for authorship in that they have participated in the conception, execution, or interpretation, of at least that part of the publication in their field of expertise;

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

editor or publisher of journals or other publications, and (c) the head of the responsible academic unit, and

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Please state the publication title and date of publication or status: Are psychological interventions effective on anxiety in cancer patients? A systematic review and meta‐analyses. Published 2018.

Contributor Statement of contribution

Saira Sanjida Conception and design, extraction and assembly of data, data analysis and interpretation, drafting of manuscript, critical revision and final approval of manuscript Sign


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

Data analysis and interpretation, critical revision and final approval of manuscript

Professor David Kissane Critical revision and final approval of manuscript

Dr Jeremy Couper Critical revision and final approval of manuscript

Dr Joanne Shaw Critical revision and final approval of manuscript

Dr Melanie A Price Planning of the research, critical revision and final approval of manuscript

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I have sighted email or other correspondence from all Co‐authors confirming their certifying authorship.

Name: Professor Monika Janda

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Date: 18.02.2020

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


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


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


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.


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;


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


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


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


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)


‐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


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


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


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


Pre‐surgical ‐Stress management training ‐Single


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 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


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


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


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


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


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)


‐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


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


‐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


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


Nurse, doctor

T: 1 hr/10 home visit each for 2‐3 months F: 3‐month, 6‐month, 12‐month, 24‐month


Sandgren & McCaul 2003 (USA)

‐N = 222 ‐54.5(30‐84) ‐Female


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


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


‐ 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)


‐N = 647 ‐64.5 ‐Both

‐Colorectal ‐I‐IIIB

<3 months of cancer diagnosis


Volunteer

T: 3‐week F: 3‐month

‐HADS ‐Reduced

Willems et al 2016 (Netherlands)

‐N = 409 ‐56.27 ‐Both

‐Mixed ‐All

Completed cancer treatment


‐ 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


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


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.


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


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


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.


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


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


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


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


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


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


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


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


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


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


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


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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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


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

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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


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


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


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

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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.


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


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


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


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].


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.


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.


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.


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


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.


Statement of Contribution of Co–Authors for Thesis by Published Paper


of any thesis chapter which includes a co–authored publication.







Please state the publication title and date of publication or status: How many patients enter endometrial cancer surgery with psychotropic medication prescriptions, and how many receive a new prescription perioperatively? Published 2019.


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 Sign


Date: 18.02.2020


Professor Steven M McPhail Data analysis and interpretation, critical revision and final approval of manuscript


Professor Andreas Obermair

Critical revision and final approval of manuscript

Professor Jeremy Couper Critical revision and final approval of manuscript

Associate Professor James Scott



I have sighted email or other correspondence from all Co–authors confirming their certifying

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Date: 18.02.2020

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





Australia.


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


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


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].


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


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)


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


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 –


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


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


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


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


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


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.

5.7 References






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184

Chapter 6: Anxiety and depression in


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


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


women with endometrial cancer; or established the treatments received for


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










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.


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

Sign QUT Verified Signature

Date: 18.02.2020



Data analysis and interpretation, critical revision and final approval of manuscript





I have sighted email or other correspondence from all Co–authors confirming their certifying authorship.



Date: 18.02.2020


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*






Australia.




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.


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


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


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)


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.


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 =


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


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


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


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


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).


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




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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43. Mielcarek P, Nowicka–Sauer K, Kozaka J. Anxiety and depression in patients

with advanced ovarian cancer: a prospective study. J Psychosom Obstet

Gynaecol. 2016;37(2):57–67.

216

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.


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


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.











Please state the publication title and date of publication or status: Psychological wellbeing in long‐term endometrial cancer survivors. Manuscript in preparation.


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

Sign QUT Verified Signature

Date: 18.02.2020

Professor Monika Janda Conception and design, conduct interview, drafting of manuscript, critical revision and final approval of manuscript






I have sighted email or other correspondence from all Co–authors confirming their certifying authorship.



Date: 18.02.2020

222


Psychological wellbeing in long‐term endometrial cancer survivors

Saira Sanjida1, Steven M. McPhail1,2, Andreas Obermair3, Monika Janda1,4





Australia.




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


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.


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


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.


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)


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).


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


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:


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:


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:


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:


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

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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


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


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

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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



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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mortality in women with early stage endometrial cancer. Br J Health Psychol.

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8. Jeppesen MM, Mogensen O, Dehn P, Jensen PT. Needs and priorities of women

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AJ, et al. Long–term antidepressant use: a qualitative study on perspectives of

patients and GPs in primary care. Br J Gen Pract. 2016;66(651):e708–719.

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views of antidepressants: from first experiences to becoming expert. Br J Gen

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patients. Med J Aust. 1996;165(10):545–548.

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Feasibility of homeopathic treatment for symptom reduction in an integrative

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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


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


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.


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

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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.


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


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

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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


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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Psychological and pharmacological of anxiety and ... · Saira Sanjida Bachelor of Pharmacy (Hons), Master of Pharmacy, Master of Applied Science (Research) Submitted in fulfilment

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