A mixed method study on the prevalence, severity and experience of genitourinary symptoms and the impact on sexual function and QoL in postmenopausal women on endocrine therapy for early

MARIANA S. SOUSA

ARE WE MISSING THE ISSUES THAT REALLY MATTER?

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ARE WE MISSING THE ISSUES THAT REALLY MATTER?

A mixed method study on the prevalence, severity and experience of genitourinary symptoms and the impact on sexual function and quality of life in postmenopausal women on endocrine therapy for early breast cancer

Mariana de Souza e Sousa

A thesis in fulfillment of the requirements for the degree of Doctor of Philosophy

Prince of Wales Clinical School Faculty of Medicine University of New South Wales

2015

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PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: de Souza e Sousa First name: Mariana Other name/s: N/A Abbreviation for degree as given in the University calendar: PhD

School: Prince of Wales Clinical School Faculty: Medicine

Title: Are we missing the issues that really matter? A mixed-method study on the prevalence, severity and experience of genitourinary symptoms and the impact on sexual function and Qol in postmenopausal women on endocrine therapy for early breast cancer

Abstract 350 words maximum: (PLEASE TYPE)

The underlying hypothesis of this PhD Is that the negative Impact of adjuvant endocrine therapy on genitourinary symptoms In postmenopausal women with early breast cancer has been underestimated In clinical trials and that there are a myriad of genitourinary symptoms related to or exacerbated by endocrine therapies that are commonly not reported by women to their oncologists. These symptoms can be troublesome and may lead to noncompliance with treatment, especially If associated with other side effects. This Issue has not been comprehensively addressed, resulting In uncertainty regarding the frequency and severity of genitourinary adverse effects associated with antlestrogens and their potential impact on quality of life (QoL). Furthermore, no studies have comprehensively and prospectively evaluated the full range of genitourinary symptoms from before therapy begins and over time. These symptoms include urinary frequency, urgency, Incontinence, dysuria, prolapse among others. This study fills an Important gap In the current literature and Is clinically Important as Interventions could be used to better manage and treat many of these symptoms.

A number of data collection methods and Instruments were used In this project, selected on their ability to address the proposed research questions. Using a qualitative approach, with semi-structured Interviews, Study I sought an In-depth Insight of the genitourinary symptoms experienced by women with early breast cancer on antlestrogen therapy and an understanding on how symptoms Impact on dally life and sexual function. Study II employed a prospective design, using carefully selected validated instruments, to measure the prevalence and severity of genitourinary symptoms In postmenopausal women with breast cancer (prior to adjuvant endocrine therapy) and documented the trajectory of symptoms over time. The Impact of genitourinary symptoms on sexual function and QoL was also Investigated. The study attempted to Identify predictors for which women were more likely to develop significant genitourinary symptoms, and In particular, whether there Is an Identifiable sub-group of women at high-risk of developing severe genitourinary symptoms. This research project was conducted In the hope that the findings would Inform clinical practice and lead to greater efforta to early recognition and appropriate management of postmenopausal women who develop significant genitourinary symptoms as a result of adjuvant endocrine therapy.

Declaration relating to disposition of project thesis/dissertation

I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation .

I also authorise University Micr films to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only) 1 ~.,.:_. ~ . J,.~ .. m. 16-o::!C

The University recognises that there may be exceptional circumstances requiring restrictions on copying or cond ~ on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research .

FOR OFFICE USE DNLY Date of completion of requirements for Award:

THIS SHEET IS TO BE GLUED TO THE INSIDE FRONT COVER OF THE THESIS

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“Often I think women who had breast cancer have very little opportunity to talk to people and a lot of the issues are very shaming so it is really important to offer them that chance.”

― Memorable quote from one of the participants in this research project [GT, Post, 06]

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ABSTRACT

The underlying hypothesis of this PhD is that the negative impact of adjuvant endocrine therapy on genitourinary symptoms in postmenopausal women with early breast cancer has been underestimated in clinical trials and that there are a myriad of genitourinary symptoms related to or exacerbated by endocrine therapies that are commonly not reported by women to their oncologists. These symptoms can be troublesome and may lead to noncompliance with treatment, especially if associated with other side effects. This issue has not been comprehensively addressed, resulting in uncertainty regarding the frequency and severity of genitourinary adverse effects associated with and their potential impact on quality of life (QoL). Furthermore, no studies have comprehensively and prospectively evaluated the full range of genitourinary symptoms from before therapy begins and over time. These symptoms include urinary frequency, urgency, incontinence, dysuria, prolapse among others. This study fills an important gap in the current literature and is clinically important as interventions could be used to better manage and treat many of these symptoms.

A number of data collection methods and instruments were used in this project, selected on their ability to address the proposed research questions. Using a qualitative approach, with semi- structured interviews, Study I sought an in-depth insight of the genitourinary symptoms experienced by women with early breast cancer on therapy and an understanding on how symptoms impact on daily life and sexual function. Study II employed a prospective design, using carefully selected validated instruments, to measure the prevalence and severity of genitourinary symptoms in postmenopausal women with breast cancer (prior to adjuvant endocrine therapy) and documented the trajectory of symptoms over time. The impact of genitourinary symptoms on sexual function and QoL was also investigated. The study attempted to identify predictors for which women were more likely to develop significant genitourinary symptoms, and in particular, whether there is an identifiable sub-group of women at high-risk of developing severe genitourinary symptoms. This research project was conducted in the hope that the findings would inform clinical practice and lead to greater efforts to early recognition and appropriate management of postmenopausal women who develop significant genitourinary symptoms as a result of adjuvant endocrine therapy.

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ACKNOWLEDGEMENTS

I have a lot of people to thank for their continued support and love over the past three years.

Firstly I would like to acknowledge the brave and courageous women who were willing to give their time and share their very personal experiences with breast cancer and the impact on their lives. Your words and stories are illuminating and the experience has been humbling.

Next I need to express my gratitude to Prof. Michael Friedlander, my supervisor, for mentoring me through this journey of research. Thank you for allowing me to stay close to my area of interest and your encouraging guidance throughout the process, especially when I thought I had no more strength to ‘hang in there’. Prof. Martha Hickey, thank you for sharing your deep knowledge and helping me to navigate the world of women’s needs. I would like to especially thank Dr Michelle Peate for guiding me through each and every step of this thesis, all the countless hours of technical and moral support, motivating and inspiring me. You are an encouraging and invaluable friend.

I would like to acknowledge the support of the Breast Cancer Network Australia (BCNA) Consumer Representative, Ms Yvonne Shaw, for so much meaningful advice and input in this project. I would like to also thank Ms Sherin Jarvis, A/Prof. Craig Lewis, Dr. Marcus Carey and Prof. Richard Millard for the expertise that they contributed.

On a more personal note, I would like to thank my parents, Miratan and Thais, for being so supportive of my career and giving me the will to chase my ambitions. I know that you are proud of me and that means so much. Thank you to my sister, Camila, you helped me reach my goal still smiling. One year ago, you and Ryan gave me the perfect gift, my little nephew William, who have brought great joy to my life.

I would also like to thank my new extended family. As one beautiful family in Brazil was not love heart filling enough, I was blessed with a second family in Australia. Thank you tio Sahir, tia Olivia, abuelito Camilo, abuelita Cristina, tia Magaly, tio Alek, tio Fernando and tia Edith, little sister Marcela, big sisters Cindy and Claudia, Patrick, Michael and my nephews, Ariel, Elijah and Jonah and niece Natalia for all your love and encouragement and for making my life here so at home.

Thank you to all my friends, Belinda, Sian, Margaret, Barbara, Amanda, Penny, Cecilia, Angela, Fernando, Rosamaria, Esteban, Kari, Sri, Anne, Maria and Anastasia for your constant encouragement, friendship and for reminding me there is a whole world outside of my PhD.

Finally I thank the love of my life, Celso, for your unrelenting care and attention, for handling the stress and strain of daily life and for always being there reminding me to breathe, eat and sleep. Without your love and understanding I would not have completed this thesis. Thank you for a decade of unconditional love and for marrying me at the end of this journey. I love you.

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This thesis is dedicated to my step-father, Cidinho (1958 – 2013).

Thank you for raising me as if I was your own. The hardest part of PhD was that I had to say goodbye to you. You left us too soon but we know you are now in a better place. We miss you.

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ORIGINALITY STATEMENT

‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’

Signed ……………………………………………......

Date ……………………………………………......

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CONTENTS PAGE

ABSTRACT vii ACKNOWLEDGEMENTS ix ORIGINALITY STATEMENT xiii CONTENTS PAGE 1 LIST OF FIGURES 5 LIST OF TABLES 6 LIST OF ABBREVIATIONS 7 PUBLICATIONS AND PRESENTATIONS 9 CHAPTER 1 11 Introduction and Background 11 1. Introduction 13 1.1 A guide to the thesis 15 1.2 Literature Search Strategy 16 1.3 References 17 CHAPTER 2 21 A Review of Receptor-Positive Early Breast Cancer 21 2. Breast cancer 23 2.1. Early stage breast cancer 26 2.2. Hormone receptor expression and hormonal therapy in breast cancer 28 2.3. Hormone receptor-positive targeted therapies 31 2.4. Differences between and inhibitors – is it clinical significant? 36 2.5. Compliance to endocrine therapy 46 2.6. Summary 47 2.7. References 47 CHAPTER 3 59 A Review of Genitourinary Symptoms 59 3. Genitourinary Symptoms 61 3.1 Symptoms definitions 61 3.2. Genitourinary changes associated with deprivation 65 3.3. Risk factors 70 3.4. Prevalence of genitourinary symptoms in general postmenopausal women 71 3.5. Prevalence of genitourinary symptoms among women with breast cancer 73 3.6. Genitourinary symptoms in women with breast cancer – the difficulty with interpreting reported findings 75 3.7. The impact of genitourinary symptoms on sexual function 84 3.8. The impact of genitourinary symptoms on quality of life 86 1

3.9. Genitourinary symptoms-related information provision and help-seeking behaviour 87 3.10. Summary 88 3.11. References 89 CHAPTER 4 99 Management of Genitourinary Symptoms 99 4. A practical approach to the management of genitourinary symptoms in breast cancer survivors on endocrine therapy 101 4.1. Introduction 101 4.2. Lifestyle advice 102 4.3. Control of underlying medical conditions 102 4.4. Nonhormonal treatment options 103 4.5. Complementary and alternative therapies 104 4.6. Hormone replacement therapy (HRT) 106 4.7. 108 4.8. 110 4.9. Selective Modulator (SERM) 111 4.10. Lower urinary tract symptoms (LUTS) management 112 4.11. Pelvic floor muscle training (PFMT), pelvic floor muscle control, bladder training and behavioural modification techniques 113 4.12. Electrical stimulation 114 4.13. Vaginal/ Urethral support devices 115 4.14. Pharmacological interventions for UI 115 4.15. Sexual concerns 116 4.16. Conclusion and recommendations 117 4.17. References 119 CHAPTER 5 127 Rationale for Choice of Methodology 127 5. Selection of research methods 129 5.1. A combined qualitative and quantitative methodological approach 129 5.2. Phase 1 of this research project – a qualitative research design 132 5.3. Phase 2 of this research project – a prospective observational research design 135 5.4. Summary 138 5.5 References 142 CHAPTER 6 145 Study I: Exploring knowledge, attitudes and experience of genitourinary symptoms in women taking adjuvant endocrine therapy for early stage breast cancer 145 6. Study I 147 6.1. Introduction 147 6.2. Method 148 6.3. Results 151 6.4. Discussion 172 6.5. Conclusion 174 2

6.6. Study strengths and limitations 174 6.7. References 175 CHAPTER 7 177 Study II: PEGASUS - Prevalence and severity of genitourinary symptoms and impact on sexual function and quality of life in postmenopausal women receiving adjuvant endocrine therapy for early breast cancer 177 7. Study II 179 7.1. Introduction 179 7.2. Aims and hypotheses 179 7.3. Methods 181 7.4. Results 192 7.5. Discussion 219 7.6. Clinical implications 224 7.7. Study limitations 225 7.8. Study strengths 225 7.9. Conclusion 226 7.10. References 226 CHAPTER 8 231 Conclusion and Recommendation 231 8.1. Summary of key findings 233 8.2. Clinical implications 234 8.3. Strengths 235 8.4. Limitations 236 8.5. Recommendation and future work 237 APPENDICES 239

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LIST OF FIGURES

Figure 2.1 Breast cancer incidence in Australia (observed for 1982-2007, projected to 2020) Figure 2.2 Age-specific incidence rates for breast cancer, 2015 Figure 2.3 Breast cancer relative survival by time period, females, Australia (1982 -1987 to 2006-2010) Figure 2.4 Percentage of patients with a given ER/PR-status by age Figure 2.5 Mechanisms of action of tamoxifen and aromatase inhibitors Figure 3.1 Female pelvic organs and pelvic floor Figure 3.2 Vagina and vulva Figure 3.3 Female bladder and urethra Figure 5.1 Research flow diagram Figure 6.1 Flowchart detailing recruitment Figure 7.1 Flowchart detailing recruitment Figure 7.2 Frequency and degree of severity of urinary and vaginal symptoms at baseline (1) and six months (2); Significance tested with Wilcoxon Signed Ranks Test; Scales: ICIQ-FLUTS, ICIQ-VS and FACT-ES; (N=177) Figure 7.3 Radar chart showing urinary incontinence (ICIQ-FLUTS-IS), voiding (ICIQ-FLUTS- VS) and storage symptoms (ICIQ-FLUTS-FS) scores, and total urinary (ICIQ- FLUTS) and vaginal symptoms (ICIQ-VS) scores at baseline and six months (N=177). Numbers indicate scores. Figure 7.4 Prevalence (%) and severity of clinically significant incontinence (score of 2 or greater on the item), voiding and storage symptoms and vaginal symptoms at baseline (1) and six months (2); p-value (McNemar’s test 2) differences between the two time points. Figure 7.5 Frequency (%) and degree of impact of urinary symptoms on QoL (ICIQ-LUTSqol) at baseline (1) and six months (2) Figure 7.6 Four selected sexual function-related questions from PISQ-12 to participants reporting no sexual activity at baseline (1) (N=177) and six months (2) (N=92) Figure 7.7 Box plots of change scores from baseline by group (TAM vs AI): ICIQ-FLUTS (a); ICIQ-VS (b); ICIQ-FLUTS-FS (c); ICIQ-FLUTS-IS (d); ICIQ-FLUTS-VS (e)

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LIST OF TABLES

Table 2.1 Tumour, Node and (TNM) staging of breast cancer Table 2.2 Aromatase inhibitors categorised by generation and by mechanism of action Table 2.3. Summary of disease free survival in trials with an in the adjuvant setting Table 2.4 Summary of profile of tamoxifen and aromatase inhibitors in clinical trials Table 3.1 Symptoms associated to genitourinary atrophic changes Table 3.2 Frequency of genitourinary symptoms associated with adjuvant endocrine therapies Table 3.3 Summary of studies assessing genitourinary symptoms in breast cancer survivors receiving endocrine therapy Table 6.1.Sociodemographic and clinical characteristics of the sample (N=32) Table 6.2.Summary of reported genitourinary problems Table 6.3. Summary of participants’ treatment expectations regarding genitourinary symptoms Table 7.1 Sociodemographic and clinical characteristics of the sample at baseline Table 7.2 Prevalence of urinary and vaginal symptoms (N=177) Table 7.3 Frequency (%) and mean scores of bother associated with genitourinary symptoms at baseline and six-month follow up. Table 7.4 Univariate and multivariate regression of influencing factors of bothered by genitourinary symptoms. Table 7.5 Impact of genitourinary symptom on QoL (prevalence and mean scores) Table 7.6 Frequency and mean vaginal-related sexual matter scores at baseline and six months Table 7.7 PISQ-12 scores in sexually active women at baseline and six months Table 7.8. Frequency (%) of genitourinary symptoms in general and clinically meaningful symptoms at six months by group (TAM vs AI)

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LIST OF ABBREVIATIONS

AACR Australasian Association of Cancer Registries ACP American College of physicians AI Aromatase inhibitor AIHW Australian Institute of Health and Welfare AJCC American Joint Committee on Cancer ANA ARNO Arimidex Nolvadex ABCSG Austrian Breast Cancer Study Group ASCO American Society of Clinical Oncology ATAC Arimidex Tamoxifen Alone or in Combination ATLAS Adjuvant Tamoxifen Longer Against Shorter ATTom Adjuvant Tamoxifen Treatment offers more? BCN Breast care nurse BCPT Breast cancer Prevention Trial BMI Body mass index BIG Breast Cancer International Group CAP College of American Pathologists CE Conjugated estrogen CES-D Centers for Epidemiologic Studies – Scale CI Confidence interval CYP2D6 2D6 DFS Disease free survival DHEA EBCTCG Early Breast Cancer Trialists' Collaborative Group EMBASE Excerpta Medica Database ER Estrogen receptor ER+ Estrogen receptor positive EXE FACT-B Functional Assessment of Cancer Therapy Breast Subscale FACT-ES Functional Assessment of Cancer Therapy Endocrine Subscale FSH Follicle stimulation hormone GSM Genitourinary Syndrome of HER2 Human epidermal growth factor receptor 2 HR Hazard Ratio HRT Hormone replacement therapy ICS International Continence Society ICIQ International Consultation on Incontinence Questionnaire IES Intergroup Exemestane Study IHC Immunohistochemical IIQ-7 Incontinence Impact Questionnaire short form IMS International Menopause Society ITA Italian Tamoxifen Anastrozole LET LDL Low density lipoprotein LH Luteinising hormone

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LUTD Lower urinary tract disorder LUTS Lower urinary tract symptoms MA.17 North-American Breast Intergroup MEDLINE Medical Literature Analysis and Retrieval System Online MENQOL Menopause Specific Quality of Life Questionnaire MOS Medical Outcomes Study MOSSF36 Medical Outcomes Study 36-Item Short Form Health Status Survey NAMS North American Menopause Society NCIC CTG National Cancer Institute of Clinical Trials Group NSABP National Surgical Adjuvant Breast and Bowel Project OAB Overactive bladder OS Overall survival PEGASUS Prevalence and Severity of Genitourinary Symptoms in Postmenopausal Women Receiving Adjuvant Endocrine Therapy for Early Stage Breast Cancer PERI Perimenopausal PFMT Pelvic floor muscle training pH Potential of Hydrogen PISQ Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire POP Pelvic organ prolapse POST Posmenopausal PR receptor PR+ Progesterone receptor positive PRE Premenopausal PubMed Public/Publisher MEDLINE QoL Quality of life RCT Randomised Controlled Trial RR Relative risk SAQ Sexual Activity Questionnaire SERM Selective estrogen receptor modulator SD Standard deviation SF-36 Short Form 36-item Health Survey SNRI Serotonin Norepinephrine Reuptake Inhibitor SPSS Statistical Program for the Social Sciences SSRI Selective Serotonin Reuptake inhibitor STEAR Selective Tissue Estrogenic Activity Regulator TAM Tamoxifen TNM Tumour, Node and Metastasis TSEC Tissue-selective Estrogen Complex UDI-6 Urogenital Distress Inventory Short Form UI Urinary incontinence UTI Urinary tract VAS Visual Analogue Scale WHI Women’s Health Initiative

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PUBLICATIONS AND PRESENTATIONS

Addresses at conferences Oral presentations (International Conferences):

1. 18th October 2014 – 18th SIS World Congress on Breast Healthcare, Orlando, Florida, US. PEGASUS – Prevalence and severity of genitourinary symptoms and impact on sexual function and QoL in postmenopausal women receiving endocrine therapy for early breast cancer.

2. 11th October 2013 – Global Breast Cancer Conference (GBCC) 2013, Seoul, Korea. Qualitative analysis of women’s knowledge, attitudes and experiences regarding genitourinary symptoms with aromatase inhibitors for early stage breast cancer.

Poster presentations (National Conferences):

1. 10th November 2014 - POW Hospital Tow Award Day, Sydney, Australia. Sousa MS, Meiser B, Hickey M, Peate M, Jarvis S, Lombard J, Chirgwin J, Segelov E, Friedlander M. PEGASUS – Prevalence and severity of genitourinary symptoms and impact on sexual function and quality of life in postmenopausal women receiving adjuvant endocrine therapy for early stage breast cancer. Invited presentation

2. 13th November 2013 - Clinical Oncological Society of Australia (COSA) Conference 2013, Adelaide, Australia. Sousa, MS, Meiser, B, Hickey, M, Jarvis, S, Peate, M, Lewis, C, Friedlander, M. Qualitative analysis of knowledge, attitudes and experiences regarding genitourinary symptoms among postmenopausal women taking aromatase inhibitors for early stage breast cancer. Published: Asia-Pacific Journal of Clinical Oncology (2013) Nov; 9(Suppl. 3): 61–165. doi:10.1111/ajco.12144. (p.143;P291)A135

Poster presentations (International Conferences):

1. 16th October 2014 – North American Menopause Society (NAMS) 25th Annual Meeting, Washington, DC, US. Sousa M, Meiser B, Hickey M, Jarvis S, Lombard J, Chirgwin J, Segelov E, Friedlander M. PEGASUS – Prevalence and severity of genitourinary symptoms and impact on sexual function and quality of life in postmenopausal women receiving adjuvant endocrine therapy for early stage breast cancer – A prospective study. Published: Menopause (2014) Dec 2014; 21(12):1320-1369. DOI 10.1097/GME.0000000000000370

2. 8th November 2014 - 15th Biennial Meeting of the International Gynecologic Cancer Society (IGCS), Melbourne, Australia. Sousa M, Meiser B, Hickey M, Jarvis S, Lombard J, Chirgwin J, Segelov E, Lewis C, Friedlander M, for the PEGASUS study collaborative group. PEGASUS – Prevalence and severity of genitourinary symptoms and impact on sexual function and QoL in postmenopausal women receiving endocrine therapy for early breast cancer. Published: Journal of Gynecological Cancer (2014) Nov 2014; 24(9).

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CHAPTER 1

Introduction and Background

This Chapter is a short introduction to the background underpinning the research questions, which will be expanded on in Chapters Two to Four. Following the introduction, there is a brief guide to the thesis outlining its structure and a final section, which documents the literature search strategies that have been employed in this research project.

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Chapter 1: Introduction and background

1. Introduction

Breast cancer ranks as the leading cancer affecting women worldwide, including Australia, where over 15.000 new cases are expected to be diagnosed in 2015.1-3 Over the last three decades, early diagnosis and the use of adjuvant therapies including endocrine therapy for women with hormone-sensitive breast cancer have led to significant increase in survival rates.4-6

At present, the majority of women with estrogen receptor-positive early breast cancer are recommended adjuvant endocrine therapy for between five to ten years. Despite its proven benefits, adjuvant endocrine therapy is also associated with many potential side effects primarily related to both the acute and long-term consequences of estrogen blockade or deprivation,7 which may impair a woman’s life in many ways, and influence compliance with treatment.7-12 Consequently, the side effects of treatment are of concern to most patients and managing them remains an important challenge to clinicians.13

Most side effects associated with endocrine therapy have been well studied, and interventions to control or ameliorate some of them identified.14-20 In contrast, very little is known about genitourinary adverse effects of endocrine therapy, in particular the patient reported prevalence and severity of genitourinary symptoms. These include urinary frequency, urgency, dysuria, incontinence, pelvic discomfort, genital prolapse, etc. Although there is some evidence that these symptoms occur and may interfere with patients’ quality of life (QoL).17, 20, 21 Our current understanding of most adverse effects of tamoxifen (TAM) and aromatase inhibitors (AIs) in patients receiving these therapies are derived from comparative assessments in randomised trials where recurrence rates and survival are the primary endpoints and QoL a secondary endpoint.16,

20, 22 Furthermore, the adverse effects are often reported and graded by clinicians, not patients.

Thus, it is likely that some important genitourinary adverse effects may have been overlooked or underestimated in these studies due to the instruments used, the limited amount of information on genitourinary concerns collected and the fact that patients have not graded their adverse effects and possibly not self-reported embarrassing symptoms such as incontinence.

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Chapter 1: Introduction and background

A number of studies conducted in the general postmenopausal population have reported that genitourinary concerns are often associated with sexual concerns.23-28 Furthermore, it has also been shown that, regardless of the specific symptom, genitourinary problems have a detrimental impact on a woman’s QoL28, 29 and result in increased costs to the healthcare system due to more frequent visits to doctors and subsequent investigations.30 The relationship between genitourinary symptoms, sexual dysfunction and impaired QoL in women with breast cancer, however, has not been addressed or well-studied. This is surprising given the high prevalence of sexual dysfunction in women on adjuvant endocrine therapy which is commonly ascribed to

‘vaginal dryness’ (but the aetiology is likely to be much more complex). Arguably, more research in women with breast cancer is required to understand the impact of genitourinary symptoms on their sexual function and QoL. This is particularly important, as there are specific interventions available to manage many genitourinary symptoms, which could help to improve these aspects of a patient’s life.

In summary, this thesis focuses on postmenopausal women with early breast cancer receiving adjuvant endocrine therapy. Typically, most patients start adjuvant endocrine therapy after completion of primary treatment (surgery +/- and radiotherapy) and are recommended to remain on therapy for at least five years. These patients are reviewed in the clinic every three to six months and genitourinary treatment-related side effects may easily be overlooked as the standard consultation is short and there are many issues to deal with including a physical examination. There is evidence that genitourinary side effects are common, but the true frequency and the impact on patients still need to be more carefully addressed in a focused and well-designed study. These findings could be used to identify subgroups of patients at risk of developing genitourinary symptoms and also to offer appropriate interventions early to prevent and ameliorate symptoms, which are likely to have a negative impact on QoL and sexual function, and may ultimately contribute to a low/noncompliance with treatment.

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Chapter 1: Introduction and background

1.1 A guide to the thesis

Chapter Two provides a summary of the current information available regarding the epidemiology of breast cancer in women, including trends and survival rates in Australia, as well as an overview of hormone receptor expression as a prognostic and predictive factor and its clinical-related implications. This Chapter also describes the recommended treatment for hormone receptor-positive breast cancers and summarises the reports on compliance with treatment as well as the reasons for noncompliance.

The range of terms used to describe genitourinary symptoms and the risk factors associated with symptoms are described in Chapter Three. Additionally, the published data on the prevalence of genitourinary symptoms, both in the general female population and amongst women with a diagnosis of breast cancer taking endocrine therapy are reviewed. The difficulties with interpreting the findings in women with breast cancer are discussed and they include the variation between measurement tools in existing studies, such as who reports and grades the symptoms. This section of the thesis also includes a summary of the available data on the impact of genitourinary symptoms on women’s sexual functioning and QoL. Overall, Chapter

Two and Three comprise a thorough literature review of the relevant knowledge to support the research questions.

Chapter Four provides an overview to the management of genitourinary symptoms, with emphasis on the available options for women with breast cancer taking endocrine therapy.

A detailed rationale supporting the design and research methods employed in this thesis is discussed in Chapter Five. Accordingly, selected methods of data collection are explained and the different design approaches are discussed in this Chapter.

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Chapter 1: Introduction and background

Chapters Six and Seven describe the methodology and findings of each study undertaken as part of this PhD research project and the implications of the findings. Firstly, to qualitatively explore knowledge, attitudes and experiences of genitourinary symptoms, help-seeking behaviour, and degree of satisfaction regarding the current provision of information in women with breast cancer taking endocrine therapy, Study I was carried out and is reported in detail in Chapter Six.

The views and demands identified by participants in this study provided very good preliminary insights into the genitourinary symptoms-related information needs and perceived barriers to uptake treatment for their symptoms. The qualitative study included interviews with 32 breast cancer survivors attending the oncology clinics at major teaching hospitals in Sydney and who were taking endocrine therapy. Chapter Seven details Study II, a questionnaire-based study of

280 women with early breast cancer about to start endocrine therapy (baseline) and who were followed up prospectively at six months, and one and two years after baseline to investigate the prevalence and severity of genitourinary symptoms. This study also sought to increase understanding of the potential impact genitourinary symptoms have on their QoL and sexual functioning. The data presented as part of this thesis include a total of 177 participants who completed baseline and six-month follow-up questionnaires only, due to the time frame of submission of the thesis.

Finally, Chapter Eight summarises the findings from the thesis. A critical evaluation of the series of studies is carried out, strengths and limitations are highlighted, clinical implications are discussed and future directions for research recommended. The thesis concludes with appendices containing all the materials used in the studies.

1.2 Literature Search Strategy

To provide context for this thesis, a thorough literature search was conducted. Firstly, the databases MEDLINE, EMBASE and PubMed were searched for papers that were written in

English and published from 1980 onwards (i.e. when the first publications of clinical trials using

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Chapter 1: Introduction and background

TAM became available) using the following key words individually and in combination: breast cancer, breast , menopause, endocrine/hormonal therapy, adjuvant endocrine therapy, adjuvant therapy, selective estrogen receptor modulators, tamoxifen, aromatase inhibitors, exemestane, letrozole, anastrozole, prolapse, pelvic organ prolapse, genital prolapse, uterine prolapse, lower urinary tract symptoms, urinary bladder diseases, urinary incontinence, urinary bladder, urinary incontinence stress, overactive, urinary retention, urinary incontinence urge, dyspareunia, vaginal atrophy, urogenital atrophy, patient needs, concerns, patient preferences, quality of life, sexual dysfunction, sexual function, sexual behavior, women, woman, qualitative, prospective, longitudinal. Secondly, the reference lists found in the relevant identified papers were examined. Studies were considered eligible for inclusion in the literature review if they were published in a peer-reviewed journal, or were otherwise in the public domain. Finally, conference proceedings and general reading updates sent from institutions pertinent to the topic of this research were also consulted to keep references up-to-date.

1.3 References

1. Australian Institute of Health and Welfare (AIHW) and (NBCC)., NBCC. Breast cancer survival by size and nodal status in australia, Canberra: Australian Institute of Health and Welfare; 2007. 2. National Breast Cancer Centre. Clinical practice guidelines for the management of early breast cancer. 2nd ed, Sydney: National Breast Cancer Centre; 2001. 3. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet, 2005; 365(9472):1687-717. 4. Jatoi, I, Chen, BE, Anderson, WF and Rosenberg, PS. Breast cancer mortality trends in the according to estrogen receptor status and age at diagnosis. J Clin Oncol, 2007; 25(13):1683-90. 5. Winer, E, Hudis, C, Burstein, H and et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor positive breast cancer: Status report. J Clin Oncol., 2005; 23:619-629. 6. Australian Institute of Health and Welfare, Australasian Association of Cancer Registries and Centre, NNBC. Breast cancer in Australian women 1982-1996, ed, Centre, NBC, Canberra; 1999. 7. Murphy, CC, Bartholomew, LK, Carpentier, MY, Bluethmann, SM and Vernon, SW. Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review. Breast Cancer Res Treat, 2012; 134(2):459-78.

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Chapter 1: Introduction and background

8. McCowan, C, Shearer, J, Donnan, PT, Dewar, JA, Crilly, M, Thompson, AM and Fahey, TP. Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer, 2008; 99(11):1763-1768. 9. Partridge, AH, Wang, PS, Winer, EP and Avorn, J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol 2003; 21:602-6. 10. Fink, AK, Gurwitz, J, Rakowski, W, Guadagroli, E and Silliman, RA. Patient beliefs and tamoxifen discontinuance in older women with estrogen receptor–positive breast cancer. J Clin Oncol 2004; 22(3309-15). 11. Lash, TL, Fox, MP, Westrup, JL, Fink, AK and Silliman, RA. Adherence to tamoxifen over the five-year course. Breast Cancer Res Treat, 2006; 99:215-20. 12. Barron, TI, Connolly, R, Bennett, K, Feely, J and Kennedy, MJ. Early discontinuation of tamoxifen: a lesson for oncologists. Cancer 2007; 109:832-9. 13. Dizon, DS. Quality of life after breast cancer: survivorship and sexuality. Breast J, 2009; 15(5):500-4. 14. Jones, SE, Cantrell, J, Vukelja, S, Pippen, J, O'Shaughnessy, J, Blum, JL, Brooks, R, Hartung, NL, Negron, AG, Richards, Da, Rivera, R, Holmes, FA, Chittoor, S, Whittaker, TL, Bordelon, JH, Ketchel, SJ, Davis, JC, Ilegbodu, D, Kochis, J and Asmar, L. Comparison of menopausal symptoms during the first year of adjuvant therapy with either exemestane or tamoxifen in early breast cancer: report of a Tamoxifen Exemestane Adjuvant Multicenter trial substudy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2007; 25:4765-71. 15. Whelan, TJ, Goss, PE, Ingle, JN, Pater, JL, Tu, D, Pritchard, K, Liu, S, Shepherd, LE, Palmer, M, Robert, NJ, Martino, S and Muss, HB. Assessment of quality of life in MA.17: a randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol, 2005; 23(28):6931-40. 16. Cella, D, Fallowfield, L, Barker, P, Cuzick, J, Locker, G and Howell, A. Quality of life of postmenopausal women in the ATAC ("Arimidex", tamoxifen, alone or in combination) trial after completion of 5 years' adjuvant treatment for early breast cancer. Breast cancer research and treatment, 2006; 100:273-84. 17. Morales, L, Neven, P, Timmerman, D, Christiaens, M, Vergote, I, Van Limbergen, E, Carbonez, A, Van Huffel, S, Ameye, L and Paridaens, R. Acute effects of tamoxifen and third-generation aromatase inhibitors on menopausal symptoms of breast cancer patients. Anticancer Drugs, 2004 15(8):753-60. 18. Mortimer, BJE, Boucher, L, Baty, J, Knapp, DL, Ryan, E and Rowland, JH. Effect of tamoxifen on sexual functioning in patients with breast cancer. journal of clinical oncology, 1999; 17:1488-1492. 19. Mourits, MJ, Bockermann, I, Vries, Ed, Zee, Avd, Hoor, Kt, Graaf, Wvd, Sluiter, W and Willemse, P. Tamoxifen effects on subjective and psychosexual well-being , in a randomised breast cancer study comparing high-dose and standard-dose chemotherapy. British journal of cancer, 2002; 86:1546-1550. 20. Day, R and National Surgical Adjuvant Breast and Bowel Projet P-1 study (NSABP-1). Quality of life and tamoxifen in a breast cancer prevention trial: a summary of findings from the NSABP P-1 study. National Surgical Adjuvant Breast and Bowel Project. Ann N Y Acad Sci, 2001; 949:143-50. 21. Stanton, AL, Bernaards, CA and Ganz, PA. The BCPT symptom scales: a measure of physical symptoms for women diagnosed with or at risk for breast cancer. Journal of the National Cancer Institute, 2005; 97(6):448-56. 22. Boccardo, F, Rubagotti, a, Guglielmini, P, Fini, a, Paladini, G, Mesiti, M, Rinaldini, M, Scali, S, Porpiglia, M, Benedetto, C, Restuccia, N, Buzzi, F, Franchi, R, Massidda, B, Distante, V, Amadori, D and Sismondi, P. Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole (ITA) trial. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 2006; 17 Suppl 7:vii10-4. 23. Salonia, A, Zanni, G, Nappi, RE, Briganti, A, Dehò, F, Fabbri, F, Colombo, R, Guazzoni, G, Di Girolamo, V, Rigatti, P and Montorsi, F. Sexual dysfunction is common in women

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Chapter 1: Introduction and background

with lower urinary tract symptoms and urinary incontinence: results of a cross-sectional study. European urology, 2004; 45:642-8; discussion 648. 24. Barber, MD, Dowsett, Sa, Mullen, KJ and Viktrup, L. The impact of stress urinary incontinence on sexual activity in women. Cleveland Clinic journal of medicine, 2005; 72:225-32. 25. Paick, J-s, Cho, MC, Oh, S-j, Kim, SW and Ku, JH. Influence of Self-Perceived Incontinence Severity on Quality of Life and Sexual Function in Women With Urinary Incontinence. Neurourology and urodynamics, 2007; 26:828-835. 26. Hilton, P. Urinary incontinence during sexual intercourse: a common, but rarely volunteered, symptom. British journal of obstetrics and gynaecology, 1988; 95:377-81. 27 Korda, a, Cooper, M and Hunter, P. Coital urinary incontinence in an Australian population. Asia-Oceania journal of obstetrics and gynaecology / AOFOG, 1989; 15:313- 5. 28. Oh, SJ, Choo, MS, Kim, HS, Kim, JC, Lee, JG, Yun, JM, Kim, DY, Paick, JS, Lee, JY, Chung, BS, Min, KS, Kim, YH, Jung, HC, Son, H, Jeong, JY, Rho, J, Lee, KS, Park, WH and Ku, JH. Generic and disease-specific health-related quality of life in women with coital incontinence: a prospective, multicenter study. Gynecol Obstet Invest, 2008; 65(1):62-7. 29. Espuña Pons, M and Puig Clota, M. Coital urinary incontinence: impact on quality of life as measured by the King's Health Questionnaire. Int Urogynecol J Pelvic Floor Dysfunct, 2008; 19(5):621-5. 30. Turner, DA, Shaw, C, McGrother, CW, Dallosso, HM, Cooper, NJ and MRC Incontinence Team. The cost of clinically significant urinary storage symptoms for community dwelling adults in the UK. BJU Int, 2004; 93(9):1246-52.

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Chapter 1: Introduction and background

20

CHAPTER 2

A Review of Hormone Receptor-Positive Early Breast Cancer

The following two Chapters (Chapter Two and Three) describe and review the relevant literature, which underpin the rationale behind the research questions and provide a conceptual framework for the generation of the study hypotheses. In the first part of the review (Chapter

Two) the management of women with hormone receptor-positive early breast cancer is discussed, including treatment recommendations and the potential of antiestrogen therapy, with particular reference to the genitourinary side effects.

21

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Chapter 2: A review of hormone receptor-positive early breast cancer

2. Breast cancer

Breast cancer ranks as the leading cancer affecting women worldwide with almost 1.7 million new cases diagnosed in 2012.1 In Australia, a woman’s lifetime risk for breast cancer is one in

11 by the age of 75, and projections for 2015 estimates that 15,600 Australian females will be diagnosed with the disease.2 Standardised incidence rates of breast cancer in Australian women are shown in Figure 2.1.

Figure 2.1. Breast cancer incidence in Australia (observed for 1982 -2007, projected to

2020)

Source: Australian Institute of Health and Welfare (AIHW) and Australasian Association of Cancer Registries (AACR)3

Although breast cancer can occur at any age, the risk rises as women get older and is much greater in those over the age of 50 (Figure 2.2),2, 4 most of whom are postmenopausal.5, 6 It has been reported that about 80% of women diagnosed with breast cancer are above 50 years in age and approximately 50% are in the age group range of 50-69 years.4, 7 As a result, postmenopausal women account for more than two-thirds of all new diagnoses of breast cancer.5, 6 Most new cases are diagnosed at early stages3, 8 and approximately 70% to 80% of

23

Chapter 2: A review of hormone receptor-positive early breast cancer

tumours express estrogen receptors (ER) and/or progesterone receptors (PR)9 and are therefore, more likely to be hormone dependent.10 Postmenopausal women with hormone receptor- positive early breast cancer constitute the majority of cases in Australia and worldwide and most of these patients will be treated with an antiestrogen as adjuvant therapy.

Figure 2.2. Age-specific incidence rates for breast cancer, 2015

Source: AIHW analysis of the Australian Cancer Database (unpublished), (see source data).11 (http://canceraustralia.gov.au/affected-cancer/cancer-types/breast-cancer/breast-cancer-statistics#source- data)

Breast cancer remains one of the leading causes of cancer-related death among women, but mortality rates have continuously declined over the last decades, underscoring the importance of the impact of adjuvant treatments on improving survival.12 Worldwide, approximately five million women are survivors of breast cancer13 and in Australia, almost 90% of women are expected to survive beyond five years after diagnosis.3 See Figure 2.3 for a summary of time- period relative survival rate in Australian women from 1982-2010.

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Chapter 2: A review of hormone receptor-positive early breast cancer

Figure 2.3. Breast cancer relative survival by time period, females, Australia (1982 -1987 to 2006-2010)

Source: Australian Institute of Health and Welfare (AIHW) and Australasian Association of Cancer Registries (AACR)3

Important advances in the adjuvant treatment of early disease as well as early detection are key factors for the improved outcomes. The Australian Institute of Health and Welfare (AIHW) reports that the incidence rates of early stage breast cancer are increasing due in large part to the widespread use of mammography screening.3 Furthermore, the use of increasingly effective adjuvant endocrine therapy for women who have hormone-sensitive tumours, has also contributed to the sustained decline in cancer mortality rates.14-18 Yet, endocrine therapy is also largely responsible for many of the long-term side effects of treatment.19 Consequently, as a result of the improved survival, an increasingly important concern is the long-term side effects of breast cancer treatment that can negatively affect QoL and compliance with treatment.

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Chapter 2: A review of hormone receptor-positive early breast cancer

2.1. Early stage breast cancer

Breast cancer stage is based on either clinical or pathological findings and is used to select the most appropriate treatments and to help predict outcomes. Breast cancer is staged as Stage 0, I

(A or B), II (A or B), III (A, B, or C), or IV. 20 The stage is based on the size of the tumour and whether the cancer has spread to lymph nodes or more distant sites. For the purposes of this research, early stage is defined as invasive breast cancer confined to the breast and limited axillary involvement, that is, breast cancer that may have spread to draining lymph nodes but not to distant sites and the objective of treatment is cure. This definition corresponds to stages

IA, IB, IIA and IIB (shown in purple in the Table 2.1).

26

Chapter 2: A review of hormone receptor-positive early breast cancer

Table 2.1. Tumour, Node and Metastasis (TNM) staging of breast cancer.

Stage Tumour size Extent of lymph node Metastasis (in greatest dimension) involvement 0 Carcinoma in situ, or Paget’s None No disease of the nipple, without a detectable tumour mass IA ≤ 2cm None No IB No evidence of primary tumour Micrometastases to mobile No axillary lymph nodes (>0.2-2mm ≤ 2cm or more than 200 cells) IIA No evidence of primary tumour Metastases to mobile ipsilateral No ≤ 2cm level I, II axillary lymph nodes >2 to ≤5cm None IIB >2 to ≤5cm Metastases to mobile ipsilateral No level I, II axillary lymph nodes > 5cm None IIIA No evidence of primary tumour Metastases in ipsilateral level I, II No ≤ 2cm axillary lymph nodes that are >2 to ≤5cm clinically fixed or matted; or in clinically detected ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastases > 5cm Metastasis to mobile ipsilateral level I, II axillary lymph nodes

> 5cm Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted; or in clinically detected ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastases

IIIB Any size with direct extension None; Mobile axillary lymph No to the chest wall and/or to the nodes; Axillary lymph nodes that skin (ulceration or skin nodules) are clinically fixed or matted IIIC Any Internal mammary node, infraclavicular or supraclavicular lymph nodes IV Any size with direct extension Any Yes to the chest wall and/or to the skin (ulceration or skin nodules)

Source: Table adapted from the American Joint Committee on Cancer (AJCC), Chicago, IL.20

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Chapter 2: A review of hormone receptor-positive early breast cancer

2.2. Hormone receptor expression and hormonal therapy in breast cancer

Breast cancers are categorised according to the presence or absence of receptors for the estrogen and progesterone. Tumours that express receptors for either of these hormones, or both of them, are considered potentially hormone-responsive or -sensitive breast cancers and are commonly treated with an antiestrogen. About 65% of breast cancers diagnosed in premenopausal women and over 80% of those arising after menopause are hormone receptor- positive cancers (Figure 2.4).10, 21-23 Following the American Society of Clinical Oncology

(ASCO) and the College of American Pathologists (CAP) guideline recommendations, the determination of hormone receptor status on the basis of the immunohistochemical (IHC) expression of ER and PR has become a standard practice in the treatment of breast cancer and is therefore, routinely tested and quantitatively reported in all newly diagnosed invasive breast cancers.24, 25

Figure 2.4. Percentage of patients with a given ER/PR-status by age

100 90 80 70 60 50 40 30 20 10 0 30-39 40-49 50-59 60-69 70-79 ≥80

ER+/PR+; ER+/PR-; ER-/PR+ ER-/PR-

Source: Based on data from Dunnwald LK, Rossing MA, Li CI. Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients. Breast Cancer Res. 2007, 9(1):R6. 26

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Chapter 2: A review of hormone receptor-positive early breast cancer

Hormone receptor expression in tumour tissue is a very important and useful biomarker in breast cancers.27, 28 It is an important predictor of benefit to endocrine treatment both in the metastatic and in the adjuvant setting.29, 30 Highest response rates to endocrine therapy are observed in strongly ER/PR-positive tumours compared with those that are negative for both hormones (ER-/PR-).31-33 The improvements in breast cancer survival rates have been greater among women with ER+ tumours, partly as a result of the widespread use of adjuvant endocrine therapy.16, 34-36 More recently, it has been recognised that hormone receptor expression is also a prognostic factor.37-42 Women with tumours that are hormone receptor-positive have better prognosis26 and tend to have more indolent cancers.26, 30 Therefore, determination of ER- and

PR-status is of fundamental importance and provides the basis for treatment recommendations in women with hormone receptor-positive early breast cancer.

2.2.1. Hormone receptor-positive as prognostic factor in breast cancer

Prognostic factors are defined as the intrinsic characteristics or features in the patient and the tumour that predict clinical outcomes, independent of treatment.43 Taking these characteristics into consideration is essential and guides clinicians in making adjuvant treatment recommendations to a patient based on her risk of relapse. More importantly, prognostic factors help in selecting the subgroup of patients with hormone-responsive early breast cancer that would benefit from adjuvant endocrine therapy alone sparing patients from the potential side effects of adjuvant chemotherapy.

Hormone receptor-positivity (ER+ and/or PR+) is an important and independent prognostic factor in early breast cancer.16, 44 In the NSABP B-06 trial (National Surgical Adjuvant Breast and Bowel Project), women with early breast cancer were randomised to surgery alone or surgery followed by radiotherapy in the absence of any adjuvant therapy; women with ER+ tumours had better five-year overall survival (OS) (92% vs 82%) and disease free survival

29

Chapter 2: A review of hormone receptor-positive early breast cancer

(DFS) (74% vs 66%) compared to women with ER-negative tumours.44 However, after prolonged follow-up (i.e. more than three years) it was found that the prognostic impact of ER+ tumours was not as strongly related to improved outcome, as there was still a substantial risk of late recurrence and distant metastases.45 This suggests that expression of hormone receptors is in fact associated with more indolent tumours with longer progression free interval.

2.2.2. Hormone receptor-positive as predictive factor in breast cancer

Predictive factors are characteristics that predict response to therapy, and are used to make treatment recommendations. ER/PR positivity is a strong predictive factor and increases the likelihood of benefit from endocrine therapy.46 Overall, hormone-positive tumours have a 60-

70% response rate to endocrine therapy compared with only 5-10% for hormone-negative tumours.47 Hormone receptor-positivity is the single most important factor predicting the potential benefit of adjuvant endocrine therapy with high-quality (level1/category A) evidence to support its use.46

Many studies have evaluated the predictive role of hormone expression in early stage breast cancer.31, 48-59 The most recent overview performed by the Early Breast Cancer Trialists’

Collaborative Group (EBCTCG) provides robust evidence regarding the importance of ER- expression.59 The overview showed that about five years of adjuvant TAM in women with ER+ tumours reduced their risk of recurrence and mortality by 47% and 26%, respectively, and led to a proportional reduction of contralateral breast cancer of almost 50%. There was no benefit for

TAM in women with ER-negative tumours.59 The analysis also showed that there was a strong linear correlation between the level of ER-expression and benefit from TAM. Consistent with these findings, recent results of two large trials also confirmed that higher ER levels were associated with improved outcomes with TAM or an AI.54, 57 Hence, the vast majority of women

30

Chapter 2: A review of hormone receptor-positive early breast cancer

with hormone-positive breast cancers are offered adjuvant endocrine therapy for a minimum of five years.60

2.3. Hormone receptor-positive targeted therapies

Breast cancer treatment recommendations are based on the characteristics of the tumour and patient.13, 46 Most postmenopausal women with early breast cancer will receive locoregional treatments with surgery and radiotherapy, as well as systemic adjuvant therapy, which may include chemotherapy, monoclonal antibody therapy such as trastuzumab in women with human epidermal growth factor receptor two (HER2) positive breast cancers, endocrine therapy, or a combination of all treatments.

Even in patients with early stage of breast cancer, micrometastases may have disseminated widely prior to diagnosis and local treatment. In addition, there may still be residual tumour cells in the breast or locoregional lymph nodes following surgery. In hormone receptor-positive tumours, it is believed that circulating estrogen is an important growth factors and may contribute to the risk of local recurrence as well as distant metastases.13, 45 Adjuvant endocrine therapy plays an important role in counteracting estrogen action, thus significantly reducing the risk of tumour recurrence and increasing the likelihood of long-term survival.59

The focus of this thesis is on postmenopausal women receiving adjuvant endocrine therapy, which includes the selective estrogen receptor modulator (SERM): TAM, and the AIs: anastrozole (ANA), exemestane (EXE), or letrozole (LET). As discussed above, endocrine therapy is an essential component in the treatment of women with hormone-responsive breast cancers and will be described in more detail.

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Chapter 2: A review of hormone receptor-positive early breast cancer

Endocrine therapy

There are essentially two different endocrine therapies that are commonly used in the adjuvant setting in postmenopausal women with hormone-receptor positive tumours. They have different mechanisms of action (Figure 2.5) and either prevent estrogen from binding to its receptor (e.g.,

TAM), or reduce the endogenous synthesis of estrogen by blocking the aromatase , which converts to and to in the peripheral tissues in postmenopausal women (e.g., AIs).61

Figure 2.5. Mechanisms of action of tamoxifen and aromatase inhibitors.

TAM

AI

Androstenedione Estrone

Aromatase

Aromatase

Testosterone Estradiol

Cell membrane membrane Cell surface

2.3.1 Tamoxifen

TAM is a mixed estrogen antagonist/. The anti-tumour effect of TAM is due to its antiestrogenic effect, mediated through competitively binding to the ER on tumour cells and inhibiting tumour cell proliferation.62, 63 Postmenopausal women have low circulating levels of estrogen and progesterone and high levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).64 In these women, TAM also decreases secretion, acting as an estrogen antagonist on the neuroendocrine axis (hypothalamus-hypophysis- axis).65, 66

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Chapter 2: A review of hormone receptor-positive early breast cancer

Although TAM has a predominantly estrogen antagonist effect, it also is an estrogen agonist in certain tissues, including the endometrium, vagina, bone, and the cardiovascular and coagulation systems, which explains some of its side effects. For instance, the estrogen agonist effects of TAM on the uterus are responsible for an increased endometrial thickness and increased risk of uterine cancer.67

TAM has been a central component in the treatment of women with hormone receptor-positive breast cancer for more than 30 years,68 and is the gold standard therapy to which newer endocrine agents are compared against. The role of TAM in the adjuvant setting has been widely established and is best documented in the overview analysis conducted by the EBCTCG which data have been discussed earlier in this Chapter.58, 59 In brief, the updated 15-year follow- up outcomes in 21,457 participants from 20 randomised clinical trials (RCTs) showed that about five years of adjuvant TAM reduced the risk of recurrence and mortality in women with ER+ tumours, irrespective of the use of chemotherapy or age, in addition to reducing the incidence of contralateral breast cancer by half.59,69 The data also showed that the benefits of taking TAM persisted through to year 15, which is 10 years after treatment had stopped.

Previous practice guidelines recommended a five-year course of TAM70-73 but with recent evidence from two large trials demonstrating the benefits of a longer duration of treatment, there have been updates in the guideline to reflect the emerging data. The ATLAS trial (Adjuvant

Tamoxifen Longer Against Shorter) demonstrated that TAM for 10 years led to a significantly greater reduction in breast cancer recurrence (relative risk [RR] 0.84, p=0.002) and death (2.8% absolute reduction, p=0.01) compared to TAM for five years.74, 75 Furthermore, the reduction in breast cancer deaths appeared to outweigh the risk of and other serious side effects in women who took TAM for longer period; the absolute increased risk of death from endometrial cancer in women who took TAM for 10 years versus five years was 0.2%.74

Aligned with these findings, updated results (presented as yet-unpublished results) of the 33

Chapter 2: A review of hormone receptor-positive early breast cancer

aTTom trial (adjuvant Tamoxifen Treatment offers more?) showed that 10 years of TAM was associated with a significant reduction in recurrence (RR 0.85; p=0.003) and death (RR 0.75, p=0.007) compared with five years of TAM.76 On the basis of these findings, current clinical practice guideline recommend continuing TAM to 10 year or switching to an AI for five more years following five years of TAM (rather than discontinuing TAM at five years).77

2.3.2. Aromatase inhibitors

AIs reduce the circulating estrogen in postmenopausal women by inhibiting the activity of the aromatase enzyme, which is required in the last step of conversion of androstenedione and testosterone to (estrone and estradiol, respectively).78 Three generations of AIs have been developed over the past 30 years. Table 2.2 details anti-aromatase agents based on their classification by generation and mechanism of action. The third-generation AIs (ANA, LET and

EXE) have all been shown to have more favourable and safety profiles and have a greater clinical benefit in postmenopausal women with ER+ early breast cancer compared to the first- and second-generation agents,79-81 and are now standard of care. Two types of the third- generation agents, ANA and LET, are similar and are non-steroidal AIs, while EXE is a steroidal AI. They are all potent inhibitors of aromatase and reduce systemic estrogen levels by up to almost 99% (estradiol 92.8-95.2%, estrone 96.3-98.8%, estrone sulphate 95.3-98.9%).82-85

All studies comparing one AI with another have shown them to have equivalent safety profiles,86, 87 and all three AIs appear to be equivalent with respect to efficacy although, there have been some studies suggesting that LET may be more active, but this remains contentious.82, 88 Recent findings from the bone sub-study of the NCIC CTG MA.27 (National

Cancer Institute of Canada Clinical Trials Group), which evaluated more fully the differences between the third-generation agents ANA and EXE on bone, showed these to have a similar effect on hip and spine bone mineral density at two years.89 Therefore, current data are consistent with earlier reports demonstrating no significant differences in regards to efficacy and

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Chapter 2: A review of hormone receptor-positive early breast cancer

toxicity between the third-generation AIs in patients with hormone-receptor positive early breast cancer.

Table 2.2. Aromatase inhibitors categorised by generation and by mechanism of action

Anti-aromatase Agents Mechanism of Action Generation Non-steroidal Inhibitor Steroidal Inactivator First (Cytadren) -- Second (Afema) (Lentaron) Third Anastrozole (Arimidex) Exemestane (Aromasin) Letrozole (Femara) Vorozole (Rivizor)

There are a number of different options of endocrine treatment regimens for the treatment of women with breast cancer, including an AI alone for five years, switching to an AI for up to five years after two/three years of TAM or extending the duration of adjuvant therapy for five years with an AI following a five-years of TAM.77 There remains uncertainty regarding the benefit of continuing an AI after five years of therapy; however, it is well known that women with hormone receptor-positive breast cancers have an ongoing risk of recurrence beyond five years.13, 45 Anecdotally, many women with high risk lymph node positive breast cancers opt to continue treatment beyond five years, but the benefit of this is uncertain. To answer such question, studies of extended duration of treatment with an AI are in progress. For instance, the ongoing NSABP B-42 trial is randomising 3,966 postmenopausal women to receive five years of LET versus placebo, following five years of endocrine therapy (comprised of at least two years of an AI).90

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Chapter 2: A review of hormone receptor-positive early breast cancer

2.4. Differences between tamoxifen and aromatase inhibitors – is it clinical significant?

As more treatment options become available and the duration of adjuvant endocrine therapy has been progressively extended, a number of themes are emerging as important, including the efficacy, sequencing, duration, toxicity and profiles of the various endocrine treatment options. A number of large well-conducted trials comparing AIs to TAM in postmenopausal patients have yielded modest benefits and minimal to no survival advantages, but have shown differences in their toxicity profiles.80, 89, 91-96 Currently, the decision about which endocrine therapy is most suitable for each patient is often tailored according to tumour characteristics and patient comorbidities (e.g. osteoporosis) and preferences regarding side effects and risks. For example, AIs may be the preferred adjuvant endocrine therapy for postmenopausal women with hormone-responsive early breast cancer with higher risk of recurrence, as the short-term benefits of AIs may outweigh the risk of adverse events.79

However, a significant number of postmenopausal women cannot tolerate the side effects of AIs and will then usually be offered TAM.

2.4.1 Clinical trials comparing the efficacy profile between aromatase inhibitors and tamoxifen

Over the last 15 years, several studies have been performed to assess the value of third- generation AIs, showing benefit in terms of OS, DFS, distant disease-free survival, and contralateral breast cancer recurrence in postmenopausal patients with breast cancer who have hormone receptor-positive disease when compared with TAM.13, 45 Other studies showed beneficial effects of a sequential treatment regimen consisting of two to three years of TAM followed by two to three years of an AI when compared with TAM alone.14, 92, 96-102 While there is also strong evidence to show that extending adjuvant endocrine therapy with five years of an

36

Chapter 2: A review of hormone receptor-positive early breast cancer

AI after an initial five years of adjuvant TAM is also an effective treatment option.10, 100, 101 The trials are briefly summarized below.

ANA has been compared to TAM in the Arimidex Tamoxifen Alone or in Combination

(ATAC) study, which was one of the largest adjuvant endocrine studies ever carried out; 9,366 postmenopausal women were randomised to five years of either ANA or TAM alone or both drugs together.15 Taking a combination of drugs was no better than taking TAM alone hence, this part of the trial was stopped and women went on to take one or the other drug. For hormone receptor-positive patients (ANA n=2,618, TAM n=2,598), the 10-year analysis showed that

ANA significantly improved DFS (Hazard Ratio [HR] 0.86, p=0.003), and time to recurrence

(HR 0.79, p=0.0002) which, also increased over time (from 2.7% at year five to 4.3% at year

10), and significantly reduced the risk of contralateral breast cancers (53% relative risk reduction, p=0.001).93, 103

The Italian Tamoxifen Anastrozole (ITA) trial (n=448) and the Arimidex Nolvadex 95/Austrian

Breast Cancer Study Group 8 (ARNO 95/ABCSG8) trial (n=3,224) are two smaller studies that also demonstrated that TAM for two to three years followed by ANA, significantly reduced the risk of recurrence (HR 0.57, p=0.005 and HR 0.60, p=0.0009, respectively) compared with

TAM alone for five years.99, 104, 105 Similar results were subsequently shown at the 30.1-months analysis of the ARNO 95 trial (n=979), where patients who switched to ANA had a 34% reduction in the relative risk for disease recurrence and an absolute difference in DFS of 4.2% in favour of ANA.106 In summary, the data indicate that adjuvant ANA is more effective than

TAM alone in postmenopausal women with early stage hormone-responsive breast cancer.

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Chapter 2: A review of hormone receptor-positive early breast cancer

Clinical trials have also shown that LET is superior to TAM. The Breast Cancer International

Group (BIG) 1-98 trial randomised 8,010 patients to either upfront LET or TAM for five years, or LET for two years followed by TAM for three years, or TAM for two years followed by LET for three years.80 At the five-year data analysis, upfront LET was shown to be superior to upfront TAM treatment,92 however, at the 71-month analysis the difference in OS with upfront

TAM or LET was not statistically significant (HR 0.87, p=0.08).80 Another study conducted by the NCIC CTG MA.17 trial randomised 5,187 postmenopausal women with early breast cancer who had completed five years of TAM to either receive an additional five years of LET or placebo.107 However, the patients were unblided and trial discontinued after 30 months of follow-up when interim analysis revealed substantial improvements in DFS and a trend towards an OS advantage in the LET group.108, 123 In the data analysis after patients were unblided, at a median follow-up of 64-months, the risk of recurrence in the LET group had reduced an additional 19% (lowering it from 10.7% to 8.8%), and there was a 4.6% absolute benefit in

DFS.100, 108, 109

The steroidal anti-aromatase agent EXE was first studied in the sequential adjuvant setting in women who had received two to three years of TAM, and the results showed superiority of EXE over five years of TAM alone.94 In the Intergroup Exemestane Study (IES), 4,724 postmenopausal women who were on two to three years of TAM, were randomly assigned to either receive an additional two to three years of TAM or to switch to two to three years of EXE for a total of five years of endocrine treatment.94 At 91-months follow-up, the group that was switched from TAM to EXE had an absolute OS benefit of 2.4% and absolute DFS benefit of

4.4%.110 The results of these studies are summarized in Table 2.3.

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Chapter 2: A review of hormone receptor-positive early breast cancer

Table 2.3. Summary of disease free survival in trials with an aromatase inhibitor in the adjuvant setting

Follow-up 95% CI Absolute Regimen Trial Protocol HR (months) RR (%) Upfront ATAC ANA vs TAM 100 0.86 (0.78, 0.97) 4.3

BIG 1–98 LET vs TAM 71 0.87 (0.78, 0.99) 2.9

TAM →EXE vs Sequential IES TAM 91 0.81 (0.71, 0.92) 4.4

TAM→ANA vs ARNO 95 30.1 0.61 4.2 TAM (0.40, 0.93) TAM→ANA vs ABCSG/ARNO TAM 28 0.60 (0.44, 0.81) 3.1

TAM→ANAvs ITA 64 0.57 7.9 TAM (0.38, 0.85) TAM →LET vs LET 71 1.05 (0.84, 1.32)* NR BIG 1-98

LET→TAM vs LET 71 0.96 (0.76, 1.21)* NR

TAM→LET vs Extended MA. 17 64 0.68 (0.55, 0.83) 4.6 TAM →PLB

Abbreviations: HR, Hazard Ratio; CI, Confidence Interval; RR, Relative risk; ATAC, Arimidex, Tamoxifen, Alone or in Combination;111 ANA, anastrazole; TAM, tamoxifen; BIG, Breast International Group;95 IES, Intergroup Exemestane Study;94 EXE, Exemestane; ARNO, Arimidex-Nolvadex;112 ABCSG/ARNO, Austrian Breast and Colorectal Cancer Study Group/Arimidex-Novaldex99 ITA, Italian Tamoxifen Anastrazole;105 LET, letrozole; NR, Not reported.18 * 99% CI

2.4.1 Clinical trials comparing toxicity and tolerability profiles between aromatase inhibitors and tamoxifen

Most side effects produced by TAM and AIs are related to estrogen deprivation, and the symptoms are similar to those experienced during natural menopause.113 The profile of side effects of endocrine therapies varies in published trials and include hot flashes and other vasomotor symptoms, arthralgia, osteoporosis, fractures, cognitive problems, genitourinary disorders, , cardiovascular events, sexual dysfunction and impaired QoL 39

Chapter 2: A review of hormone receptor-positive early breast cancer

among others.93-95, 98, 99, 114, 115 This long list of potential side effects emphasizes the critical importance to evaluate the toxicity profile of long-term use of endocrine therapy to inform patients and to guide treatment recommendations decision-making.

Hot flashes

Hot flashes are a common that has been described in most clinical trials evaluating endocrine therapies with a high incidence reported regardless of the treatment received (TAM,

AIs or placebo).14, 80, 92, 96, 99 Hot flashes were the most common toxicity reported by patients that led to discontinuation of TAM therapy in the NSABP B-14 trial.116 In most trials, patients taking

TAM experienced more hot flashes than those taking ANA.95, 117 However, when compared to placebo, the rates of hot flashes were higher in patients who were assigned to an AI (i.e.

LET).107 Data on rates of hot flashes reported in clinical trials are summarised in Table 2.4.

Cognitive dysfunction

It has been hypothesized that prolonged estrogen deprivation may lead to a decline in cognitive function, thus, theoretically, TAM may adversely affect cognition.118 However, there is a paucity of comprehensive research into the adverse effects of adjuvant endocrine therapy on this specific problem. Results from a recent trial comparing TAM, EXE and healthy controls, showed that after one year of adjuvant endocrine therapy, patients receiving TAM performed significantly worse with respect to verbal memory (p<0.01) and executive functioning (p=0.01) when compared with healthy controls.119 In contrast, patients receiving EXE did not exhibit any apparent negative effects on cognitive functioning.119 Following this report, a sub-study of the

BIG 1-98 trial compared the potential cognitive effects of TAM and LET in postmenopausal women with early stage breast cancer during their fifth year of treatment. The investigators

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reported that patients taking adjuvant LET had better cognitive function than those taking

TAM.120

Lipid and cardiovascular symptoms

TAM appears to have cardioprotective effects with significant reduction of risk in myocardial infarction deaths associated with use.121 In addition, TAM use has been related with slight decrease of 6% to 28% in total and LDL cholesterol.122 In contrast, AIs have been associated with increase in cardiovascular events,14, 94-96, 123 serum cholesterol and triglycerides.94, 95, 117, 124, 125 Data on hypercholesterolemia and cardiovascular toxicity derived from clinical trials are summarised in Table 2.4.

Bone loss and osteoporosis

Estrogen plays an important role in bone metabolism and homeostasis and is crucial for the maintenance of bone mass. As TAM exhibits estrogen agonistic activity on bone, it has a protective effect on bone in postmenopausal breast cancer patients.126 Conversely, AI therapy has been associated with increasing rate of skeletal events, particularly osteoporosis and bone fractures in all clinical trials regardless of the AI administered (ANA, LET or EXE).94, 103, 107, 117,

127, 128 Data on bone-related toxicity are summarised in Table 2.4.

Musculoskeletal symptoms

Arthralgia is one of the most common reported adverse effects associated with the AIs,79 and the blanket term ‘arthralgia’ may encompass a much wider range of symptoms including arthritis, osteoarthritis, myalgia, fibromyalgia, amongst others.129 AI therapy has consistently been associated with significantly higher rates of musculoskeletal complaints compared with TAM.

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94, 99, 117, 130 These symptoms typically occur soon after commencing treatment and tend to gradually improve over time in many patients. Data on musculoskeletal toxicity from trials are summarised in Table 2.4.

Adverse gynaecologic events

TAM has been shown to have both estrogen agonist and antagonist effects in normal tissue, including the genitourinary system. Long-term use of TAM has been associated with more serious treatment-related adverse gynaecologic events.131-134 A meta-analysis that included 22 trials with 52,929 patients reported that TAM was associated with a significantly increased risk of endometrial cancer (RR 2.70; 95% CI 1.94-3.75).121 In addition, when compared with placebo, an increased incidence of vaginal bleeding, polyp formation, endometrial thickening and ovarian cysts has also been reported in patients taking TAM.135

Compared to an AI, vaginal bleeding events,92, 96 vaginal discharge,96, 136 and incidence of urinary disorders (including incontinence and urinary tract , both analysed as non- predefined adverse events in one trial)117 have been reported more frequently in women receiving TAM. Similarly, TAM users reported more bladder control problems137 and lower urinary tract disorders104 compared to placebo groups. Although TAM has been associated with some important genitourinary side effects, several studies have shown significantly more genitourinary atrophy-related symptoms associated with AI-treatment than with TAM.138-140 For instance, vaginal dryness is a very common reported side effect, which may lead to dyspareunia and contribute to impaired sexual dysfunction and is more frequently described among AI-users compared with TAM.141 Data on gynaecological toxicity reported in clinical trials are summarised in Table 2.4.

42

Table 2.4. Summary of toxicity profile of tamoxifen and aromatase inhibitors in

Side effects Trial (Protocol) ABCSG-8/ IES MA. 17 ITA NSABP ATAC BIG 1–98 ARNO-95 (TAM →EXE vs (TAM→LET vs (TAM→ANA (EXE vs (ANA vs TAM) (LET vs TAM) (TAM→ANA TAM) TAM →PLB) vs TAM) PLA) vs TAM) Hot flashes 35.7% vs 40.9%, 32.8% vs 37.4% 46% vs 44.7% 58% vs 54%, 50% vs 48% -- -- p<0.0001 p=0.003

Lipid metabolism and cardiovascular symptoms Hypercholesterolemia 9.0% vs 3%, 50.6% vs 24.6%, 7.2% vs 6%, 16% vs 16%, ------p<0.0001 p<0.001 p=0.12 p=0.79

Cardiovascular events Ischemic All cardiac events: Cardiovascular Cardiovascular ------cardiovascular 5.5% vs 5%, events: 16.5% vs disease: 5.8% vs events: 4.1% vs p=0.48 15%, p=0.16 5.6%, p=0.76 3.4%, p=0.10 Ischemic heart Ischemic cardiac disease: disease: 8% vs 2.2% vs 1.7%, 6.9%, p=0.17 p=0.21 Myocardial Cardiac failure: infarction: 1.3% 1% vs 0.6%, vs 0.8%, p=0.08 p=0.14 Bone loss and osteoporosis Fractures 11% vs 8%, 5.7% vs 4%, 7% vs 4.9%, 5.3% vs 4.6%, 2.4% vs 1.2%, -- -- p<0.0001 p<0.001 p=0.003 p=0.25 p=0.015

Osteoporosis 11% vs 7%, -- 9.2% vs 7.2%, 8.1% vs 6%, ------p<0.0001 p=0.01 p=0.003

43

Musculoskeletal symptoms Arthralgia 35.6% vs 29.4%, 20% vs 13.5%, 11.8% vs 18.6%, 25% vs 21%, 19% vs 16%, -- -- p<0.0001 p<0.001 p<0.0001 p<0.001 p=0.054

Muscle pain -- 7.1% vs 6.1%, 16% vs 21%, 15% vs 12%, ------p=0.19 p<0.0001 p=0.004 Adverse gynaecologic events Vaginal bleeding 5.4% vs 10.2%, 3.3% vs 6.6%, 5.2% vs 7.6%, -- 6% vs 8%, 17% vs 18%, 21.96% vs p<0.0001 p<0.001 p=0.002 p=0.005 p=0.94 21.26%, RR=1.03 Vaginal discharge 3.5% vs 13.2%, -- 7.6% vs 17.7%, -- -- 17% vs 18%, p<0.0001 p<0.001 p=0.94 --

Vaginal dryness 18.5% vs 9.1%, -- 23.5% vs 26.3% 17% vs 18% ------p=NR

Dyspareunia 28% vs 9%, -- 14.9% vs 22.5% ------p=0.002 Urologic events UI: 2% vs 4%, -- -- LUTD: 4.7% vs -- 54.7% vs Bladder p<0.0001 4.4%, p=0.6 34.13%, control UTI: 8% vs 10%, RR=1.60 52.5% vs p=0.002 46.7%, RR=1.13 Abbreviations: ATAC, Arimidex, Tamoxifen, Alone or in Combination;111 ANA, anastrazole; TAM, tamoxifen; BIG, Breast International Group;95 LET, letrozole; IES, Intergroup Exemestane Study;94 EXE, exemestane; MA. 17;18 ABCSG-8/ARNO-95, Austrian Breast and Colorectal Cancer Study Group/Arimidex-Novaldex;99 ITA, Italian Tamoxifen Anastrazole (trial);105 NSABP, National Surgical Adjuvant Breast and Bowel Project;142, 143 RR, Risk relative; UI, Urinary Incontinence; UTI, Urinary Tract Infection; LUTD, Lower Urinary Tract Disorders.

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Quality of life

Typically, side effects that negatively impact on patients’ QoL are often not life threatening and therefore, may be overlooked by clinicians during follow-up. The impact of endocrine therapy on patient-reported QoL has been investigated in sub-studies of three trials, ATAC, IES and

MA.17.144-146 In the ATAC trial, ANA was compared to TAM using the Functional Assessment of Cancer Therapy-Breast plus Endocrine Subscale (FACT-B + ES) questionnaires.147 No difference on overall impact on QoL between ANA and TAM was demonstrated in the study.

Additionally, compared to baseline, improvements in QoL were reported across both drugs over a period of five years.145 In the IES trial, EXE was compared to TAM, using the FACT-B + ES questionnaires147 with no significant difference between the two groups evident over a two year period.146 Finally, the impact on overall QoL with extended adjuvant LET compared with placebo, was evaluated in a QoL sub-study of MA.17 trial using the Short Form 36-item Health

Survey (SF-36) and the Menopause Specific Quality of Life Questionnaire (MENQOL).130

Small, yet statistically significant differences (<0.2 SD) in favour of placebo were seen in a number of QoL domains (physical functioning, bodily pain and vitality in the SF-36 and vasomotor and sexual domains in the MENQOL).144

The effect of adjuvant endocrine treatment on sexual functioning

It is increasingly recognised that sexual dysfunction is a common problem in patients treated with endocrine therapy but often overlooked or not fully addressed with breast cancer patients in the clinical practice.148, 149 The symptoms are mostly related to estrogen depletion and can include vaginal dryness, dyspareunia and loss of libido, all of which may also negatively impact on QoL. Ganz et al. have stressed that interest in sexual activity is one of the most important concerns influencing QoL issues in breast cancer survivors.150

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Overall the results from clinical trials of adjuvant endocrine therapy have found that AI-treated patients report a greater degree of impaired sexual functioning than TAM-treated patients.

Although no difference in overall QoL was demonstrated, in the ATAC trial decreased libido

(39% vs 12%, p=0.0001) and dyspareunia (28% vs 9%, p=0.002) were reported significantly more often during therapy with ANA compared with TAM.140, 151 Similarly, QoL analysis in the

MA. 17 trial showed significantly worse sexual problems with LET compared to placebo.144

Disappointingly, the specific sexual concerns were not described by the authors. In the IES trial, dyspareunia and diminished libido were reported with EXE, but these symptoms were not statistically different to those observed with TAM.146

2.5. Compliance to endocrine therapy

Despite the unequivocal benefits of adjuvant endocrine therapy, compliance is often suboptimal.

Partridge et al. reported that only 50% of patients were compliant by the fourth year of treatment with TAM.152 Likewise, another three studies reported that 23% to 50% of patients who were prescribed endocrine therapy ceased treatment early.153-155 A systematic review by

Murphy et al., reported that up to 31% to 73% of patients do not complete the recommended five years of adjuvant endocrine treatment.156 The reasons for discontinuation are many, and include the development of unacceptable side effects.157-160 Specifically, Owusu et al. reported that around 65% of patients stopped TAM in the first year due to side effects.161 Similarly, 34% of women taking EXE and 29% of those on ANA in the NCIC CTG MA.27 trial discontinued therapy mostly because of adverse effects of these medications.162 Arguably, if side effects could be better controlled (for instance, with more information of anticipated events and prompt management of symptoms) compliance may increase.

Poor compliance with adjuvant endocrine therapy may significantly affect patient outcome and contribute to increased healthcare spending.163-166 McGowan et al. reviewed the prescription

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Chapter 2: A review of hormone receptor-positive early breast cancer

records of 1,633 women on TAM and found a better outcome in patients who were compliant with treatment and took it for five years.167 Non-adherence may also reduce or eliminate the drug’s therapeutic effects and thus, result in more visits to the doctor, higher hospitalisation rates, and increased length of stay in hospitals.152, 168 Additionally, lack of adherence prevents clinicians from conducting accurate assessments of the therapeutic and toxic effects of the prescribed.169 Subsequently, patients may develop negative views about their care providers, which may compromise the patient-doctor relationship.170

2.6. Summary

Notable improvements in mortality rates of breast cancer have resulted from both mammographic screening programs and advances in the adjuvant treatment of women with early stage breast cancer. After primary treatment, the majority of women with hormone receptor-positive breast cancer will be offered adjuvant endocrine therapy, including TAM and the AIs, for at least five years to reduce the risk of recurrence and death. With current clinical practice guidelines, women may receive up to 10 years of total endocrine therapy. There are a considerable number of side effects from use of TAM and AIs, which are often poorly managed in follow-up. These side effects are of considerable concern to patients. Consequently, there is now increased interest and more attention directed towards the prevention and management of long-term side effects of adjuvant treatment in breast cancer survivors, which can negatively affect QoL and has been identified as the primary reason for low/noncompliance with therapy.

2.7. References

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138. Morales, L, Neven, P, Timmerman, D, Christiaens, M, Vergote, I, Van Limbergen, E, Carbonez, A, Van Huffel, S, Ameye, L and Paridaens, R. Acute effects of tamoxifen and third-generation aromatase inhibitors on menopausal symptoms of breast cancer patients. Anticancer Drugs, 2004 15(8):753-60. 139. Mourits, MJ, Bockermann, I, Vries, Ed, Zee, Avd, Hoor, Kt, Graaf, Wvd, Sluiter, W and Willemse, P. Tamoxifen effects on subjective and psychosexual well-being , in a randomised breast cancer study comparing high-dose and standard-dose chemotherapy. British journal of cancer, 2002; 86:1546-1550. 140. Cella, D, Fallowfield, L, Barker, P, Cuzick, J, Locker, G and Howell, A. Quality of life of postmenopausal women in the ATAC ("Arimidex", tamoxifen, alone or in combination) trial after completion of 5 years' adjuvant treatment for early breast cancer. Breast cancer research and treatment, 2006; 100:273-84. 141. Conte, P and Frassoldati, A. Aromatase inhibitors in the adjuvant treatment of postmenopausal women with early breast cancer: Putting safety issues into perspective. Breast J, 2007; 13(1):28-35. 142. McCaskill-Stevens, W, Wilson, JW, Cook, ED, Edwards, CL, Gibson, RV, McElwain, DL, Figueroa-Moseley, CD, Paskett, ED, Roberson, NL, Wickerham, DL and Wolmark, N. National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and trial: advancing the science of recruitment and breast cancer risk assessment in minority communities. Clin Trials, 2013; 10(2):280-91. 143. Day, R, Ganz, PA, Costantino, JP, Cronin, WM, Wickerham, DL and Fisher, B. Health- related quality of life and tamoxifen in breast cancer prevention: a report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Clin Oncol, 1999; 17(9):2659-69. 144. Whelan, TJ, Goss, PE, Ingle, JN, Pater, JL, Tu, D, Pritchard, K, Liu, S, Shepherd, LE, Palmer, M, Robert, NJ, Martino, S and Muss, HB. Assessment of quality of life in MA.17: a randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol, 2005; 23(28):6931-40. 145. Cella D, Fallowfield L and on behalf of the ATAC Trialists’ Group. Five-year quality of life (QOL) follow-up of adjuvant endocrine therapy for postmenopausal women in the Arimidex (A), Tamoxifen (T), Alone or in Combination (ATAC) Trial. Journal of Clinical Oncology ASCO Annual Meeting Proceedings, 2005; 23(16S ):577a. 146. Fallowfield, LJ, Bliss, JM, Porter, LS, Price, MH, Snowdon, CF, Jones, SE, Coombes, RC and Hall, E. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2006; 24:910-7. 147. Fallowfield, LJ, Leaity, SK, Howell, A, Benson, S and Cella, D. Assessment of quality of life in women undergoing hormonal therapy for breast cancer: validation of an endocrine symptom subscale for the FACT-B. Breast Cancer Research & Treatment, 1999; 55(2):189-199. 148. Hordern, AJ and Street, AF. Constructions of sexuality and intimacy after cancer: patient and health professional perspectives. Soc Sci Med, 2007; 64(8):1704-18. 149. Hordern, AJ and Street, AF. Communicating about patient sexuality and intimacy after cancer: mismatched expectations and unmet needs. Med J Aust, 2007; 186(5):224-7. 150. Ganz, PA. Sexual functioning after breast cancer: a conceptual framework for future studies. Ann Oncol, 1997; 8(2):105-7. 151. Fallowfield, L, Cella, D, Cuzick, J, Francis, S, Locker, G and Howell, A. Quality of life of postmenopausal women in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Adjuvant Breast Cancer Trial. Journal of Clinical Oncology, 2004; 22(21):4261- 71. 152. Partridge, AH. Non-adherence to endocrine therapy for breast cancer. Ann Oncol, 2006; 17(2):183-4.

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153. Fink, AK, Gurwitz, J, Rakowski, W, Guadagroli, E and Silliman, RA. Patient beliefs and tamoxifen discontinuance in older women with estrogen receptor–positive breast cancer. J Clin Oncol 2004; 22(3309-15). 154. Lash, TL, Fox, MP, Westrup, JL, Fink, AK and Silliman, RA. Adherence to tamoxifen over the five-year course. Breast Cancer Res Treat, 2006; 99:215-20. 155. Barron, TI, Connolly, R, Bennett, K, Feely, J and Kennedy, MJ. Early discontinuation of tamoxifen: a lesson for oncologists. Cancer 2007; 109:832-9. 156 .Murphy, CC, Bartholomew, LK, Carpentier, MY, Bluethmann, SM and Vernon, SW. Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review. Breast Cancer Res Treat, 2012; 134(2):459-78. 157. Kahn, KL, Schneider, EC, Malin, JL, Adams, JL and Epstein, AM. Patient centered experiences in breast cancer: predicting long-term adherence to tamoxifen use. Med Care, 2007; 45(5):431-9. 158. Demissie, S, Silliman, RA and Lash, TL. Adjuvant tamoxifen: predictors of use, side effects, and discontinuation in older women. J Clin Oncol, 2001; 19(2):322-8. 159. Henry NL, AF, Desta Z, et al. Predictors of aromatase inhibitor discontinuation due to treatment-emergent symptoms in early-stage breast cancer. J Clin Oncol, 2012; 30:936- 942. 160. Hadji P, JC, bolten W, et al. COMPliance and Arthralgia in Clinical therapy: the COMPACT trial, assessing the incidence of arthralgia and compliance within the first year of adjuvant anastrozole therapy. Ann Oncol, 2014; 25:372-377. 161. Owusu, C, Buist, DS, Field, TS, Lash, TL, Thwin, SS, Geiger, AM, Quinn, VP, Frost, F, Prout, M, Yood, MU, Wei, F and Silliman, RA. Predictors of tamoxifen discontinuation among older women with estrogen receptor-positive breast cancer. J Clin Oncol, 2008; 26(4):549-55. 162. Paul E. Goss, JNI, Kathleen I. Pritchard, Matthew J. Ellis, George W. Sledge, G. Thomas Budd, Manuela Rabaglio, Rafat H. Ansari, David B. Johnson, Richard Tozer, David P. D'Souza, Haji Chalchal, Silvana Spadafora,Vered Stearns, Edith A. Perez, Pedro E.R. Liedke, Istvan Lang, Catherine Elliott, Karen A. Gelmon, Judy-Anne W. Chapman, and Lois E. Shepherd. Exemestane Versus Anastrozole in Postmenopausal Women With Early Breast Cancer: NCIC CTG MA.27—A Randomized Controlled Phase III Trial. J Clin Oncol, 2013; 31(11):1398-1404. 163. World Health Organization. Adherence to Long-Term Therapies: Evidence for Action. 2003 [last accessed 2012 April]; Available from: http://www.who.int/chp/knowledge/publications/adherence_full_report.pdf. 164. Balkrishnan, R. The importance of medication adherence in improving chronic-disease related outcomes: what we know and what we need to further know. Med Care, 2005; 43(6):517-20. 165. Haynes, RB, Ackloo, E, Sahota, N, McDonald, HP and Yao, X. Interventions for enhancing medication adherence. Cochrane Database Syst Rev, 2008; (2):CD000011. 166. Osterberg, L and Blaschke, T. Adherence to medication. N Engl J Med, 2005; 353(5):487-97. 167. McCowan, C, Shearer, J, Donnan, PT, Dewar, JA, Crilly, M, Thompson, AM and Fahey, TP. Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer, 2008; 99(11):1763-1768. 168. Waterhouse, DM, Calzone, KA, Mele, C and Brenner, DE. Adherence to oral tamoxifen: a comparison of patient self-report, pill counts, and microelectronic monitoring. J Clin Oncol, 1993; 11(6):1189-97. 169. Danilak, M and Chambers, CR. Adherence to adjuvant endocrine therapy in women with breast cancer. J Oncol Pharm Pract, 2013; 19(2):105-10. 170. Martin, LR, Williams, SL, Haskard, KB and DiMatteo, MR. The challenge of patient adherence. Ther Clin Risk Manag, 2005; 1(3):189-99.

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CHAPTER 3

A Review of Genitourinary Symptoms

Chapter Three reviews specific literature on the impact of estrogen deprivation on the genitourinary tract, including the use of endocrine therapy for breast cancer. In the last instance, an assessment of the impact of genitourinary symptoms in a woman’s sexual function and overall QoL will be explored.

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3. Genitourinary Symptoms

3.1 Symptoms definitions

For clarity, the definitions of the genitourinary symptoms that are discussed in this thesis are described here.

3.1.1. Genitourinary syndrome of menopause

Decline in estrogen (estradiol) concentrations may lead to a variety of genitourinary symptoms that are now collectively termed as genitourinary syndrome of menopause (GSM).1 This new terminology covers a range of symptoms including (but not exclusively limited to) vaginal dryness, burning, irritation, itching, frequency, urgency, dysuria, urinary incontinence (UI), recurrent urinary tract infections (UTIs) and discomfort or pain with vulvovaginal touch/penetration. This in turn can complicate the process of sexual arousal and achievement of orgasm, thus, leading to sexual dysfunction.2

3.1.2. Vulvovaginal symptoms

Vaginal dryness is characterized by the lack of lubrication of the vagina. With reduced estrogen levels (specifically estradiol), the normal vaginal lubrication process is disrupted, affecting the amount and consistency of vaginal moisture.3 Along with vaginal dryness, women may also complain of vaginal bleeding or spotting (also known as postmenopausal bleeding), vulvovaginal itching/irritation (itching and stinging in the external genital area or around the vaginal opening and in the lower part of the vagina), vulvovaginal burning and vaginal soreness, which in turn may further contribute to pain during intercourse.4 Vaginal discharge refers to secretions from the vagina, and these can vary in consistency, colour and odour.5

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3.1.3. Urinary symptoms

Lower urinary tract symptoms (LUTS) are in general, classified into three broad domains according to the phase of micturition affected: storage (increased daytime frequency, nocturia, urgency, and UI), voiding (slow stream, splitting or spraying, intermittent stream, hesitancy, straining, and terminal dribble), and post micturition (feeling of incomplete emptying and post micturition dribble).6, 7 Abrams et al.6 reported a standardized nomenclature for symptoms (what is described by the woman), signs (what is observed by the clinician), urodynamic observations

(what is shown in urodynamic studies) and conditions associated with lower urinary tract dysfunction. According to the guidelines of the International Continence Society (ICS)

Standardisation Sub-committee,6 the definitions of urinary symptoms, succinctly, can be described as follows:

Storage (filling) symptoms are experienced during the storage phase of the bladder and are associated to difficulties in retaining (storing) in the bladder.6 Amongst the storage symptoms, women may complain of increased daytime frequency (voiding too often during the day), nocturia (get up at night one or more times to urinate), urgency (an urge to urinate that comes on very suddenly and which is difficult to defer) or UI (involuntary urinary leakage). The latter is classified into three subtypes: stress incontinence (involuntary leakage that occur as the abdominal pressure goes up, usually following effort or exertion, or on sneezing or coughing); urge incontinence (involuntary leakage accompanied by or immediately preceded by a sudden strong urge to urinate); or women may experience mixed urinary incontinence (that is, a combination of the two types, stress and urge incontinence).6 Importantly, further to investigating the type of UI, the ICS guidelines also acknowledge other relevant factors associated with UI that should be considered. These include, frequency of leakage episodes, severity of symptoms, social impact of symptoms and their effect on QoL, and whether or not women seek or desire help because of their symptoms.6

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Voiding symptoms are usually associated with obstructive causes and occur during or immediately following the emptying (voiding) phase of micturition. 6 Slow stream is defined as the women perception of reduced urine flow; splitting or spraying of the urine stream is characterised by urine splitting into two or more different directions during urination, rather than having a single discrete stream. Women may also experience intermittent stream (urinary stream which stops and starts on one or more occasions during urination), hesitancy (difficulty in starting urination) and terminal dribble (the end of micturition is prolonged as the flow slows to a trickle/dribble). The term straining is used to describe the muscular effort required to either start, maintain or increase the urinary stream.6

Post micturition symptoms are symptoms occurring immediately after urination and consist of the feeling of incomplete emptying (feeling of filled-up bladder experienced after voiding) and post micturition dribble (involuntary leaking of urine at the end of normal voiding).6

3.1.4. Bother and bothersome

The term bother and bothersome are commonly used when referring to severity of symptoms, and imply the degree of annoyance or interference caused by genitourinary symptoms, which may not always correlate with level of physical change.8, 9 In this context, variation in bother is specific to each woman and regard how they perceive and cope with individual symptoms; what might be bothersome for one woman may be quite acceptable for another.10

3.1.5. Symptoms associated with pelvic organ prolapse

Pelvic organ prolapse (POP) occurs when one or more of the pelvic organs (bladder, uterus, and rectum) bulge or protrude into or outside the vagina.11 Different parts of the vagina may be affected by different types of POP; the structures that may be involved include the anterior

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vaginal wall (i.e. anterior vaginal wall prolapse or cystocele), the posterior vaginal wall (i.e. posterior vaginal wall prolapse or rectocele), the vaginal cuff scar – after hysterectomy (i.e. prolapse of the apical segment of the vagina or apical prolapse), or cervix/uterus – if cervix/uterus intact (i.e. uterine prolapse).6 POP is often accompanied by urinary, bowel, sexual, or other local symptoms. The feeling of a lump coming out of the vagina, pelvic pressure, heaviness or fullness sensation, bearing-down pain (felt in the lower part of the abdomen and low back), pain with intercourse, vaginal bleeding, or the need to digitally replace the prolapse in order to defaecate or urinate, are amongst the symptoms women who have a

POP may describe.6

3.1.6. Symptoms associated with sexual activity

Sexual dysfunction is defined as difficulty during any stage of the sexual act, including disorders of desire, arousal, inhibited or absent orgasm and sexual pain or discomfort that prevents the individual or couple from enjoying sexual activity.12 Sexual dysfunction may negatively influence QoL and partnership; for most women it is physically disconcerting, emotionally distressing and socially disruptive.13 The term sex life used in this thesis includes sexual relationships and sexual activity, which in turn can include caressing, foreplay, masturbation and vaginal intercourse.14 Dyspareunia (painful sexual intercourse), vulvovaginal dryness and incontinence (involuntary urine leakage) are among the symptoms women may report during or after sexual intercourse.6 Coital incontinence characterises the involuntary loss of urine with coitus and can be further divided into two subtypes based on when urinary leakage occurs; that is, coital incontinence with penetration and coital incontinence at orgasm.15

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3.1.7. Genital and lower urinary tract pain

Genitourinary pain, discomfort and pressure are part of a range of abnormal sensations that can be felt and referred by the woman.6 In general, pain produces the greatest impact on the patient and may be characterised by location in: bladder pain (which can be associated with storage or voiding phases of micturition thus, be continuous or felt immediately after micturition), vulval pain or vulvodynia (most often described as a burning pain felt in and around the external genitalia) or vaginal pain (felt internally, that is above the vaginal opening – introitus).6

3.1.8. Genitourinary symptoms-related QoL

The concept of QoL is complex and diverse. Although QoL encompasses a broad range of many related aspect of an individual’s life, including the sense of overall wellbeing; for all practical purposes the concept of QoL in this thesis refer to genitourinary symptoms-related quality of life. As such, it will cover the wide variety of subjective experiences related to impact of urinary and vaginal symptoms, and their effects on a woman's physical, psychological, emotional and social health.16 Specifically, it incorporates the impact of genitourinary symptoms on a woman’s ability to perform day-to-day activities, have relationships with family members, friends and partner, enjoy her lifestyle and sexual activities.

3.2. Genitourinary changes associated with estrogen deprivation

Estrogen plays an important role in maintaining the physiological structure and function of the female genitourinary system.17 In fact, the genitourinary epithelium is rich in estrogen receptors.18-21 Consequently, the reduction in stimulation of these receptors due to the decline in estrogen concentration can result in significant cytologic and structural changes in the vulva, vagina and lower urinary tract, thus leading to symptoms which are now collectively classed

GSM.22, 23 For guidance to this section, the female pelvic organs and pelvic floor, vulva and 65

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vagina, and bladder and urethra, are shown diagrammatically in Figures 3.1, 3.2 and 3.3 respectively.

Figure 3.1. Female pelvic organs and pelvic floor

Figure 3.2. Vagina and vulva

Figure 3.3. Female bladder and urethra

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Vulvovaginal changes

With decreased estrogenisation, the vulvovaginal epithelium becomes thin, pale, shiny and dry; there is a gradual loss of vaginal rugae, and labial and vulvar fullness.24 In addition, reduced estrogen leads to loss of collagen content resulting in a less elastic vagina, which becomes slightly shortened and narrow with reduced dispensability; constriction of the introitus and occasional vaginal stenosis can also occur.25 Over time, there is a progressive loss of the protective outer vaginal layer, and the vaginal squamous epithelium becomes friable with petechiae, ulcerations, and sometimes bleeding on minimal trauma.21

Concomitantly, as estrogen declines, vaginal pH rises from acidic to basic levels (i.e. typically rising from the normal range of 3.5-5.0 to greater than five).26, 27 This breakdown in the natural acidic vaginal pH can lead to changes in normal flora, resulting in colonisation of the vagina by pathogenic bacteria and enteric flora.27 This in turn, can further predispose women to many problems such as vaginal and urinary infections.28 Moreover, secondary to the imbalance in the vaginal pH levels, a thin, greyish or yellow and sometimes malodorous (‘fishy smell’) watery discharge can also be experienced.29

Estrogen depletion also results in reduction in vaginal blood flow, which contributes to the decrease in the volume of vaginal secretion leading to reduced and delayed lubrication.30-32

While the factors influencing orgasmic pleasure are complex and predominantly thought to result from clitoral stimulation, the lack of estrogen may lessen vestibular sensation, subsequently diminishing intensity of orgasmic pleasure.30, 33 When sexual activity is attempted under these conditions, it is often painful and can result in an overall unpleasant experience for the woman, as well as her partner.32

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Urinary tract changes

Like the vulvovaginal tissue, the urinary tract epithelium undergoes atrophic changes with estrogen deprivation contributing to a variety of lower urinary tract problems.34 The urethral mucosa progressively lose epithelial thickness, becoming thin, pale, short and narrow.17 The collagen content in the periurethral tissue diminishes as well as its perfusion, and sensitivity of the urethral smooth muscle is decreased, all of which partially contribute to symptoms of stress incontinence.17, 35 Normally, urethral pressure exceeds bladder pressure in order to maintain urinary continence. In this regard, the integrity of the urethral epithelium, musculature and connective and vascular tissues are essential – of note, these are greatly influenced by estrogen levels.36 Consequently, as the bladder becomes progressively deprived of estrogen, loss of elasticity may occur causing a reduction of bladder capacity, and uninhibited detrusor muscle contractions can also occur.37 These atrophic changes may lead to loss of urethral closure pressure, alteration of the normal angle between urethra and bladder with urethral or bladder neck hypermobility and overactivity of the detrusor muscle; factors alone strongly associated with lack of continence.38, 39 The urethral incompetence and detrusor uninhibited contractions, may lead to stress and urge UI, respectively. These in turn, can contribute to both incontinence with penetration and incontinence with orgasm.40

In addition to problems with UI, estrogen-related atrophic changes may predispose women to repeated episodes of urinary tract infection (UTI).41 Besides increasing the likelihood of vaginal colonisation by pathogens due to higher vaginal pH levels, estrogen loss may also raise the risk of recurrent UTI by permitting pelvic laxity, thus increasing the post micturition residual volume of urine in the bladder.42

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Finally, estrogen loss also effects on the pelvic floor musculature, which loses its vigour. Hence, a hypoestrogenic state may play a role in the development and progression of pelvic floor laxity and POP.43 It has been suggested that POP has a negative impact on some aspects of sexuality in women, for instance, fear of bulging of genital organs during sexual activity.44

Together, these vulvovaginal and urinary tract atrophic changes can result in genitourinary symptoms including vulvovaginal irritation, burning, dryness, bleeding, itching, discharge, frequency, urgency, incontinence, nocturia amongst others.4, 45,46 As the integrity of the lower urinary tract depends on estrogen, irritative symptoms such as dysuria may also occur29 and incidence of UTI may be increased.47 These symptoms can impact on women’s QoL48 and sexual health.46 Low estrogen levels disrupt the normal function of genital and urinary tissues during sexual activity contributing to pain during intercourse, complicating the process of sexual arousal and achievement of orgasm, thus, leading to sexual dysfunction.46 Table 3.1 summarises the common presentations of genitourinary atrophy complaints (or as per new terminology, GSM).

Table 3.1. Symptoms associated to genitourinary atrophic changes

Vaginal Urinary Dryness Frequency Irritation/burning Urgency Pruritus (itching) Incontinence

Pressure Dysuria Discharge/ infections Nocturia Tightening Recurrent UTI Prolapse Voiding difficulties Dyspareunia/sexual disorders Postcoital bleeding

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3.3. Risk factors

It is widely accepted that increasing age is a risk factor for the development of genitourinary symptoms49 and that estrogen decline following menopause is significantly linked to genitourinary atrophy in postmenopausal women and with the development of GSM.21 Cigarette smoking has been linked to atrophic changes on the vaginal squamous epithelium.50 Similarly, reports indicate that vulvovaginal atrophy in nulliparous (women who have never given vaginal birth) are harder to manage.51 Diabetes, lower body mass index (BMI) and a sedentary lifestyle have all been associated with multiple vaginal symptoms including vaginal dryness and itching,52 and with increased risk of painful intercourse.52 While, Leiblum et al. suggested that women with higher mean levels of androgens (testosterone and androstenedione) after menopause, and who continue to be sexually active throughout the perimenopausal transition had less severe atrophic changes.53

The risk factors for urinary symptoms, also include parity, age and obesity.54 As the number of vaginal births increases, women are at greater risk for stress and mixed UI, but not for urge UI.55

Other potential risk factors for UI, either alone or in association, include lack of physical activity,56 history of pelvic surgeries such as hysterectomy,57 consumption,58 heavy smoking,59 high BMI,60 UTIs,61 perineal traumas62 and the metabolic syndrome.63, 64

Additionally, POP and some medical conditions such as diabetes and multiple sclerosis have been described to increase the risk of UTI.42, 65 A recent review highlighted that aging factors, such as biomechanical abnormalities in connective tissue composition, hormonal deficiency, and irregular tissue metabolism are among the most important risk factors for POP.66 The same study reported that at least 50% of all women develop a mild form of genital prolapse after .66

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3.4. Prevalence of genitourinary symptoms in general postmenopausal women

The onset of vulvovaginal and urinary atrophic changes leading to genitourinary symptoms is often insidious and tend to worsen over time.67 The prevalence and severity of symptoms have been evaluated in numerous studies with varying results. The Women’s Health Initiative (WHI) study68 reported that 41% of women aged 50-79 years, experience at least one genitourinary symptom, while other studies identified up to 55% of postmenopausal women in the general population suffering from genitourinary problems.21, 69-71

In observational studies, the prevalence of vaginal atrophy has been reported to range from as low as 7% to as high as 57% in healthy postmenopausal women.72-74 Vaginal dryness is the most frequently reported symptom, occurring in 27% to 57% of women,35, 70, 75-77 followed by vaginal irritation or itching (19%) and vaginal discharge (11%).73 In a large population-based cohort of community-dwelling postmenopausal women who were followed up for two years, nearly half of women reported at least ‘a little’ problem with one or more vaginal symptoms, including vaginal dryness (50%) and itching (33%), and 40% of sexually active women reported painful intercourse at baseline.52 Approximately half of those women reporting baseline vaginal symptoms were symptomatic after two years.52 Moreover, in a web-based survey, vaginal dryness was regarded as the most bothersome atrophic symptom (82%), followed by dyspareunia (75%).78 Likewise, in a large survey study conducted among 2,290 postmenopausal women, of whom 59% reported experiencing genitourinary atrophic symptoms, 92% out of the symptomatic group rated their symptoms as at least ‘somewhat’ bothersome while nearly half rated them as ‘moderately’ or ‘very’ bothersome.79

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The prevalence of urinary symptoms is also wide, with approximately 25% to 45% of postmenopausal women experiencing any UI,80, 81 and 12% reporting difficulty with voiding.82

The reported incidence of UTIs in generally healthy postmenopausal women varies from 5% to

9%65, 83, 84 depending on the presence of risk factors such as uncontrolled diabetes,85 incontinence,84 and POP.42 Furthermore, postmenopausal women reporting frequent UTIs are nearly twice as likely to also experience UI.82 Coital incontinence has been reported to occur in

24% to 34% of sexually active women with pelvic floor disorders.86 The reported prevalence of

POP varies depending on the type; apical prolapse, posterior wall prolapse and anterior wall prolapse have been reported in 20%, 27% and 51% of postmenopausal women, respectively.82

Many studies have reported that genitourinary disorders are associated with adverse effect on sexual function and interest in sexual activity among the general female population.39,43-48 The incidence of sexual dysfunction in sexually active women with UI is as high as 47%, with 25% reporting incontinence during sexual intercourse.87 According to the Menopause Epidemiology

Study, a cross-sectional population-based study conducted among sexually active postmenopausal women (n=1,480), as many as 55% of participants were experiencing sexual dysfunction and they were identified as being four times more likely to have genitourinary atrophy than women without sexual dysfunction.70 It has also been reported that pain during intercourse can affect up to one-third of postmenopausal women,30 while low desire, inability to climax and difficulty with vaginal lubrication are described in 43%, 34% and 39% of these women, respectively.88

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3.5. Prevalence of genitourinary symptoms among women with breast cancer

Large clinical studies in breast cancer patients have constantly reported that these women experience bothersome menopausal symptoms, including genitourinary symptoms which often get worse over time. At present, comprehensive research investigating the frequency of a wide range of genitourinary symptoms in women with breast cancer and their trajectory over time has not been conducted. However, the prevalence of some genitourinary symptoms, mostly vaginal dryness, have been reported in isolated studies using a number of QoL scales and single questions about these symptoms. In postmenopausal women with breast cancer not receiving endocrine therapy, the rates of genitourinary symptoms are generally high, but likely to be similar to that in an age matched general population. The available literature suggests an increase in the incidence and progression of genitourinary symptoms following endocrine therapy for breast cancer,89 particularly among women receiving an AI.90 The estimated prevalence of women with breast cancer who experience one or more genitourinary symptoms is that of 50% to 73% (albeit using non standardised scales)83, 91 which is much higher than the prevalence reported in the general female population. The frequency of reported genitourinary symptoms associated with adjuvant endocrine therapy is shown in Table 3.2.

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Table 3.2. Frequency of genitourinary symptoms associated with adjuvant endocrine therapies

Symptom AI TAM Vaginal dryness 18.5% - 42.4% 9.1% - 26.3% Vaginal bleeding 3.3% - 5.4% 6.6% - 18% Vaginal discharge 1.2% - 7.6% 4.1% - 17.6% Vaginal itching/irritation 3.4% - 9.3% 5% - 12.6% Decreased sexual interest/libido 34% - 41.2% 26.1% - 45.4% Dyspareunia 14.9% - 61.5 7.5% - 34.8% Urinary disorders 4.7% - 15% 4.4% - 9% Frequency 63.2% 67.6% Urgency 63.6% 55.9% Stress incontinence 69.7% 52.5% - 72.7% or discomfort 24.2% 17.6% Difficulty with voiding 15.6% 17.6% UTI 3.5% - 8% Up to 11% Source: Fallowfield et al. (2004);92 Morales et al. (2004);93 Jakesz et al. (2005);94 Goss et al (2005); 95 Cella et al. (2006);96 Baumgart et al (2013);97 Buzdar et al (2006);98 Boccardo et al (2006);99 Coates et al. (2007);100 Coombs et al. (2007);101 Eisen et al.(2008);102 Chin et al. (2009);90 Baumgart et al (2011).103

A review focused on reported symptoms of genitourinary atrophy in breast cancer survivors found that 55% of women experience vaginal dryness, 55% ‘urinary disorders’, and up to 60% report sexual issues.104 Increased vaginal dryness and UI were also reported at a median 6.3 year follow-up in a longitudinal study in breast cancer survivors.105 Further, it has been demonstrated that the severity of symptoms can negatively affect women’s QoL.106 Gupta et al. noted a highly significant correlation between severity of vaginal dryness and effect on sexual life, and impact on self-perceived QoL as well as partner’s QoL.106 While, vaginal dryness has been rated as

‘severe’ or ‘very severe’ in 46% of women on endocrine therapy.90

A recent cross-sectional survey investigating the prevalence and severity of postmenopausal symptoms in women treated for breast cancer found that 41% of women receiving endocrine therapy reported urinary urgency, 36% incontinence and 11% increased frequency of episodes of UTI.90 Among women taking AI and TAM the incidence of UTI ranged between 3.5% to 8% and up to 11%, respectively, 90, 98 which is similar to the rates observed in the general

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population. Overall, the prevalence of urinary symptoms in postmenopausal women with breast cancer taking endocrine therapy is estimated to be in the range of 12% (dysuria)90 to 73% (stress incontinence),103 and most women rated their symptoms as ‘mild’ or ‘severe’ in studies.107

In regards to prevalence of sexual-related symptoms, studies have identified a number of problems. In a study conducted by Meyerowitz et al.108 among breast cancer survivors, 52% reported vaginal dryness with a resulting significant negative effect (p= 0.0005) on their sex lives. Sexually active women reported ‘very little’ or ‘no’ lubrication when excited (38%), compared to 14% prior to their diagnosis.108 Significant dyspareunia (p<0.0001) was experienced by 26% of women compared to 7% before diagnosis, and the pain experienced interfered with sexual pleasure.108 Morales et al. found a significant increase in ‘severe’ and

‘intolerable’ dyspareunia in women assigned to an AI (11% at baseline vs. 25% after three months, p=0.001), which was strongly correlated with severe vaginal dryness (p<0.0001).93

More recent studies have demonstrated that current endocrine therapy for breast cancer has an even more profound impact on vaginal dryness during intercourse (73%).90

3.6. Genitourinary symptoms in women with breast cancer – the difficulty with interpreting reported findings

As discussed above, there are reasonable grounds to hypothesise that potential adverse effects of endocrine therapy on the genitourinary tract are much more common than has been recognised to date. However, with previous studies using varied and restricted definitions for ‘genitourinary symptoms’, as well as measurement tools with limited utility (in this context), along with small sample sizes and a lack of comprehensive prospective measure of a wide range of genitourinary symptoms (Table 3.3), it seems likely that the negative impact of adjuvant endocrine therapy on genitourinary symptoms in postmenopausal women with early breast cancer may be underestimated.109

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An important consideration is that the definition of genitourinary symptoms varies considerably between studies. Despite the term ‘genitourinary symptoms’ infer multiple related genital, urologic, psychosocial and sexual disorders,1, 67 no studies have thoroughly investigated each and every one of these domains, and typically, the symptoms are collectively termed ‘urinary problems’ or ‘vaginal dryness’. With varying definitions, it perhaps is unsurprising that a big limitation with many of the studies reported include the variability of the measurement used, the limited number of specific questions regarding genitourinary symptoms and the paucity of detailed information collected on the large range of potential genitourinary symptoms. In most studies to date, assessments have focused in only one or two items regarding genitourinary concerns, such as the Menopause Specific Quality of Life Questionnaire (MENQOL),110 and the

Breast Cancer Prevention Trial (BCPT) Symptom Checklist.111 For example, four studies have reported results on “bladder control problems”, based on responses to two items in the BCPT

Symptom Checklist scale (“difficulty with bladder control when laughing or crying” and

“difficulty with bladder control at other times”).105, 112-114

Another important consideration is that most investigations of endocrine symptoms and side effects in patients receiving TAM and AIs have been carried out in large randomised trials, where genitourinary symptoms were observed as a secondary endpoint (and using QoL scales) and graded by clinicians not patients. In such scenario, patients may not self-report embarrassing symptoms such as incontinence unless specifically asked.

Other studies have assessed urinary symptoms in many different ways; for instance, in a comparative longitudinal study of women with breast cancer, Morales et al. reported urinary problems (“frequent urination and urgency and urine loss when coughing, sneezing and laughing”) in 15% of women on AIs and in 9% of those on TAM. 115 In contrast, lower numbers were found in the ITA Trial,99 where 4.7% of women who continued on TAM and 76

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4.4% of those who switched to ANA after two to three years of TAM, reported lower urinary tract disorders, but specific instruments to accurately assess urinary symptoms were not used in either study.

Furthermore, few studies have considered the presence of pre-existing comorbidities and risk factors in individual patients that might have influenced the development and course of symptoms. It has been suggested that in breast cancer survivors, “urine loss with coughing or sneezing” increased in frequency with age116 and women with higher BMI were more likely to report urinary problems.117

There are also limitations with regards to sample size in many studies. In a recent cross- sectional study specifically designed to assess genitourinary symptoms in postmenopausal breast cancer patients, including the use of validated measures to assess symptoms, only a small number of women were included in the study.103 Although Baumgart et al. found that UI symptoms did not differ between AI- or TAM-treated breast cancer patients and control subjects, whereas vaginal atrophy symptoms were significantly more common in AI- and TAM- treated patients than controls, this study only included 34 women on TAM and 33 on AIs.103

Hence, it is difficult to draw any conclusions in regards to the generalizability of this data.

Indeed, the authors commented that further controlled studies on UI symptoms in different adjuvant endocrine treatment settings were warranted.

Finally, and perhaps most importantly, no studies have prospectively assessed the full range of genitourinary symptoms in postmenopausal breast cancer patients, including the use of comprehensive and specific measurement tools to assess all genitourinary symptoms prior to the commencement of endocrine therapy and during treatment. The few prospective studies attempting to measure genitourinary outcomes associated with endocrine therapy, have not fully

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addressed the problem. For instance, Morales et al. used a prospective design to measure menopausal symptoms in postmenopausal breast cancer survivors, but the study included only two questions assessing genitourinary symptoms (i.e. “in the past seven days: 1) Have you had vaginal dryness? 2) Did you have urinary problems?”).117 Hence, there are limited data available about when all the genitourinary symptoms develop (i.e. prior to treatment or not) and the trajectory of these symptoms over time. The disparate findings reported to date strengthen the case for more research using validated and sensitive instruments to document the genitourinary outcomes of adjuvant endocrine therapies and to identify which patients are most at risk of developing significant symptoms.

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Table 3.3. Summary of studies assessing genitourinary symptoms in breast cancer survivors receiving endocrine therapy

Author(s) Study Disease Menopausal Measures used Results (year) Design Characteristics % Status %

Alfano et al. Longitudinal Localized, 56.4 PRE, 18.3 16-items from 46% reported ‘difficulty with bladder control when (2006)118 N=803 (TAM n=361) Regional, 21.4 POST, 75.9 BCPT Symptom laughing or crying’, 58.2% ‘difficulty with bladder In situ, 22.2 Unclassifiable, Checklist control at other times’, 37.5% vaginal discharge, 34.4% 5.8 genital itching/ irritation. Vaginal symptoms scale scores were higher in women taking TAM and in those who received chemotherapy. The UI scale score was not significantly associated with TAM use.

Baumgart et Cross-sectional Stage I-II POST only FACT-B AI- and TAM-treated patients reported more ‘mod/sev’ al. (2011)103 N=202 – 2 groups: IIQ-7 vaginal atrophy (p<0.01) than controls. No difference in Breast cancer patients UDI-6 frequency or severity of UI symptoms between AI- and n=97 (TAM n=34, AI TAM-treated patients and controls. n=33); controls n=105

Baumgart et Cross-sectional Stage I-II POST only 4 statements AI-treated patients reported significantly (P<0.05) more al. (2013)97 N=187 – 2 groups: addressing sexual common ‘dissatisfaction with their sex life in general’ Breast cancer patients dysfunctions (i.e. (42.4%) and ‘low sexual interest’ (50% ) than TAM- n=82 (TAM n=47, AI sexual interest, treated patients and controls, as well as more ‘common n=35); controls n=105 orgasmic insufficient lubrication’ (73.9%) and ‘dyspareunia’ dysfunction, (56.5%) than controls. TAM-treated patients reported insufficient significantly more dyspareunia (31.3%; P<0.05) but lubrication and resembled controls in all other concerns. dyspareunia)

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Chin et al. Cross-sectional survey Early stage, 84 POST only FACT-ES, SAQ, 48% of women reported vaginal dryness (mod/sev 56%), (2009)90 N=251 (TAM n=78, AI Metastatic, 16 and 4 additional 41% urgency (mod/sev 35%), 32% dyspareunia n=173) questions (mod/sev 38%), 36% UI (mod/sev 15%), 27% vaginal assessing urinary itching/irritation (mod/sev 13%), 26% vaginal discharge symptoms (mod/sev 11%), 12% dysuria (mod/sev 5%), 11% increased UTI (mod/sev 11%), 5% vaginal bleeding (mod/sev 2%). Overall, genitourinary side effects were reported by 63% of the surveyed women.

Couzi et al. Cross-sectional N=190 In situ, 15 POST only 66-item 36% of women reported difficulty with bladder control (1995)107 (TAM n=67) Early stage, 85 questionnaire (55% mild, 22% moderate and 23% severe), 48% vaginal developed by dryness, 24% vaginal itching/ irritation, 22% vaginal investigators discharge and 26% dyspareunia. TAM use was significantly associated with vaginal discharge (p<0.001) and vaginal itching (p=0.008).

Day et al. HRQoL component of NR PRE, 34 104-item TAM showed consistent increase in gynaecological (2001)119 NSABP-P1 multicenter POST, 66 questionnaire: symptoms, difficulty in certain domains of sexual RCT (N =11,064); CES-D, MOS functioning but no difference in QoL compared to PLA. TAM (n=5,527) vs study SF-36, Results reported TAM vs PLA: Dyspareunia, 28% vs PLA (n=5,537) MOS sexual 24% (RR, 1.17); genital itching 47% vs 38% (RR, 1.23); functioning scale, bladder control (laugh), 53% vs 47% (RR 1.13); bladder symptom control (other), 53% vs 48% (RR,1.11); vaginal checklist. discharge, 55% vs 34% (RR1.60); vaginal bleeding 22% vs 21% (RR 1.03)

Ganz et al. Cross-sectional survey Stages 0 - II PRE, 20 Abbreviated list of 40% reported vaginal dryness; TAM therapy in women (1998)120 N= 864, (TAM n=406) POST, 80 symptoms from ≥50y was not associated with poorer sexual functioning. BCPT Symptom Checklist

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Ganz et al. RCT Stage I or II POST only 7-items adapted 71% reported vaginal dryness and 51% “stress (2000)121 N=72 (TAM n=40) from BCPT incontinence” (difficulty with bladder control while Symptom laughing or crying, difficulty with bladder control at Checklist other times) at baseline.

Ganz et al. Longitudinal (follow- Stage I or II NR Abbreviated list of Frequency of bladder problems when laughing or crying (2002)105 up from previous symptoms from (p =0.003) and at other times (p=0.007), and vaginal study)120 N=763 (TAM BCPT Symptom dryness (p=0.013) increased significantly over time. Checklist There was no change in the frequency of dyspareunia, current or ever used however, sexual activity with a partner declined n=460) significantly (from 65% to 55%, p =0 .001). Survivors with no past systemic adjuvant therapy had a better QoL than those who had received systemic adjuvant therapy.

Ganz et al. Cross-sectional Stage 0, I, or II PRE, 16 PERI, BCPT Symptom An age relationship was most notable for vaginal dryness (2003)122 N=577 (TAM current 13 POST, 60 Checklist, SAQ (25-34 y, 21%; 35-39 y, 44%; 40-44 y, 50%; 45-51 y, or ever used n=216) unclassifiable, 55%) and dyspareunia (25-34 y, 22%; 35-39 y, 32%; 40- 11 44 y, 33%; 45-51 y, 32%). Urine loss with sneezing or coughing also increased in frequency with age (25-34 y, 21%; 35-39 y, 19%; 40-44 y, 35%; 45-51 y, 38%).

Greendale et Cross-sectional N=61 Stage I-II POST only Items from BCPT UI score mean (SD), 14.8 (20.2); range = 0-100 al. (2001)123 (TAM current n=37)

Gupta et al. Cross-sectional survey NR PRE, 6.1 PERI, Menopausal Current treatment with TAM did not affect the (2006)106 N=200 (TAM n=112, 9.1 POST, 65.5 Rating Scale prevalence of urinary symptoms (40% TAM users vs AI n=15) 40% non-TAM users). Overall, 55% reported urinary problems (mod/sev, 39%), 55% vaginal dryness (mod/sev, 34%).

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Leining et al. Cross-sectional survey Stage 0, 27 PRE/ +TAM, 22 16 - items from Overall, 51% of women reported vaginal dryness (22% (2006)124 N=371 (TAM ever Stage I, 95 PRE/-TAM, 48 BCPT Symptom PRE/+TAM, 39% POST/+TAM), 54% vaginal discharge n=180, AI ever n=13; Stage II, 191 POST/+TAM, 9 Checklist (38% PRE/+TAM, 32% POST/+TAM), 26% loss of current TAM n=135, Stage III, 47 POST/-TAM, 12 bladder control when laughing (8% PRE/+TAM, 20% current AI n=10) Ova suppr, 9 POST/+TAM), 25% loss of bladder control at other occasions (11% PRE/+TAM, 10% POST/+TAM), 39% dyspareunia (21% PRE/+TAM, 34% POST/+ TAM).

Morales et Prospective, single- NR POST only 20-items Leuven Mod/sev vaginal dryness (baseline, 1-mos, 3-mos follow al. (2004)93 centre, randomised, Menopause Form up): TAM-35%, 37%, 47%; AI-32%, 50%, 50%; trial- blinded trial; N= 164 developed by 20%, 32%, 34%; crossover-25%, 26%, 21% Mod/sev 4 groups: TAM (n=49), investigators (1- urinary problems (baseline, 1 mos and 3-mos follow up): AI (n=28), blinded item assessing TAM-27%, 37%, 45%; AI-39%, 43%, 50%; trial-26%, (TAM/AI) (n=67), urinary problems 31%, 38%; crossover-25%, 37%, 15%. AI induce more crossover TAM to AI and 1-item for atrophic symptoms (vaginal dryness and dyspareunia) vs (n=20) vaginal dryness) TAM. No differences between TAM and AI from baseline to 3 mos concerning urinary symptoms.

Mourits et al. Longitudinal interview NR PRE, 72 Interviews based Overall, during TAM use, patients reported many (2002)125 study n= 98 (all on POST, 28 on self-reported symptoms: vaginal dryness 40%; dyspareunia, 30%; TAM) symptoms list decreased sexual desire, 44%. After discontinuation of TAM, symptoms decreased significantly. Prevalence of symptoms in paired patients - during versus 3–6 mos after TAM: vaginal dryness, 45% vs 26% (p<0.05); dyspareunia, 34% vs 21% (p<0.05); decreased sexual desire, 51% vs 28% (p<0.05). Sexual interest correlated with vaginal dryness (p<0.0005) and/or dyspareunia (p<0.0005).

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Schover et RCT N=48 (TAM in Stage 0-IIIA PRE, 19 7-items adapted 46% urinary symptoms, 39% vaginal symptoms. al. (2006)126 past n=8; TAM current POST, 81 from BCPT n=12) Symptom Checklist

Stanton et al. Cross-sectional Sample 1, stage 0-II; NR 42-item from Bladder control problems were significantly more (2005)127 N= 2,408 – 4 groups: BCPT Symptom bothersome for Samples 1 and 4 [mean score: Sample 1, Sample 1 (n=863), TAM Sample 2, stage 0-II; Checklist 0.52 (range, 0.47-0.58); Sample 2, 0.38 (range, 0.33- current n=406; Sample 2 0.43); Sample 3, 0.32 (range, 0.28-0.38); Sample 4, 0.40 (n=577), TAM current Sample 3, stage I-II; (range, 0.31-0.50)]; vaginal problems were more severe n=104; Sample 3 for Sample 2 [mean score: Sample 1, 0.71 (range, 0.64- (n=560), TAM current Sample 4, no cancer, 0.78); Sample 2, 0.88 (range, 0.79-0.98); Sample 3, 0.49 n=302; Sample 4 but high risk for (range, 0.41-0.56); Sample 4, 0.29 (range, 0.22-0.38)]. (n=208) TAM current Overall, TAM users reported more bladder control n=0 problems than nonusers.

Abbreviations: Tamoxifen (TAM); Premenopausal women (PRE); Postmenopausal women (POST); the Breast Cancer Prevention Trial (BCPT) Symptom Checklist; Urinary incontinence (UI); Functional Assessment of Cancer Therapy– Breast Subscale (FACT-B); Incontinence Impact Questionnaire short form (IIQ-7); the Urogenital Distress Inventory short form (UDI-6); Aromatase Inhibitors (AI); Health-related quality of life (HRQoL); Arimidex, Tamoxifen, Alone or in Combination trial (ATAC); Functional Assessment of Cancer Therapy– Endocrine Symptom Subscale (FACT-ES); Sexual Activity Questionnaire (SAQ); moderate to severe (mod/sev); Urinary Tract Infection (UTI); Not reported (NR); National Surgical Adjuvant Breast and Bowel Project (NSABP); Placebo (PLA); Quality of Life (QOL); Centers for Epidemiologic Studies–Depression Scale (CES-D); Medical Outcomes Study (MOS); Medical Outcomes Study 36-Item Short Form Health Status Survey (MOS SF36); Relative risk (RR); Randomized Controlled Trial (RCT); Perimenopausal women (PERI); Standard deviation (SD); Ovarian Suppression (Ova Suppr); mos (months).

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3.7. The impact of genitourinary symptoms on sexual function

Sexual function involves a complex interaction of physical, psychological, emotional, and partner-related factors.128 Disruption of any of these elements can affect sexual wellbeing, which is an important aspect of women’s health.129 A number of studies among the general female population133, 134 and a few in breast cancer survivors97, 123, 130 have reported that genitourinary disorders such as pelvic floor dysfunction, LUTS and vulvovaginal atrophy may have a negative impact on women’s sex drive, arousal and orgasm, as well as cause pain during intercourse. This in turn, may negatively influence sexual motivation and activity, marital or other intimate relationship,131 and significantly impair QoL.132

In a healthy population-based cross-sectional study, women reporting sexual dysfunction were nearly four times more likely to have symptoms of vulvovaginal atrophy than women not reporting sexual symptoms.70 Similarly, in a web-based survey conducted by Culmming et al,133

56% of postmenopausal women reported dyspareunia secondary to vaginal dryness. Of those,

87% identified vaginal dryness as a causal factor of reduced libido.133 UI has also consistently been associated to problems with sexual function in the general population,21, 134 with studies reporting that women with UI are almost five times less satisfied with their sexual life.135

Despite the leakage itself, which is already a burden on women’s daily life, the possibility of involuntary leakage during sexual activity also worries them.136, 137 Research suggests that women with coital incontinence have significantly worse QoL138 and tend to have more severe urinary symptoms compared to women without complaints of coital incontinence.137, 139 This is supported by two other studies, which reported a negative impact of coital incontinence on women’s sex life135, 140 and the correlation between patient-perceived incontinence severity and detrimental impact on health-related QoL.140 Moreover, Bekker et al. reported that women with

UI have a lower overall sexual function (p=0.02), lower frequency of intercourse (p=0.02) and more often show avoidance behaviour in regards to sexual activity (p=0.02) than those without

UI.87 Finally, the presence of prolapse and chronic pelvic pain have also been described as lower 84

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urinary tract-related factors compromising sexual functioning.132 Prolapse appears to cause several problems with sexual discomfort, UI at orgasm and at penetration, obstruction and dryness during intercourse.141, 142 While chronic pelvic pain is associated with problems in finding a comfortable position, performance worries, fear of exacerbating pain and loss of self- confidence.143 Verit et al. reported higher rates of sexual dysfunction in women with chronic pelvic pain than in women without the condition (68% vs. 32%, p<0.0001).144 While Novi et al. described worse sexual outcomes in women with POP compared with controls (81.4 ±7.3 vs.

106.4 ±15.5, p<0.001).145

In women with a diagnosis of breast cancer, sexual problems may cause extra distress. Besides affecting sexual self-image, treatment can prompt new symptoms or further exacerbate pre- existing sexual problems.97, 123 Although often overlooked, sexuality and intimacy are important concerns for breast cancer patients146 and assist in the recovery process.147 Findings from a cross-sectional analysis of baseline trial data examining correlations of sexuality and a number of characteristics in 61 sexually active postmenopausal breast cancer survivors showed that vaginal discomfort and UI were associated with sexual interest, dysfunction, and satisfaction.123

Although there is an increasing body of research assessing sexual dysfunction in women diagnosed with breast cancer, or those undergoing treatment for breast cancer, there is a paucity of data regarding the potential influence of underlying conditions such as genitourinary symptoms secondary to endocrine treatment on sexual function in breast cancer patients.

Undoubtedly, there is a close multifactorial relationship between genitourinary problems and sexual problems;148 nonetheless most studies in breast cancer survivors have usually regarded sexual concerns as ‘vaginal dryness’ and ‘dyspareunia’ only. For example, in a study of postmenopausal breast cancer patients receiving endocrine therapy, 56% of sexually active women reported dyspareunia, and 73% experienced vaginal dryness during sexual intercourse.90

As highlighted in previous research, special attention should be given to women with breast

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cancer who are at very high risk of genitourinary atrophy and subsequently, sexual dysfunction as consequence of breast cancer treatment, including adjuvant endocrine therapy.149 Hence, more research is needed to understand the contributions of both AIs and TAM to the full range of potential genitourinary symptoms and how they correlate with sexual dysfunction in women with breast cancer. This is particularly important as there are specific and effective interventions available to manage symptoms such as UI, which could improve sexual activity in breast cancer survivors.

3.8. The impact of genitourinary symptoms on quality of life

Although not life-threatening, genitourinary symptoms can impose limitations in physical, social and emotional functioning resulting in poor QoL.150 Genitourinary symptoms affect the ability of women to carry out daily activities,151 form and maintain social relationships,140 and may lead to depression, embarrassment, psychological distress and social isolation.152-154

For example, studies with women from the general population have documented that UI can severely impair mobility and, disrupt social interaction, as women tend to avoid travelling and visiting places due to fear of leakages152 and are distressed by not having easy access to toilets.155 In support of these findings, Fultz et al. found that incontinent respondents, in a telephone survey, reported feeling more depressed, lonely or sad compared with continent respondents.156 Women with vulvovaginal disorder, were more likely to report that their condition affected how close they can be with those they love and limited their ability to show affection.157 In addition, a recent review on the impact of UI on QoL, showed that among chronic disorders UI represented one of the most bothersome conditions affecting physical functioning, comparable with stroke and Alzheimer disease.158 In an online survey among 1,578 postmenopausal women across and North America, 52% of the respondents reported that vaginal discomfort has a negative impact on various aspects of life in general, including negative consequences for their sex life (40%), marriage or relationships (13%), QoL (14%), 86

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self-esteem (17%) and social life (7%).159 While another study of women experiencing vaginal dryness/discomfort found that 61% reported hiding their symptoms from their partner and 62% reported symptoms affected their self-confidence.133

Many factors influence the perception of genitourinary symptoms as a significant health problem. These can include type of disorder, concurrent comorbidities, duration of symptoms and most importantly, the severity of symptoms.160 It has been described that the more severe the UI and POP, the more harmful their effects on QoL.161 Surprisingly, most women do not seek treatment despite significant impairment on QoL.150 Amongst those who seek medical care, subjective assessment of the severity of symptoms and perceived effects on QoL are important contributing factors.162

QoL also remains an important consideration for women with breast cancer, thereby constituting priority research area. The impact of genitourinary symptoms on the overall QoL in the general population underscores the importance of increasing awareness amongst clinicians treating breast cancer survivors regarding this issue.

3.9. Genitourinary symptoms-related information provision and help- seeking behaviour

Research suggests that in general, genitourinary and sexual concerns are often overlooked or not fully addressed with patients in clinical practice.163 It is estimated that only 25-50% of symptomatic women seek medical help for their genitourinary complaints.71, 130, 164, 165

Furthermore, many women neglect to report their condition to clinicians due to the misconception that their symptoms are a normal and inevitable part of the aging process and past childbirth that cannot be treated.34 Another reasons is a lack of sufficient knowledge regarding treatment options, availability of care and where and/or when to seek help.104, 166

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Additionally, breast cancer survivors do not necessarily associate the symptoms with their endocrine treatment and unless specifically raised by clinicians, the topic is rarely discussed during follow-up consultations.104 Some practitioners might underestimate the importance of genitourinary atrophy and consequent sexual disorders to the patient and misjudge the impact of symptoms on patients’ QoL.167 It has been reported that clinicians may be reluctant to inquire about these issues due to lack of expertise in assessment and treatment, time constraints and uncertainty about treatment options,168 along with beliefs that sex is not a priority for older patients.169 Consequently, genitourinary disorders often go underdiagnosed and undertreated.166,170, 171

It is important that practitioners take initiative and endeavour to identify patients with genitourinary symptoms as it is clear that only a minority of women seek help.172 It has been reported that simple interventions could significantly improve symptoms in up to 70% of patients.173 In North America, for instance, in recognition of this important health issue, it has been recommended that all practitioners consulting postmenopausal women, should routinely ask them for genitourinary atrophy symptoms.174 The lack of patient autonomy in this area infers a need for clinicians to be more proactive in inquiring patients and offering multidisciplinary care management. Available options for managing genitourinary symptoms in women with breast cancer receiving endocrine therapy will be discussed in Chapter Four.

3.10. Summary

It is well recognised that there is a direct association between low estrogen concentrations and atrophy of the genitourinary tract, which in turn may lead to the development of genitourinary symptoms and contribute to sexual dysfunction and impaired QoL. It is plausible that anti- estrogen therapy for breast cancer may have a greater effect on genitourinary function than that described to date in the literature. As summarised in this Chapter, the reported incidence and

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severity of genitourinary symptoms are quite variable and findings are conflicting. A recent review has pointed out the paucity of studies specifically designed to assess the relationship of endocrine therapy to genitourinary symptoms, as well as the fact that specific instruments to accurately assess the full range of symptoms have not been used in any of the large adjuvant trials.109 This underscores the importance of the research aims of this study, which are to determine the prevalence, severity and risk factors of genitourinary symptoms, in order to inform the development of strategies to prevent or minimise adverse symptoms in postmenopausal women receiving endocrine therapy for early breast cancer.

3.11. References

1. Portman, DJ and Gass, ML. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society. Menopause, 2014; 21(10):1063-8. 2. Burich, R and Degregorio, M. Current treatment options for vulvovaginal atrophy. Expert Review of Obstetrics and Gynecology, 2011; 6(2):141-151. 3. Leiblum, SR, Hayes, RD, Wanser, RA and Nelson, JS. Vaginal dryness: a comparison of prevalence and interventions in 11 countries. J Sex Med, 2009; 6(9):2425-33. 4. Katz, A. When sex hurts: menopause-related dyspareunia. Vaginal dryness and atrophy can be treated. Am J Nurs, 2007; 107(7):34-6, 39. 5. Bishop GB. Cinical Methods: The History, Physical, and Laboratory Examinations, In: Walker HK, Hall WD and Hurst JW, editors. Vaginal Discharge. Boston: Butterworths. 1990. pp. Chapter 172. 6. Abrams, P, Cardozo, L, Fall, M, Griffiths, D, Rosier, P, Ulmsten, U, van Kerrebroeck, P, Victor, A and Wein, A. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Am J Obstet Gynecol, 2002; 187(1):116-26. 7. Abrams, P, Andersson, KE, Birder, L, Brubaker, L, Cardozo, L, Chapple, C, Cottenden, A, Davila, W, de Ridder, D, Dmochowski, R, Drake, M, Dubeau, C, Fry, C, Hanno, P, Smith, JH, Herschorn, S, Hosker, G, Kelleher, C, Koelbl, H, Khoury, S, Madoff, R, Milsom, I, Moore, K, Newman, D, Nitti, V, Norton, C, Nygaard, I, Payne, C, Smith, A, Staskin, D, Tekgul, S, Thuroff, J, Tubaro, A, Vodusek, D, Wein, A and Wyndaele, JJ. Fourth International Consultation on Incontinence Recommendations of the International Scientific Committee: Evaluation and treatment of urinary incontinence, pelvic organ prolapse, and fecal incontinence. Neurourol Urodyn, 2010; 29(1):213-40. 8. Kinchen, KS, Lee, J, Fireman, B, Hunkeler, E, Nehemiah, JL and Curtice, TG. The prevalence, burden, and treatment of urinary incontinence among women in a managed care plan. J Womens Health (Larchmt), 2007; 16(3):415-22. 9. Perry, S, Shaw, C, Assassa, P, Dallosso, H, Williams, K, Brittain, KR, Mensah, F, Smith, N, Clarke, M, Jagger, C, Mayne, C, Castleden, CM, Jones, J and McGrother, C. An epidemiological study to establish the prevalence of urinary symptoms and felt need in

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121. Ganz, P, Greendale, G, Petersen, L and et al. Managing menopausal symptoms in breast cancer survivors: Results of a randomized controlled trial. J Natl Cancer Inst, 2000; 92:1054-64. 122. Ganz, P, Greendale, G, Peterse, L and al., e. Breast cancer in younger women: Reproductive and late health effects of treatment. Journal of Clinical Oncology, 2003; 21:4184-4193. 123. Greendale, G, Petersen, L, Zibecchi, L and Ganz, P. Factors related to sexual function in postmenopausal women with a history of breast cancer. Menopause, 2001; 8(2):111-9. 124. Leining, MG, Gelber, S, Rosenberg, R, Przypyszny, M, Winer, EP and Partridge, aH. Menopausal-type symptoms in young breast cancer survivors. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 2006; 17:1777- 82. 125. Mourits, MJ, Bockermann, I, Vries, Ed, Zee, Avd, Hoor, Kt, Graaf, Wvd, Sluiter, W and Willemse, P. Tamoxifen effects on subjective and psychosexual well-being , in a randomised breast cancer study comparing high-dose and standard-dose chemotherapy. British journal of cancer, 2002; 86:1546-1550. 126. Schover, LR, Jenkins, R, Sui, D, Adams, JH, Marion, MS and Jackson, KE. Randomized trial of peer counseling on reproductive health in African American breast cancer survivors. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2006; 24:1620-6. 127. Stanton, AL, Bernaards, Ca and Ganz, Pa. The BCPT symptom scales: a measure of physical symptoms for women diagnosed with or at risk for breast cancer. Journal of the National Cancer Institute, 2005; 97:448-56. 128. Kammerer-Doak, D. Assessment of sexual function in women with pelvic floor dysfunction. Int Urogynecol J Pelvic Floor Dysfunct, 2009; 20 Suppl 1:S45-50. 129. Oh, S-J, Ku, JH, Choo, M-S, Yun, JM, Kim, DY and Park, W-H. Health-related quality of life and sexual function in women with stress urinary incontinence and overactive bladder. Int J Urol, 2008; 15(1):62-7; discussion 67. 130. Schover, LR, Baum, GP, Fuson, LA, Brewster, A and Melhem-Bertrandt, A. Sexual problems during the first 2 years of adjuvant treatment with aromatase inhibitors. J Sex Med, 2014; 11(12):3102-11. 131. Tan, O, Bradshaw, K and Carr, BR. Management of vulvovaginal atrophy-related sexual dysfunction in postmenopausal women: an up-to-date review. Menopause, 2012; 19(1):109-17. 132. Nickel, JC, Tripp, D, Teal, V, Propert, KJ, Burks, D, Foster, HE, Hanno, P, Mayer, R, Payne, CK, Peters, KM, Kusek, JW and Nyberg, LM. Sexual function is a determinant of poor quality of life for women with treatment refractory interstitial cystitis. J Urol, 2007; 177(5):1832-6. 133. Cumming, GP, Currie, HD, Moncur, R and Lee, AJ. Web-based survey on the effect of menopause on women's libido in a computer-literate population. Menopause Int, 2009; 15(1):8-12. 134. Karlovsky ME. Female Urinary Incontinence During Sexual Intercourse (Coital Incontinence): A Review, in The female patient, Educational support provided by Novasys Medical, I, Editor. 2009. p. 32-36. 135. Beji, NK, Ozbas, A, Aslan, E, Bilgic, D and Erkan, HA. Overview of the Social Impact Of Urinary Incontinence with A Focus on Turkish Women. Urologic nursing, 2010; 30:327-334. 136. Bekker, M, Beck, J, Putter, H, Venema, P, Lycklama a Nijeholt, A, Pelger, R and Elzevier, H. Sexual function improvement following surgery for stress incontinence: the relevance of coital incontinence. J Sex Med, 2009; 6(11):3208-13. 137. Espuña Pons, M and Puig Clota, M. Coital urinary incontinence: impact on quality of life as measured by the King's Health Questionnaire. Int Urogynecol J Pelvic Floor Dysfunct, 2008; 19(5):621-5.

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138. Tennstedt, SL, Fitzgerald, MP, Nager, CW, Xu, Y, Zimmern, P, Kraus, S, Goode, PS, Kusek, JW, Borello-France, D and Mallett, V. Quality of life in women with stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct, 2007; 18(5):543-9. 139. Oh, SJ, Choo, MS, Kim, HS, Kim, JC, Lee, JG, Yun, JM, Kim, DY, Paick, JS, Lee, JY, Chung, BS, Min, KS, Kim, YH, Jung, HC, Son, H, Jeong, JY, Rho, J, Lee, KS, Park, WH and Ku, JH. Generic and disease-specific health-related quality of life in women with coital incontinence: a prospective, multicenter study. Gynecol Obstet Invest, 2008; 65(1):62-7. 140. Paick, J-s, Cho, MC, Oh, S-j, Kim, SW and Ku, JH. Influence of Self-Perceived Incontinence Severity on Quality of Life and Sexual Function in Women With Urinary Incontinence. Neurourology and urodynamics, 2007; 26:828-835. 141. Pakbaz, M, Persson, M, Löfgren, M and Mogren, I. 'A hidden disorder until the pieces fall into place'--a qualitative study of vaginal prolapse. BMC women's health, 2010; 10:18. 142. Jha, S and Toozs-Hobson, P. Prolapse and sexual function. Journal of the Association of Chartered Physiotherapists in Women's Health, 2009; 104:20-26. 143. Ambler, N, Williams, AC, Hill, P, Gunary, R and Cratchley, G. Sexual difficulties of chronic pain patients. Clin J Pain, 2001; 17(2):138-45. 144. Verit, FF, Verit, A and Yeni, E. The prevalence of sexual dysfunction and associated risk factors in women with chronic pelvic pain: a cross-sectional study. Arch Gynecol Obstet, 2006; 274(5):297-302. 145. Novi, JM, Jeronis, S, Morgan, MA and Arya, LA. Sexual function in women with pelvic organ prolapse compared to women without pelvic organ prolapse. J Urol, 2005; 173(5):1669-72. 146. Ganz, PA, Desmond, KA, Belin, TR, Meyerowitz, BE and Rowland, JH. Predictors of sexual health in women after a breast cancer diagnosis. J Clin Oncol, 1999; 17(8):2371- 80. 147. Gilbert, E, Ussher, JM and Perz, J. Sexuality after breast cancer: a review. Maturitas, 2010; 66(4):397-407. 148. Raina, R, Pahlajani, G, Khan, S, Gupta, S, Agarwal, A and Zippe, CD. Female sexual dysfunction: classification, pathophysiology, and management. Fertil Steril, 2007; 88(5):1273-84. 149. Sadovsky, R, Basson, R, Krychman, M, Morales, AM, Schover, L, Wang, R and Incrocci, L. Cancer and sexual problems. J Sex Med, 2010; 7(1 Pt 2):349-73. 150. Parish, SJ, Nappi, RE, Krychman, ML, Kellogg-Spadt, S, Simon, JA, Goldstein, JA and Kingsberg, SA. Impact of vulvovaginal health on postmenopausal women: a review of surveys on symptoms of vulvovaginal atrophy. Int J Womens Health, 2013; 5:437-47. 151. van der Vaart, CH, de Leeuw, JR, Roovers, JP and Heintz, AP. Measuring health-related quality of life in women with urogenital dysfunction: the urogenital distress inventory and incontinence impact questionnaire revisited. Neurourol Urodyn, 2003; 22(2):97-104. 152. Monz, B, Chartier-Kastler, E, Hampel, C, Samsioe, G, Hunskaar, S, Espuna-Pons, M, Wagg, A, Quail, D, Castro, R and Chinn, C. Patient characteristics associated with quality of life in European women seeking treatment for urinary incontinence: results from PURE. Eur Urol, 2007; 51(4):1073-81; discussion 1081-2. 153. Lagro-Janssen, T, Smits, A and Van Weel, C. Urinary incontinence in women and the effects on their lives. Scand J Prim Health Care, 1992; 10(3):211-6. 154. Grimby, A, Milsom, I, Molander, U, Wiklund, I and Ekelund, P. The influence of urinary incontinence on the quality of life of elderly women. Age Ageing, 1993; 22(2):82-9. 155. Swithinbank, LV, Donovan, JL, du Heaume, JC, Rogers, CA, James, MC, Yang, Q and Abrams, P. Urinary symptoms and incontinence in women: relationships between occurrence, age, and perceived impact. Br J Gen Pract, 1999; 49(448):897-900. 156. Fultz, NH and Herzog, AR. Self-reported social and emotional impact of urinary incontinence. J Am Geriatr Soc, 2001; 49(7):892-9.

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157. Ponte, M, Klemperer, E, Sahay, A and Chren, MM. Effects of vulvodynia on quality of life. J Am Acad Dermatol, 2009; 60(1):70-6. 158. Bartoli, S, Aguzzi, G and Tarricone, R. Impact on quality of life of urinary incontinence and overactive bladder: a systematic literature review. Urology, 2010; 75(3):491-500. 159. Nappi, RE and Kokot-Kierepa, M. Vaginal Health: Insights, Views & Attitudes (VIVA) - results from an international survey. Climacteric, 2012; 15(1):36-44. 160. DeMaagd, GA and Davenport, TC. Management of Urinary Incontinence. P t, 2012; 37(6):345-361h. 161. Barentsen, JA, Visser, E, Hofstetter, H, Maris, AM, Dekker, JH and de Bock, GH. Severity, not type, is the main predictor of decreased quality of life in elderly women with urinary incontinence: a population-based study as part of a randomized controlled trial in primary care. Health Qual Life Outcomes, 2012; 10:153. 162. Kinchen, KS, Burgio, K, Diokno, AC, Fultz, NH, Bump, R and Obenchain, R. Factors associated with women's decisions to seek treatment for urinary incontinence. J Womens Health (Larchmt), 2003; 12(7):687-98. 163. Hordern, AJ and Street, AF. Communicating about patient sexuality and intimacy after cancer: mismatched expectations and unmet needs. Med J Aust, 2007; 186(5):224-7. 164. Kingsberg, S, Kellogg, S and Krychman, M. Treating dyspareunia caused by vaginal atrophy: a review of treatment options using vaginal estrogen therapy. Int J Womens Health, 2010; 1:105-11. 165. Couture, JA and Valiquette, L. Urinary incontinence. Ann Pharmacother, 2000; 34(5):646-55. 166. Morris, K. Tackling the taboo of urinary incontinence. Lancet, 1999; 353(9147):128. 167. Kelley, C. Estrogen and its effect on vaginal atrophy in post-menopausal women. Urol Nurs, 2007; 27(1):40-5. 168. Krychman, M. Vaginal estrogens for the treatment of dyspareunia. Journal of Sexual Medicine, 2011; 8(3):666-674. 169. Herbenick, D, Reece, M, Schick, V, Sanders, SA, Dodge, B and Fortenberry, JD. Sexual behavior in the United States: results from a national probability sample of men and women ages 14-94. J Sex Med, 2010; 7 Suppl 5:255-65. 170. Avis, N, Crawford, S, Manuel, J and et al. Quality of life among younger women with breast cancer. Journal of Clinical Oncology, 2005; 23:3322-3330. 171. Zibecchi, L, Greendale, GA and Ganz, PA. Continuing education: Comprehensive menopausal assessment: an approach to managing vasomotor and urogenital symptoms in breast cancer survivors. [Review] [45 refs]. Oncology Nursing Forum, 2003; 30(3):393- 407. 172. Hagglund, D, Walker-Engstrom, ML, Larsson, G and Leppert, J. Changes in urinary incontinence and quality of life after four years. A population-based study of women aged 22-50 years. Scand J Prim Health Care, 2004; 22(2):112-7. 173. Seim, A, Sivertsen, B, Eriksen, BC and Hunskaar, S. Treatment of urinary incontinence in women in general practice: observational study. BMJ, 1996; 312(7044):1459-62. 174. SOGC clinical practice guidelines. The detection and management of vaginal atrophy. Number 145, May 2004. Int J Gynaecol Obstet, 2005; 88(2):222-8.

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CHAPTER 4

Management of Genitourinary Symptoms

Chapter Four covers the most up-to-date literature on the management of genitourinary symptoms, with emphasis on the available options for women with breast cancer taking endocrine therapy.

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4. A practical approach to the management of genitourinary symptoms in breast cancer survivors on endocrine therapy

4.1. Introduction

There is increasing attention and concern about managing the adverse effects of adjuvant endocrine therapy for women with early breast cancer; in particular, as the side effects of therapy influence compliance and can impair QoL.1 The genitourinary side effects of endocrine therapy can be managed effectively in many women but requires early recognition and treatment.2 Nonetheless, many oncologists are uncertain about how to treat these symptoms in breast cancer survivors and do not have experience in the appropriate management.3 This

Chapter provides an overview of the practical approach to the management of genitourinary symptoms in women receiving adjuvant endocrine therapy for breast cancer.

The primary goal of treatment of genitourinary symptoms is to improve or alleviate symptoms and to reverse the atrophic changes from estrogen deprivation.4 Therefore, the optimal therapy for estrogen-deficiency symptoms is usually based on systemic or vaginal estrogen administration. However, estrogen is contraindicated in women with a history of hormone receptor-positive breast cancer2 and currently, there are no safety data of vaginal (an alternative to estradiol) in patients on AIs or TAM. As a result, patients and their clinicians are not usually prepared to use topical estrogens5 and alternative approaches, with nonhormonal lubricants and moisturisers, are usually preferred. The major disadvantage of nonhormonal agents is that they only partially or temporally relieve local symptoms.

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4.2. Lifestyle advice

As an initial approach, women experiencing bothersome genitourinary symptoms should be educated and counselled about simple lifestyle changes, which may improve and prevent the onset of new symptoms.6 For example, smoking cessation and weight control should be encouraged. Cigarette smoking is associated with a three-fold increase in risk of urgency and frequency,7 and accelerated vulvovaginal atrophy8 while weight loss of 5% to 10% of total body weight has been shown to improve UI.9 For a sustained weight loss in midlife women, the North

American Menopause Society (NAMS) and International Menopause Society (IMS) recommend a combination of reducing daily caloric intake by 400 to 600 Kcal, performing regular physical exercises, limiting total intake of fats and oils (olive oil consumption is encouraged) and increasing servings of fruits and vegetables/day.10, 11 In addition to promoting a healthy lifestyle, regular sexual stimulation should also be encouraged as it can increase blood flow to the genital area, helping keep this tissue healthy (i.e. non-atrophic).12

4.3. Control of underlying medical conditions

Women with a number of pre-existing comorbidities are more likely to develop UI, vaginal atrophy, and sexual dysfunction.13 Thus, optimal management of coexisting diabetes, obesity

(BMI>30) and may also help to improve genitourinary and sexual health.13, 14

Furthermore, underlying depression and distress should be investigated and treated as it has been shown to improve both sexual functioning6 and QoL in breast cancer patients.15 If an antidepressant is needed, clinicians should discuss potential sexual-related side effects of therapy, drug-drug interactions, personal preferences and the overall risk-benefit balance before initiating therapy. Evidence suggests that some psychotropic medications, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants, have been associated with decreased libido,16 delayed orgasm,17 continence and flow dysfunction.18 Furthermore, antidepressants that are strong CYP2D6

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(Cytochrome P450 2D6) inhibitors may decrease the efficacy of TAM and are relatively contraindicated.19 A treatment option that may be appropriate for TAM users is the SNRI venlafaxine, which increased libido in women with early breast cancer without interfering with the metabolism of TAM.19 Similarly, desvenlafaxine has been shown to have a low potential for and is another option in TAM users.20

4.4. Nonhormonal treatment options

Several over-the-counter vaginal moisturisers, as well as water-, oil- and silicone-based precoital lubricants are widely used first-line nonhormonal therapies to alleviate symptoms such as vaginal dryness, dyspareunia, itching and burning.21 Particularly for women with mild symptoms and those who want to avoid, or are concerned about local estrogens (i.e. the majority of breast cancer patients).21-23 Nevertheless, the efficacy of these formulations is limited (Level

II); in a double-blind, crossover RCT assessing 45 breast cancer survivors with a history of vaginal complaints (dryness and/or itching), a polycarbophil-based vaginal moisturiser was no more effective than placebo in relieving vaginal dryness and dyspareunia.24

With limited nonhormonal effective options at hand, clinicians treating breast cancer patients need to be more aware of women’s expectations about treatment outcome and inquire about type and severity of their symptoms. For example, if the most important concern for a woman is pain during intercourse, lubricants applied before and after sexual intimacy25 may be recommended to promote temporary relief of friction-induced vaginal discomfort for the patient.5 Lubricants and moisturisers may also be used effectively in combination. An intervention to improve genitourinary symptoms and related sexual issues used a combination of olive oil as a lubricant, pelvic floor muscle relaxation exercises and a vaginal moisturiser, reported improvements in dyspareunia and sexual function in women with breast cancer.26

Additionally, use of vaginal moisturisers on a regular basis may promote hydration of the

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epithelium and consequently lubrication of the vaginal wall thus, providing more long-term (2-3 days) relief of symptoms such as itching, irritation and dyspareunia.27 However, these therapies may not completely solve the problem, especially in women complaining of severe symptoms.

If nonhormonal methods failed in symptomatic survivors, short-term hormonal therapy may be considered, following appropriate counselling and assessment of risk-benefits.28

A recent randomised, double-blinded, placebo-controlled study investigated the effect of a vaginal pH-balanced gel (containing lactic acid) on vaginal symptoms and atrophy in breast cancer survivors.29 Vaginal pH-balanced gel improved both vaginal dryness and dyspareunia, lowered vaginal pH and enhanced vaginal maturation index with minimal side effects (mild irritation during the first four weeks of therapy administration).29 These results suggest that vaginal pH-balanced gel is an alternative option to alleviate vulvovaginal symptoms in symptomatic patients and can ultimately protect against vaginal colonisation by nonvaginal microflora, which predispose women to vaginal infections and UTIs.

Finally, it is important to acknowledge that there are available resources for vaginal health promotion in cancer survivors. Carter et al. have developed a patient handout, which summarises how to best use vaginal lubricants, moisturisers and pelvic floor exercises.30

4.5. Complementary and alternative therapies

Complementary and alternative therapies (such as ‘natural’ products, acupuncture and mind- body practices) are being used by breast cancer survivors,31 with an estimated 48%32 to 83%33 of patients using at least one type of these therapies following diagnosis. This is despite limited and not yet well-established evidence of the effectiveness (and toxicity) of these therapies in managing GSM in breast cancer survivors.20, 34 This is concerning, particularly as about half of breast cancer patients do not discuss their use of an alternative therapy with their clinicians.32, 35

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Vitamin E and D

Anecdotal evidence suggests that vaginal application of oil from vitamin E capsules before intercourse increases vaginal lubrication and provides some atrophic-related symptom relief,13, 34 while vitamin D supplementation may help squamous maturation of the vaginal epithelium.36, 37

However, there were no significant improvements in vulvovaginal symptoms or pH. 38

Therefore, the available evidence does not support the use of vitamin D for relief of genitourinary symptoms.39

Dietary and ‘natural’ products

The use of dietary supplements with ‘natural’ products, such as soy, black cohosh, and some other herbs did not show any superiority over placebo in relieving a range of genitourinary symptoms, in clinical trials.10 Despite this, breast cancer patients are still very attracted to

‘natural’ products and generally convey the impression that they are less toxic than conventional medicine.40, 41 As per current data, the safety of many of these products is unknown42 and there may be possible interactions with TAM and unknown effects on breast cancer cells.40, 41

Furthermore, important side effects such as facio-oral oedema, cutaneous vasculitis and liver failure have been described with the use of ‘natural’ products.43, 44 Indeed, there is increasing concern about the lack of ‘rigorous quality-control measures with regard to purity and levels of active compound’ by some manufactures of herbal medicines as pointed out by the NAMS.10

Clearly, there is the need to investigate in long-term adequately designed RCTs whether these products are of any help to breast cancer patients experiencing GSM related symptoms. Most importantly, a risk assessment should be performed to help define their safety. Until such evidence-based data is available, their use merits caution.35

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Acupuncture and behavioural interventions

There are very limited clinical data for the efficacy of acupuncture and behavioural interventions in the management of genitourinary symptoms and most of the published literature has been done on healthy women. The data on acupuncture suggests it can improve bladder capacity, urgency and frequency45 and a significant decrease in the urogenital subscale scores on the Menopause Rating Scale has been described.46 Despite these reports, the evidence of benefits of acupuncture remains ‘unconvincing’ without evidence-base data.47

Cognitive behavioural therapy, physical exercise and a combination of both lessened urinary symptoms (p=0.002) and increased sexual activity (p=0.027) in patients with breast cancer experiencing treatment-induced menopausal symptoms compared to controls in a RCT.48

Interestingly, women who did not report reduction in the frequency of symptoms reported symptoms as less burdensome.47 Further studies should confirm the efficacy of these techniques on GSM in breast cancer survivors. In the interim, the use of cognitive behavioural therapy for

GSM related symptoms can only be tentatively recommended as per current scientific evidence.

4.6. Hormone replacement therapy (HRT)

Estrogen-containing treatments have been shown in many studies to alleviate symptoms of vulvovaginal dryness, irritation, pruritis, and dyspareunia.49 Estrogen restores vaginal pH, improves elasticity of vaginal tissues, increases maturation of the vaginal and urethral epithelium,50 enhances genitourinary blood flow and improves lubrication.51 According to the position statement by the NAMS on the treatment of vulvovaginal atrophy, vaginal preparations of estrogen are well tolerated and are considered to be the best treatment for isolated, moderate to severe atrophic symptoms in the general healthy female population.22

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Although the role of estrogen therapy for vulvovaginal concerns in healthy postmenopausal women has been well established, the evidence to support a role of estrogen therapy in the management of urinary tract symptoms is conflicting.52-54 According to a 2012 Cochrane review,55 systemic (oral) HRT with unopposed estrogen results in worse incontinence symptoms than placebo (RR 1.32; 95% CI: 1.17-1.48). Similar worsening effects on incontinence were seen for combined regimens (estrogen and progestin) compared to placebo (RR 1.11; 95% CI:

1.04-1.18).55 In addition, one of the large trials analysed in the review reported that women who were continent at baseline were more likely to develop incontinence after one year of HRT compared to women on placebo.54, 55 The authors, however, suggested that the use of local

(vaginal) estrogen therapy (e.g. creams or pessaries) for incontinence may be beneficial (RR

0.74; 95% CI: 0.64 – 1.48), and less frequency and urgency was also reported. 55 Several limitations of the studies included in the review were noted, these included heterogeneity in regards to type, dose and duration of exposure to estrogens between trials as well as the length of follow-up.55

Another Cochrane review (2006) on the impact of estrogens in preventing recurrent UTIs suggested that vaginal estrogen reduced the incidence of UTI and prolonged the time to UTI recurrence.56 Estrogen use has also been recommended for the treatment of symptoms of overactive bladder (OAB) in postmenopausal women with vaginal atrophy.49, 52 Further, local estrogen has been shown to improve sexual desire, arousal, coital satisfaction and orgasm by increasing blood flow to the genital area, and consequently, improving vaginal lubrication and sensation in the vaginal tissues.12, 57

Despite the indications of the benefit of HRT for some genitourinary symptoms, since 2002 the evidence base regarding its use has changed significantly.11 Concerns about the use of HRT increasing risk of breast cancer recurrence have limited its prescription to women with breast

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cancer.58 Nonetheless, QoL concerns, magnitude of symptoms and endocrine therapy compliance may justify the use of HRT in selected cases.43 Patients who wish to consider HRT after a diagnosis of breast cancer should be informed that definitive evidence on HRT influence in prognosis of breast cancer is lacking. The results of observational studies, which are fraught with potential biases have been reassuring59-61; however, a single RCT suggested that HRT had an adverse effect on recurrence rates.62 Alternative nonhormonal options should always be considered first option in these patients, but if symptoms persist and QoL is seriously impaired, then individual women with a low risk of tumour recurrence may wish to explore the option of

HRT.63, 64 In these selected cases management of symptoms should take both women’s needs and the recommendations of their oncologists into consideration.28 The American Cancer

Society has no position or guideline regarding HRT. Nonetheless, they recommend that if needed it is best to use it at the lowest possible dose for as short a time as possible.65

4.7. Androgens

Researchers have looked for safer and effective alternative approaches to improve GSM-related symptoms. Androgens, such as dehydroepiandrosterone (DHEA) and testosterone, have provided some hope with studies evaluating androgen therapy suggesting improvements in vaginal atrophy with concomitant improvement in sexual function in postmenopausal women.66-

69

The basis for the potential genitourinary effect of DHEA is its role in the androgen metabolism.70 DHEA is one of the main precursors of androgens, which in turn are converted to estrone (by aromatization) and testosterone (by 5-alpha reduction).70 There is a fair amount of supporting evidence for its efficacy in improving genitourinary symptoms. Studies have shown intravaginal DHEA to increase the vaginal maturation index and decrease vaginal pH without increasing the serum levels of estrogen above the postmenopausal range.71, 72 In addition, results from a randomised double-blind placebo-controlled phase III clinical trial reported this therapy 108

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to exert beneficial effects across all four aspects of sexual function, including desire/interest, arousal, orgasm and pain at sexual activity.73 Following this result, a 2015 Cochrane review73 analysed the effectiveness and safety of administering DHEA to women with menopausal symptoms and found that it was associated with improvements, albeit small, in sexual function by contrast with placebo and hormonal therapy. However, only a small subset of the 28 trials included in the review analysed sexual function outcomes and there were insufficient data available from the included trials to compare the effects of DHEA to hormone therapy for menopausal symptoms, mostly due to discrepancy in measurements between studies.73 The specific action and safety of the final metabolites have not yet been clarified and further research is underway.22 Meanwhile, DHEA cannot be assumed to be safer in breast cancer survivors and hence, cannot be recommended for the management of genitourinary and sexual related disorders.10

Testosterone has also been a proposed treatment for genitourinary atrophy,67, 69 with some studies showing this therapy to be associated with higher frequency of sexual activity, and increased interest, desire, enjoyment, arousal, and pleasure.74 Furthermore, vaginal administration of testosterone has been evaluated for the treatment of symptomatic genitourinary atrophy in postmenopausal women with breast cancer.72, 75 Witherby et al.72 reported results of a phase I/II pilot study on the effect of intravaginal testosterone (cream containing either 150μg or 300μg of testosterone) in breast cancer patients taking AIs. The severity of vaginal dryness and dyspareunia improved significantly with treatment and was sustained one month after completion of treatment. The study also documented that the vaginal maturation index improved, pH decreased and that lubrication was increased.72 Similarly, 12 postmenopausal women with breast cancer who were receiving an AI and were experiencing sexual dysfunction, were assigned to 300μg testosterone vaginal cream daily for four weeks.76

Results described significant improvement on sexual health (desire, p=0.000; arousal, p=0.002;

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lubrication, p=0.018; orgasm, p=0.005; satisfaction, p=0.0001; and pain, p=0.000) and QoL

(p=0.000).76

As AIs inhibit the aromatase enzyme from converting androgens to estrogens, circulating testosterone would theoretically not be converted to estradiol in women receiving AIs.72

Anecdotally, the use of vaginal testosterone has been reported to be a potential alternative to vaginal estrogen treatment in women with breast cancer on AIs.76 However, data on the effects of increased serum levels of testosterone is still lacking and its efficacy and safety have not been well established in healthy women or women with a cancer diagnosis.77, 78 Testosterone or other androgens cannot be recommended in women with a history of breast cancer.10

4.8. Tibolone

Tibolone is a synthetic steroid that after absorption is rapidly converted to its active form which has weak estrogenic, progestagenic, and androgenic properties.59 It is classified as a selective tissue estrogenic activity regulator (STEAR),59, 79 and has been shown to improve vaginal dryness80, 81 and may have a favourable effect on sexual dysfunction.82 Although tibolone has been approved worldwide for at least 20 years, it is not currently approved by the FDA for use in the United States.

The most important findings for breast cancer survivors are the results of the LIBERATE trial which was the first trial to study tibolone effects in a large breast cancer population compared with placebo.83, 84 The study showed that tibolone (2.5mg) is effective in improving menopausal symptoms including vaginal dryness (p<0.0001), and enhanced QoL, however, it was also associated with a significantly increased risk of breast cancer recurrence (HR1.40; CI95%:1.14-

1.70, p=0.0009) and is contraindicated after breast cancer, with the authors warning that any off-label use incurs a proven risk.83, 84 This recommendation has been endorsed by the

International Menopausal Society (IMS).11 110

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4.9. Selective Estrogen Receptor Modulator (SERM)

SERMs were identified over 50 years ago and have been used for over three decades.85 The understanding of their pharmacological profile is still evolving and they are currently used in several different settings, including the: prevention of breast cancer (tamoxifen, raloxifene), treatment of breast cancer (tamoxifen, ), prevention and treatment of osteoporosis

(CE/, raloxifene), treatment of moderate to severe dyspareunia due to vaginal atrophy (),10 and treatment of moderate to severe vasomotor symptoms associated with menopause (CE/bazedoxifene). Some other SERMs are under investigation and/or process of being approved ().

Ospemifene is the only SERM approved in the United States for treatment of moderate to severe dyspareunia associated with vulvovaginal atrophy in healthy postmenopausal women.86 Daily dose of ospemifene 60mg was reported to improve vaginal maturation index, vaginal pH and vaginal dryness in subjective and objective evaluations.87 In a randomised double-blind 40-week safety extension study, ospemifene demonstrated no clinically significant endometrial changes and was not associated with carcinoma; an increased incidence of vasomotor symptoms was observed, however.88 Ospemifene has not yet been adequately studied in a breast cancer population, so it is not recommended for use in this group.89 Future studies defining the safety profile in breast cancer patients and safety of prolonged used (i.e. greater than one year) are eagerly awaited.

Bazedoxifene combined with (CE), namely tissue-selective estrogen complex (TSEC) has been approved for the treatment of vasomotor symptoms and the prevention of osteoporosis in women with a uterus. Findings from two large clinical trials found that bazedoxifene 20mg/CE (0.45mg or 0.625mg) significantly improved vaginal atrophy with no endometrial safety signals (low rates, <1%, of endometrial hyperplasia which was similar to placebo).90, 91 Other trials also supported the benefits of bazedoxifene in improving vaginal

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maturation index, vaginal pH, vaginal dryness and reduction of most bothersome vaginal symptoms (p<0.05).92 Despite these findings it has not been registered for this indication and no studies have investigated drug safety in breast cancer survivors, therefore, it should not be recommended in women with breast cancer.

4.10. Lower urinary tract symptoms (LUTS) management

Treatments for LUTS are related to the underlying cause of the particular pelvic/urinary disorder and range from conservative options to surgery.93 Importantly, most LUTS can often be managed in the primary care setting.94 Clinicians are encouraged to indicate nonpharmacological treatments as first-line therapy, where possible, and use their clinical judgment when deciding whether a referral to a specialist is needed for further investigation and/or treatment.93 A multidisciplinary approach for breast cancer survivors who are experiencing symptoms may also be beneficial, including the involvement of counselling professionals and/or psychologists to help minimise the negative impact of LUTS on wellbeing.95

The conservative treatment options include: lifestyle interventions and behavioural therapy

(bladder training, exercises, fluid and dietary modification, weight control), electrical stimulation, pelvic floor muscle training (PFMT), watchful waiting therapy and anti- incontinence/vaginal supporting devices (e.g.vaginal pessaries, vaginal cones and urethral inserts). Pharmacological therapy is more commonly used for urgency UI and include: anticholinergics, possibly vaginal estrogens in selected cases (and with patient’s informed consent), and more recently the use of botulinum toxin injection into the detrusor muscle. SRNI has also been indicated for stress UI.96

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Surgical treatment options can include: anti-incontinence procedures (e.g. retropubic urethropexy, autologous fascial slings, urethral bulking agents, and synthetic mid-urethral slings, etc.), pelvic organ prolapse (POP) corrective surgeries (e.g. sacral colpopexy, transvaginal mesh uterosacral colpopexy, etc.). Several different surgical procedures have been described and no single one is optimal for all patients.97 Hence, multiple factors should be considered such as safety, cost-effectiveness, invasiveness, surgeons-personal experience, etc. in order to tailor a therapy to the desires and needs of the individual patient.97 As it is not in the scope of this project to describe each of the several available surgical procedures, emphasis will be given to the conservative approaches.

Finally, it should be noted that guidelines for the management of urinary symptoms in women with breast cancer are currently not available, therefore, all recommendations provided in this section (unless otherwise stated) is based on current practice in women in the general population and during midlife. As such, it is important to use clinical judgment and individualised approach to treating symptomatic breast cancer survivors.

4.11. Pelvic floor muscle training (PFMT), pelvic floor muscle control, bladder training and behavioural modification techniques

PFMT is recommended by the International Continence Society (ICS)94 as first-line therapy in women with stress, urge, or mixed UI.98 The main purposes of PFMT are to improve strength of the pelvic organ support, as well as increase intraurethral pressure during effort thus, maximising women’s ability to maintain continence.96 A 2014 Cochrane review comparing 21 trials evaluating PFMT versus no treatment for UI concluded that, overall, women who performed PFMT were 17 times more likely to report resolution or improvement of incontinence symptoms (RR 17.33, 95%CI 4.31-69.64), have fewer urinary leakage episodes per day and have less leakage than controls.99 In addition, PFMT had a positive impact on

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QoL.98 Importantly, it was noted that women under regular supervision relating to PFMT were more likely to report improvement than those who received little or no supervision.99 PFMT has been highly recommended (high quality evidence) as a first-line management for women with

UI,99 with the NAMS also endorsing behavioural therapies and pessaries as alternative options for UI.10 Furthermore, promising results for the use of PFMT for prolapse symptoms and severity were reported using pooled data from six trials.100 A 17% higher chance of improvement in prolapse stage was reported with PFMT compared to no intervention.100 Thus,

PFMT is a viable option for breast cancer patients reporting UI and prolapse.

Bladder training and behavioural modification techniques may help urgency and OAB as these interventions are focused on improving voluntary control of the bladder function by gradually increasing time interval between toilet stops, aiming to reduce the number of voids per day (up to approximately four to six voids during the day and one to two voids at night).101, 102 These techniques may help urgency and OAB, and early studies suggest that UI may also be improved; however, there are limited data and further studies are needed to confirm this observation.103 In the meantime, the recommendation is that all patients with suspected OAB should be educated regarding bladder training.94

4.12. Electrical stimulation

Electrical stimulation is a treatment option for urinary urgency and urge incontinence; however, it is not commonly indicated as it is invasive and not without risk.104 Vaginal and/or anal transducers can be used to administer electrical stimulation, where the physiological objectives are to produce muscle hypertrophy, normalise the reflex activity of the lower urinary tract (i.e. inducing reflex contraction of the periurethral muscles and reflex inhibition of the detrusor muscle) and to increase blood flow to pelvic muscles.105 According to some reviews, electrical

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neurostimulation and neuromodulation can result in a 30% to 50% clinical success rate,104 however, it was shown to be similar to PFMT in improving UI.105

4.13. Vaginal/ Urethral support devices

Mechanical devices (vaginal or urethral) are also described as an easy-to-insert and cheap option for women who want to delay/avoid surgery for UI.106 However, the latest Cochrane review (2014)106 on the topic concluded that there is no evidence to suggest that one device is better than another and, most importantly, there is insufficient evidence to claim that mechanical devices are better than no treatment.106 Similarly, another systematic review assessing the use of pessaries to treat POP, could not draw conclusions on the use of different types of devices, the indications or the pattern of replacement and follow-up care as only one trial was included in the analysis and methodological flaws were noted in the study.107 Finally, weighted vaginal cones for UI were also reviewed.108 Again, the lack of larger, high-quality trials, made it difficult for the authors to be conclusive. There were suggestions, however, that weighted vaginal cones were better than no active treatment (RR for failure to cure UI 0.84, 95% CI 0.76-0.94) in women with stress UI and may be as effective as PFMT (RR 1.01, 95% CI 0.91 – 1.13) and electrostimulation (RR 1.26, 95% CI 0.85 – 1.87). 108 Therefore, vaginal cones may constitute an alternative option for management of stress UI, although the evidence of its effectiveness is weak.

4.14. Pharmacological interventions for UI

Duloxetine is a SNRI recommended for treatment of stress UI.109 It increases the urethral sphincter tone resulting in a decrease in stress-induced leakage. Results from a systematic review conducted by Mariappan et al.109 found that duloxetine 80mg/daily was superior to placebo with respect to subjective perception of symptom resolution and improvement in incontinence.109 However, was a common side effect and about one in eight women 115

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discontinued therapy because of side effects.109 Duloxetine has been described as well tolerated in breast cancer patients, and a trial is now investigating its use to treat musculoskeletal pain caused by AIs.110 To date, the most common adverse events described so far were , dry mouth, nausea and .110

Anticholinergic medications such as darifenacin, fesoterodine, oxybutynin, solifenacin, propiverine, and tolterodine have demonstrated positive effects on urgency UI and mixed UI compared to placebo in general population, 111 with less episodes of leakage and reduced number of voids in 24 hours.112 These drugs suppress bladder contractions via muscarinic receptors of the bladder wall, where acetylcholine is the transmitter substance.113 Side effects such as dry mouth are commonly reported, tolerability is good and discontinuation of therapy is not significant.112 Therapy combining anticholinergics and bladder training was shown to be more effective than bladder training alone in one review, but it remains unclear if it is more effective than medication alone.114

The American College of Physicians (ACP) recommends that selection of pharmacological interventions for urgency UI should be based on drug tolerability and cost effectiveness, and should be considered when bladder training is unsuccessful.111

4.15. Sexual concerns

Although sexual issues may not be a patient’s main concern during her diagnosis and primary treatment of breast cancer, it may become more of an important concern after this stage of her treatment.41 It is also evident that sexuality and intimacy are often overlooked or not properly addressed with breast cancer patients in clinical practice.115, 116 Studies suggest that initiating the discussion about sexual-related side effects of cancer therapy with patients early on their

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treatment may make them more willing to be open about any issues they may experience in the future.41

Treatment of sexual complaints may require a multi-modal treatment approach, including the use of lubricants and moisturisers, liquid lidocaine,117 ultralow concentration of vaginal estrogen

(usually as a last resort, and only upon risk assessment and informed consent from patient),118 counselling and sex therapy (alone or couple-based), PFMT and use of vaginal devices such as dilators or pessaries,22 in addition to treatment of underlying depression and anxiety.22 Topical use of testosterone has been suggested but more research in breast cancer patients is needed.22

Most importantly, it is essential to encourage women to maintain regular sexual activity, which results in improved blood flow to the vagina, reducing further atrophy.22 In a systematic review specifically addressing interventions for sexual problems following breast cancer, it was suggested, that the most effective intervention for this issue was couple-based psycho- educational interventions that include an element of sexual therapy, although this was based on moderate evidence of its effectiveness.119 A new approach to dyspareunia involves the application of aqueous lidocaine prior to penetration, which potentially acts reducing pain in the vulvar vestibule (i.e. entryway to the vagina).117 The application of 4% topical liquid lidocaine to the vulvar vestibule for four weeks reduced sexual distress and allowed for comfortable intercourse in postmenopausal women with breast cancer reporting severe dyspareunia in a proof-of-concept double-blind RCT involving 46 breast cancer patients.117 New studies focusing on the physiopathology of the coital pain may shed some light and bring hope to the many survivors experiencing pain with intercourse.

4.16. Conclusion and recommendations

Appropriate and timely management of the adverse side effects of antiestrogens, including genitourinary symptoms is critically important to all postmenopausal women who are on

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adjuvant endocrine therapy after the diagnosis of early breast cancer. The side effects of treatment may negatively impact on QoL and also result in early discontinuation. Many women are recommended 10 years of adjuvant endocrine therapy and unless the side effects are adequately managed they will either stop treatment early or suffer with multiple symptoms for years. This Chapter has focused on the management of genitourinary symptoms and outlined the possible management options in women with breast cancer. HRT is not recommended in women with a history of breast cancer, but there is a wide range of other management options available that can improve genitourinary symptoms in these women. They include lifestyle and behavioural changes, lubricants, moisturisers, and nonhormonal pharmacological interventions, among others.

Topical estrogens are controversial given safety concerns, but the limited evidence on the effect low-/ultralow- dose vaginal estrogen is promising though still needs more work. Topical estriol formulations theoretically should be safe but more clinical data on their safety and effectiveness are needed. There is inconclusive evidence on whether systemic absorption after topical use of estrogens increases the risk of breast cancer recurrence. If topical estrogens are prescribed, the lowest possible dose should be used after discussing the potential risks.

Future studies to define the safety and efficacy of ospemifene, as well as topical testosterone are needed as they do appear to offer some benefit. Clinicians should actively question breast cancer patients on adjuvant endocrine therapy about signs or symptoms of genitourinary atrophy as well as about any sexual concerns or problems. These topics are frequently not discussed and early interventions are much more likely to be effective than treatment after years of estrogen deprivation. A Multidisciplinary team approach is often required and treatment needs to be tailored to the individual patients’ specific needs and circumstances.

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4.17. References

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57. North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause, 2012; 19(3):257-71. 58. von Schoultz, E and Rutqvist, LE. Menopausal hormone therapy after breast cancer: the Stockholm randomized trial. J Natl Cancer Inst, 2005; 97(7):533-5. 59. Biglia, N, Peano, E, Sgandurra, P, Moggio, G, Panuccio, E, Migliardi, M, Ravarino, N, Ponzone, R and Sismondi, P. Low-dose vaginal estrogens or vaginal moisturizer in breast cancer survivors with urogenital atrophy: a preliminary study. Gynecol Endocrinol, 2010; 26(6):404-12. 60. Manson, JE, Goldstein, SR, Kagan, R, Kaunitz, AM, Liu, JH, Pinkerton, JV, Rebar, RW, Schnatz, PF, Shifren, JL, Stuenkel, CA, Gass, ML and Utian, WH. Why the product labeling for low-dose vaginal estrogen should be changed. Menopause, 2014; 21(9):911- 6. 61. Santen, RJ, Pinkerton, JV, Conaway, M, Ropka, M, Wisniewski, L, Demers, L and Klein, KO. Treatment of urogenital atrophy with low-dose estradiol: preliminary results. Menopause, 2002; 9(3):179-87. 62. Holmberg, L and Anderson, H. HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet, 2004; 363(9407):453-5. 63. Loibl, S, Lintermans, a, Dieudonné, aS and Neven, P. Management of menopausal symptoms in breast cancer patients. Maturitas, 2011; 68:148-54. 64. Pfeiler, G, Glatz, C, Konigsberg, R, Geisendorfer, T, Fink-Retter, A, Kubista, E, Singer, CF and Seifert, M. Vaginal estriol to overcome side-effects of aromatase inhibitors in breast cancer patients. Climacteric, 2011; 14(3):339-44. 65. Society, TAC. [last accessed 2014; Available from: http://www.cancer.org/cancer/cancercauses/othercarcinogens/medicaltreatments/menopau sal-hormone-replacement-therapy-and-cancer-risk. 66. Sherwin, BB and Geland, MM. The role of androgen in the maintenance of sexual functioning in oophorectomized women. Psychosomatic Medicine, 1987; 49:2195-2198. 67. Shulman, LP. Androgens and menopause. Minerva Ginecol, 2009; 61(6):491-7. 68. Hubayter, Z and Simon, JA. Testosterone therapy for sexual dysfunction in postmenopausal women. Climacteric, 2008; 11(3):181-91. 69. Raghunandan, C, Agrawal, S, Dubey, P, Choudhury, M and Jain, A. A comparative study of the effects of local estrogen with or without local testosterone on vulvovaginal and sexual dysfunction in postmenopausal women. J Sex Med, 2010; 7(3):1284-90. 70. Labrie, F. DHEA, important source of sex in men and even more in women. Prog Brain Res, 2010; 182:97-148. 71. Ibe, C and Simon, JA. Vulvovaginal atrophy: current and future therapies (CME). J Sex Med, 2010; 7(3):1042-50; quiz 1051. 72. Witherby, S, Johnson, J, Demers, L, Mount, S, Littenberg, B, Maclean, CD, Wood, M and Muss, H. Topical testosterone for breast cancer patients with vaginal atrophy related to aromatase inhibitors: a phase I/II study. Oncologist, 2011; 16(4):424-31. 73. Scheffers, CS, Armstrong, S, Cantineau, AE, Farquhar, C and Jordan, V. Dehydroepiandrosterone for women in the peri- or postmenopausal phase. Cochrane Database Syst Rev, 2015; 1:CD011066. 74. Castelo-Branco, C, Cancelo, MJ, Villero, J, Nohales, F and Julia, MD. Management of post-menopausal vaginal atrophy and atrophic vaginitis. Maturitas, 2005; 52 Suppl 1:S46-52. 75. Derzko, C, Elliott, S and Lam, W. Management of sexual dysfunction in postmenopausal breast cancer patients taking adjuvant aromatase inhibitor therapy. Curr Oncol, 2007; 14 Suppl 1:S20-40. 76. Dahir, M and Travers-Gustafson, D. Breast cancer, aromatase inhibitor therapy, and sexual functioning: a pilot study of the effects of vaginal testosterone therapy. Sex Med, 2014; 2(1):8-15.

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77. Von Schoultz, E and Rutqvist, L. Menopausal hormone therapy after breast cancer: The Stockholm randomized trial. J Natl Cancer Inst, 2005; 97:533-5. 78. Hickey, M, Saunders, C, Partridge, a, Santoro, N, Joffe, H and Stearns, V. Practical clinical guidelines for assessing and managing menopausal symptoms after breast cancer. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 2008; 19:1669-80. 79. Indhavivadhana, S, Leerasiri, P, Rattanachaiyanont, M, Laiwejpithaya, S, Tanmahasamut, P, Techatraisak, K and Angsuwathana, S. Vaginal atrophy and sexual dysfunction in current users of systemic postmenopausal hormone therapy. J Med Assoc Thai, 2010; 93(6):667-75. 80. Rymer, J, Chapman, MG, Fogelman, I and Wilson, PO. A study of the effect of tibolone on the vagina in postmenopausal women. Maturitas, 1994; 18(2):127-33. 81. Nappi, RE, Ferdeghini, F, Sampaolo, P, Vaccaro, P, De Leonardis, C, Albani, F, Salonia, A and Polatti, F. Clitoral circulation in postmenopausal women with sexual dysfunction: a pilot randomized study with hormone therapy. Maturitas, 2006; 55(3):288-95. 82. Albertazzi, P, Di Micco, R and Zanardi, E. Tibolone: a review. Maturitas, 1998; 30(3):295-305. 83. Kenemans, P, Bundred, NJ, Foidart, JM, Kubista, E, von Schoultz, B, Sismondi, P, Vassilopoulou-Sellin, R, Yip, CH, Egberts, J, Mol-Arts, M, Mulder, R, van Os, S and Beckmann, MW. Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial. Lancet Oncol, 2009; 10(2):135-46. 84. Sismondi, P, Kimmig, R, Kubista, E, Biglia, N, Egberts, J, Mulder, R, Planellas, J, Moggio, G, Mol-Arts, M and Kenemans, P. Effects of tibolone on climacteric symptoms and quality of life in breast cancer patients--data from LIBERATE trial. Maturitas, 2011; 70(4):365-72. 85. Wardell, SE, Nelson, ER and McDonnell, DP. From empirical to mechanism-based discovery of clinically useful Selective Estrogen Receptor Modulators (SERMs). Steroids, 2014; 90:30-8. 86. Portman, D, Palacios, S, Nappi, RE and Mueck, AO. Ospemifene, a non-oestrogen selective oestrogen receptor modulator for the treatment of vaginal dryness associated with postmenopausal vulvar and vaginal atrophy: a randomised, placebo-controlled, phase III trial. Maturitas, 2014; 78(2):91-8. 87. Portman, DJ, Bachmann, GA and Simon, JA. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause, 2013; 20(6):623-30. 88. Simon, JA, Lin, VH, Radovich, C and Bachmann, GA. One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. Menopause, 2013; 20(4):418-27. 89. Glaser, RL and Dimitrakakis, C. Reduced breast cancer incidence in women treated with subcutaneous testosterone, or testosterone with anastrozole: a prospective, observational study. Maturitas, 2013; 76(4):342-9. 90. Pickar, JH, Yeh, IT, Bachmann, G and Speroff, L. Endometrial effects of a tissue selective estrogen complex containing bazedoxifene/conjugated estrogens as a menopausal therapy. Fertil Steril, 2009; 92(3):1018-24. 91. Lobo, RA, Pinkerton, JV, Gass, ML, Dorin, MH, Ronkin, S, Pickar, JH and Constantine, G. Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile. Fertil Steril, 2009; 92(3):1025-38. 92. Kagan, R, Williams, RS, Pan, K, Mirkin, S and Pickar, JH. A randomized, placebo- and active-controlled trial of bazedoxifene/conjugated estrogens for treatment of moderate to severe vulvar/vaginal atrophy in postmenopausal women. Menopause, 2010; 17(2):281-9.

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93. Committee on Gynecologic Practice and American Urogynecologic Society. Committee Opinion No. 603: Evaluation of uncomplicated stress urinary incontinence in women before surgical treatment. Obstet Gynecol, 2014; 123(6):1403-7. 94. Newman DK, Ee CH, Gordon D, Srini VS, Williams K, Cahill B, Gordon B, Griebling T, Nishimura K and Norton, N. Incontinence, Proceedings from the 4th International Consultation on Incontinence. , In: Abrams P, Cardozo L, Khoury S and A., W, editors. Continence promotion, education & primary prevention. Plymouth, UK: Health Publication. 2009 95. Wengstrom, Y. Effectively nursing patients receiving aromatase inhibitor therapy. Breast, 2008; 17(3):227-38. 96. Lins S, Hayder-Beichel D, Kunath F, Cartwright R, Motschall E and Antes G. Pelvic floor muscle training versus other active treatments for urinary incontinence in women (Protocol). . Cochrane Database Syst Rev, 2014; (6):Art. No.:CD007173. DOI: 10.1002/14651858.CD007173.pub3. 97. Rovner, ES and Wein, AJ. Treatment Options for Stress Urinary Incontinence. Rev Urol, 2004; 6(Suppl 3):S29-47. 98. Dumoulin, C and Hay-Smith, J. Pelvic floor muscle training versus no treatment, or inactive control treatments, for urinary incontinence in women. Cochrane Database Syst Rev, 2010; (1):CD005654. 99. Hay-Smith, EJ, Herderschee, R, Dumoulin, C and Herbison, GP. Comparisons of approaches to pelvic floor muscle training for urinary incontinence in women. Cochrane Database Syst Rev, 2011; (12):CD009508. 100. Hagen, S and Stark, D. Conservative prevention and management of pelvic organ prolapse in women. Cochrane Database Syst Rev, 2011; (12):CD003882. 101. Burgio, KL. Current perspectives on management of urgency using bladder and behavioral training. J Am Acad Nurse Pract, 2004; 16(10 Suppl):4-7. 102. Burgio, KL. Influence of behavior modification on overactive bladder. Urology, 2002; 60(5 Suppl 1):72-6; discussion 77. 103. Wallace, SA, Roe, B, Williams, K and Palmer, M. Bladder training for urinary incontinence in adults. Cochrane Database Syst Rev, 2004; (1):CD001308. 104. Hajebrahimi S, Sadeghi-Bazargani H, Taleschian Tabrizi N, Farhadi F and F., SG. Non- drug treatment for lower urinary tract symptoms in women with voiding dysfunction (Protocol). Cochrane Database of Systematic Reviews 2015; (1):Art. No.: CD011470. DOI: 10.1002/14651858.CD011470. . 105. Ghaderi, F and Oskouei, AE. Physiotherapy for Women with Stress Urinary Incontinence: A Review. J Phys Ther Sci. 2014 Sep;26(9):1493-9. Epub 2014 Sep 17 doi:10.1589/jpts.26.1493. 106. Lipp, A, Shaw, C and Glavind, K. Mechanical devices for urinary incontinence in women. Cochrane Database Syst Rev, 2014; 12:CD001756. 107. Bugge, C, Adams, EJ, Gopinath, D and Reid, F. Pessaries (mechanical devices) for pelvic organ prolapse in women. Cochrane Database Syst Rev, 2013; 2:CD004010. 108. Herbison, GP and Dean, N. Weighted vaginal cones for urinary incontinence. Cochrane Database Syst Rev, 2013; 7:CD002114. 109. Mariappan, P, Alhasso, A, Ballantyne, Z, Grant, A and N'Dow, J. Duloxetine, a serotonin and noradrenaline reuptake inhibitor (SNRI) for the treatment of stress urinary incontinence: a systematic review. Eur Urol, 2007; 51(1):67-74. 110. Henry, NL, Banerjee, M, Wicha, M, Van Poznak, C, Smerage, JB, Schott, AF, Griggs, JJ and Hayes, DF. Pilot study of duloxetine for treatment of aromatase inhibitor-associated musculoskeletal symptoms. Cancer, 2011; 117(24):5469-75. 111. Qaseem, A, Dallas, P, Forciea, MA, Starkey, M, Denberg, TD and Shekelle, P. Nonsurgical management of urinary incontinence in women: a clinical practice guideline from the American College of Physicians. Ann Intern Med, 2014; 161(6):429-40.

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112. Nabi, G, Cody, JD, Ellis, G, Herbison, P and Hay-Smith, J. Anticholinergic drugs versus placebo for overactive bladder syndrome in adults. Cochrane Database Syst Rev, 2006; (4):CD003781. 113. Yoshimura, N and Chancellor, MB. Neurophysiology of Lower Urinary Tract Function and Dysfunction. Rev Urol, 2003; 5(Suppl 8):S3-S10. 114. Rai, BP, Cody, JD, Alhasso, A and Stewart, L. Anticholinergic drugs versus non-drug active therapies for non-neurogenic overactive bladder syndrome in adults. Cochrane Database Syst Rev, 2012; 12:CD003193. 115. Hordern, AJ and Street, AF. Constructions of sexuality and intimacy after cancer: patient and health professional perspectives. Soc Sci Med, 2007; 64(8):1704-18. 116. Hordern, AJ and Street, AF. Communicating about patient sexuality and intimacy after cancer: mismatched expectations and unmet needs. Med J Aust, 2007; 186(5):224-7. 117. Goetsch, MF, Lim, JY and Caughey, AB. A Practical Solution for Dyspareunia in Breast Cancer Survivors: A Randomized Controlled Trial. J Clin Oncol, 2015. 118. van Londen, G, Beckjord, E, Dew, M, Cuijpers, P, Tadic, S and Brufsky, A. Breast cancer survivorship symptom management: current perspective and future development. Breast Cancer Manag, 2013; 2(1):71-81. 119. Taylor, S, Harley, C, Ziegler, L, Brown, J and Velikova, G. Interventions for sexual problems following treatment for breast cancer: a systematic review. Breast Cancer Res Treat, 2011; 130(3):711-24.

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CHAPTER 5

Rationale for Choice of Methodology

This Chapter briefly describes and justifies the design and methods underpinning the current research. It discusses how the study methodologies were selected to best answer the research questions.

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5. Selection of research methods

5.1. A combined qualitative and quantitative methodological approach

There are two main approaches to research and these are quantitative and qualitative, and both approaches can be complimentary and help address different aspects of the research questions.

Essentially, quantitative methods focuses on the quantification of participants responses, testing existing hypotheses or theories and, the aim being that the results will be generalizable to larger groups.1 In contrast, qualitative methods aim to explore the reasons for and the meaning of specific behaviours, emotions, beliefs and experiences at an individual level (i.e. understanding the event of interest in a more comprehensive manner).2

Typically, qualitative and quantitative methods are used independently. Nonetheless, the integration of qualitative and quantitative research methods, namely ‘mixed-methods research’, has increasingly gained acceptance among the research community, with both approaches being used concurrently or sequentially.3, 4 The selection of a mixed-method research design may involve a number of rationales; in particular: to elaborate or expand the understanding gained from a prior method (for instance, using a qualitative approach to help explore extreme results from quantitative data);5 to complement the data generated through obtaining additional viewpoints, thereby deepening insights into a question; and for completeness by ensuring that a total representation of experiences or associations is attained.6, 7 Further purposes include: to

(initiate) test hypotheses, which were raised by previous studies; and to compare and contrast the findings of the different methods in order to explore whether they converge, diverge or are contradictory.6, 7

In summary, qualitative and quantitative approaches to research are both potentially very informative. Each method has its strength and limitations; combining research methods can

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offset the of using one method alone, while exploiting the strength of each method.

6, 7 The integration of qualitative and quantitative research methods is thus likely to enhance the overall research design and reinforce the integrity and applicability of the research findings than either approach could alone.7, 8

5.1.1. Qualitative Research

Qualitative research is geared towards improving understanding of a particular question by focusing in depth on personal and shared experiences, beliefs, values and behaviours in individual patients9 – rather than on an objective record of the event itself as is with quantitative research (e.g. translating findings into numerical form).10 Generally, the aim of qualitative research is not to produce generalizable data but instead, to yield data that can be

“extrapolated”, in the sense used by Patton et al.,11 who defined extrapolations as “modest speculations on the likely applicability of findings to other situations”.

Individual behaviour involves factors that may not always be observable (for instance, what goes on inside an individual’s mind or consciousness).7, 8 Furthermore, individuals act differently in different social settings, as well as they place meanings and significance on things and events, which do not always correspond to those of others.12 Hence, researchers who are trying to gain in-depth insights into the meanings individuals attach to their experiences by observing their behaviour alone frequently encounter difficulties. In view of this, qualitative research strives to translate and interpret events from the perspective of those people under investigation and the results are often broader and richer in detail than those obtained through quantitative approach.9

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The in-depth exploration of a particular experience or event is especially useful in studying health issues, because it allows researchers to gain thorough understanding of the ‘hows’ and

‘whys’ of individuals’ behaviour, and the different types and nature of their needs, as well as to learn the different terminology used by participants to express these experiences.13 The main advantage of qualitative approach is that it helps to generate hypotheses in areas of research where relatively little is known.14 For instance, qualitative findings can be used to inform questionnaire item development and thus improve the quality of questionnaire-based research. It may also help clarify the interpretation of quantitative findings. Furthermore, qualitative research methods can also produce quantitative data, while the same is not true in reverse.15

The approach adopted by qualitative methods of inquiry usually involves recording and analysing textual data as a means to recognise and understand events, which may be occurring within a particular group.5 The qualitative content analysis is mainly inductive and seeks to identify themes or patterns within the data collected, while providing a richer description of the events.5 Careful data preparation, coding, and rigorous interpretation ensure that findings are relevant and support valid and reliable inferences.14,7 Furthermore, findings from qualitative studies can support the development of hypotheses or new theories, as well as validating existing ones. Ultimately, both qualitative and quantitative approaches intend to provide recommendations and/or to contribute to the solution of a problem at hand.16, 17

5.1.2 Quantitative Research

The use of quantitative methods of inquiry is particularly valuable in testing hypotheses, addressing questions derived from theories or drawing causal inferences, thus verifying existing previous empirical research or questioning theories across a larger number of participants.17

Quantitative methods are also necessary in order to estimate the size of a phenomenon of

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interest. They can identify the frequency and variability of events within a group, as well as their relationship with other variables.7, 8 Most importantly, quantitative data yield useful information that can be generalized from a research sample to a broader population so that predictions can be made about how larger groups might respond. Therefore, they can be used to measure a phenomenon in order to draw statistically significant conclusions from a representative sample.18, 19

Quantitative approaches to gathering information require data collection instruments (e.g. standardized and validated tools) that fit the events of interest into fixed response categories.20

Subsequently, statistical analysis of these quantitative data allows determining a variety of relationships between variables, as well as overall patterns and the extent to which one variable influences another.21 This usually involves converting data into numerical formats, thus facilitating comparisons and producing results which are easily summarised.22

An important principle in quantitative research is to ensure that external factors are controlled for as they can affect the results. Nonetheless, some contributing factors cannot be eliminated entirely and thus should be acknowledged by the researcher.15 Objectivity is another key principle in quantitative research.22 Therefore, it is essential that researchers constantly review their methods during the research process to minimise the risk of bias, to identify and address potential confounders, and to become highly skilled at undertaking complex data analyses. 22

5.2. Phase 1 of this research project – a qualitative research design

In the first phase of this research project, the focus was on understanding the range of experiences and information needs, in addition to the impact of, and attitudes towards

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genitourinary symptoms among breast cancer survivors receiving adjuvant endocrine therapy.

Research in the area of genitourinary adverse effect of endocrine therapy for breast cancer often focuses on quantitative outcomes, which means that more subtle nuances in women’s experiences of genitourinary symptoms can be missed.23 A qualitative assessment of breast cancer patients’ perceptions of genitourinary symptoms has the potential to supplement the existing quantitative data. In addition, qualitative research on women’s information preferences regarding genitourinary symptoms can inform the development of educational strategies to assist in symptom management. Therefore, a qualitative approach using in-depth semi- structured interviews was employed.

Perhaps the most important advantage of interviews is that they enable the researcher to establish a personal connection with participants, which in turn may result them feeling more comfortable to discuss highly sensitive and personal issues. In-depth interviews also allow probing of responses (e.g. ‘why’, ‘how’, ‘in what context’, ‘which one do you prefer’ etc.) to obtain more detailed and potentially more accurate descriptions of participants’ views.

Furthermore, interviews enable participants to further elaborate on topics that were not anticipated by researchers, thus allowing unprompted responses.11 In contrast, survey-based studies have fixed answer choices (e.g., check the box) and probing is not possible.

In other words, unlike questionnaires with closed-ended question format, semi-structured interviews do not limit respondents to a set of pre-determined answer choices. While questions are typically directed by an interview guide, they do not necessarily need to be asked in a specified order, nor do all questions need to be asked. The interviewer may omit/skip some questions which are either not pertinent or may have been already answered by the participant, while new questions may be prompted by responses given.24-26 In summary, additional lines of

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enquiry can allow the interviewer to further explore particular themes or responses that emerge during discussion, including information not anticipated by the researcher, which in turn may increase validity of the data.27 The most important skill to effectively ensure the flow of the interview is thus to establish a good rapport and to use good communication and listening skills to enable the interviewer to quickly frame appropriate questions and probes.28

Given the high sensitivity of the topic, both face-to-face and telephone interviews were deemed more appropriate data collection methods than focus group discussions in this phase of the project. It was felt that some participants might be reluctant, or become distressed, when sharing sensitive and personal information in front of others, as is with focus groups, for instance.29

It was decided that the sampling framework for the study should correspond to that of the second phase of this research project, i.e. women taking adjuvant endocrine therapy for early breast cancer. Therefore, women who attended the oncology clinics of two major teaching hospitals in Sydney, Australia, and met the eligibility criteria to the study were recruited.

Sampling ceased once saturation of information and themes was achieved, i.e. no new themes were emerging.30, 31 Interviews were audiotaped, with participants’ written consent, and then transcribed verbatim whilst protecting the identity of each participant.

Data analysis in qualitative research is usually performed using an iterative approach. In the current study, data analysis was informed by the conceptual qualitative framework of Huberman and Miles.32 Effectively, this approach involves a continual process of thematic analysis applied to textual data derived from the interviews. The process consists of repeatedly reading through the transcripts, identifying and coding themes and issues introduced by participants (data reduction), organising the themes into meaningful hierarchical clusters (data display), and then

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interpreting the structure and content of the themes in a rigorous, yet inductive way (conclusion drawing/verification).14 Nonetheless, themes are also identified deductively in accordance with the pre-defined aims.33 Recurrent themes and patterns of experience are then compared and contrasted across the groups to capture the transferability of the experience of genitourinary symptoms transcending from the individual meanings.9 This iterative and interpretative process enhances the richness of the findings.32 It is important to point out though that, in contrast to quantitative surveys, the aim in qualitative studies is not to quantify the frequency of an event or experience; therefore, numerical values are not essential. Krane et al. noted that rare experiences or views are no less meaningful, useful or important than more common ones; indeed they can be the most important events to consider in qualitative analyses.34 Reliability was ensured by maintaining an audit log, including independent categorization by one of the supervisors who was also experienced in qualitative analysis, as proposed by Burnard.35 Finally, to further support the validity of the interpretation of findings, quotations from the interviews illustrate the experiences of the participants. More detailed information on the methodology and findings of

Phase 1 of this project is provided in Chapter Six.

5.3. Phase 2 of this research project – a prospective observational research design

In the second phase of this research the focus was to investigate the frequency, severity and risk factors for genitourinary symptoms in breast cancer survivors taking adjuvant endocrine therapy. It was hoped that the data could be used to better inform patients and clinicians about the potential genitourinary side effects of antiestrogens. A secondary aim was to determine whether there was an association between genitourinary symptoms and sexual functioning, as well as with symptom-related QoL. It was hypothesized that women with significant genitourinary symptoms would also have significant sexual dysfunction and impaired QoL. In

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order to test the study hypotheses and generate findings that could be generalized to larger population, a prospective questionnaire-based design was selected to follow the initial qualitative approach.

Prospective studies are appropriate when researchers attempt to predict the outcome of an event.

They allow for recurrent observation of the same participants and documentation of the presence or absence of an event of interest during the study period.36 This period of time may be quite brief (e.g. days, weeks), or very long in that participants could be followed up for life.

Moreover, a prospective research design permits observation of outcomes or events that occur subsequent to the identification of the group being investigated.21 In this study, women are being followed up for up to two years after enrolment to document the frequency and trajectory of genitourinary symptoms occurred over time. To achieve a true baseline measurement, data were collected prior to the commencement of adjuvant endocrine therapy and while therapy is ongoing.

Another key feature of quantitative studies is that in order to generalize findings from the group being investigated to a larger group, the researcher needs to be confident that the study population consist of either all members of a particular group (which rarely occurs) or constitutes a representative sample of the wider population.37 As such, the sample assessed consists of women who have been diagnosed with hormone-receptor positive, early stage breast cancer, who were receiving adjuvant endocrine therapy as part of their treatment.

Although side effects of cancer therapy in general and of endocrine therapy in particular are an important concern to all women diagnosed with breast cancer, this research has focused on women diagnosed with early stage breast cancer (i.e. stages IA, IB, IIA and IIB). The rationale

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underpinning this decision is that in order to prospectively investigate potential genitourinary outcomes associated with the use of adjuvant endocrine therapy, there was a need to include a group of women with breast cancer that was as homogeneous as possible in regards to treatment received (without confounding effects that could be associated with metastatic disease).

Furthermore, we wanted to assess the long term impact of treatment and have a long follow-up period of two years with as few patients dropping out as possible.

A well-known drawback of prospective designs, is the occurrence of withdrawals over the time, which may weaken the internal validity.38 Nonetheless, experience with similar design and population, demonstrate good response rates indicating that women with breast cancer are intrinsically motivated to participate in research.39, 40 Some studies offer an incentive in order to improve response rate; in this study, no incentives were offered due to a lack of resources.

In the current study participants were asked to complete self-administered questionnaires, which were issued with a unique ID (combination of letters and numbers) and did not contain any directly identifying information as is best practice;41 the participant information pamphlet emphasized confidentiality and privacy.42

The selection of validated questionnaires and instruments specifically designed to assess a full spectrum of urinary disorders, pelvic organ prolapse, vulvovaginal symptoms, sexual matters and symptom-related QoL, was carefully considered after extensive literature review and expert input and based on recommendation of expert groups, e.g. The Third International Consultation on Incontinence.43 Hence, they represent standardised measures of the hypotheses and variables the study intended to assess.

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Finally, data were collected, prepared and entered into SPSS 21.0 (Statistical Program for the

Social Sciences, version 21.0; SPSS Inc., Chicago, IL) database for analysis. Results are described in Chapter Seven along with further information on the methodology employed as part of phase two of this project.

5.4. Summary

The use of complementary approaches may offset the weaknesses of each method, hence potentially strengthening the ability to explore complex issues. As evidenced in the literature reviewed in Chapters Two and Three, a lack of comprehensive research documenting the impact of genitourinary symptoms in women receiving adjuvant endocrine therapy for early stage breast cancer is notable. Similarly, the effect of such symptoms on sexual function and QoL of these women is also under-researched. To address this gap in the literature this research project explored all aspects of genitourinary symptoms in women with breast cancer, including patients’ subjective concerns related to physical, emotional and social aspects of symptomatology, as well as patterns of help-seeking behaviour and information needs. The literature reviewed informed the design of the current research project. A qualitative approach using in-depth semi-structured interviews, in parallel with a questionnaire-based prospective approach, was implemented to address the research questions. The research flow diagram below illustrates how the different phases of this research addressed the gaps within the literature. The following two chapters will report on the qualitative (Chapter Six) and quantitative (Chapter

Seven) findings of Study I and Study II of the present series of studies.

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Fig. 5.1. Research flow diagram

ENDOCRINE THERAPY FOR BREAST CANCER MAY LEAD TO THE DEVELOPMENT OR EXARCEBATION OF GENITOURINARY SYMPTOMS IN POSTMENOPAUSAL WOMEN DUE TO ITS ANTIESTROGENIC EFFECT

HOWEVER

GENITOURINARY ADVERSE EFFECTS OF ADJUVANT ENDOCRINE THERAPY ARE UNDERSTUDIED

FURTHERMORE

THERE IS A LACK OF RESEARCH ON THE IMPACT OF GENITOURINARY SYMPTOMS ON SEXUAL FUNCTION AND QOL IN THIS GROUP OF WOMEN

THEREFORE

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GENITOURINARY SYMPTOMS IN BREAST CANCER PATIENTS RECEIVING ADJUVANT ENDOCRINE TREATMENT NEED TO BE MORE CLEARLY AND ACCURATELY DOCUMENTED

WHAT IS THE IMPACT GENITOURINARY SYMPTOMS HAVE ON BREAST CANCER PATIENTS’ DAILY LIVES?

WHAT ARE PATIENTS’ VIEWS OF AND ATTITUDES TOWARDS GENITOURINARY SYMPTOMS? QUALITATIVE STUDY BASED ON PATIENTS’ EXPERIENCES, WHAT DO THEY SUGGEST COULD BE IMPROVED, IF ANYTHING?

ARE PATIENTS SATISFIED WITH THE AMOUNT AND TYPE OF INFORMATION THEY RECEIVE REGARDING GENITOURINARY CONCERNS DURING THEIR CANCER TREATMENT?

WHAT IS THE PREVALENCE AND SEVERITY OF GENITOURINARY SYMPTOMS IN POSTMENOPAUSAL WOMEN RECEIVING ENDOCRINE THERAPY FOR EARLY BREAST CANCER? PROSPECTIVE STUDY

ARE THERE RISK FACTORS PREDICTIVE OF THE DEVELOPMENT OR

PROGRESSION OF GENITOURINARY SYMPTOMS IN THIS GROUP OF WOMEN?

BMI AGE CHEMO PARITY ASSOCIATED

ENDOCRINE

COMORBIDITIES TYPE/SEVERITY OF SYMPTOMS BASELINE SYMPTOMS TYPE OF ENDOCRINE THERAPY

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DO WORRIES ABOUT GENITOURINARY SYMPTOMS INTERFERE WITH PATIENT’S SEXUAL FUNCTION? PROSPECTIVE STUDY DO GENITOURINARY SYMPTOMS IMPACT ON THE QOL OF BREAST CANCER PATIENTS?

POTENTIAL BENEFITS AND OUTCOMES

FINDINGS FROM THESE RESEARCH QUESTIONS PROVIDE BOTH PATIENTS AND CLINICIANS WITH MORE INFORMATION REGARDING THE POTENTIAL GENITOURINARY ADVERSE EFFECTS OF ADJUVANT ENDOCRINE THERAPY.

IT ALSO PROVIDES THEORETICAL EVIDENCE TO INFORM CLINICAL PRACTICE TO FACILITATE RECOGNITION AND MANAGEMENT OF POTENTIAL GENITOURINARY ADVERSE EFFECTS OF ADJUVANT ENDOCRINE THERAPY.

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5.5 References

1. Mason, J. Qualitative Research. SAGE, London, 1996. 2. Thomas, A and Johnson, H. Not Only Reinforcing But Also Different Stories: Combining Case Studies and Survey to Investigate How Postgraduate Programmes Can Build Capacity For Development Policy and Management, in Combined Methods conference. 2002, Centre for Development Studies: Swansea. p. 1-2. 3. Morse, J. Approaches to qualitative-quantitative methodological triangulation. Nursing Research in Nursing and Health, 1991; 40:120-123. 4. Morgan, D. Practical strategies for combining qualitative and quantitative methods: Applications to health research. Qualitative Health Research, 1998; 8:362-376. 5. Creswell, JW, Fetters, MD and Ivankova, NV. Designing A Mixed Methods Study In Primary Care. Ann Fam Med, 2004; 2(1):7-12. 6. Brannen, J. Mixed Method Research: A discussion paper. ESRC National Centre for Research Methods NCRM Methods Review Papers NCRM/005, 2005:1-30. 7. Venkatesh, V, Brown, SA and Bala, H. Bridging the qualitative-quantitative divide: Guidelines for conducting mixed methods research in information systems. MIS Quarterly, 2013; 37(1):21-54. 8. Creswell, JW. A Concise Introduction to Mixed Methods Research. SAGE Publications, Inc Oaks, CA, 2014. 9. Morse JM. Qualitative Nursing Research. A Contemporary Dialogue. Sage, London, 1991. 10. Becker, S, Bryman, A and Ferguson, H. Understanding Research for Social Policy and Social Work: Themes, Methods and Approaches. Policy Press, Bristol, UK, 2012. 11. Patton, M. Qualitative evaluation and research method. 3rd ed. Sage Publications, Inc., London, 2002. 12. Al-Busaidi, ZQ. Qualitative Research and its Uses in Health Care. Sultan Qaboos Univ Med J, 2008; 8(1):11-9. 13. Thewes, B, Meiser, B, Rickard, J and Friedlander, M. The fertility- and menopause- related information needs of younger women with a diagnosis of breast cancer: a qualitative study. Psycho Oncology, 2003; 12(5):500-11. 14. Miles, MB and Huberman, AM. Qualitative data analysis: An expanded sourcebook. 2nd ed. Sage, London, 1994. 15. Moser, C. Q-squared: Qualitative and quantitative methods of poverty appraisal, In: Kanbur, R, editor. Apt illustration’ or ‘anecdotal information’. Can qualitative data be robust or representative? Washington, DC: Permanent Black. 2003. 16. Bickman, L and Rog, D. Applied research design: A practical approach. , In: Bickman, L and Rog, D, editors. Handbook of applied social research methods. Oaks, CA: Sage. 2009. pp. 3-43. 17. Denzin N and Lincoln Y. The Handbook of Qualitative Research, In: Denzin N and Lincoln Y, editors. The discipline and practice of qualitative research. 2nd ed. Sage Publications, Thousand Oaks, CA, 2000. 18. Riegelman, RK. Section I: Studing a study. Studying a Study and Testing a Test: How to Read the Medical Evidence. Philadelphia, PA: Lippincott Williams & Wilkins. 2005. 19. Thompson, S. Sampling. 3rd ed. wiley, 2012. 20. Bhattacharyya, D. Cross-Cultural Management: Text And Cases. PHI Learning Private Limited, New Delhi, 2010. 21. Berger, ML, Dreyer, N, Anderson, F, Towse, A, Sedrakyan, A and Normand, SL. Prospective observational studies to assess comparative effectiveness: the ISPOR good research practices task force report. Value Health, 2012; 15(2):217-30.

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22. Explorable.com. 2009. Quantitative and Qualitative Research. Retrieved Nov 19, 2014 from Explorable.com: https://explorable.com/quantitative-and-qualitative-research. 23. Doshani, A, Pitchforth, E, Mayne, C and Tincello, DG. The value of qualitative research in urogynaecology. BJOG, 2009; 116(1):3-6. 24. Dean, SG, Smith, JA and Payne, S. Chapter 10: Low back pain: exploring the meaning of exercise management through interpretative phenomenological analysis, In: Finlay L and Ballinger, C, editors. Qualitative Research for Allied Health professionals: Challenging Choices: John Wiley & Sons, Limited. 2006. 25. Breakwell GM, Hammond, S and FifeSchaw, C. Chapter 17: Interviewing, In: Breakwell GM, Hammond, S and FifeSchaw, C, editors. Research methods in Psychology: Sage Publications Limited. 2004. pp. 280. 26. Bryman, A. Social research methods. Chapter 5 Structured Interviewing. Oxford University Press, 2001. 27. Greg Guest, EEN, In: Guest, G and Namey, EE, editors. Public Health Research Methods. Sage, Thousand Oaks, CA, 2014. 28. Marshall, C and Rossman, G. Designing qualitative research. 2nd ed. Sage, London, 1995. 29. Rodica, MZ, Grundey, D and Stancu, A. Qualitative research methods: a comparison between focus-group and in-depth interview. . Annals of the University of Oradea, Economic Science Series, 2008; 17(4):1279-1283. 30. Marshall, MN. Sampling for qualitative research. Family Practice, 1996; 13(6):522-526. 31. Morse, JM. The Significance of Saturation. Qualitative Health Research, 1995; 5(2):147- 149. 32. Huberman, A and Miles, M. The qualitative researcher's companion. Sage Publications Inc, CA, 2002. 33. Pope, C, Ziebland, S and Mays, N. Qualitative research in health care. Analysing qualitative data. BMJ, 2000; 320(7227):114-6. 34. Krane, V, Andersen, MB and Strean, WB. Issues of qualitative research methods and presentations. . Journal of Sport and Exercise Psychology, 1997; 19(213-218). 35. Burnard, P. A method of analysing interview transcripts in qualitative research. Nurse Educ Today, 1991; 11(6):461-6. 36. Vandenbroucke, JP, von Elm, E, Altman, DG, Gotzsche, PC, Mulrow, CD, Pocock, SJ, Poole, C, Schlesselman, JJ and Egger, M. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): Explanation and elaboration. Int J Surg, 2014. 37. Yin, RK. Case Study Research: Design and Theory. Applied Social Research Methods Series, no. 5. 3rd ed. SAGE, Thousand Oaks, CA, 2003. 38. Christ, TJ. Experimental Control and threats to internal validity of concurrent and nonconcurrent multiple baseline designs Psychology in the Schools, 2007; 44(5):451-459. 39. Thewes, B, Meiser, B, Taylor, A, Phillips, K, Pendlebury, S, Capp, A, Dalley, D, Goldstein, D, Baber, R and Friedlander, M. The Fertility- and Menopause-Related Information Needs of Younger Women with a Diagnosis of Early Breast Cancer. Journal of Clinical Oncology, 2005; 23(22):5155-5165. 40. Peate, M, Meiser, B, Friedlander, M, Zorbas, H, Rovelli, S, Sansom-Daly, U, Sangster, J, Hadzi-Pavlovic, D and Hickey, M. It's now or never: fertility-related knowledge, decision-making preferences, and treatment intentions in young women with breast cancer--an Australian fertility decision aid collaborative group study. J Clin Oncol, 2011; 29(13):1670-7. 41. NHMRC and ARC. Revision of the joint NHMRC/AVCC statement and guidelines on research practice - Australian Code for the responsible conduct of research, Canberra: Commonwealth of Australia; 2007. 42. McCarthy, CR and Porter, JP. Confidentiality: the protection of personal data in epidemiological and clinical research trials. Law Med Health Care, 1991; 19(3-4):238-41.

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43. 3rd International Consultation on Incontinence - Recommendations of the International Scientific Committee : Evaluation and Treatment of Urinary Incontinence , Pelvic Organ Prolapse and Faecal Incontinence. 2005.

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CHAPTER 6

Study I: Exploring knowledge, attitudes and experience of genitourinary symptoms in women taking adjuvant endocrine therapy for early stage breast cancer

The aim of this study was to explore knowledge, attitudes and experience of genitourinary symptoms in the daily life of women receiving endocrine therapy for early breast cancer. Thirty- two in-depth interviews were conducted and qualitative content analysis was performed. Results are reported.

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6. Study I

6.1. Introduction

Research on genitourinary symptoms in women with breast cancer is sparse and has focused largely on quantitative outcomes, which means that more subtle nuances regarding individual experiences of these symptoms and the impact on women’s lives can be missed.1 Recent publications acknowledged the need of addressing this often neglected issue in a more thorough way.2, 3 Additionally, the high background incidence of genitourinary symptoms in the general population4 emphasizes the importance of increasing awareness amongst clinicians and patients that these symptoms may be amplified by endocrine therapy.

As part of this PhD research project examining genitourinary symptoms and impact on sexual function and QoL in women with breast cancer receiving adjuvant endocrine therapy, Study I sought to perform an in-depth and comprehensive investigation of women’s views about these symptoms. Specifically, this qualitative study aimed to explore women’s knowledge, attitudes and experiences of genitourinary symptoms in breast cancer patients receiving antiestrogen therapy. The study also sought to understand personal views of the impact of genitourinary symptoms on daily life, sexual activity, healthcare-seeking behaviour, and information women might have desired or received regarding genitourinary symptoms. Finally, it explored women’s preferences regarding type, source and timing of provision of information and interventions related to genitourinary concerns. It was envisaged that this study would provide insight into how important these symptoms were and would facilitate future research into strategies to help in symptom management, which could improve QoL in women prescribed long-term antiestrogen therapy.

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6.2. Method

6.2.1. Participants

Eligible participants were identified from the patient database of the Department of Medical

Oncology of two metropolitan hospitals based in Sydney’s eastern suburbs, Australia. One is a public teaching large metropolitan tertiary referral hospital that receives patients from all over the state of New South Wales and the other is a private tertiary hospital. The following inclusion criteria were used: female; diagnosed with early stage breast cancer (stages IA, IB, IIA and

IIB);5 aged 18 years and over; competent in English; and who were receiving adjuvant endocrine therapy (either TAM or an AI). Women were excluded if they had a history of genitourinary cancer; were unable to give informed consent; or were not competent in English.

Therefore, women who attended the oncology clinics of these major hospitals and who met the eligibility criteria to the study were recruited.

It was decided not to include ‘presence of at least one genitourinary symptom’ as inclusion criteria, as it might have led to the exclusion of potential participants who had not mentioned genitourinary symptoms to their oncologists. Instead, a screening question was included at the beginning of the interview guide (Appendix V): ‘Do you have any genitourinary symptoms?

(Prompt: such as burning, incontinence, urgency, or others)’. If participants answered ‘no’ to the screening question, only sociodemographic and clinical information were collected and they were thanked for their time. If participants reported any type of genitourinary symptom, the interviewer proceeded with the rest of the interview.

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6.2.2. Procedure

Patients were invited to the study by a letter sent by their treating medical oncologist. The PhD candidate had previously approached two general medical oncologists who agreed to sign the letters to be sent to their patients. Along with the introductory letter (Appendix I), a detailed information pamphlet (Appendix II), consent form (Appendix III), an opt-in response sheet

(Appendix IV) and a reply-paid envelope were sent. Respondents were then directly approached by the PhD candidate (MS) to obtain informed consent and to arrange a time for a face-to-face or telephone interview (depending on the woman’s preference). Face-to-face interviews were conducted in an interview room at the treating hospital and/or nearby teaching university.

Women who did not wish to take part in the study also had the option of returning the response sheet or leaving a message on a free-of-charge telephone number indicating their wish to decline participation.

All in-depth semi-structured interviews were audio-recorded and transcribed verbatim.

Interviews followed a topic guide developed after a review of the relevant literature and expert consultation; experts included an oncologist, urologist, psychologist, pelvic floor physiotherapist, consumer, and two gynaecologists. All participants were asked sociodemographic questions at the beginning of the interview, including items eliciting age, marital status, parity, highest level of education, employment status, occupation and language spoken at home. In addition, clinical information, such as menopause status, age at diagnosis of breast cancer, forms of surgery procedures and additional treatment undertaken for breast cancer, as well as type and length of ongoing endocrine therapy, were collected. Examples of open-ended questions included ‘Can you tell me how genitourinary problem(s) have affected your daily life?’, ‘Did you speak to a doctor about your genitourinary symptom(s)?’, ‘Tell me what you think would have been most helpful to you in dealing with your genitourinary

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problem(s)?’. Probes were used as appropriate to allow participants to expand on issues around the topic.

Interviews lasted an average of 25 minutes and were conducted between January 2013 and

January 2014. Sampling ceased once informational redundancy was achieved in each group.6, 7

Specifically, Group A (GA) was comprised of women who received an AI and reported at least one genitourinary symptom, and Group T (GT) of women who received TAM and reported at least one genitourinary symptom.

6.2.3. Ethics

Ethical approval for this study was granted by the relevant institutional ethics committee.

Written informed consent was obtained from all participants prior to data collection.

6.2.4. Analysis

Data analysis was informed by the conceptual qualitative framework of Huberman and Miles.8

A preliminary coding tree was developed through independent coding of a random sample of transcripts by the PhD candidate and one supervisor (MP). Coding discrepancies were resolved through discussion and the coding tree was refined before each transcript was fully coded line- by-line by the PhD candidate using a qualitative analysis software package (NVivo 10).

Descriptive statistics were used to explore quantitative data (sociodemographic and clinical characteristics) using IMB SPSS 21.0 (IBM Corp., Armonk, NY).

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Throughout this Chapter quotations are denoted according to the type of endocrine therapy undertaken by participants (i.e. their group; GA = AI; GT = TAM) and menopausal status at diagnosis (Pre= premenopausal, Post= postmenopausal), followed by their unique identifier.

6.3. Results

6.3.1. Sample

A total of 67 letters of invitation were sent (Figure 6.1). Twenty-two women did not respond. Of the 45 responders, 11 declined participation, one could not be contacted for interview, one was ineligible to participate (due to discontinuation of endocrine therapy), and 32 opted for either a telephone (n=23) or face-to-face (n=9) interview. Out of the 32 women interviewed, 13 (41%) reported no genitourinary concerns (five on TAM and eight on AIs) only sociodemographic and clinical information were collected. The other 19 women (59%) who fulfilled the study criteria and reported experiencing at least one genitourinary symptom completed the interview (GA=11 and GT=8). The sociodemographic and clinical characteristics of all women are shown by group in Table 6.1. The average age of GA was 66 years (range=56-77), and that of the GT, 52 years

(range=42-67). Nearly half (47%) of these women were married or partnered, and the average time in that relationship was 34 years. The majority of women (68%) were postmenopausal at the time of diagnosis and the average time since menopause was 11 years. Almost 70% had children (average two vaginal births). The average time since diagnosis of breast cancer was three years and participants had been taking endocrine treatment for an average of 26 months.

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Figure 6.1. Flowchart detailing recruitment

Invited n=67 Excluded n=35  Declined n=11  Did not respond n=22  Ineligible n=1  Uncontactable n=1 Interviewed n=32 Telephone n=23 Face-to-face n=9

Reported at least Reported NO one genitourinary genitourinary symptom n=19 symptoms n=13

GA (AI) GT (TAM) n=11 n=8

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Table 6.1. Sociodemographic and clinical characteristics of sample (N=32)

Variable Reported at least one Reported no genitourinary symptom genitourinary Total symptoms GA (n=11) GT (n=8) (n=13) (N=32) Mean ± SD Mean ± SD Mean ± SD Mean ± SD or n (%) or n (%) or n (%) or n (%) Age, year 66.4 ± 5.5 51.9 ± 8.7 54 ± 10.6 57.7 ± 10.6

Children Yes 9 (82) 4 (50) 12 (92) 25 (78) No 2 (18) 4 (50) 1 (8) 7 (22) Parity, children 1.9 ± 1.3 2.3 ± 1.3 1.9 ± 1.0 2.0 ± 1.1 Marital Status Not partnered 6 (54) 4 (50) 3 (23) 13 (41) Partnered 5 (46) 4 (50) 10 (77) 19 (59) Length of time in a relationshipa 46.0 ± 4.2 19.8 ± 12.0 24.5 ± 12.2 29.1 ± 14.6 (years) Highest Education No post-school qualification 5 (45) 5 (62) 9 (69) 19 (60) Post-school qualification 6 (55) 3 (38) 4 (31) 13 (40) Employment Status Full-time/ Part-time 3 (27) 5 (63) 8 (62) 16 (50) Retired/Unemployed/Homemaker 8 (73) 3 (37) 5 (38) 16 (50) Age at diagnosis of breast cancer 63.5 ± 5.9 48.7 ± 8.5 50.6 ± 9.5 54.6 ± 10.3 (years) Menopausal status at the time of interview Premenopausal 0 (0) 1 (13) 2 (15) 3 (9) Postmenopausal 11 (100) 7 (87) 11 (85) 29 (91) Menopausal status at diagnosis Premenopausal 1 (9) 5 (62) 6 (46) 12 (37) Postmenopausal 10 (91) 3 (38) 7 (54) 20 (63) Time since menopause (years) 11.4 ± 6.4 6.9 ± 13.5 8.2± 7.8 10.2 ± 7.0 Duration of endocrine therapy use 26.6 ± 23.1 24.0 ± 19.1 27.8 ± 19.1 26.5 ± 19.9 (months) Additional treatment Radiation therapy 9(82) 6(75) 11(85) 26(81) 0 (0) 1(13) 1(8) 2(6) Oophorectomy 0 (0) 0 (0) 1(8) 1(3) aIf married or partnered

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6.3.2. Understanding the experiences of genitourinary symptoms

In the interviews, women were encouraged to talk about their experience of, and attitudes regarding genitourinary symptoms. Participants acknowledged and described their genitourinary problems, their beliefs about their causes, the impact of symptoms on their daily routine and on relationships and sexual function, and any action taken to help manage symptoms.

Reporting of genitourinary symptoms

Across GA and GT, involuntary leakage (GA=8, GT=6) and urgency (GA=7, GT=6) were the most frequently mentioned symptoms. Other symptoms reported included urinary frequency

(GA=2, GT=5), nocturia (GA=5, GT=2), recurrent urinary tract infection (UTI) (GA=2, GT=2), genital prolapse (GA=3, GT=1), burning (GA=1, GT=2), discomfort/soreness (GT=2), overactive bladder (GT=1) and dyspareunia (GA=1). Table 6.2 provides a summary of the reported genitourinary problems with quotations as exemplars of how women described their experiences.

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Table 6.2. Summary of the participants’ reported genitourinary problems

Genitourinary Quotation problems Frequency “I go very often to the toilet.” [GA,Post,011] “I do tend to go to the bathroom quite often.” [GT,Pre,05] “I would say almost like every half hour I might feel the need that I have to go to the bathroom.” [GT,Pre,02] Urgency “…it’s a bit urgent for me.” [GA,Post,013] “I do get a bit of urgency.” [GA,Post,015] “When I want to go [to the toilet], I want to go all of a sudden.” [GA,Post,019] “I seriously have to go to the toilet. The minute that I feel that I have to go to the toilet, I can’t hold it […] I need the toilet.” [GT,Pre,04] Incontinence/ “I think it is incontinence […] if I’m not close to a bathroom, I’m leakage/ dripping usually going to have a leak.”[GT,Pre,01] “It’s incontinence […] I can just start to randomly leak I don’t know what’s going to happen.” [GA,Pre,09] “I have dripping.” [GA,Post,017] “I sometimes wet myself a little bit.” [GA,Post,010] “…it was very irritating the leakage.” [GT,Post,06] Urinary tract “I would go years without getting a urinary tract infection whereas infection now I probably get, maybe two or three a year.” [GT,Post,07] “I have urinary tract infections.” [GA,Post,016] Burning “Only very rarely burning sensation.” [GA,Post,014] Overactive bladder “I think it’s called overactive bladder, where I keep going to the toilet all the time.” [GT,Pre,03] Discomfort/ soreness “I thought I was very sore […] as soon as I started taking tamoxifen, the first week, it was sore [down there], it was uncomfortable.” [GT,Post,08] Prolapse “And I had the word prolapse coming to my mind.” [GA,Post,014] “I just think my bladder has dropped.” [GA,Post,012]

Nocturia “I go to the toilet a lot more during the night, now, I wake up at least twice.” [GT,Pre,04] “I might get up at one o’clock, I might get up at three o’clock, five o’clock.” [GA,Post,012] Dyspareunia “…no matter how much lubrication I use for intercourse, […] I have unbelievable pain now with penetration.” [GA,Post,018]

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Identification of the cause and attitudes towards genitourinary symptoms

Although many women were not sure about the specific cause of their genitourinary symptoms, the majority associated the onset or worsening of symptoms with their breast cancer treatment, particularly commencement of adjuvant endocrine therapy (Table with quotes provided in

Appendix VI). One participant, who was told by her oncologist about the possibility of extending endocrine therapy to ten years duration, suggested: “you take me off tamoxifen”

[GT,Post,07] as the most helpful thing in dealing with her genitourinary problems. Another, who was experiencing urgency, incontinence and nocturia, was hopeful that: “as soon as I get off the

Arimidex, these [symptoms] will stop.”[GA,Post,019]. Noticeably, the perceived association with cancer therapy underpinned a very accepting attitude towards symptoms, i.e. symptoms were normalised and seen as something that women had “to get on with”, so that “the cancer doesn’t come back”. In this context, women often minimised, accepted or disregarded altogether the physical and social restriction that resulted from genitourinary symptoms while weighing up the benefits of cancer therapy.

“I first had a problem with my bladder when I had the cycle of Femara […]

it all happened around the time of my cancer treatment and it’s still

happening. […] But I don’t want to stop […] the medicine my specialist

wants me to have, unless it’s really bad and he can change it, but they all are

going to have problems so if that’s the worst thing, you know, I have, ‘cause

it works for me.” [GA,Pre,09].

“…the doctors put me on this [medication] for a good reason and I'm going

to give it the best shot.[…] So if I have any symptoms with it or problems

with it, I will put up with them in order to maintain the long-term effect that

these drugs are going to give me.” [GA,Post,018]

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Ageing and menopause were mentioned as further reasons for changes in their genitourinary health with some participants specifically pinpointing the abrupt onset of “medically-induced early menopause” and “lack of oestrogen” as the underlying causes of their symptoms. Once again, these causal attributions were not an important precursor to worry or act upon.

“I think it’s got something to do with the ‘mini’ menopause […] it just affects

everything. […] I am in a medically-induced early menopause, it must have

something to do with that ‘old’ thing.” [GT,Pre,01]

“I think, with the lack of oestrogen, I was really sensitive to oestrogen and

[…] I got cancer and I, then I went onto the treatment which blocks

oestrogen […] and, you know, it really has dried me up quite significantly,

you know, I have to have lubricants, yeah.” [GT,Post,07]

Impact of symptoms on daily life

Participants also discussed wide-ranging impacts of genitourinary symptoms on their lives, indicating the profound ramifications symptoms had on their ability to engage in daily tasks and interactions. For instance, urinary urgency disrupted normal daily functioning, as it required frequent access to a bathroom. This in turn, discouraged normal social interactions leading to a lack of confidence in their ability to go out for long periods of time, or perform routine tasks such as shopping and exercising.

“I can’t hold on to even get to a public toilet or a bathroom, it’s horrible,

sometimes I can be in a shop and I can just start to randomly leak.”

[GA,Pre,09]

“…a little bit to worry to going out and thinking ‘oh, you know, am I going

to find toilets in unfamiliar places?’” [GA,Post,014] 157

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Similarly, it impacted on women’s confidence to work efficiently.

“It was horrible at work actually, I had one horrible boss and she saw me

leaving the office too many times and so she was being like a bully and then I

said ‘well I have bladder problems, how can I come to work?’” [GA,Pre,09]

Nocturia leading to sleep disturbance had implications during the day as participants described being tired.

“Well it was waking me up every two hours to go to the toilet, I was

exhausted.” [GA,Post,019]

Having these genitourinary problems caused feelings of anxiety, distress and worry.

Additionally, respondents expressed their embarrassment of leaking in public or going to the toilet more often and in more of a rush than other people.

“Look, I don’t like it. I’ve become really quite anxious, if I am not near a

known bathroom. I feel embarrassed, especially if I do leak, yeah. And even

when I go to sleep I just sometimes worry that I’m going to have an accident

in bed, and I have had one or two.” [GT,Pre,01]

Impact of symptoms on sexual function

Two women reported leakage occurring during intercourse and another two, who reported not being sexually active, felt that genitourinary symptoms would not affect sexual function.

“No, I don’t have a sexual relationship at the moment, I don’t think it would

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Only one woman complained of painful intercourse as limiting sexual activity. Women more often described decrease or lack of sexual intimacy being related to concerns with body image as well as the breast cancer diagnosis itself, including its treatment as opposed to genitourinary problems.

“Absolutely, for me, ever since the chemo, the cancer, no sexual intimacy at

all.” [GA,Post,015]

“I couldn’t stand to look at my body and […] somehow all of these things

come together and they make up for a situation where sex doesn’t become

important any longer.” [GA,Post,018]

6.3.3. Help-seeking behaviour

Motivations for seeking help

In total, nine women had discussed their current genitourinary concerns with their general practitioner (GP) (GA=5, GT=4) who then referred them to a gynaecologist (n=3) and/or a urogynaecologist (n=2). Only two participants who had seen the GP also saw their oncologist regarding genitourinary problems, with one woman being referred to a menopause clinic by her oncologist. Another woman mentioned that besides her GP, she also saw a continence nurse advisor. These low rates of help-seeking behaviour reflected women’s hesitancy to seek assistance, and were also expressed in the interviews. The reported obstacles and motivators to seeking help are presented in Appendix VII.

Women’s assessments about whether symptoms were important enough to act on, seemed to be closely associated with participants’ normative thinking, rapport with healthcare professional

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and perceived nature and duration of the presenting symptoms. An important motivator factor to seek help for genitourinary symptoms was the fear that such symptoms might be associated with a recurrence of cancer. For example, such concern prompted some women who were experiencing incontinence to see their GP for a referral.

“There is the possibility that this symptom could be related to cancer. First

of all I would want to set aside any issue, you know, that there could be

something worse […] Is the first thing to look at.” [GA,Post,014]

“…to get checked, make sure there was nothing else that might’ve been

another cancer or something, ‘cause I just want to make sure I don’t have

another cancer.” [GA,Pre,09]

Participants also reported on the importance of the doctor-patient relationship, and that they found it easier to talk to a female doctor.

“Because she is a lady, and she is very nice doctor and loves me and

explains to me everything and she has patience, she is not in a hurry you

know, to see me.” [GA,Post,011]

Obstacles to seeking help

More than half of the participants (n=10) did not contact or see a healthcare professional about their genitourinary symptoms. Reasons for not doing so included the feeling that genitourinary concerns were of relatively little importance, when compared with breast cancer concerns.

“Absolutely, not a big, not a big issue, it’s nothing to compare to the other

things that I’m dealing with.” [GA,Post,015]

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The perception that symptoms were not sufficiently bothersome or “nothing sort of bad enough” to prompt a consultation was another important obstacle articulated as inhibiting to help-seeking. Findings suggest that acknowledgement and acceptance of the presence of a problem were not always straightforward.

“I don’t find that there is a symptom, the urgency, no it doesn’t, because I

don’t soak myself.” [GA,Post,017]

Additional obstacles were uncertainty about the causes and triggers, and in particular, the “lack of information” about available treatment options for genitourinary concerns. For instance, a number of respondents assumed that surgical procedures were the only available treatment to address genitourinary problems.

“… and are there, are there treatments?[…] Really?[…] What happens

then? Is there a surgery? […] I haven’t done anything simply because as I

said, I didn’t have any information. It should be available.” [GA,Post,017]

“…having some urologist deciding that I need a bladder surgery or

something? Because like, I don’t know if I would want to have any more

surgeries, I mean, certainly not at the moment […] and that’s what I think

would happen.” [GA,Post,018]

Another woman had the impression her genitourinary problems could not be solved because she would still be on endocrine therapy for breast cancer for a while.

“If I can do an operation, I don’t want to do it because I’m still going to be

taking the tablet [Femara]” [GA,Pre,09]

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Some women were reluctant to seek help due to a desire to avoid further medical appointments based on previous negative experiences with the healthcare system or appointment overload from their breast cancer treatment and follow-up.

“I tell myself ‘why are you going to the doctors?’ I don’t want to see any

more doctors, you know, I am sick of the doctors.” [GA,Post,011]

“It’s waiting in hospitals, waiting to get help in some way, I think that’s one

of the reasons […] I don’t feel myself sitting in waiting rooms like, you know,

because that’s how the situation now is, just wait, and sit in waiting rooms

for ages” [GA,Post,013]

Financial burden was also noted, with appointment fees and treatment expenses identified as strong motivators for delaying help-seeking.

“…you hardly ever find a gynaecologist who isn’t going to charge you.[…]

plus there’s a lot of people that can’t afford it […] I’ve got no money these

days. I put a lot of money for my reconstruction and it’s really set me back a

lot, you know” [GA,Post,013]

“The cost and the issue around taking antibiotics and the cost of consultation

and prescription potentially must be quite high if this is just a side effect of

taking, of being on this medication” [GT,Post,06]

Moreover, differences in attitudes to disclosure about personal matters also prevented women from seeking advice.

“I guess it is very personal. Not easy for a lot of people to discuss.”

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[GA,Post,015]

There was also evidence that genitourinary symptoms caused women embarrassment. When asked to identify the specific obstacles that potentially discouraged them from seeking treatment, comments such as: “Well I guess it’s the embarrassing thing” [GT,Pre,03] were often mentioned. Indeed, many of the women revealed the desire to seek treatment in a confidential setting to ensure privacy and avoid potential embarrassment.

“Always confidential, I live with forty-five other women but I don’t tell them,

you know, no one knows that I have this problem.” [GA,Post,016]

Help-seeking behaviour for sexual concerns

Most women with a partner had not mentioned any sexual issues to anyone, including their healthcare provider. Only two women claimed they would have or had openly discussed their sexual problems with their partners. Women were uncertain who to talk to regarding these sexual concerns as well as experiencing embarrassment about the topic. Nonetheless, a number of participants expressed a desire for support and/or treatment for sexual concerns.

“Nobody looks at the whole person they don’t ask you how all of this impact

in your sex life, and your self-esteem and everything else and I said ‘inside I

am dead’. […] Really, I’ve got to say that there is a terrible hole out there in

the post-cancer treatment. […] Nobody asks you these questions for a start.

So if people don’t even ask you or come anywhere close to the topic […] I

know that the majority of people probably even couldn’t get to that point so

they would never even dare to ask, they don’t even ask, they don’t seek, they

just suffer in silence.” [GA,Post,018]

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6.3.4. Treatment received and appraisal

Less than half (n=9) of the women interviewed had accessed treatment (including over-the- counter products and treatment offered by health professionals), and most of these women had experienced management as ineffective. Five women reported doing pelvic floor exercises intermittently (mostly because of being forgetful), without any noticeable effect on their symptoms.

“They gave me the little machine to put inside to make your muscles work […]

but it didn’t really work much, I mean, I forget to, I know there’s exercises and

I just forget about it, you know.” [GA,Post,010]

Six respondents reported using either dietary supplements such as “cranberry juice” and probiotics, or medications including transdermal patches for overactive bladder, antibiotics and anticholinergic drugs. Similarly, most did not notice any improvements or they experienced bothersome side effects and eventually discontinued therapy.

“He started me on the patches and that wasn’t doing anything and he started

me on a tablet, yeah, I haven’t taken them because I won’t, well I took them

for a while, but […] the only thing they made me dry in the mouth and yeah,

not where I wanted to be dry.” [GA,Post,012]

Typically, women thought a meaningful treatment outcome would be a significant (70-100%) improvement in their symptoms, but had more modest expectations of treatment in reality.

“Yes, I guess it’s not going to be fair eighty percent […] That’s too high, it’s

ambitious.” [GT,Pre,03]

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Overall, participants’ expectations about treatment outcomes could be grouped into five key domains, which are represented on Table 6.3.

Table 6.3. Summary of participants’ treatment expectations regarding genitourinary symptoms

Key domains of expectations of treatment Quotation outcome

‘I don’t care, as long as it is not something “…as long as I knew I didn’t have cancer I serious like cancer’ wouldn’t, I wouldn’t care.” [GA,Pre,09]

‘I don’t think I can be helped at all’ “I don’t know if anything is going to help me that’s all.” [GA,Post,010]

‘To be completely cured’ “Yeah, so I only want that fixed up […] yes, cured.” [GA,Post,012]

“Yeah, I just hope it to go away […] Cured, yes, yes.” [GT,Post,07]

‘To prevent new symptoms or worsening “I guess that they don’t get any worse.” of the ones already installed’ [GA,Post,015]

“To prevent new symptoms […] that would be good.” [GA,Post,016]

‘To improve symptoms and/or functioning “…to relieve my symptoms would be possible […] (including symptom relief and improve whatever is wrong with me.”[GA,Post,013] enhancement of ability to engage in routine activities and well-being)’ “That I wouldn’t need to, no longer need to wear a pad, yeah. A bit more confidence in going for walks and exercising without having to worry, yes.” [GT,Pre,05]

“I would love it if I don’t leak and I would love it if I don’t, if I can hold myself.” [GT,Pre,01]

“I guess not to have to have the urge so much to go, and hopefully when I go only a little bit comes out and it’s not like a lot, I would like to be more normal, or on the normal range sort of thing.” [GT,Pre,03]

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6.3.5. Information needs and preferences

Unmet needs

The majority of women reported difficulties in accessing information about genitourinary symptoms as part of their breast cancer treatment.

“Well maybe, a little bit of more information of what’s going to happen,

could happen, from the oncologist, you know. I’ve been just kind of

discovering it myself, you know what I mean.” [GT,Post,07]

Most women reported not having received advice that was actively offered by their healthcare providers. Instead, they indicated having sought information on genitourinary symptoms from multiple sources, including libraries, internet, or by prompting for information during consultations.

“Well I only got it [information] because I went to the doctor.” [GA,Pos,09]

One woman pointed out that she felt apprehensive about the credibility of information acquired through self-initiated efforts (e.g., searches on the internet) and would value information received from her treating doctor more.

“I just decided not to look anything more up because I don’t know who’s the

author of a lot of these like, I prefer, I’ve got good doctors and I prefer

[information from] them, like.” [GA,Pre,09]

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It was also apparent that when women actively sought assistance, clinicians were not always helpful. Some women described receiving limited information, clinicians being dismissive of their concerns and sometimes the lack of a physical examination or consistent monitoring of symptoms was voiced by participants. A woman who received prescription for antibiotics noted:

“He didn’t examine me or anything, he took my word.” [GA,Post,016]

Another participant who was experiencing dyspareunia stressed:

“I mentioned it [‘I have unbelievable pain with penetration’] to one of my

oncology associated people with my treatment […] because that aspect of

our lives was very important to the two of us and so I mentioned that and the

answer was ‘if intercourse is a problem there’re other ways of pleasuring

each other’. I think it was a very patronising comment and it wasn’t really

helping me at all in dealing with the most problem that I have.”

[GA,Post,018]

Overall, the importance of communication about the potential side effects of cancer treatment, including genitourinary symptoms emerged as common themes in women’s responses. Most women wanted to be told about the possibility of genitourinary symptoms before going on the medication.

“I think the primary thing is to advise women or have a lot more information

out there of what can be a side effect caused of being on […] endocrine

based therapy, it’s very popular for women to be on that now for an extended

length of time. But really, more information based on the women and more

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very little opportunity to talk to people and a lot of the issues are very

shaming so it is really important to offer them that chance.” [GT,Post,06]

“I think it should be openly discussed by a treater, like the GP, or the, you

know, the breast care nurse, or the oncologist, or breast surgeon […] it

should be told so we don’t feel, ‘hold on a second what’s happening in

here?’. It’s just to be made aware of, and then maybe say ‘look, ok it will all

happen […] expect this but maybe if you do this, it could help you’.”

[GT,Pre,01]

Finally, one woman believed that clinicians should have a checklist to prompt discussion of genitourinary and other symptoms during follow-up visits and encourage patients to report symptoms.

“I don’t think I heard any [information regarding genitourinary symptoms],

so, yes, I guess […] some sort of a checklist, well I think one should […]

probably have a regular check-up so I think yes, it’s good to have some

questions ready isn’t it?” [GA,Post,014]

Preferred source of information

Health professionals

Most women considered information provided by either their GP or specialist by far the most important and valued source of information (n=17). This was related to a number of factors, including respect for healthcare providers’ clinical expertise and good rapport.

“I think when I go and see my local GP […] I’ve known this fella for many

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years so I can talk to him about anything.” [GA,Post,013]

“Maybe the gynaecologist, ‘cause it in his area.” [GT,Pre,03]

Written source

Women also acknowledged that their health professionals might not be their only source of information. A majority of women (n=16) also indicated a preference for printed information such as a brief leaflet or booklet provided with their medication or by the health professional.

“Yes, it could just be a handout, for me it would be fine if he hand it out and

say, look you need to be aware of this, you got to take care of stuff like that.”

[GT,Post,07]

“Of urination? They could’ve given some kind of brochure or something

about it, when they send you to take the tablet, I think, I think just the

pamphlets, and if you have anything you ask your doctor.” [GT,Pre,03]

On the other hand one participant stated that written sources may not reach all women:

“I think that not many people take time to read fact sheets and things like

that, I’m talking really about people in my age group, my generation group,

the baby boomers’ age group, you know, I mean, I don’t think they should go

bother reading fact sheets and things like that.” [GA,Post,013]

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Further, some women (n=7) felt that web-based resources provided greater accessibility and would enable them to gain a better understanding of their symptoms; but then again, they also discussed concerns about the accuracy of health information acquired via the internet.

“I think a lot of people would like an online resource to use.” [GT,Pre,01]

“…but sometimes you don’t know the right website to go to.” [GA,Post,014]

Group talks

A minority of women (n=4) indicated they “didn’t mind” group talks as a means to gather information on genitourinary concerns. However, five women indicated this would not be of real value to them, particularly, based on previous experience from breast cancer support groups.

“One of the problems with talks is that a lot of people think they will go,

think about going but they don’t end up going […] so it’s not as successful as

a mean to reaching people really is it? The professionals love it; people who

are a bit professional like going to talks, talk goers.” [GA,Post,014]

Publicity in mainstream media

Two participants recognised that publicity in the media increased awareness about symptoms; however, women felt it did not prompt them to ask for medical support. On the contrary, participants believed that media publicity may strengthen breast cancer patients’ beliefs that genitourinary disorders are a widespread problem among older/menopausal women, and hence patients may feel it would not be appropriate to seek medical support.

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“I must admit since the ad has been on the television, you know, it’s a, like

bladder leakage, I really do think that that has… well personally has made a

difference. Because I think that’s one of the reasons why I haven’t sought

treatment as well. Because I seem to think well, it is a common problem

amongst women perhaps getting to a certain age so, yes.” [GT,Pre,05]

Preferred amount of information and timing of its delivery

Although most women wanted “as much [information] as possible”, there was some variation in terms of the amount of information desired and the timing of its delivery, as illustrated below.

“So when you get cancer you know, you just start to wonder and probably

after a year or something, then it would be a good time to someone to talk to

you about ‘oh this could happen, or this could happen’, or something […]

because you don’t take much, you just think, ‘am I going to live?’ you know,

or ‘am I going to die?’ you know. And you have to deal with all the emotion

of people and everything, you just […] but after a year everything is kind of

back underneath normal hopefully.” [GT,Post,07]

“I would like a one a very simple, very relatively small information piece to

advise people, you know, what the symptoms may be or may not be,

sometimes they develop as a result of being on aromatase inhibitors and I

would like them to, I would yeah. And then more of what you should do about

it.” [GT,Post,06]

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6.4. Discussion

This is the first study to qualitatively explore understanding of genitourinary symptoms and associated impact on daily life, and sexual functioning in women with early breast cancer receiving adjuvant endocrine therapy. Although there were similarities between the experiences described by women with breast cancer in this study and those of healthy women reported in the literature, distinct attitudes and concerns that appear to be unique to breast cancer survivors were also observed. Our findings support existing evidence that genitourinary symptoms impact on personal, social and physical activities,9 are often attributed to anxiety and stress,10 and a source of embarrassment,11 consequently impairing daily activities.12 It was also apparent that women with breast cancer minimised genitourinary symptoms and perceived that their symptoms were a ‘normal’ part of aging or menopause.13-15 Even health professionals seemed casual in their approach to these symptoms based on the patient reports. Most women appeared resigned to “put up with” symptoms, because others, including their clinicians, seemed to accept them as ‘normal’.16-18 These results suggest that there needs to be a shift in perspective and this can only occur if genitourinary symptoms are recognised as an important issue that needs to be addressed, rather than accepting them as the norm.

This study also highlights the relatively little attention the women in this study give to genitourinary concerns (even if negatively impacting on everyday life) compared to their fears and concerns about breast cancer spread and recurrence. The potential benefit of adjuvant endocrine therapy and their desire to continue on the prescribed treatment were the main reason for accepting and tolerating symptoms. This finding is consistent with the findings of other studies and the attitudes of women with breast cancer about other treatment-related side effects

(e.g. fatigue, cognitive disturbance, pain).19, 20

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An important finding was the limited access to information related to genitourinary symptoms/side effects that was made available or communicated to women during their breast cancer treatment. This led to misconceptions about the symptoms and most women had not attempted to seek any help. Many women in this study felt that their treating clinicians had not fully informed them about the potential impact of adjuvant endocrine therapy on their genitourinary tract, consistent with previous research.3 Some researchers have identified that a lack of knowledge or awareness of treatment options,13 may affect help-seeking for genitourinary concerns, which was supported by findings in this study. Additionally, participants believed that the availability of information materials that address the potential adverse effects of therapy and potential treatment options should be improved.

Most women preferred brief and to-the-point paper-based resources alongside information obtained directly from healthcare professionals. Some breast cancer survivors appeared less confident to actively search for information and regarded information received from GPs or oncologists to be a more reliable and acceptable form of communication.21 Even so, breast cancer survivors also felt that genitourinary symptoms are a very common problem and they should be warned that this may occur at some point and have a healthcare professional inquire about symptoms during their breast cancer follow-up visits. This suggestion implied that the onus to initiate the discussion around potential genitourinary symptoms related to endocrine therapy should be on the clinician. Educating clinicians, especially GPs and oncologists about the factors associated with help-seeking as well as the available treatment options may make it more likely that survivors receive timely information and care for genitourinary symptoms.

Further work should investigate whether symptom checklists and/or patient prompt sheets are successful strategy in promoting breast cancer patient-doctor communication about genitourinary symptoms.

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6.5. Conclusion

Genitourinary symptoms have a negative impact on daily life, underscoring the importance of increasing awareness regarding this issue among healthcare professionals caring for women with breast cancer (especially GPs and oncologists). Additionally, findings clearly indicate that these women require information regarding the potential effect of endocrine therapy on genitourinary tract and potential interventions or treatment options for genitourinary symptoms.

Increased knowledge of genitourinary problems may reduce women’s concerns and may facilitate timely help-seeking and result in improved well-being. Further research on perceived breast cancer patient and physician barriers to the discussion of genitourinary problems would also be of use. These findings will assist in the design and conduct of future studies exploring genitourinary symptoms and associated impact on daily life and sexual function in breast cancer survivors receiving endocrine therapy.

6.6. Study strengths and limitations

Consistent with qualitative designs, this study aimed for maximum variation and not numerical representation. This approach allows for a more explorative assessment of viewpoints and motivations, but the study findings may not be representative of the general breast cancer population as all the participants in this study were recruited from two oncologist’s practices at two major tertiary hospitals in a large city (Sydney). Moreover, by not using genitourinary symptoms as criteria for eligibility this study was able to identify a gap in patient-clinician communication of these symptoms as most women in the study were experiencing symptoms but had not discussed it with clinicians. Future larger quantitative studies may be of use in verifying the informational needs and preferences of these women, determining the factors influencing women’s help-seeking behaviour as well as identifying associations between daily life impairment and seeking further treatment.

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6.7. References

1. Doshani, A, Pitchforth, E, Mayne, C and Tincello, DG. The value of qualitative research in urogynaecology. BJOG, 2009; 116(1):3-6. 2. Niravath P, Rimawi MF and CK., O. Aromatase inhibitor adverse effects: are we sweeping them under the rug? J Clin Oncol, 2014; 32(33):3779. 3. Lester, JL and Bernhard, La. Urogenital atrophy in breast cancer survivors. Oncology nursing forum, 2009; 36(6):693-8. 4. Portman, DJ and Gass, ML. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society. Menopause, 2014; 21(10):1063-8. 5. American Joint Committee on Cancer (AJCC). Breast Cancer Staging, In: Edge SB, Byrd DR, Compton CC and et al, editors. Cancer Staging Manual New York: Springer-Verlag. 2010. pp. 347-77. 6. Marshall, MN. Sampling for qualitative research. Family Practice, 1996; 13(6):522-526. 7. Morse, JM. The Significance of Saturation. Qualitative Health Research, 1995; 5(2):147- 149. 8. Huberman, A and Miles, M. The qualitative researcher's companion. Sage Publications Inc, CA, 2002. 9. DeMaagd, GA and Davenport, TC. Management of Urinary Incontinence. P t, 2012; 37(6):345-361h. 10. Coyne, KS, Wein, AJ, Tubaro, A, Sexton, CC, Thompson, CL, Kopp, ZS and Aiyer, LP. The burden of lower urinary tract symptoms: evaluating the effect of LUTS on health- related quality of life, anxiety and depression: EpiLUTS. BJU Int, 2009; 103 Suppl 3:4- 11. 11. Goldstein, I, Dicks, B, Kim, NN and Hartzell, R. Multidisciplinary overview of vaginal atrophy and associated genitourinary symptoms in postmenopausal women. Sex Med, 2013; 1(2):44-53. 12. Papanicolaou, S, Hunskaar, S, Lose, G and Sykes, D. Assessment of bothersomeness and impact on quality of life of urinary incontinence in women in France, Germany, Spain and the UK. BJU Int, 2005; 96(6):831-8. 13. Shaw, C, Tansey, R, Jackson, C, Hyde, C and Allan, R. Barriers to help seeking in people with urinary symptoms. Fam Pract, 2001; 18(1):48-52. 14. Shaw, C, Brittain, K, Tansey, R and Williams, K. How people decide to seek health care: a qualitative study. International journal of nursing studies, 2008; 45:1516-24. 15. Bush, TA, Castellucci, DT and Phillips, C. Exploring women's beliefs regarding urinary incontinence. Urol Nurs, 2001; 21(3):211-8. 16. Skoner, MM and Haylor, MJ. Managing incontinence: women's normalizing strategies. Health Care Women Int, 1993; 14(6):549-60. 17. Fu, MR, Xu, B, Liu, Y and Haber, J. 'Making the best of it': Chinese women's experiences of adjusting to breast cancer diagnosis and treatment. J Adv Nurs, 2008; 63(2):155-65. 18. Cowley, L, Heyman, B, Stanton, M and Milner, SJ. How women receiving adjuvant chemotherapy for breast cancer cope with their treatment: a risk management perspective. J Adv Nurs, 2000; 31(2):314-21. 19. Binkley, JM, Harris, SR, Levangie, PK, Pearl, M, Guglielmino, J, Kraus, V and Rowden, D. Patient perspectives on breast cancer treatment side effects and the prospective surveillance model for physical rehabilitation for women with breast cancer. Cancer, 2012; 118(8 Suppl):2207-16. 20. Rosedale, M and Fu, MR. Confronting the unexpected: temporal, situational, and attributive dimensions of distressing symptom experience for breast cancer survivors. Oncol Nurs Forum, 2010; 37(1):E28-33.

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21. Perera, J, Kirthinanda, DS, Wijeratne, S and Wickramarachchi, TK. Descriptive cross sectional study on prevalence, perceptions, predisposing factors and health seeking behaviour of women with stress urinary incontinence. BMC Womens Health, 2014; 14:78.

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Study II: PEGASUS - Prevalence and severity of genitourinary symptoms and impact on sexual function and quality of life in postmenopausal women receiving adjuvant endocrine therapy for early breast cancer

The focus of this research study was to document the prevalence and severity of genitourinary symptoms in postmenopausal women who were to begin adjuvant endocrine therapy and the trajectory over time. Additional study goals were to determine the relationships between these symptoms and sexual function and QoL, and to identify baseline factors, which predict subsequent development or progression of severe symptoms. This research was conducted with the goal to use findings to inform clinical practice and facilitate greater efforts for the early recognition and appropriate management of significant genitourinary symptoms as a result of adjuvant endocrine therapy.

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7. Study II

Why PEGASUS?

Pegasus the original symbol, creative spirit and power of the Muses of Greek mythology brought inspiration and beauty to the lives of all he encountered and is an appropriate acronym for a study attempting to improve quality of life in women with early breast cancer.

7.1. Introduction

It has been extensively discussed throughout this thesis the recognised direct association between low estrogen levels and atrophy of the genitourinary tract,1 which can result in genitourinary symptoms and contribute to sexual dysfunction and impaired QoL in postmenopausal women.2 That there are relatively few comprehensive studies specifically addressing the impact of genitourinary adverse effects of adjuvant endocrine therapy in postmenopausal women with early breast cancer has also been discussed, limiting our understanding of the incidence and severity of genitourinary symptoms in these women.

Therefore, there is a strong case for more focused research, using validated and sensitive instruments, to document the frequency and severity of genitourinary symptoms in breast cancer patients on adjuvant endocrine therapies and to identify which patients are most at risk of developing significant symptoms, particularly as early intervention may improve symptoms.

7.2. Aims and hypotheses

Specific Aims

(i) To prospectively investigate the prevalence and severity of genitourinary symptoms in postmenopausal women receiving adjuvant endocrine therapy for early breast cancer.

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(ii) To determine whether there is an association between genitourinary symptoms, and sexual dysfunction and the overall impact of symptoms on QoL.

(iii) To identify baseline factors which predict for the subsequent development of severe genitourinary symptoms, and to identify subgroup of women at high risk of developing severe symptoms.

(iv) To compare and contrast the prevalence and severity of genitourinary symptoms in patients receiving TAM or AIs.

Hypotheses

(i) Compared to baseline (prior to any adjuvant endocrine therapy), the prevalence and severity of genitourinary problems will increase over time (at six-month, one-year and two-year follow- up time points) in postmenopausal women with breast cancer on adjuvant endocrine therapy.

(ii) Women with pre-existing genitourinary symptoms at baseline will be more likely to experience worsening in their symptoms.

(iii) There will be deterioration in symptoms-related QoL over time in women who develop significant genitourinary symptoms.

(iv) There will be a decline in sexual function amongst women experiencing genitourinary symptoms.

(v) Women who develop significant genitourinary symptoms are more likely to have other side- effects associated with endocrine therapy.

(vi) Compared to TAM, women taking AIs will have more severe genitourinary symptoms.

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(vi) Women who develop significant genitourinary symptoms will be more likely to cease treatment or switch from an AI to TAM.

7.3. Methods

7.3.1. Participant selection and recruitment

Inclusion Criteria

Eligible participants for this study included postmenopausala women at diagnosis, aged 75 years or younger, who had been diagnosed with hormone-receptor positive early breast cancer,b were scheduled to start adjuvant endocrine therapy (TAM or AI), and were able to read, write and understand English. Women were eligible regardless of which breast cancer treatment modalities they had (e.g. surgery, chemotherapy, radiotherapy) prior to commencing endocrine therapy.

Exclusion Criteria

Women were excluded from the study if they were currently receiving HRTc (including vaginal estrogen), had been diagnosed with locally recurrent cancer or metastatic disease, and were not fluent in English (as study participation involved the completion of self-administered questionnaires).

a Postmenopausal status defined as 12 months of amenorrhea after the last bleeding event. b Early stage refers to invasive breast cancer confined to the breast that corresponds to stages IA, IB, IIA and IIB.3 c Women who had taken HRT must had stopped therapy for at least one month prior to study entry. However, participants were not asked to stop their standard care, and this was a discussion between patient and clinician.

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Number of centres

Potential participants were identified and recruited from 17 sites across Australia: Prince of

Wales Hospital, Westmead Hospital, St. George Hospital, Wollongong Hospital, Royal North

Shore Hospital, St Vincent's Clinics, The Mater, Royal Prince Alfred Hospital, Prince of Wales

Private Hospital, Nepean Hospital, Calvary Mater Newcastle Hospital, Newcastle Private

Hospital, The Breast and Endocrine Centre at Gateshead, Sydney Adventist Hospital and

Campbelltown Hospital in New South Wales (NSW), and Box Hill Hospital and Maroondah

Hospital in Victoria (VIC).

Study process

Women were screened for eligibility and invited into the study at participating oncology clinics.

Eligible women were approached initially and briefly introduced to the study by breast care nurses (BCNs) or by their treating oncologists (medical oncologists, surgeons, radiation oncologists, etc.). The BCNs and oncologists checked that the woman fulfilled the eligibility criteria using a checklist on the Recruitment Sheet (Appendix VIII) and asked eligible women if they would be interested in participating in the study using a Recruitment Process and a

Recruitment Script (Appendices IX and X, respectively). The name and contact details of women who had provided preliminary verbal consent to be contacted about the study were noted in the Recruitment Sheet, which was faxed to the PhD student. Recruiting BCNs and oncologists also had the option to complete a fax sheet recording the reason eligible women declined.

Upon receipt of the recruitment sheet, the PhD student sent to each eligible woman a Letter of

Invitation (Appendix XI), Consent Form (Appendix XII), Participant Information Pamphlet

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(Appendix XIII) and baseline Questionnaire (Appendix XIV). The Participant Information

Pamphlet provided details about the purpose of the research, the time commitment involved, how the data would be stored, how the results would be disseminated and the possible risks and benefits of participation. Additionally, each woman was telephoned by the PhD student who addressed any questions women had about the study. Women who declined the BCNs’ or oncologists’ invitation to participate were not contacted by the student.

Women who agreed to be involved in the study were asked to sign the Consent Form and to complete self-administered questionnaires prior to the commencement of endocrine therapy

(Q1), and at six months (Q2), one year (Q3) and two years (Q4) after baseline (Appendix XV).

Participants who had not returned the questionnaires within two weeks were given a reminder call. A follow-up protocol for non-returned questionnaires was established, and included three phone calls at different times of the day. If phone contact could not be made, a replacement questionnaire was sent.

Confidentiality and privacy were emphasised. When participants were invited to the study, it was explained that the decision to participate or not to participate would not impact on their medical care in any way, and that they could withdraw from the study at any time without affecting their current or future relationship with their treating clinicians or the treating hospital.

This information was also stated in the Participant Information Pamphlet and Consent Form.

Contact details for the PhD student and relevant ethics committees were provided to address any questions or concerns participants may have had.

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7.3.2 Ethics

Ethical approval for this study was granted by the relevant institutional ethics committees.

Written informed consent was obtained from all participants prior to data collection.

7.3.3. Measures

The following measures were included in patient questionnaires:

(1) Demographic and clinical information

At baseline, data were collected on age, marital status and length of relationship, parity, method of childbirth, education, employment status, and time since menopause. Women were also asked to provide information regarding time since diagnosis of breast cancer and details of their adjuvant treatment (i.e., chemotherapy, radiotherapy and type of surgery). Information on height, alcohol use, smoking status, comorbidities and previous pelvic surgery was also collected. Additionally, at each follow-up time point, information on participant’s weight, current endocrine therapy being taken, previous medication received (if they switched treatment), use of antidepressants/ or any medication for urogynaecological conditions and compliance with endocrine therapy was also sought.

(2) Urinary symptoms and impact of symptoms on QoL

The International Consultation on Incontinence Questionnaire on Female Lower Urinary Tract

Symptoms (ICIQ-FLUTS)4-6 long form is a valid and reliable questionnaire based on the

BFLUTS7 and was used to assess the occurrence and severity of a large range of lower urinary

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tract symptoms and how bothersome the symptoms were to respondents. The questionnaire was highly recommended (Grade A) by the Second International Consultation on incontinence.8 The

18-item scale assesses key dimensions of urinary symptoms and is divided into three subscales evaluating urinary incontinence (ICIQ-FLUTS-IS – six-item, IS1 to IS6, score 0-24), storage or filling symptoms (ICIQ-FLUTS-FS – four-item, FS1 to FS4, score 0-16), and voiding symptoms (ICIQ-FLUTS-VS –eight-item, VS1-VS8, score 0-29). Responses range from

“never” to “all of the time”, “no problem” to “serious problem”, and zero to four with four representing the most severe symptoms. A total score is calculated by summing the three subscale scores and ranges from zero (no symptoms) to 69 (severe symptoms) with higher scores indicating greater severity of symptoms. Each item is followed by a question about the perceived impact of individual symptoms, assessed on a Likert-type 11-category scale (0-10), with total score ranging from zero (not bothered) to 150 (bothered a great deal). Bothered scores are not incorporated in the overall urinary symptoms score. Additionally, the impact of urinary symptoms on a woman’s QoL, was evaluated using the ICIQ-LUTSqol.4 This validated questionnaire is based on the King’s Health Questionnaire8 and is designed to evaluate various dimensions of urinary symptom-related QoL. A total score is calculated by summing the scores of the 19-items, and scores range from 19 to 76 with greater values indicating increased impact on QoL. Each item is followed by a question about perceived bother (i.e. “How much does this bother you?”), which is not incorporated in the overall score but indicates impact of individual symptoms for the patient – zero (not bothered), 200 (bothered a great deal).

(3) Vaginal symptoms, associated sexual symptoms and impact on QoL

To assess the presence and severity of vaginal symptoms (including dryness, soreness, prolapse, etc.) and the degree of bother caused by such symptoms, as well as associated sexual matters and impact on QoL, the International Consultation on Incontinence Questionnaire on Vaginal

Symptoms (ICIQ-VS)9 was used. The ICIQ-VS is a 14-item, psychometrically robust self- 185

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administered questionnaire recommended by the Third International Consultation on

Incontinence.10 It is scored by a three or four tailed scale ranging from zero to 53 for vaginal symptoms score, zero to 58 for sexual matters associated with vaginal symptoms score and zero to 10 for symptom-related impact on QoL. Worsening of vaginal or sexual symptoms and QoL is accompanied by an increase in the scores. Each item on the vaginal and sexual matter scales is linked to a question about perceived bother, which is based on a Likert-type scale ranging from zero to 10 with 10 indicating the greatest bother.

(4) Sexual function

Sexual function was evaluated separately using the Pelvic Organ Prolapse/Urinary

Incontinence Sexual Questionnaire (PISQ-12)11 short form. The PISQ-12 is a validated questionnaire that evaluates sexual function in women with genitourinary symptoms. A total of

12 items are separated into a behavioural-emotive domain, a physical domain and a partner related domain. Questions are answered on a scale of 0=“never”/ 1=“seldom”/ 2=“sometimes”/

3=“usually”/ 4=“always and total scores range from zero (severe symptoms) to 48 (no symptoms), i.e. higher scores reflecting better sexual functioning.12 Participants were asked whether they had a current sexual partner and whether they had engaged in sexual activity in the last month. The questionnaire clearly stated that this measure covered material that was sensitive and personal, reassuring participants that their responses would be kept strictly confidential and that questions were optional.

(5) Dyspareunia

Pain intensity was evaluated using Visual Analogue Scale (VAS) Pain Assessment of

Dyspareunia (VAS-DYSPAR).13 VASs were initially devised as measures of well-being,14 have

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been successfully adapted to measure the degree of pain15 and, more specifically, pain during intercourse.16 This technique involves use of an 11 point scale representing a continuum of the person's perception of the degree of pain experienced where 0=“no pain at all" and 10="pain as intense as you could imagine". A two-point difference on the VAS indicates clinically significant alleviation/deterioration of pain symptoms.

(6) Endocrine symptoms

Subjective endocrine-related symptoms were assessed by using the validated 18-item

Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES)17, 18 subscale, developed for breast cancer research. It has a five-point response scale ranging from zero to four

(0=“not at all”/ 1=“a little bit”/ 2=“somewhat”/ 3=“quite a bit”/ 4=“very much”). Scores range from zero to 72 with high scores indicating fewer endocrine symptoms. The ES subscale has good face and content validity, internal consistency (α= 0.79), test-retest reliability (r=0.93) and is sensitive to clinically significant change.18

(7) General QoL

General QoL was measured using the EQ-5D19 a short generic health-related QoL instrument that consists of a self-classifier and a Visual Analogue Scale (EQ-VAS). The self-classifier comprises five items relating to problems in the following domains: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each domain has three levels, namely, "no problems", "some problems" and "severe problems". Combinations of these domains define a total of 243 health states. For each health state a utility score can be deducted, called the EQ-5D

Index score.20 These EQ-5D Index scores may vary between -0.59 (worst health) and 1.00

(perfect health). On the EQ-VAS respondents can indicate their overall self-perceived health

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state on a scale ranging from zero to 100, where zero is equivalent to the worst imaginable health state and 100 is equivalent to the best imaginable health state. A substantial and growing body of literature regarding the usefulness of the EQ-5D in cancer has emerged, supporting its validity and reliability.20, 21

7.3.4. Statistical analysis

Sample size

Sample size was calculated to detect a relatively small change in the mean genitourinary symptoms score (ICIQ-FLUTS) between postmenopausal women taking TAM and those taking

AIs as adjuvant endocrine therapy for breast cancer. There is no established minimal important difference for the outcome variable of interest; however, previous studies have used ½ standard deviation (SD) of the mean baseline measurement.22 Gopal et al. showed that the difference in the mean ICIQ-FLUTS-IS score was about 2.66 with a SD of 2.81.22 Therefore, it was determined that 110 women on AI and 44 women on TAM would be needed for a two-sided alpha error of 0.05 and a power 80% (using SD=2.81) to detect a difference of ½ standard deviation in mean ICIQ-FLUTS-IS. Allowing for dropout rate of 25% and discontinuation of endocrine therapy during the two-year follow-up period, it was envisaged that this study needed to recruit a total of 280 women.

It was estimated that about 75% of participants (n=210) would receive an AI as their initial treatment while the other 25% (n=70) would receive TAM upfront. Up to 30% of those receiving an AI (n=63) and 15% of those on TAM (n=11) were expected to discontinue their treatment (e.g., due to side effects), leaving about 147 and 59 women on continuous AI and

TAM, therapy, respectively. After allowing for 25% dropout at two years, it was anticipated that

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110 women who have been on AIs continuously and 44 who have been on TAM continuously would complete the two-year follow-up and would be included in the main analysis.

Data analysis

It is important to note that recruitment for the study started in May 2013 and is still ongoing.

The numbers included in the current analysis corresponded to the figures at the end of June

2015. It is expected that recruitment for this study will be completed by end of 2015 and final analysis (including data from all four time points) will be performed in early 2018. Given recruitment and in order to be reasonably powered to show group difference between TAM and

AIs, only data on women who completed Q1 (baseline) and Q2 (six-month follow-up) and who were on either continuous TAM or AI were included in the current analysis.

Descriptive statistics and frequency distributions were generated for the sample demographic and clinical characteristics and symptom severity scores. Baseline differences between characteristics of women who were assigned to TAM and those who were assigned to an AI were assessed using Chi-square test (Fisher’s exact probability test where the sample size was small) for categorical variables, or independent Mann-Whitney U test for continuous variables

(these were based on data distribution). Variables for which there were significant (p<0.05) differences were entered as cofounders in subsequent group comparisons.

Primary outcome:

Presence of symptoms and symptom severity at baseline and follow-up were compared using

McNemar’s test (for categorical variables) and Wilcoxon signed-rank test (for continuous

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variables). Since no cut-off values have been established in published reports, the ICIQ-FLUTS scale scores and the ICIQ-VS score were analysed as both continuous and categorical measures

(as appropriate).22 Subscale score changes have been shown to be more sensitive than a single combined score for urinary symptoms (i.e. overall ICIQ-FLUTS score).22 Hence, for this analysis the focus was on the subscale scores (cumulative summary score of all questions in a particular subscale) specifically, the mean scores of ICIQ-FLUTS-IS, ICIQ-FLUTS-FS and

ICIQ-FLUTS-VS. It was defined a meaningful difference in ICIQ-FLUTS subscale scores as a change of ½ SD23 that corresponded to a difference in severity of one level on a single question in the questionnaire.22 Additionally, for categorical/binary comparisons, a score different than zero in each ICIQ-FLUTS/ ICIQ-VS item was considered as positive for having the symptom

(variables coded as “no symptom”=0, “presence of symptom”=1).24 Finally, to provide useful clinical information regarding treatment side-effects, it was determined by the working party

(PhD candidate, an oncologist, a reproductive endocrinologist and a behavioural scientist) and level worthy of clinical intervention that a score greater than two for each of the 18 items of the

ICIQ-FLUTS and the eight items of the ICIQ-VS (i.e. “sometimes”/”most of the time”/ “all of the time”; “day-time voiding ≥9-10 times”; “night-time voiding ≥2 times”; “leakages occurring

≥2-3 times per week”; “dribble”/ “pant wet”/ “floods”; “quite reduced”/”reduced a great deal”/

“no stream”) were labelled clinically significant; therefore, was dichotomised into “clinically significant”=1/ “not clinically significant”=0.24, 25 Similarly, specific items on vaginal symptoms in the FACT-ES were also dichotomised into clinically significant if they scored three or four

(corresponding to “quite a bit” or very much” a problem, respectively).26

Bivariate associations between the outcome variables (i.e. dichotomised variables of symptoms severity as indicated by women’s responses on the ICIQ-FLUTS and ICIQ-VS at six-month time point) and possible risk factors related to severe genitourinary symptoms (including known risk factors for genitourinary symptoms such as age, BMI, parity, use of antidepressants, 190

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smoking, comorbidities and prior pelvic surgery, etc.) at baseline were examined in univariate regression. Risk factors associated with the outcome with a univariate p<0.20 were included in the multivariate model.22 After controlling for baseline scores on the outcome measures (i.e.

ICIQ-FLUTS and ICIQ-VS) and treatment modalities (i.e. TAM vs AIs), multiple logistic regression modelling was conducted to examine variability in symptom severity accounted for by risk factors and p<0.05 was considered to represent statistical significance. Separate models were tested for severity of each parameter of urinary symptoms (voiding, storage and incontinence) and vaginal symptoms. A progressive, backward elimination modelling strategy was employed until a final model was obtained containing only variables with p<0.05 (predictor variables). Odds ratio and the 95% confidence interval (CI) could then be ascertained for each factor that remained in the model.

Secondary outcome:

For the analyses of differences between groups, change scores from baseline to the six-month follow-up assessment (calculated for ICIQ-FLUTS and its subscale scores and ICIQ-VS) were used. All analyses comparing AI with TAM were tested at the two-sided 95% significance level.

In addition, differences in symptom-related QoL and sexual scores were assessed using Mann

Whitney U test for comparison between groups and Wilcoxon Signed Ranks test for baseline and six months follow-up data comparison. For categorical items, differences were assessed using Chi-square analyses (McNemar’s test) between baseline and six month follow-up data.

Finally, univariate multilevel logistic regression analysis for repeated measures was performed to identify variables influencing both symptoms-related QoL and sexual function.

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Data were analysed using IMB SPSS 22.0 (Statistical Program for the Social Sciences, version

22.0; Armonk, NY: IBM Corp.).

7.4. Results

7.4.1 Sample characteristics

To date, of the 301 women invited to participate in the study (Figure 7.1), six (2%) declined participation when invited by BCN/oncologists, 50 (17%) either declined participation after being contacted by the PhD student or did not return completed baseline questionnaire (Q1), and one woman (0.3%) was ineligible (peri-menopausal). A total of 244 women (81%) completed and returned Q1 and were enrolled in the study. Over the six-month follow-up period 187 participants completed and returned Q2. One hundred and thirty-eight (74%) participants were receiving an AI and 39 (21%) were on TAM, eight (4%) switched classes of their antiestrogen medication [i.e. TAM→AI (n=1) and AI→TAM (n=7)] and two (1%) discontinued endocrine therapy because of intolerable side effects (not specified whether genitourinary or other) and subsequently withdrew from the study; these women (i.e. those who were not on continuous

TAM or AIs) were excluded from the main analysis. Allocation of women to receive TAM or an AI was determined by the treating oncologists as per standard clinical care (i.e. this study is not a randomized trial). One hundred and eighty four participants (75%) requested a summary of study findings at the end of the study.

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Figure. 7.1. Flowchart detailing recruitment

Enrolment Assessed for eligibility (n=301)

Excluded (n=57)  Not meeting inclusion criteria (n=1)  Declined to participate after contact by BCNs or oncologists (n=6)  Declined to participate after contact by PhD student/ non-respondents (n=50)

Completed Q1 (n=244) Baseline

Completed Q2 (n=187) Follow-up

 Switched ET=8  Discontinued ET=2

Analysis AI=138 TAM=39

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The baseline sociodemographic and clinical characteristics of the study cohort are displayed in

Table 7.1. The mean age at enrolment was 63 years, the majority of participants (73%) were partnered, had children (86%), were on average 14 years postmenopausal, and had a mean BMI of 28 Kg/m2. In regards to the treatment received for breast cancer, 37% had mastectomy, 41% had chemotherapy and 62% had radiotherapy. Participants were comparable regarding sociodemographic and clinical characteristics at baseline. There were no significant differences between treatment groups (TAM vs AIs) in terms of age, parity, marital status, comorbidities, years from menopause, smoking status, previous history of pelvic surgery, and mean BMI.

There were, however, significant group differences in the length of time (in months) since diagnosis of breast cancer (4.4±2.4 AI vs 3.1±2.0 TAM, p=0.001) and treatment with chemotherapy (48% AI vs 18% TAM, p=0.002). These variables were included as covariates in subsequent group comparisons. There were no other systematic differences in the characteristics among the groups.

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Table 7.1. Sociodemographic and clinical characteristics of the sample at baseline

Characteristic AI (n=138) TAM (n=39) p-value† % (n) % (n) Age (mean±SD) 62.8±6.5 62.5± 7.7 0.797 Marital Status 0.446 Married/partnered 71.7 (99) 79.5 (31) Single/separated/divorced/widowed 28.3 (39) 20.5 (8) Relationship duration (years) (mean±SD)a 32.8±12.7 33.7±13.3 0.796 Parity (mean±SD) a 2.2±1.1 2.3±1.3 0.963 Method of childbirtha 0.500 Normal/spontaneous 90.9 (110) 86.7 (26) Caesarean 9.1 (11) 13.3 (4) Highest Educationa 0.523 No post-school qualification 33.8 (46) 41.0 (16) Post-school qualification 66.2 (90) 59.0 (23) Employment Status 0.278 Workingb 42.0 (58) 30.8 (12) Not workingc 58.0 (80) 69.2 (27) Time since menopause (years) (mean±SD) a 14.0±9.1 14.2±8.2 0.548 Smoking 5.1 (7) 7.7 (3) 0.461 Alcohol 0.541 Drink everyday 18.8 (26) 23.1 (9) Drink occasionally 65.9 (91) 56.4 (22) Never 15.2 (21) 20.5 (8) Body mass index, Kg/m2 (mean±SD) a 27.7±6.0 26.8±6.5 0.222 <25 39.1 (52) 59.0 (23) 0.132 25-29 33.8 (45) 17.9 (7) 30-34 14.3 (19) 10.3 (4) ≥35 12.8 (17) 12.8 (5) Comorbidities 0.602 None 55.1 (76) 48.7 (19) ≥ 1 44.9 (62) 51.3(20) History of pelvic surgery 44.9 (62) 41.0 (16) 0.802 Taking antidepressants 13.3 (18) 23.1 (9) 0.141 Diagnosis of breast cancer(months) (mean±SD)a 4.4±2.4 3.1±2.0 0.001 Surgery (breast cancer) 0.142 Lumpectomy 59.9 (82) 74.4 (29) Unilateral/Bilateral mastectomy 40.1 (55) 25.6 (10) Chemotherapy 47.8 (66) 17.9 (7) 0.002 Radiotherapy 59.4 (82) 69.2 (27) 0.355 AI, aromatase inhibitors; TAM, tamoxifen; SD, standard deviation. aPercentages reported according to number who responded to the specific question. bInclude all participants who were full-time, part-time or self- employed. cInclude all participants who were unemployed, retired, unable to work, student or homemaker. †Significance tested with Chi-squared test and Mann-Whitney U-test, significant values are bold.

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7.4.2. Genitourinary Symptoms

Prevalence and severity

The frequency of genitourinary symptoms varied widely across the full range of symptoms and over time at baseline (prior to endocrine therapy) and after six months (Table 7.2). There was a significant increase in the prevalence of any incontinence (76% vs 82%, p=0.023), voiding

(69% vs 78%, p=0.001) and vaginal symptoms (68% vs 77%, p=0.006) reported by participants over time. Specifically, across 11 of the 29 symptoms assessed (38%) there was an increase in symptom frequency six months into endocrine therapy: intermittent urinary stream (i.e. stopping and starting more than once while urinating) (36% vs 46%, p=0.012), reduced strength of urinary stream (23% vs 31%, p=0.034), feeling of incomplete empty after urinating (33% vs

41%, p=0.041), passing urine seven times or more during the day (i.e. increased frequency)

(32% vs 41%, p=0.026) and having a sudden need to rush to the toilet (i.e. urgency) (64% vs

71%, p=0.043) were reported significantly more often at six months compared to baseline.

Similarly, participants reported having significantly more vaginal dryness (55% vs 63%, p=0.020), discharge (11% vs 18%, p=0.036), itching (15% vs 24%, p=0.024), reduced sensation or feeling in or around the vagina (24% vs 33%, p=0.017), and being more aware of a dragging pain in lower abdomen (11% vs 22%, p=0.001) and of a lump or bulge coming down in the vagina (11% vs 17%, p=0.006).

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Table 7.2. Prevalence of urinary and vaginal symptoms (N=177)

Baseline % (n) 6-month % (n) p-value† Urinary symptoms (ICIQ-FLUTS) Incontinence symptoms Urge UI 59.3 (105) 65.0 (115) NS Frequency of incontinence 54.0 (95) 58.2 (103) NS Stress UI 64.8 (114) 68.2 (120) NS Unexplained UI 13.1 (23) 8.5 (15) NS Amount of leakage 54.5 (96) 56.5 (100) NS Nocturnal enuresis 6.8 (12) 10.8 (19) NS Any incontinence symptom* 75.6 (133) 82.3 (144) 0.023

Voiding symptoms Hesitancy 18.2 (32) 23.7 (42) NS Strain to start 7.4 (13) 12.5 (22) NS Intermittent stream 35.8 (63) 45.5 (80) 0.012 Reduced strength of stream 22.7 (40) 30.7 (54) 0.034 Urinary retention 0.6 (1) 0.6 (1) NS Burning sensation 14.1 (25) 18.2 (32) NS Feeling of incomplete empty 33.3 (59) 40.9 (72) 0.041 Difficulty with stopping the flow 33.3 (59) 38.1 (67) NS Any voiding symptom* 68.8 (121) 77.8 (137) 0.001

Storage symptoms Frequency (≥7) 32.2 (57) 41.2 (73) 0.026 Nocturia (≥1) 84.7 (150) 84.2 (149) NS Urgency 63.8 (113) 70.6 (125) 0.043 Bladder pain 11.4 (20) 11.3 (20) NS Any storage symptom* 92.6 (163) 92.1 (163) NS

Vaginal symptoms (ICIQ-VS) Dragging pain in lower abdomen 11.3 (20) 22.2 (39) 0.001 Vaginal soreness 18.6 (33) 25.1 (44) NS Reduced sensation or feeling in or 24.4 (43) 33.1 (58) 0.017 around vagina Vagina too loose 19.9 (35) 22.9 (40) NS Lump or bulge felt inside 11.3 (20) 17.1 (30) 0.006 Lump of bulge seen outside 7.9 (14) 8.7 (15) NS Vaginal dryness 55.1 (97) 63.2 (110) 0.020 Digital bowel empting 6.2 (11) 9.1 (16) NS Any vaginal symptom* 68.2 (120) 76.6 (131) 0.006

Vaginal symptoms (FACT-ES) Vaginal discharge 11.0 (19) 17.9 (31) 0.036 Vaginal itching 15.1 (26) 23.6 (41) 0.024 Vaginal bleeding 2.3 (4) 3.4 (6) NS ICIQ-FLUTS, International Consultation on Incontinence Questionnaire female lower urinary symptoms, UI, urinary incontinence, NS, not significant, ICIQ-VS, International Consultation on Incontinence Questionnaire vaginal symptoms, FACT-ES, Functional Assessment of Cancer Therapy-Endocrine Scale. †Significance tested with McNemar’s test, significant values are bold.*Any meaning at least one symptom to up to all symptoms in the scale.

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Additionally, the results of changes in genitourinary symptoms indicate that there was a trend in deterioration in symptom levels (or degree of severity) over time (Figure 7.2). Increased severity was seen across 18 of the 29 symptoms assessed (62%). Participants reported significantly more severe urinary frequency (Z=-2.835, p=0.005), urge incontinence (Z=-2.893, p=0.004) and stress UI (Z=-3.012, p=0.003), with 16% reporting passing urine at least nine times a day, 10% reporting leakage when exercising, coughing or sneezing and 15% reporting a sudden need to rush to the toilet occurring between one to two thirds of the time at six months compared to 10%, 5% and 8% at baseline, respectively. Similarly, most of the vaginal symptoms significantly increased in severity over time with vaginal dryness (Z=-3.293, p=0.001), dragging pain in their lower abdomen (Z=-3.671, p<0.001), noticing a lump or bulge coming down in vagina (Z=-3.109, p=0.002), digital bowel empting (Z=-2.183, p=0.029) being most frequently reported as occurring most of the time to all of the time at six months compared to baseline reports.

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Figure 7.2. Frequency and degree of severity of urinary and vaginal symptoms at baseline (1) and six months (2); Significance tested with Wilcoxon Signed Ranks Test; Scales: ICIQ-FLUTS, ICIQ-VS and FACT-ES; (N=177)

90 85 80

75 .003 .010 70 .004 .001 65 60 55 50 .001 .003 .005 45 .042 40 .001 35 .026 30 .011 <.001 .017 .040 25 .002 .006 20 .028 15 .029 10 5 0

Most of the time/ all the time/reduced a great deal/no stream/can't stop/a lot/ freq day=11 or more/ freq night=3 or more Sometimes/quite reduced/with difficulty/somewhat/ freq day=9-10/ freq night=2 Occasionally/a little/ freq day=7-8/ freq night=1

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Overall, the parameter for vaginal and urinary symptoms each showed a significant worsening

(p<0.001) with increased scores at six months compared to baseline (shown in Figure 7.3 as mean total score as measured by ICIQ-VS and ICIQ-FLUTS, respectively). Equally, every subdomain in the urinary symptoms scale also revealed significant worsening of scores over time, i.e. voiding, storage and incontinence symptoms (p<0.001, p=0.003 and p=0.035, respectively).

Figures 7.3. Radar chart showing urinary incontinence (ICIQ-FLUTS-IS), voiding (ICIQ-

FLUTS-VS) and storage symptoms (ICIQ-FLUTS-FS) scores, and total urinary (ICIQ-

FLUTS) and vaginal symptoms (ICIQ-VS) scores at baseline and six months (N=177).

Numbers indicate scores.

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Clinically significant symptoms

Exploratory analysis of dichotomized ICIQ-FLUTS, ICIQ-VS and FACT-ES items classified as clinically significant symptoms (or not), suggested some differences between the two time points (Fig 7.4). Clinically significant stress UI was increased in frequency from baseline to six months (13% vs 21%, p=0.011). Similarly, feeling of incomplete emptying (5% vs 11%, p=0.041), and increased urinary frequency (10% vs 16%, p=0.027) were both significantly more frequent at six months. Regarding vaginal symptoms, clinically significant reduced sensation in or around the vagina (4% vs 12%, p=0.013), vaginal discharge (2% vs 6%, p=0.039), vaginal dryness (19% vs 27%, p=0.016) and noticing a “lump or bulge coming down in the vagina” (6% vs13%, p=0.006) were more frequently reported at six-month follow-up compared to baseline. Regression for exploratory demographic and clinical variables yielded no statistically significant results for the abovementioned symptoms, except for higher BMI, which was associated with a higher risk of clinically significant stress UI (B=0.073, SE=0.029,

Wald=6.39, OR=1.08, 95%CI [1.02, 1.14], p=0.011).

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Figure 7.4. Prevalence (%) and severity of clinically significant incontinence (score of 2 or greater on the item), voiding and storage symptoms and vaginal symptoms at baseline (1) and six months (2); p-value (McNemar’s test 2) differences between the two time points.

Vaginal symptoms (ICIQ-VS)

Vaginal dryness p=.016

Vaginal itching

Vaginal discharge p=.039

Lump felt inside vagina p=.006

Reduced sensation in or around vagina p=.013

Vaginal soreness

Storage symptoms (ICIQ-FLUT-FS) Urgency

Nocturia

Voiding symptoms (ICIQ-FLUTS-VS) 6 months Frequency p=.027 Baseline Ability to stop the flow

Feeling of incomplete empty

Intermitancy p=.013

Strain to start

Incontinence symptoms (ICIQ-FLUTS-IS) Hesitancy

Noctural enuresis

Urge UI

Stress UI p=.011

0 10 20 30 40 50

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Predictors of greater severity of genitourinary symptoms

Sociodemographic and clinical factors potentially associated with severe storage, voiding, incontinence and vaginal symptoms were analysed in univariate and multivariate logistic regressions. Controlling for baseline symptoms and treatment modalities, factors that predicted a greater increase in severity of genitourinary symptoms at six-month follow-up are described below.

Storage (filling) symptoms

Significant association between some demographic and clinical characteristics and severe storage symptoms were found. Smoking (B=1.59, OR= 4.97, 95%CI [1.01, 23.80], p=0.048), and presence of at least one chronic disease (B=0.60, OR= 1.82, 95%CI [1.00, 3.32], p=0.049) were both identified in univariate analysis. Similarly, greater voiding symptoms and incontinence symptoms at baseline were also associated with higher odds of storage symptoms at follow-up (B=0.22, OR=1.3, 95% CI [1.06, 1.48], p=0.007 and B=0.10, OR=1.1, 95% CI

[1.01, 1.23], p=0.038), respectively. In multivariate regression, however, no participant characteristics remained significant predictors of severity of storage symptoms.

Voiding symptoms

In univariate analysis, increased parity (B=0.34OR=1.42 95%CI [1.04, 1.92], p=0.026), having had spontaneous or vaginal deliveries (B=1.10, OR=3.00 95%CI [0.91, 9.90], p=0.071), being married (B=0.63, OR=1.88 95%CI [0.94, 3.73], p=0.073), higher BMI (B=0.05, OR=1.056

95%CI [1.00, 1.11], p=0.038) and longer time from menopause (B=0.02, OR=1.02 95%CI

[0.99, 1.06], p=0.19) were associated with severe voiding symptoms. Participants reporting lost interest in sex were more likely to also report severe voiding symptoms (B=0.61, OR=1.84

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95%CI [1.01, 3.37], p=0.046). Similarly, pre-existing incontinence symptoms (at baseline) was also associated with a higher risk of voiding symptoms at follow-up, with the odds of 6.86

(B=1.92, 95% CI [2.84, 16.52], p<0.001). However, in multiple regression only parity (B=0.42,

OR=1.53, 95%CI [1.07, 2.19], p=0.021), being married (B=1.08, OR=2.96, 95%CI [1.15, 7.60], p=0.024), and existing incontinence symptoms (B=1.51, OR=4.55, 95%CI [1.60, 13.28], p=0.006) at baseline presented significant higher odds for severe voiding symptoms.

Incontinence symptoms

Severe incontinence symptoms were associated with having children (B=0.73, OR=2.08 95%CI

[0.738, 5.86], p=0.166) and higher BMI (B=0.07, OR=1.07, 95%CI [1.02, 1.13], p=0.009) in univariate analysis. Participants reporting feeling bloated at baseline (B=0.61, OR=1.86 95%CI

[0.80, 4.29], p=0.148) were also more likely to also report severe incontinence symptoms. In multivariate analysis only one characteristic, BMI, remained significant. Participants with higher BMI were more likely to present with severe incontinence symptoms (B=0.05, OR=1.10,

95%CI, [1.00, 1.12], p=0.040).

Vaginal symptoms

Severe vaginal symptoms were associated with the following independent characteristics: marital status (B=1.26, OR =3.56, 95%CI [1.59, 7.96], p=0.002), use of antidepressant (B=0.60,

OR=1.84, 95%CI [0.80, 4.19], p=0.15), and mastectomy (B=0.66, OR=0.51, 95%CI [0.27,

0.99], p=0.046). The risk of experiencing severe vaginal symptoms was also higher in those experiencing vaginal dryness at baseline (assessed by FACT-ES) (B=2.01, OR=7.4, 95%CI

[3.11, 17.93], p<0.001). Correspondingly, worse overall endocrine symptoms were significantly associated with severe vaginal symptoms (B=0.12, OR=0.88, 95%CI, [0.84, 0.93], p<0.001). In

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multivariable analysis, the variables that remained significant were presenting vaginal dryness

(assessed by FACT-ES) at baseline (B=1.42, OR=4.17, 95%CI, [1.64, 10.61], p=0.003) and marital status (B=0.92, OR=2.53, 95%CI, [1.01, 6.35], p=0.049), which translated to a four-fold and three-fold increase in risk of severe vaginal symptoms, respectively.

Bother associated with genitourinary symptoms

Following most items on the ICIQ-FLUTS and ICIQ-VS scales is a question asking participants to rate how bothered they are about the reported genitourinary symptom. Overall, significant increases in being bothered (Table 7.3) and severity of genitourinary symptoms were seen over time, with almost 60% of participants being bothered by their vaginal symptoms at six months compared to 53% at baseline (p<0.0001). Additionally, at follow-up, 77% of participants reported being bothered by their urinary symptoms versus 74% at baseline (p=0.004), with 60% being bothered by storage symptoms (p=0.006), 42% by voiding symptoms (p=0.002) and 69% by incontinence symptoms (p=0.039) at six months compared to 58%, 38% and 63% at baseline, respectively.

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Table 7.3. Frequency (%) and mean scores of bother associated with genitourinary symptoms at baseline and six-month follow-up.

N % Mean (SD) p‡

Bother associated with Baseline 131 74.4 11.68 (16.71) 0.004 urinary symptoms 6-mo 135 77.1 15.45 (20.32)

Bother associated with Baseline 111 63.1 5.85 (9.27) 0.039 incontinence symptoms 6-mo 120 68.6 6.84 (9.20)

Bother associated with Baseline 66 37.5 2.29 (4.93) 0.002 voiding symptoms 6-mo 74 42.0 3.90 (8.54)

Bother associated with Baseline 102 58.0 3.52 (5.55) 0.006 storage symptoms 6-mo 106 59.9 4.75 (6.76)

Bother associated with Baseline 94 53.4 3.94 (7.16) <0.001 vaginal symptoms 6-mo 102 59.6 6.91 (11.85) Scales: ICIQ-FLTUTS, ICIQ-FLTUTS-IS, ICIQ-FLTUTS-VS, ICIQ-FLTUTS-FS, ICIQ-VS ‡Significance tested using Wilcoxon Signed Ranks Test, significant results are bold.

The factors influencing bother associated with genitourinary symptoms were assessed using regression with the independent significant variables associated with bother by symptoms

(Table 7.4). In univariate analysis, partnered/married was independent significant predictor of being bothered by storage (B=0.49, p=0.152) and vaginal symptoms (B=1.03, p=0.004). While presenting at least one chronic disease was associated with bother relating to storage (B=0.76, p=0.016) and incontinence symptoms (B=0.48, p=0.147). Having children was associated with bother relating to incontinence (B=1.21, p=0.006), storage (B=1.14, p=0.011) and vaginal

(B=1.09, p=0.021) symptoms. Obesity (p=0.200) and longer period from menopause (B=0.025, p=0.175) were both associated with bother relating to storage symptoms whereas having post- school qualifications was associated with bother relating to voiding symptoms (B=0.48, p=0.141).

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Multivariate logistic regression revealed significant association between bother relating to storage symptoms and presence of at least one comorbidity (B=0.72, p=0.025) and having children (B=1.41, p=0.017). Bother relating to incontinence symptoms was only substantially associated with having children (B=1.20, p=0.007). While bother relating to vaginal symptoms was significantly associated with being married/partnered (B=1.07, p=0.003) in the final model.

None of the characteristics were significantly associated with voiding symptoms in the final model. In summary, participants who were married/partnered had a three-fold higher odds of being bothered by vaginal symptoms, those who had children also had a three-fold higher odds of being bothered by incontinence and storage symptoms, while participants with at least one chronic disease had double the odds of being bothered by storage symptoms (Table 7.4).

Table 7.4. Univariate and multivariate regression of influencing factors of bothered by genitourinary symptoms.

Storage Incontinence Voiding Vaginal symptoms symptoms symptoms symptoms Characteristics OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI) Univariate Married/partnered 1.64 [0.84, 3.21] NA NA 2.81 [1.40, 5.62] (yes) Children (yes) 3.14 [1.30, 3.75] 3.38 [1.42, 8.06] NA 2.99 [1.18, 7.58] BMI≥30Kg/m2 1.59 [0.77, 3.27] NA NA NA Menopause (years) 1.03 [0.99, 1.01] NA Chronic disease (1+) 2.14 [1.15, 3.97] 1.62 [1.84, 3.11] NA NA Education (post- NA NA 1.62 [0.85, 1.04] NA school)

Multivariate Married (yes) NA NA NA 2.93 [1.45, 5.90] Children (yes) 2.97 [1.21, 7.30] 3.33 [1.39, 7.95] NA NA Chronic disease (1+) 2.06 [1.10, 3.86] NA NA NA BMI, body mass index; NA, not applicable; OR, odds ratio; CI, confidence interval. Scales: ICIQ- FLTUTS and its subscales and ICIQ-VS.

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7.5.2. QoL

Urinary and vaginal symptom-related QoL

Overall, compared to baseline participants reported significantly worse vaginal (p<0.001) and urinary (p=0.029) symptom-related QoL at follow-up assessment. The aspects of daily life that were negatively influenced by symptoms were household tasks (p=0.005), ability to travel

(p=0.014) and (reduced) amount of fluid intake (p=0.038). Moreover, participants reported feeling worn out or tired (p=0.006), anxious (p=0.049) and bad about themselves because of urinary symptoms (p=0.046). Finally, urinary symptoms impacted on relationship with partner being significantly worse at six months (p=0.041). Table 7.5 provides detailed information on all aspects of a participant’s life that were affected by genitourinary symptoms and the changes over time. Of note, questions about impact of symptoms on QoL were only answered if participants felt that they had a genitourinary problem, otherwise they could skip and go to the next section in the questionnaire. As expected, the number of participants who completed this section increased from baseline to six-month follow-up; at baseline 113 (64%) participants completed it, while at six months 136 (77%) completed the section about symptom-related QoL.

Despite the relatively high prevalence of participants reporting vaginal symptoms to interfere with their everyday life at follow-up compared to baseline (31% vs. 17%, p<0.001), the majority (62%) rated the degree of impairment as a 1-3 on a 0-10 Likert scale. While the percentage of participants who reported severe (a lot/ very much/ all the time) negative effect of urinary symptoms in any aspect of their lives at baseline and follow-up was 39% and 46%, respectively (p=0.026) (Figure 7.5).

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Table 7.5. Impact of genitourinary symptoms on QoL (prevalence and mean scores) N % Mean (SD) P value† Vaginal symptoms(ICIQ-VS) How much vaginal symptoms interfere with Baseline 31 17.5 0.48 (1.29) <0.001 everyday life 6-mo 52 30.4 1.04 (2.03) Urinary symptoms(ICIQ-LUTSqol) Influence on household tasks Baseline 16 14.0 1.14 (0.35) 0.005 6-mo 30 21.7 1.29 (0.53) Ability to complete daily activities outside the Baseline 15 13.2 1.15 (0.38) NS home (including job) 6-mo 22 15.9 1.21 (0.51) Influence on physical activities Baseline 30 26.4 1.34 (0.62) NS 6-mo 44 31.9 1.42 (0.62) Ability to travel Baseline 9 7.9 1.08 (0.28) 0.014 6-mo 20 14.4 1.21 (0.49) Influence on social life Baseline 6 5.3 1.06 (0.23) NS 6-mo 9 6.5 1.08 (0.28) Ability to see/visit friends Baseline 2 1.8 1.02 (0.14) .NS 6-mo 3 2.2 1.03 (0.17) Influence on relationship with partnera Baseline 5 4.4 1.10 (0.48) 0.041 6-mo 9 7.8 1.12 (0.35) Influence on sex lifeb Baseline 8 7.8 1.16 (0.57) NS 6-mo 13 11.3 1.22 (0.58) Influence on family lifec Baseline 5 4.5 1.05 (0.22) NS 6-mo 5 3.9 1.06 (0.28) Depressed about urinary problems Baseline 11 9.6 1.09 (0.29) NS 6-mo 17 12.4 1.14 (0.38) Anxious or nervous Baseline 19 16.7 1.18 (0.45) 0.049 6-mo 28 20.4 1.27 (0.54) Bad about self Baseline 11 9.6 1.11 (0.39) 0.046 6-mo 17 12.4 1.19 (0.71) Sleep disturbance Baseline 47 41.6 1.49 (0.75) NS 6-mo 55 40.1 1.57 (0.06) Worn out/tired Baseline 80 69.6 1.91 (0.78) 0.006 6-mo 107 78.7 2.16 (0.81) Wear pads to keep dry Baseline 45 39.1 1.70 (1.06) NS 6-mo 49 36.0 1.78 (1.10) Reduction of fluid intake Baseline 27 23.5 1.30 (0.58) 0.038 6-mo 47 34.6 1.44 (0.70) Underclothes changing when they get wet Baseline 62 53.9 1.89 (1.03) NS 6-mo 71 52.2 1.89 (1.00) Worry about smelling Baseline 32 27.8 1.39 (0.76) NS 6-mo 40 29.6 1.51 (0.86) Embarrassment because of urinary symptoms Baseline 25 21.7 1.26 (0.53) NS 6-mo 27 19.9 1.31 (0.64) Overall impact of urinary symptoms on QoL Baseline 99 87.6 24.25 (5.95) 0.029 6-mo 117 86.0 25.42 (6.99) QoL, quality of life; NA, not applicable. a 7 NA at baseline and 23 NA at 6-month; b 11 NA at baseline and 23 NA at 6-month; b 2 NA at baseline and10 NA 6-month; †Wilcoxon Signed Ranks Test, significant values are bold; p value based on negative ranks, i.e. there was an impairment in these aspects of QoL over time.

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Figure 7.5. Frequency (%) and degree of impact of urinary symptoms on QoL (ICIQ-LUTSqol) at baseline (1) and six months (2)

85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0

Slightly/sometimes Moderately/often A lot/ very much/all the time

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Sociodemographic and clinical characteristics were tested for their contributions to genitourinary symptom-related QoL (assessed by dichotomized ICIQ-LUTSqol and ICIQ-

VSqol) through regression. Only the presence of at least one chronic disease was identified as a potential contributor to impaired urinary symptom-related QoL (B=1.40, OR=4.09, 95%CI

[1.28, 13.04], p=0.018). Whereas having children was associated with worse vaginal symptom- related QoL (B=0.10, OR=2.99, 95%CI [1.18, 7.58], p=0.021). Furthermore, baseline incontinence symptoms was significantly associated with impaired urinary symptom-related

QoL (B=0.35, OR=1.43, 95%CI [1.12, 1.84], p=0.005) and with vaginal symptoms-related QoL

(B=1.31, OR=1.12, 95%CI [1.00, 1.25], p<0.047). Storage and voiding symptoms in turn, were only associated with vaginal symptom-related QoL (B=1.30, OR=1.24, 95%CI [1.02, 1.50], p=0.030, and B=1.01, OR=1.31, 95%CI [1.09, 1.59], p<0.004, respectively). In summary, presence of chronic disease (1+) and severe incontinence symptoms at baseline had higher risk of impaired urinary symptom-related QoL at six months. While, having children and severe incontinence, voiding and storage symptoms at baseline, were all highly associated with impaired vaginal symptom-related QoL at follow-up.

7.5.4. Impact of genitourinary symptoms on sexual function

To assess the impact on sexual function attributed to genitourinary symptoms two questionnaires were completed by participants in the study: ICIQ-VS-SexMatter and PISQ-12.

To the first screening question: “Do you have a sex life at present?”, 38% (n=68) at baseline and 42% (n=75) at six months responded “yes” (p=0.230). Out of the 52% (n=109) of those answering “no”, 6% (n=11) at baseline and 9% (n=16) at follow-up identified their vaginal symptoms as the reason why they did not have a sex life.

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Compared to baseline, analysis of the mean sexual matters scores (assessed by ICIQ-

VSSexMatter) showed significant deterioration in sexual function (i.e. higher scores) at six

months (6.93 ±12.97 vs. 10.53 ±15.23, p=0.005) (Table 7.6). Similarly, participants were

significantly more bothered by sexual symptoms at follow-up compared to baseline (3.74 ±5.85

vs. 2.29 ±4.40, p=0.001). Worries about their vagina significantly interfered with sex life

(p=0.005) while participants also reported their sex life being substantially spoilt by their

vaginal symptoms (p=0.024).

Table 7.6. Frequency and mean vaginal-related sexual matter scores at baseline and six

months

Baseline 6 months p-value N N Sex life at present 0.230§ Yes 68 38.4% 75 42.4% No 109 61.6% 102 57.6% N Mean (SD) N Mean (SD) ICIQ-VS-Sex Matter Score Overall scores 68 6.93 (12.99) 73 10.53 (15.23) 0.005† Worries about vagina interfere with sex 68 0.40 (0.78) 73 0.62 (0.88) 0.005† life Relationship with partner affected by 68 0.34 (0.66) 73 0.47 (0.80) 0.084† vaginal symptoms Sex life spoilt by vaginal symptoms 68 1.04 (2.37) 73 1.88 (2.89) 0.024† Total score bothered by symptoms 68 2.29 (4.40) 72 3.74 (5.85) 0.001† §McNemar’s test, †Wilcoxon Signed Ranks Test, significant values are bold;

The regression model examined the relationship between sociodemographic variables and

clinical characteristics of the sample interfering with sexual function. Selection of covariates

was based on factors associated with sexual dysfunction and lower urinary tract symptoms in

existing literature (e.g. age, BMI, comorbidity, parity, time since menopause and use of

antidepressants). Additionally, some clinical characteristics such as time from diagnosis of

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breast cancer, type of surgery, chemotherapy and radiotherapy and genitourinary and endocrine symptoms at baseline were also entered in the model. Having had radiotherapy (B=2.43,

OR=11.47, 95%CI [3.59, 36.55], p<0.001) was significantly associated with increased risk for sexual dysfunction, as were baseline vaginal symptoms (B=0.33, OR=1.40, 95%CI [1.13, 1.73], p=0.001) and endocrine symptoms (B=0.25, OR=1.76, 95%CI [1.02, 1.93], p=0.003). None of the other factors remained independently associated with the sexual dysfunction at a significant level.

If participants had not engaged in sexual activity in the month prior to completing questionnaire, they were asked to answer a short version of the PISQ-12 scale to evaluate sexual desire and potential genitourinary symptoms which could have limited their sexual activity. This included four out of the 12 questions in the scale, in addition to a question about whether they had a current partner. The rate of absence of sexual activity despite being partnered was 70% (n=82) at baseline and 59% (n=54) at six months. There was no statistically significant difference between responses to the four questions at baseline and six months (Figure 7.6).

Among participants reporting being sexually active, the overall PISQ-12 scores were significantly higher (i.e. worse symptoms) at six months (37.09 ±5.54) in comparison to baseline (34.69 ±7.20, p=0.041) (Table 7.7). Deterioration of the behavioural emotive factor score was observed (p=0.015). At six months participants reported being significantly less sexually excited when having sexual activity (p=0.012) and less intensity of orgasm compared to their previous orgasm experiences (i.e. in the past six months) (p=0.003). Climax, sexual desire, satisfaction, pain during intercourse, problems associated with partners having an erection and premature ejaculation were not significantly different between the two time points.

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Figure 7.6. Four selected sexual function-related questions from PISQ-12 to participants reporting no sexual activity at baseline (1) (N=117) and six months (2) (N=92)

80

70

60

50

40

30

20

10

0

Seldom/sometimes/less than once a month/monthly

Usually/ always/weekly/daily

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Table 7.7. PISQ-12 scores in sexually active women at baseline and six months

Baseline 6 months p- value N % N % Sexually activea 0.006 Yes 55 31.3% 75 42.4% No 121 68.8% 102 57.6%

N Mean (SD) N Mean (SD) PISQ-12 scores Overall scores 53 37.09 (5.54) 71 34.69 (7.20) 0.041

Behavioural-emotive 53 0.81 (3.18) 71 9.52 (3.69) 0.015 Sexual desire 53 2.51 (0.89) 69 2.33 (1.02) 0.153 Climax (orgasm) when having sexual 53 2.40 (1.08) 71 2.21 (1.25) 0.475 activity Sexually excited when having sexual 53 3.04 (0.90) 70 2.61 (1.11) 0.012 activity Satisfaction with current sexual activity 52 2.96 (0.86) 71 2.52 (1.20) 0.125

Physical 53 18.28 (1.94) 71 17.39 (3.35) 0.102 Do you feel pain during intercourse 53 2.79 (1.29) 71 2.74 (1.39) 0.678 Urinary incontinence during sexual 53 3.85 (0.49) 71 3.79 (0.70) 0.317 activity Sexual activity restricted by fear of urine 53 3.89 (0.46) 71 3.78 (0.71) 0.063 leakage Avoiding sexual intercourse due to 53 3.93 (0.54) 71 3.85 (0.74) 0.991 prolapse Negative emotional reactions such as fear, 53 3.91 (0.56) 71 3.65 (0.98) 0.238 disgust, shame or guilt during sexual activity

Partner related 53 8.25 (2.39) 71 8.06 (2.27) 0.807 Does your partner have problems with 53 3.26 (1.25) 71 3.10 (1.41) 0.984 erection that affects your sexual activity Does your partner have problems with 52 3.52 (1.06) 71 3.59 (0.97) 0.159 premature ejaculation that affects your sexual activity Compared to orgasms you have had in the 53 1.63 (0.77) 71 1.35 (0.86) 0.003 past, how intense are the orgasm you have had in the past six months PISQ-12, Pelvic organ prolapse/urinary incontinence sexual questionnaire. PISQ-12 has a range from 0 to 48 with higher scores indicating better sexual function. Comparison using Wilcoxon Signed Ranks test unless otherwise stated, significant values are bold. a one participant did not respond to this question.

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Difference between groups (TAM vs AIs)

There was no significant differences between the two groups on their change scores in overall and derived urinary symptoms and vaginal symptoms. Scores tended towards the low end of the scales. Urinary symptoms (ICIQ-FLUTS) mean change scores for TAM and AIs were

1.87±5.05 vs 1.35±3.82, p=0.211 (Figure 7.7.a) while vaginal symptom (ICIQ-VS) mean change scores were 1.16±3.74 vs 1.85±4.23, p=0.619 (Figure 7.7.b). Comparably, there was no statistically significant difference between TAM and AIs in either of the urinary symptoms subscale change scores from baseline, that is, storage (0.33±1.71 vs 0.40±1.49, p=0.943)

(Figure 7.7.c), incontinence (0.87±2.72 vs 0.25±1.88, p=0.073) (Figure 7.7.d) and voiding symptoms (0.67±1.91 vs 0.72±1.96, p=0.897) (Figure 7.7.e).

Despite difference in frequency of symptoms over time, clinically meaningful symptoms between participants taking TAM and AIs, did not reach statistical significance (Table 7.8). The exception was clinical meaningful vaginal discharge (‘quite a bit’/’very much’), which was significantly higher in participants taking TAM than in those on AIs (8% vs. 0%, p=0.011).

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Figure 7.7. Box-plots of change scores from baseline by group (TAM vs AI): ICIQ-FLUTS

(a), ICIQ-VS (b), ICIQ-FLUTS-FS (c), ICIQ-FLUTS-IS (d) and ICIQ-FLUTS-VS (e).

(a) (b)

(c) (d)

(e)

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Table 7.8. Frequency (%) of genitourinary symptoms in general and clinically meaningful symptoms at six months by group (TAM vs. AI)

Overall Symptoms Clinically meaningful symptoms TAM AI TAM AI OR 95%CI Urinary symptoms (ICIQ-FLUTS) % % % % Incontinence symptoms Urge UI 72% 63% 13% 12% 1.05 [0.36, 3.04] Frequency of incontinence 54% 59% 28% 20% 1.62 [0.72, 3.65] Stress UI 62% 70% 23% 20% 1.22 [0.52, 2.89] Unexplained UI 13% 7% 5% 1% 7.41 [0.65, 83.93] Amount of leakage 51% 58% 3% 1% 3.58 [0.22, 58.56] Nocturnal enuresis 15% 10% 13% 12% 1.05 [0.36, 3.04] Voiding symptoms Hesitancy 23% 24% 5% 9% 1.77 [0.38, 8.30] Strain to start 5% 15% 3% 4% 1.74 [0.20, 14.91] Intermittent stream 51% 44% 8% 2% 5.63 [0.91, 34.95] Reduced strength of stream 26% 32% 13% 10% 1.29 [0.44, 3.84] Urinary retention 0% 0% 39% 38% 1.02 [0.49, 2.12] Burning sensation 15% 19% 5% 9% 1.77 [0.38, 8.30] Feeling of incomplete empty 46% 39% 3% 4% 1.74 [0.20, 14.91] Difficulty with stopping the flow 39% 38% 8% 2% 5.63 [0.91, 34.95] Storage symptoms Frequency (≥7) 39% 42% 15% 16% 1.04 [0.39, 2.78] Nocturia (≥1) 90% 83% 26% 34% 1.50 [0.67, 3.34] Urgency 72% 70% 26% 16% 1.82 [0.78, 4.26] Bladder pain 13% 11% 5% 3% 1.81 [0.32, 10.28] Vaginal symptoms (ICIQ-VS) Dragging pain in lower abdomen 21% 23% 8% 4% 2.28 [0.52, 10.01] Vaginal soreness 34% 23% 8% 6% 1.38 [0.35, 5.49] Reduced sensation or feeling in or 37% 32% 11% 12% 1.12 [0.35, 3.59] around vagina Vagina too loose 24% 23% 5% 14% 2.89 [0.64, 13.04] Lump or bulge felt inside 11% 19% 3% 9% 3.61 [0.45, 28.69] Lump of bulge seen outside 3% 10% 26% 28% 1.12 [0.50, 2.53] Digital bowel empting 3% 11% 3% 6% 2.30 [0.28, 18.94] Vaginal discharge 41% 11% 8% 0% 5.91† [1.57, 22.16] Vaginal itching 28% 22% 5% 3% 1.04 [0.27, 3.99] ICIQ-FLUTS, International Consultation on Incontinence Questionnaire female lower urinary symptoms, UI, urinary incontinence, NS, not significant, ICIQ-VS, International Consultation on Incontinence Questionnaire vaginal symptoms, FACT-ES, Functional Assessment of Cancer Therapy- Endocrine Scale. †Wilcoxon Signed Ranked Test, significant value bold.

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Equally, there was no significant difference in genitourinary symptom-related QoL change scores for TAM or AIs (N=103, Mean=1.35±4.67, U=753.0, Z=-1.717, p=0.086). In regards to sexual activity, during follow-up, there was a significant increase in frequency of participants taking AIs who reported engaging in sexual activities in the past month compared to baseline reports (30% vs 40%, p=0.040). This was not significant among women taking TAM (35% vs

51%, p=0.701). Furthermore, mean change scores of PISQ-12 (N=47, Mean=-1.70±5.42,

U=154.5, Z=-1.587, p=0.113), and ICIQ-VS-SexMatter (N=58, Mean=3.86±9.50, U=251.5,

Z=-1.396, p=0.163) were both not significant between the two groups.

7.5. Discussion

This study expands the current knowledge of changes in frequency and severity of genitourinary symptoms in postmenopausal breast cancer patients after six months of adjuvant endocrine therapy with either TAM or AIs in a number of ways. First, findings indicate that these symptoms were highly prevalent in participants before endocrine therapy began. This is not surprising given the menopausal status of the study sample; that is, all participants were postmenopausal (for 14 years on average) prior to breast cancer diagnosis, and there is extensive literature supporting genitourinary tract changes closely related to estrogen depletion following onset of menopause.27-30

Second, consistent with study hypothesis, the prevalence and, of foremost concern, the severity of symptoms, remarkably increased six months into endocrine therapy with statistical significance at 38% and 62% of the 29 symptoms assessed, respectively. This study did not assess genitourinary symptoms in non-cancer controls and thus was unable to directly compare prevalence rates. Nonetheless, as noted in Table 7.2 and in Chapter 3 (section 3.4), the majority

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of the prevalence rates for each of the 29 genitourinary symptoms reported in this study are higher than the prevalence rates reported in the general population of a similar age.31, 32 This is in accordance with previous controlled study reports.33 Of note, approximately 40% of the symptoms that increased in severity in participants were also classified as clinically meaningful symptoms as per cut-off point chosen in this study 22, 24-26 and were significantly more frequent at follow-up. Specifically, for stress UI, incomplete emptying, increased daytime frequency, as well as reduced vulvovaginal sensation, vaginal discharge, dryness and genital prolapse, 6% to

27% of the sample was found to have clinically meaningful symptoms. These findings warrant additional research because of the growing body of literature that suggests that the occurrence of genitourinary symptoms is associated with significant morbidity, leading to increased discomfort, impaired QoL, sexual dysfunction,34, 35 as well as increased costs due to frequent visits to doctors and subsequent investigations.33

Third, the diversity in symptom definition and assessment across published studies, and in this study, makes direct comparisons of genitourinary symptom prevalence rates difficult. In general, however, compared with studies that investigated genitourinary symptoms in breast cancer patients on adjuvant endocrine therapy, the rates reported in this study are somewhat higher than previous reports.33, 36, 37 A recent cross-sectional survey examining the prevalence and severity of postmenopausal symptoms in women treated for breast cancer found that 41% of women receiving endocrine therapy reported urinary urgency, 36% incontinence and 12% dysuria.36 Whereas the corresponding numbers in this study were 71% for urgency, 82% for any incontinence (with 65% for urge UI, and 63% for SUI) and 18% for dysuria. This interesting and seemingly incongruent finding (i.e. much higher rates in this study) demands additional exploration. A possible reason could be that in the cross-sectional study women were on average 23 months into endocrine therapy compared to six months in this study, therefore, more likely to accommodate or normalise symptoms (as also evidenced in Study I). It is also likely

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that there may be a level of improvement in symptoms over time. With the planned longer follow-up assessment at one year and two years into treatment, this study will be better able to compare and report on this. Study findings regarding stress UI, however, are in accordance with results reported by Baumgart et al., who conducted a controlled cross-sectional study in breast cancer patients on endocrine therapy (on average 29 to 33 months) and reported stress UI to be

70% among these women.33 Authors also reported that UI symptoms did not differ between AI- or TAM-treated patients, which is also in line with our findings but goes in contrast with the study hypothesis.

Another important finding, consistent with study hypothesis and the literature,38 is that severity of symptoms negatively influenced some aspects of participant’s daily life, such as household tasks, ability to travel, relationship with partner, etc. Yet, impairments were most frequently rated at the lower end of the scales. This may reflect the relatively low importance women give to genitourinary concerns compared to breast cancer concerns (or other issues they may be facing in their breast cancer journey);38 therefore, related to the normalisation of symptoms, as identified in Study I of this PhD project and in previous reports.39-41 It may also be related to the tendency of women to accommodate symptoms within their everyday life experiences, for instance when they avoid potential triggers.

Some sociodemographic and clinical characteristics of participants were associated to some degree with severity of symptoms and/or impaired symptom-related QoL. The association of higher BMI as a factor that promotes urinary incontinence symptoms has been uniformly described by others in a non-cancer context.42 It is also consistent with what Morales et al. observed in a longitudinal study examining short-term menopausal adverse effects of endocrine therapy in postmenopausal breast cancer patients.43 The authors reported that those with a higher BMI were more likely to report urinary problems. It is important to note that only a few studies have considered the presence of pre-existing comorbidities and risk factors in individual 221

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breast cancer patients that might have influenced the development and course of symptoms, making comparisons difficult. The other predictors identified have not been previously reported, thus these findings are both unique and important. The presence of at least one chronic disease and severe incontinence symptoms at baseline had higher risk of impaired urinary symptom- related QoL at six months. While, having children and severe incontinence, voiding and storage symptoms at baseline, were all highly associated with impaired vaginal symptom-related QoL at follow-up. Potential clinical implication of these findings is that clinicians could target women who fit these categories for intervention. For example, recommending treatment for incontinence such as pelvic floor exercises and/or making referrals as appropriate.

Results suggest an overall trend of deterioration in sexual function due to genitourinary symptoms despite a trend of increased frequency of sexual activity over time. Essentially, factors that predicted deterioration in sexual function were related to presence of endocrine and vaginal symptoms at baseline. This suggest that women who were experiencing symptoms related to genitourinary syndrome of menopause (GSM) at baseline were the ones more likely to also report sexual dysfunction after six months of endocrine therapy. Previous studies have identified similar results and have reported that vaginal dryness had a significant negative effect on breast cancer survivors’ sex life44 and was associated with an increase in ‘severe’ and

‘intolerable’ dyspareunia.43 In a cross-sectional study aiming to provide a detailed view of sexual problems during the first two years of adjuvant AI therapy, findings revealed that 93% of women had sexual dysfunction and although only about half of women were sexually active, almost 80% of them experienced new sexual problems after starting on an AI, with 39% consulting a physician about vaginal dryness.45 This is supported and substantiated by findings in this study, where women reported their sex life being substantially spoilt by their vaginal symptoms at follow-up assessment. These finding suggest that if baseline symptoms are left untreated, overall levels of bothersomeness and interference of symptoms in sexual activities caused by these symptoms is likely to increase over time. Such findings could be used to design 222

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ameliorative and supportive interventions, especially targeting women who report symptoms related to GSM at baseline, where appropriate. However, it is important to consider that there is a growing body of evidence suggesting that sexual dysfunction may be due to a combination of interrelated factors. Thus there may be other factors that may explain our findings. For instance, women with breast cancer, in general, have problems with body image that are independent risk factor for sexual problems in breast cancer survivors.46, 47 The complex interaction between self- perception and self-reported symptoms may inflate the problem of sexual dysfunction attributed to genitourinary symptoms in women with breast cancer on endocrine therapy. Additionally, it is important to highlight that some sexual activity/function may have improved or deteriorated less than it otherwise would have, if the women had not recently had chemotherapy.48 These aspects were not measured in our study and should, therefore, be further expanded in future research.

Non-compliance is an important issue as it can have an effect on survival and recurrence, thus it is beneficial to understand why some women stop therapy, particularly if the reason is related to genitourinary outcomes. Although, study questionnaires covered compliance with therapy, with a specific question asking participants whether or not they took their medication regularly and reasons for not doing so, little is known about whether the motivations why two participants discontinued therapy and a further eight switched classes of drugs were a result of genitourinary side effects. Study participants stated that the main reason for discontinuation was the non- specific side effects of their medication. Our non-compliance rate (less than 1%) was much lower than what is currently reported in the literature (23% to 50%),49, 50-52 we nevertheless, would benefit from knowing why some women stopped therapy, particularly if the reason related to genitourinary side effects. Moreover, the very small sample of participants who switched or discontinued endocrine therapy (n=10) meant it was not possible to perform analysis on characteristics of groups who discontinued or switched treatments over time as primarily intended (it was hypothesised that women who develop significant genitourinary 223

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symptoms would be more likely to cease treatment or switch form an AI to TAM). This will also be investigated in future analysis of longer-term follow-up data.

Finally, there are no differences between the effects of TAM and AIs early in the course of therapy (after six months). However, as recruitment for the study is still ongoing and power calculations were based on having N=44 participants receiving TAM continuously (but current results are based on N=39 participants on continuous treatment with TAM), it is not clear whether the lack of significance is showing a true picture of events. With additional data and higher power, differences may still be detected. As per current data, group comparisons should be interpreted with care. Also, longer follow-up will allow for a clearer picture of the long-term implications of the different endocrine therapies. It is expected that a reassessment after one and two years will give a deeper insight on the evolution of genitourinary symptoms as well as the progression in the different therapy groups.

7.6. Clinical implications

These research findings have the potential to influence clinical practice as they could lead to identification of symptomatic/at risk patients and early interventions to prevent and treat the genitourinary side-effects of endocrine therapy. Additionally, the findings of this in-depth study provide patients and clinicians with more information regarding the prevalence and impact of genitourinary adverse effects of adjuvant endocrine therapy in postmenopausal women.

Oncologists and general (family) practitioners (GP’s) are in an ideal position to screen patients for genitourinary symptoms prior to starting treatment and during the course of treatment and to identify patients who require referral for management of genitourinary symptoms.

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7.7. Study limitations

The study did not include a control group of postmenopausal women with early breast cancer who were not treated with endocrine therapy, but did include an assessment of symptoms at baseline prior to commencing adjuvant endocrine therapy. Furthermore, since allocation to

TAM/AI was clinically determined, the relative recent change in practice resulted in only a small number of participants being prescribed TAM and it was not possible to show statistically significant difference between TAM and AI groups. Hence, results of non-significance difference between TAM and AI-users in this study should be interpreted with some caution. It could be that there was no difference between groups but also and more likely, the sample was not big enough to show the difference. In addition, a more homogeneous sample would have enabled a more definitively determine effect of other cancer therapy (e.g. chemotherapy) on genitourinary symptoms. Despite these limitations, the current study adds to the limited knowledge of the genitourinary-adverse effect of endocrine therapy in which symptoms develop or worsen over time and further informs prevention and treatment efforts.

7.8. Study strengths

The present study is the first to comprehensively document the prevalence and severity of a wide range of genitourinary symptoms in postmenopausal women on adjuvant endocrine therapy for breast cancer. Furthermore, it assessed symptoms prospectively, i.e. prior to starting- treatment with endocrine therapy (baseline) and with multiple follow-ups during endocrine therapy (six-, 12- and 24-months) – this is the first study to do this. This is essential in order to evaluate whether symptoms predate the use of an AI or TAM in some women and how symptoms may change over time. This study also included a relatively large sample compared with previous studies and it assessed and controlled for a number of known risk factors (e.g., smoking, BMI, use of some anti-depressive medication and medical comorbidities). Finally, it

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used the ICIQ-FLUTS, a well-known and psychometrically sound measure widely recommended for use when investigating prevalence of genitourinary symptoms.10 Although the results reported here are based on the data received by the time of writing these results, this study will continue following up these women for up to two years. In addition to a six-month follow-up, it is intended to report the data collected after one year and two years from baseline.

7.9. Conclusion

Genitourinary symptoms are highly prevalent in postmenopausal women with breast cancer on adjuvant endocrine therapy. They significantly impact on QoL and sexual activity and can be predicted by baseline characteristics. Results from this study can be used to inform clinical practice and lead to greater efforts to early recognition and appropriate management of significant genitourinary symptoms as a result of adjuvant endocrine therapy.

7.10. References

1. Kelley, C. Estrogen and its effect on vaginal atrophy in post-menopausal women. Urol Nurs, 2007; 27(1):40-5. 2. Panay, N and Fenton, A. Vulvovaginal atrophy--a tale of neglect. Climacteric, 2014; 17(1):1-2. 3. American Joint Committee on Cancer (AJCC). Breast Cancer Staging, In: Edge SB, Byrd DR, Compton CC and et al, editors. Cancer Staging Manual New York: Springer-Verlag. 2010. pp. 347-77. 4. Abrams, P, Avery, K, Gardener, N and Donovan, J. The International Consultation on Incontinence Modular Questionnaire: www.iciq.net. J Urol, 2006; 175(3 Pt 1):1063-6; discussion 1066. 5. Avery, K, Donovan, J, Peters, TJ, Shaw, C, Gotoh, M and Abrams, P. ICIQ: a brief and robust measure for evaluating the symptoms and impact of urinary incontinence. Neurourol Urodyn, 2004; 23(4):322-30. 6. Brookes, ST, Donovan, JL, Wright, M, Jackson, S and Abrams, P. A scored form of the Bristol Female Lower Urinary Tract Symptoms questionnaire: data from a randomized controlled trial of surgery for women with stress incontinence. Am J Obstet Gynecol, 2004; 191(1):73-82.

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7. Jackson, S, Donovan, J, Brookes, S, Eckford, S, Swithinbank, L and Abrams, P. The Bristol Female Lower Urinary Tract Symptoms questionnaire: development and psychometric testing. Br J Urol, 1996; 77(6):805-12. 8. Kelleher, CJ, Cardozo, LD, Khullar, V and Salvatore, S. A new questionnaire to assess the quality of life of urinary incontinent women. Br J Obstet Gynaecol, 1997; 104(12):1374-9. 9. Price, N, Jackson, SR, Avery, K, Brookes, ST and Abrams, P. Development and psychometric evaluation of the ICIQ Vaginal Symptoms Questionnaire: the ICIQ-VS. BJOG, 2006; 113(6):700-12. 10. Abrams P, Andersson KE, Brubaker L, Cardozo L, Denis L, Donovan D, Fonda C, Fry, C, Griffiths D, Hanno, P, Herschorn, S, Homma Y, Hu T, Hunskaar S, van Kerrebroeck P, Khoury, S, Madoff, R, Morrison J, Mostwin J, Newman, D, Nijman R, Payne, C, Richard F, Smith, A, Staskin, D, Thuroff, J, Tubaro, A, Vodusek, D, Wall L, Wein, A, Wilson D, Wyndaele JJ and The Members of the Committees. Third International Consultation on Incontinence Recommendations of the International Scientific Committee: Evaluation and treatment of urinary incontinence, pelvic organ prolapse, and fecal incontinence. Neurourol Urodyn, 2005; 29(1):1589-1630. 11. Rogers, RG, Coates, KW, Kammerer-Doak, D, Khalsa, S and Qualls, C. A short form of the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12). Int Urogynecol J Pelvic Floor Dysfunct, 2003; 14(3):164-8; discussion 168. 12. Rogers, RG, Kammerer-Doak, D, Villarreal, A, Coates, K and Qualls, C. A new instrument to measure sexual function in women with urinary incontinence or pelvic organ prolapse. Am J Obstet Gynecol, 2001; 184(4):552-8. 13. Carlsson, AM. Assessment of chronic pain. I. Aspects of the reliability and validity of the visual analogue scale. Pain, 1983; 16(1):87-101. 14. Clarke PRF and FG., S. Reliability and sensitivity in the self assessment of wellbeing. Bull Br Psychol soc, 1964:17:55. 15. Bond, MR and Pilowsky, I. Subjective assessment of pain and its relationship to the administration of analgesics in patients with advanced cancer. J Psychosom Res, 1966; 10(2):203-8. 16. Revill, SI, Robinson, JO, Rosen, M and Hogg, MI. The reliability of a linear analogue for evaluating pain. Anaesthesia, 1976; 31(9):1191-8. 17. Brady, MJ, Cella, DF, Mo, F, Bonomi, AE, Tulsky, DS, Lloyd, SR, Deasy, S, Cobleigh, M and Shiomoto, G. Reliability and validity of the Functional Assessment of Cancer Therapy-Breast quality-of-life instrument. J Clin Oncol, 1997; 15(3):974-86. 18. Fallowfield, LJ, Leaity, SK, Howell, A, Benson, S and Cella, D. Assessment of quality of life in women undergoing hormonal therapy for breast cancer: validation of an endocrine symptom subscale for the FACT-B. Breast Cancer Res Treat, 1999; 55(2):189-99. 19. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy, 1990; 16(3):199-208. 20. Kimman, ML, Dirksen, CD, Lambin, P and Boersma, LJ. Responsiveness of the EQ-5D in breast cancer patients in their first year after treatment. Health Qual Life Outcomes, 2009; 7:11. 21. Pickard, AS, Wilke, CT, Lin, HW and Lloyd, A. Health utilities using the EQ-5D in studies of cancer. Pharmacoeconomics, 2007; 25(5):365-84. 22. Gopal, M, Sammel, MD, Arya, LA, Freeman, EW, Lin, H and Gracia, C. Association of change in estradiol to lower urinary tract symptoms during the menopausal transition. Obstet Gynecol, 2008; 112(5):1045-52. 23. Norman, GR, Sloan, JA and Wyrwich, KW. Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Med Care, 2003; 41(5):582-92.

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24. Delgado, D, White, P, Trochez, R and Drake, MJ. A pilot randomised controlled trial of the pelvic toner device in female stress urinary incontinence. Int Urogynecol J, 2013; 24(10):1739-45. 25 .Hay-Smith, J, Herderschee, R, Dumoulin, C and Herbison, P. Comparisons of approaches to pelvic floor muscle training for urinary incontinence in women: an abridged Cochrane systematic review. Eur J Phys Rehabil Med, 2012; 48(4):689-705. 26. Cella, D, Fallowfield, L, Barker, P, Cuzick, J, Locker, G and Howell, A. Quality of life of postmenopausal women in the ATAC ("Arimidex", tamoxifen, alone or in combination) trial after completion of 5 years' adjuvant treatment for early breast cancer. Breast cancer research and treatment, 2006; 100:273-84. 27. Nappi, RE and Lachowsky, M. Menopause and sexuality: prevalence of symptoms and impact on quality of life. Maturitas, 2009; 63(2):138-41. 28. Levine, KB, Williams, RE and Hartmann, KE. Vulvovaginal atrophy is strongly associated with female sexual dysfunction among sexually active postmenopausal women. Menopause, 2008; 15(4 Pt 1):661-6. 29. Calleja-Agius J and Brincat MP. Urogenital atrophy. Climacteric, 2009; 12(4):279-85. 30. Palacios, S. Managing urogenital atrophy. Maturitas, 2009; 63:315-8. 31. Pastore, LM, Carter, RA, Hulka, BS and Wells, E. Self-reported urogenital symptoms in postmenopausal women: Women's Health Initiative. Maturitas, 2004; 49(4):292-303. 32. Huang, AJ, Moore, EE, Boyko, EJ, Scholes, D, Lin, F, Vittinghoff, E and Fihn, SD. Vaginal symptoms in postmenopausal women: self-reported severity, natural history, and risk factors. Menopause, 2010; 17(1):121-6. 33. Baumgart, J, Nilsson, K, Stavreus-Evers, A, Kask, K, Villman, K, Lindman, H, Kallak, T and Sundstrom-Poromaa, I. Urogenital disorders in women with adjuvant endocrine therapy after early breast cancer. American Journal of Obstetrics & Gynecology, 2011; 204(1):26.e1-7. 34. Avis, N, Crawford, S, Manuel, J and et al. Quality of life among younger women with breast cancer. Journal of Clinical Oncology, 2005; 23:3322-3330. 35. Zibecchi, L, Greendale, GA and Ganz, PA. Continuing education: Comprehensive menopausal assessment: an approach to managing vasomotor and urogenital symptoms in breast cancer survivors. [Review] [45 refs]. Oncology Nursing Forum, 2003; 30(3):393- 407. 36. Chin, SN, Trinkaus, M, Simmons, C, Flynn, C, Dranitsaris, G, Bolivar, R and Clemons, M. Prevalence and severity of urogenital symptoms in postmenopausal women receiving endocrine therapy for breast cancer. Clinical Breast Cancer, 2009; 9(2):108-17. 37. Couzi, R, Helzlsouer, K and Fetting, J. Prevalence of menopausal symptoms among women with a history of breast cancer and attitudes toward estrogen replacement therapy. 1995:2737-2744. 38. Gupta, P, Sturdee, DW, Palin, SL, Majumder, K, Fear, R, Marshall, T and Paterson, I. Menopausal symptoms in women treated for breast cancer: the prevalence and severity of symptoms and their perceived effects on quality of life. Climacteric : the journal of the International Menopause Society, 2006; 9:49-58. 39. Skoner, MM and Haylor, MJ. Managing incontinence: women's normalizing strategies. Health Care Women Int, 1993; 14(6):549-60. 40. Fu, MR, Xu, B, Liu, Y and Haber, J. 'Making the best of it': Chinese women's experiences of adjusting to breast cancer diagnosis and treatment. J Adv Nurs, 2008; 63(2):155-65. 41. Cowley, L, Heyman, B, Stanton, M and Milner, SJ. How women receiving adjuvant chemotherapy for breast cancer cope with their treatment: a risk management perspective. J Adv Nurs, 2000; 31(2):314-21. 42. Dwyer, PL, Lee, ET and Hay, DM. Obesity and urinary incontinence in women. Br J Obstet Gynaecol, 1988; 95(1):91-6. 43. Morales, L, Neven, P, Timmerman, D, Christiaens, MR, Vergote, I, Van Limbergen, E, Carbonez, A, Van Huffel, S, Ameye, L and Paridaens, R. Acute effects of tamoxifen and 228

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third-generation aromatase inhibitors on menopausal symptoms of breast cancer patients. Anticancer Drugs, 2004; 15(8):753-60. 44. Meyerowitz, BE, Desmond, KA, Rowland, JH, Wyatt, GE and Ganz, PA. Sexuality following breast cancer. J Sex Marital Ther, 1999; 25(3):237-50. 45. Schover, LR, Baum, GP, Fuson, LA, Brewster, A and Melhem-Bertrandt, A. Sexual problems during the first 2 years of adjuvant treatment with aromatase inhibitors. J Sex Med, 2014; 11(12):3102-11. 46. Pérez, M, Liu, Y, Schootman, M, Aft, RL, Schechtman, KB, Gillanders, WE and Jeffe, DB. Changes in sexual problems over time in women with and without early-stage breast cancer. Menopause, 2010; 17(5):924-37. 47. Helms, RL, O'Hea, EL and Corso, M. Body image issues in women with breast cancer. Psychol Health Med, 2008; 13(3):313-25. 48. Pinto, AC. Sexuality and breast cancer: prime time for young patients. J Thorac Dis, 2013; 5(Suppl 1):S81-6. 49. Partridge, AH. Non-adherence to endocrine therapy for breast cancer. Ann Oncol, 2006; 17(2):183-4. 50. Fink, AK, Gurwitz, J, Rakowski, W, Guadagroli, E and Silliman, RA. Patient beliefs and tamoxifen discontinuance in older women with estrogen receptor–positive breast cancer. J Clin Oncol 2004; 22(3309-15). 51. Lash, TL, Fox, MP, Westrup, JL, Fink, AK and Silliman, RA. Adherence to tamoxifen over the five-year course. Breast Cancer Res Treat, 2006; 99:215-20. 52. Barron, TI, Connolly, R, Bennett, K, Feely, J and Kennedy, MJ. Early discontinuation of tamoxifen: a lesson for oncologists. Cancer 2007; 109:832-9.

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CHAPTER 8

Conclusion and Recommendation

Chapter Eight summarises the findings from the thesis. A critical evaluation of the series of studies is carried out, strengths and limitations are highlighted, clinical implications are discussed and future directions for research recommended. The thesis concludes with appendices containing all the materials used in the studies.

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8.1. Summary of key findings

This thesis explored the experience, prevalence and severity of a range of genitourinary symptoms in a sample of postmenopausal women with breast cancer receiving endocrine therapy. In particular, this series of studies comprehensively addressed the uncertainty regarding the frequency and severity of genitourinary adverse effects related to or exacerbated by antiestrogens, as they are typically not reported by women to their oncologists. It also investigated everyday experiences of breast cancer patients living with genitourinary symptoms, specific information women desired or received about symptoms and about treatment options, and the potential impact of symptoms on sexual function and QoL. Adverse effects of TAM and

AIs are particularly important as they can significantly affect wellbeing of women with breast cancer and possibly also contribute to noncompliance with therapy, thus presenting an ongoing concern for clinicians.

The results from this mixed method study adds to the published literature by increasing our knowledge of impact of adjuvant endocrine therapy on genitourinary symptoms in women with early breast cancer. The study results highlight the importance of increasing awareness regarding genitourinary adverse effect of endocrine therapy among healthcare professionals caring for women with breast cancer (especially GPs and oncologists). The key findings include:

 Genitourinary symptoms have a negative impact on daily life of women with breast

cancer taking endocrine therapy. Symptoms influenced personal, social and physical

activities, were often attributed to anxiety and stress, and a source of embarrassment.

 Limited information was communicated or made available to patients regarding

genitourinary symptoms/side effects of endocrine therapies or potential interventions or

treatment options to manage the symptoms. This seemed to negatively influence help-

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seeking behavior and women commented that availability of information material

should be improved.

 Women’s concerns may be reduced with increased knowledge of genitourinary

problems and this may facilitate timely help-seeking and result in improved wellbeing.

 The frequency of genitourinary symptoms has been underestimated in previous clinical

trials. Additionally, findings support the hypothesis that deterioration in QoL and sexual

function attributed to genitourinary symptoms increased in frequency after six months

of endocrine therapy.

 Women who experienced vaginal and endocrine symptoms at baseline were more likely

to develop worse sexual dysfunction after six months of endocrine therapy.

Comparably, those who reported at least one chronic disease and severe incontinence

symptoms at baseline were more likely to have impaired urinary symptom-related QoL

at six months. While, having children, severe incontinence, voiding and storage

symptoms at baseline, were likely to result in greater impairment of vaginal symptom-

related QoL at follow-up.

 There appeared to be no difference in the genitourinary effects between groups on TAM

or AIs early in the course of therapy, after six months. However these data need to be

carefully interpreted due to the short-term nature of the current analysis and power

concerns. It is expected that a reassessment after one and two years will give a deeper

insight on the evolution of genitourinary symptoms as well as the progression under the

different therapy groups.

8.2. Clinical implications

Overall, participants in this study reported a high prevalence of symptoms at baseline, as well as worse genitourinary symptoms, symptom-related QoL and sexual function after commencement

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of endocrine therapy. Both the qualitative study and the PEGASUS study underscore the need for clinicians to inform postmenopausal women with breast cancer that genitourinary symptoms are a potential adverse effect of antiestrogens and that women who already have genitourinary symptoms before therapy are likely to get more and worse symptoms within 6-months of starting AIs or TAM. As there are interventions that could be used to better manage and treat many of these genitourinary symptoms, women at higher risk of sexual dysfunction and impaired QoL attributed to genitourinary symptoms should be identified early. Oncologists and family practitioners are in an ideal position to screen patients for genitourinary symptoms prior to starting treatment and during the course of treatment and to identify patients who require referral for management of genitourinary symptoms. Both a physical assessment of genitourinary atrophy and a specific enquiry about the existence of symptoms and whether any treatments to ameliorate symptoms have been used, should be included in the care of breast cancer survivors to identify their effect on vulvovaginal and urinary symptoms, sexuality, and

QoL issues.

The findings of this thesis highlight the need to make a greater effort to provide women with more information about the adverse effects of treatment and the early recognition and appropriate management of patients with significant genitourinary symptoms as a result of adjuvant endocrine therapy. This should enhance clinical care and help improve the outcomes for women with breast cancer.

8.3. Strengths

The integration of qualitative and quantitative research methods in this thesis enhanced the overall research design and reinforced the integrity and applicability of the research findings. To

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the best of our knowledge, the present study is the first to qualitatively explore women’s views, knowledge and information needs about genitourinary symptoms while receiving adjuvant endocrine therapy. It is also unique in that it prospectively and comprehensively documented the prevalence and severity of a wide range of genitourinary symptoms in postmenopausal women prior to starting treatment with endocrine therapy (baseline) and in multiple follow-ups during endocrine therapy (six-, 12- and 24-months). Furthermore, the use of standardised and widely recommended symptom scales in this study accentuated its advantage as it allowed a broad range of genitourinary symptoms to be systematically evaluated which no other study has done previously. Therefore, this study was able to evaluate the impact of each of the assessed genitourinary symptoms on breast cancer patients.

8.4. Limitations

The most important limitation in this study was the lack of adequate power to draw definitive conclusions regarding the possible differences in genitourinary symptoms between TAM and AI groups. At the time of data analysis, there were a small number of participants on TAM. It is however, expected that in future reports from PEGASUS study, sample size will be sufficiently powered to show whether there are significant differences in symptoms across treatment groups, which could also be of use to clinicians if there is a higher risk of severe symptoms between the different treatment groups.

Additionally, with longer follow-up this study will be better able to report whether symptoms stabilise, improve or deteriorate after six months, at one year and two years into therapy, as well as analyse the characteristics of groups who discontinue or switch treatments over time. This was not possible in this primary analysis due to the very small number of participants who

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switched or discontinued endocrine therapy (n=10). Noncompliance is an important issue and will be further investigated in future analysis. Although, study questionnaires covered compliance with therapy, with one specific question asking participants whether or not they take their medication regularly, little is known about the reasons why two women discontinued therapy and a further eight switched classes of drugs. Although this noncompliance rate is much better than that reported to date, it would be interesting to know why these women failed to complete their evaluations, particularly if the reason is related to genitourinary side effects of treatment.

8.5. Recommendation and future work

Despite some limitations, the current thesis adds to the knowledge base of the genitourinary- adverse effect of endocrine therapies and shows that symptoms develop or worsen over time and that these symptoms are important to women with early breast cancer. Study findings accentuate the importance of increasing awareness among oncologists to screen for genitourinary symptoms prior to recommending endocrine therapy as well as for continuous monitoring of these symptoms during follow-up consultations allowing for timely diagnosis and management of symptoms. These topics are frequently not discussed and early interventions are much more likely to be effective than treatment after years of estrogen deprivation. Thus, clinicians should be more proactive in inquiring about genitourinary symptoms in patients on adjuvant endocrine therapy as well as asking about any sexual concerns or problems and offering advice and referrals when appropriate. A multidisciplinary team approach is often required and treatment needs to be tailored to the individual patients’ specific needs and circumstances.

There are a number of issues detailed in this thesis that warrant further study. Further work should explore the views of noncompliant patients in regards to whether genitourinary outcomes

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of endocrine therapy have an impact on their decision to discontinue therapy. It would also be of interest to investigate whether symptom checklists and/or patient prompt sheets would be a useful strategy in promoting breast cancer patient-doctor communication about genitourinary symptoms. Moreover, further larger quantitative research may also be of use in verifying perceived barriers (from clinicians and patients) to the discussion of genitourinary problems. In regards to treatment options, future studies to define the safety and efficacy of ospemifene, as well as topical testosterone are needed, as they do appear to offer benefit. Finally, the results of this study could be used to develop information kits on genitourinary symptoms and management options for patients and clinicians.

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APPENDICES

I Invitation Letter for Study I II Patient Information Pamphlet Study I III Consent Form Study I IV Opt-in Response Slip Study I V Interview Guide Study I VI Summary of participants’ perceived causes of genitourinary symptoms VII Summary of motivations and obstacles to help seeking VIII Recruitment Sheet Study II IX Recruitment Process Study II X Recruitment Script Study II XI Invitation Letter for Study II XII Consent Form Study II XIII Patient Information Pamphlet Study II XIV Baseline questionnaire (Q1) Study II XV Follow-up Questionnaire (Q2-Q4) Study II

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APPENDIX I. Invitation Letter for Study I

[LETTERHEAD]

Dear < Name>,

I am writing to invite you to take part in a study, which is being conducted by researchers from the Prince of Wales Hospital, Sydney into possible genitourinary side effects of hormone therapy, such as Tamoxifen, Arimidex, Femara or Aromasin.

Many women who experience genitourinary symptoms such as frequency, urgency, burning as well as incontinence, often find it difficult to talk about their symptoms. In view of this we don’t know how commonly they occur and how much they affect day to day living.

The study aims to better understand the genitourinary side effects of hormonal therapy for early breast cancer and their effect on quality of life and to research what can be done to treat or possibly prevent the symptoms.

You are invited to this study because you have previously been diagnosed with an early breast cancer and are currently taking hormonal therapy.

Participation in the study would involve being interviewed by [name of Researcher] over the telephone or face-to-face at Prince of Wales Hospital, depending on your preference, at a time that is convenient to you. The interview will last between 30 minutes and one hour. Your interview responses will be completely confidential and their content will not be shared with me or anyone else.

The enclosed Participant Information Pamphlet provides detailed information about the study. If, after having read the Participant Information Pamphlet you do wish to participate in the study, please:

1. Complete the enclosed Response Sheet to indicate your interest 2. Sign the study Consent Form, and 3. Return both forms to [name of Researcher], using the reply-paid envelope provided, within the next 5 days if possible.

[Name of Researcher] will then contact you to tell you more about the study, answer any questions you might have regarding the study, and arrange for an interview time. If you have any questions about the study, please call [name of Researcher], on 1800 814 403 (free of charge) and leave a message.

Participation in this study is completely voluntary. It is up to you whether or not you participate. If you do not wish to participate, please also complete the enclosed Response Sheet and we will not contact you again in relation to the study.

Your participation in this study would be invaluable and allow us to understand the frequency and potential importance of the genitourinary side effects of hormone therapy. Many thanks for considering our request.

Yours sincerely,

[Head of Department of Oncology]

Letter of Invitation dated 05/10/2012, version 2 Page 1 of 1

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APPENDIX II. Patient information pamphlet Study I

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APPENDIX III. Consent Form Study I

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APPENDIX IV. Opt-in Response Slip Study I

RESPONSE SHEET

Study Title: Experiences of genitourinary symptoms in women receiving adjuvant hormonal therapy for early stage breast cancer - A qualitative study

Your name: ______

Please indicate, by ticking the appropriate box, whether or not you would like participate in this study:

I would like to participate in this study, have signed the Consent Form and will return the Consent Form together with this Response Sheet in the reply paid envelope provided. I am happy to be contacted by telephone to arrange an interview time. Below are the best times and numbers to contact me.

I am interested in being involved in this study, but would like to find out more about what is involved before I sign the Consent Form. Please contact me by telephone/email to give me more information.

The best way to contact me is by: Telephone at home (Tel no: ______Best times: ______) Telephone at work (Tel no:______Best times: ______) Mobile (Tel no: ______Best times: ______) Email – my email address is:______

I do not wish to participate in this study.

Thank you for returning this card in the reply paid envelope supplied.

Response sheet dated 05/10/2012, version 2 Page 1 of 1

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APPENDIX V. Interview Guide Study I

Introductory Script

1. Thank you for agreeing to take part in this study.

2. This study is about understanding the experiences of genitourinary symptoms in women receiving hormonal therapy for early breast cancer. We want to know how these women perceive their genitourinary symptoms as well as their treatment expectations and reasons for seeking help.

3. We would also like to find out more about the possible impact that hormonal therapy for breast cancer can have on genitourinary symptoms. Learning about your experience will help us to better understand this issue and also to research what can be done to treat or possibly prevent these symptoms in the future.

4. Firstly, I want to check with you whether you have read the Information Pamphlet that was sent to you. If not, I will call you back shortly so that you will have the opportunity to read it before the interview.

5. Is it alright if we digitally record this interview for research purposes? The recording will remain anonymous and will only be used for purpose of analysing the results of the study. I would like to reassure you that your answers are confidential and you have the right to stop the interview at any time. Besides, you are free to talk about any aspect of your experience or attitudes. There are no right or wrong or even typical answers to any of the questions that we will discuss. Are you happy for the interview to be recorder?

6. The interview will take approximately 30 to 60 minutes. There will be an opportunity to de-brief afterwards.

7. Do you have any questions before we start?

8. Ok. I am now going to switch on the digital recorder.

9. The digital recorder is on – we are going to start with some general demographic questions…

PARTICIPANT ID:______

DATE: ______

TIME:______

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Demographics Information

I will now ask some questions about you.

What is your current age? ______(years)

What is your present marital status?

1 Single 2 Married 3 In a committed relationship, not living together 4 De facto (not married but living together) 5 Separated/Divorced 6 Widowed If in a relationship, what is the length of relationship: ______(years)

Do you have children?

0 No 1 Yes. Number of normal deliveries:______

What is the highest level of education you have completed?

1 Year 10 or below 2 Year 12 - HSC

3 TAFE or College certificate/ diploma 4 Bachelor’s degree 5 Postgraduate diploma/ degree 6 Other, please specify: ______

What is your current employment status?

1 Full-time employed 2 Part-time employed 3 Unemployed 4 Self-employed 5 Homemaker 6 Full-time student 7 Part-time student 8 Permanently unable to work 9 Retired 10 Other, please specify: ______

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What is your main occupation (if not currently working or retired, what was your past occupation)? ______

When you are at home, what language do you mostly speak?

1 English

2 Other, please specify language: ______

Medical Information

Now, I will ask some questions about your medical history. Are you happy to be asked questions about this?

Had your menstrual periods stopped (menopause)

0 No 1 Yes. How long has it been since your last menstrual period? ____months/______years

What was your age at the time of your diagnosis of breast cancer? ______years

What form(s) of surgery for breast cancer did you undergo? (More than one may apply)

1 Lumpectomy 2 Unilateral mastectomy (one breast) 3 Bilateral mastectomy (both breasts) 4 Prophylactic mastectomy (preventive) 5 Reconstruction

What form(s) of additional treatment have you received or are currently receiving for breast cancer other than surgery? (More than one may apply)

1 No additional treatment 2 Chemotherapy 3 Radiotherapy 4 Tamoxifen 5 Aromatase inhibitors [anastrozole (Arimidex), exemestane (Aromasin) or letrozole (Femara)] 6 Zoladex 7 Oophorectomy (surgical removal of ) 8 Other: ______

Which endocrine therapy are you receiving right now and for how long?

1 Tamoxifen ______months 2 Anastrozole (Arimidex) ______months 3 Exemestane (Aromasin) ______months 4 Letrozole (Femara) ______months 5 I am currently not receiving any endocrine therapy

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Have you previously received an endocrine therapy different to the one you are taking now?

0 No 1 Yes. What was the name of medication: ______For how long did you receive it? ______months

Understanding

People describe their illness in many different ways. There is no right or wrong answer and sometimes it can be hard to explain.

Do you have any genitourinary symptom? (Prompt: Such as burning, incontinence, urgency, or others)

If participant answers no: Thank you very much for your time and for willing to help us in this study. I really appreciate it. As you answered no to this question you don’t have to answer the rest of the interview.

Can you please describe your genitourinary symptom(s) to me?

Can you tell me about when your symptom(s) started? (Prompt: When did you first become aware that this was happening?) How did you feel about it?

What has it been like for you since this (these) symptom(s) started?

What has been the worst thing about having this (these) symptom(s)?

What do you think was the cause of your genitourinary symptom(s)?

Was there any relationship with the commencement of your symptom(s) and the commencement of hormonal therapy? Do you have any new symptoms that started after you received hormonal therapy?

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Can you tell me how genitourinary problem(s) have affected your daily life?

And what about contact with friends and family? How has this affected your relationships with others?

(If living with a partner) How has your genitourinary symptom(s) affected your husband/ partner? (Prompt: Does your genitourinary problem(s) influence your relationship with your partner?)

What about the intimate side of your life, how has it affected your marital life/sex life? Do any genitourinary symptom(s) prevent you from having intercourse with your partner? (Prompt: To what extent do your genitourinary problem(s) interfere with your sexual performance?)

Can you tell me how do you manage your symptom(s)?

How would you describe your general health at the moment?

Reasons for seeking help

Have you spoken to anyone about your symptom(s)? (Prompts: YES/NO)

IF YES:

Who did you talk to first about your genitourinary problem(s)? (Prompt: friend, partner, doctor, etc.) What sort of support or advice did you receive?

Did you speak to a doctor about your genitourinary symptom(s)? How long did it take you to go see a doctor?

What specifically prompted you to see a doctor for your genitourinary symptom(s)? How helpful did you find it?

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Or (if not seeing a doctor) Why didn’t you see a doctor yet?

(If refereed to the specialist) What led up to your referral to the specialist?

IF NO:

Why didn’t you seek any help yet?

CONTINUATION:

If you need to seek for any help with sexual problems related to your genitourinary symptom(s), would you know where to go?

(Depending on the response above) Do you think______(doctor/specialist, GP, oncologist, gynaecologist, etc.) would have more understanding of what’s going on?

What do you consider would be an obstacle for you to seek for treatment regarding your sexual problems?

Acceptability/ treatment expectations

What form(s) of treatment have you received or are currently receiving for genitourinary concerns? (Prompt: None, bladder surgery, bladder training, exercises/biofeedback, nutritional supplements, medications, vaginal moisturizers, others)

What is your treatment expectation? (Prompts: to be completely cured, relief of symptoms, to prevent new symptoms, to feel comfortable, a quick-fix, others)

What kind of change in your symptom(s) would be meaningful to you? (Prompt: When deciding if your treatment is working, what symptom(s)/ issue(s) do you consider?) 251

What would be a meaningful change in terms of percentage improvement for you? (Prompt: For example, would a 20% improvement be meaningful to you?)

Information needs and preferences

Can we talk about the ways that you think you could have been helped?

Tell me what you think would have been most helpful to you in dealing with your genitourinary problem(s)?

What problems did you have with getting care, if any?

Would you prefer to seek treatment in a confidential setting to minimize potential embarrassment?

How do you think people who have similar problem(s) to yours should be helped?

Why do you think people who have similar problem(s) to yours sometimes find it difficult to get the help they need?

It would be helpful to us to know what women’s preferences are with regard to when and how information regarding genitourinary symptoms is delivered.

What do you think about the availability of information regarding genitourinary symptoms?

At what time point would you prefer to receive information about genitourinary concerns? (Prompt: What would be the perfect timing for receiving this type of information?)

How much information (if any) would you like to receive as part of your breast treatment regarding genitourinary symptoms? (Prompt: What would you define as the “perfect” amount of information you would like to receive?)

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How would you like to receive information about genitourinary symptoms? (Prompts: Information leaflet, question prompt sheet, information video, consultation with expert, talks provided by experts, Internet, etc.)

Who would be your preferred health professional (if any) to receive information about genitourinary symptoms from? (Prompts: Medical oncologist, surgeon, nurse specialising in breast cancers, gynaecologist, urologist, etc.)

Interview debriefing and closure script

1. Thank you! We have finished the questions!

2. Finally I would like to give you the opportunity to debrief in case the content raised questions for you or caused you any distress…

3. How did you feel taking part in the interview?

4. Do you still have the free-call study number (1800 814 403) in case you would like to contact the research team in the future?

5. Do you have any questions about what I have been asking you, or has our conversation brought up anything you’d like to talk about?

6. [if not] If you have any questions about this later please call this number back.

7. [If yes, talk to participant] If there is anything else you are worried about please see your medical staff.

8. Would you like to receive a free summary of the study findings at the end of the study? 0 No 1 Yes [If yes: write name and address or email address in appropriate sheet] 253

Your contact details are written on separate sheet from your responses to the study. They will remain confidential and will only be used for the purposes of sending you the study summary. The sheet will not be linked to your responses or the audio recording and will be shredded after the study summary is sent to you.

9. Would you like to arrange a time to talk with a member of the research team about anything further?

0 No 1 Yes

10. Thank you for sharing your experiences.

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Appendix VI. Summary of participants’ perceived causes of genitourinary symptoms

Participant Perceived causes Quotation

[GT,Pre,01] Menopause, age, “I think it’s got something to do with the ‘mini’ menopause that, you know, the menopause something, it just endocrine therapy affects everything. It’s going to be some sort of link between… ‘cause I am sure, I think from what I know is that usually women that are older tend to have […] because I am in a medically-induced early menopause, it must have something to do with that ‘old’ thing. I know this year certainly got really much worse again so I don’t know if it was the tamoxifen.”

[GT,Pre,02] Breast cancer treatment, “just more frequent than what I remember previously, prior to having breast cancer […] so basically from menopause the time that I probably started chemotherapy […] oh I thought was the combination of chemotherapy and then going into menopause, and all the symptoms that come with menopause basically.”

[GT,Pre,03] Endocrine therapy, age, “I don’t know if it’s got worse because I had the tamoxifen or if it’s just something that I’m just getting weaken bladder/pelvic older and it’s getting worse anyway […] and I also had some weak, a little bit of a weak pelvic floor, so like floor, psychological if I sneeze or cough sometimes there would be a little bit of leakage […] may be related to anxiety.”

[GT,Pre,04] Breast cancer treatment, “I’m not sure if it’s been the injection [Zoladex], or the tablets [tamoxifen], or both? A combination of endocrine therapy, both? […] I don’t know if that’s normal menopause or if it’s because of the medication” menopause

[GT,Pre,05] Age, menopause, “I just thought it was part of aging […] Well it’s hard to say I think, because I was going through endocrine therapy menopause at the same time as taking the tamoxifen so the lines were a little bit blurred because I definitely have you know night sweats and things like that, which I believe could be exacerbated by the tamoxifen.”

[GT,Post,06] Endocrine therapy, “I think it was within, it was within two weeks of starting with the tamoxifen and I think with high anxiety I psychological have also had symptom a couple of times when I have been on Aromasin.”

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[GT,Post,07] Endocrine therapy, “it’s more often now because I think the medication dried it off, so I kind of went through menopause twice menopause, age, weaken […] I was true menopause and then they put me on medication […] my body, it all sort of dried out and bladder/pelvic floor then […] I don’t know though if it’s to do with… because I am sixty you know, you get older. I just, my pelvic floor it’s probably not quite strong […] it’s probably a little bit more frequent since I have been taking the medication […]so four years […] so I was good and then, then I got cancer and I then, I went onto the treatment which blocks estrogen, that’s how it… and you know, it really has dried me up quite significantly.”

[GT,Post,08] Endocrine therapy, age “The first time I’ve been on the tamoxifen I thought I was very sore […] I think the urinary tract is a bit more large[…] yes, as soon as I started taking tamoxifen, the first week […] I can’t wait to finish the tamoxifen because it feels uncomfortable down there[…] maybe it was a coincidence, maybe when once I’ve reached sixty-five it would’ve happened anyway.”

[GA,Pre,09] Breast cancer treatment, “When I look back I had the first bladder problems when I was having the cycle of Femara, I got a bladder endocrine therapy infection with the first days and then after that I just noticed my bladder’s irritated a lot often […] like it’s all happened around the time of my cancer treatment and it’s still happening.”

[GA,Post,010] Childbirth, weaken “I suppose I had a big child, my first boy was nine pounds […] I don’t know if that’s true or not I said nah, bladder/pelvic floor people say it’s because of having children […] well I’ve always been weak in that area, I am, I have , I do have weakness.”

[GA,Post,011] Endocrine therapy “I go very often to the toilet, with the Femara, I mean, with the Femara and before I have a problem but now more often”

[GA,Post,012] Breast cancer treatment “…really when I was going to chemo and radiation, I was ok until then, up to then I was fine, yeah.”

[GA,Post,013] Age, childbirth, weaken “I put it down to aging and having babies or weaken bladder.” bladder/pelvic floor

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[GA,Post,014] weaken bladder/pelvic “…you know with the bladder […] there is a sphincter or sort of muscle, you know, it could be an issue and floor, personal maybe it’s changing […] wondered about wine.” behaviour

[GA,Post,015] Age, breast cancer “… ‘cause since having the chemotherapy I guess you lose a lot of muscle control in your body […] I just treatment, weaken thought my age […] having gone through the chemo and knowing the loss of the muscle tone of the body, it bladder/pelvic floor still isn’t back, I have very weak muscle tone […] the core strength just isn’t there.”

[GA,Post,016] Psychological “Maybe run down, maybe, a bit run down.”

[GA,Post,017] Age, weaken “It is old age, your muscles get loose I suppose […] I honestly think it is the age factor because I think your bladder/pelvic floor muscles aren’t as good as when you are younger.”

[GA,Post,018] Behaviour “…because I have a cup of tea last thing going to bed, I love a nightcap cup of tea and I drink a lot of water.” [GA,Post,018]

[GA,Post,019] Age “Old age.”

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Appendix VII. Summary of motivations and obstacles to help seeking

Perceived motivations and obstacles

Motivations

Fear of cancer “First of all I would want to set aside any issue, you know, that there could be something worse[…] it is the first thing to look at […]There is the possibility that this symptom could be related to cancer.” [GA,Post,014]

“…to get checked, make sure there was nothing else that might’ve been another cancer or something[…] ‘cause I just want to make sure I don’t have another cancer.”[GA,Pre,09]

Severity or duration of symptoms “You know the symptoms were so severe that I was at the doctors immediately.” [GA, Post,018]

Appraisal of personal relationship “Because she is a lady, and she is very nice with and gender of healthcare doctor and loves me and explains to me professionals everything and she has patience, she is not in a hurry you know, to see me.”[GA,Post,011]

New treatment available “I’ve been told that there is a new thing now, it’s like a, another band aid, elastic, a thing to back it up.” [GA, Post,012]

The need of medication/ prescription “I knew that I had to have an antibiotic, you know or referrals and to get the script.” [GA, Post,016]

Obstacles

Perception of symptoms as not as “Absolutely, not a big, not a big issue, it’s important or not-life threatening nothing to compare to the other things that I’m dealing with.”[GA,Post,015]

Uncertainty about available treatment “… and are there, are there treatments?[…] options/ lack of information Really?[…] What happens then? Is there a surgery?[…] I haven’t done anything simply because as I said, I didn’t have any information. It should be available.”[GA,Post,017]

“…having some urologist deciding that I need a bladder surgery or something? Because like, I don’t know if I would want to have any more surgeries, I mean, certainly not at the moment[…] and that’s what I think would happen.”[GA,Post,018]

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Lack of any obvious physical sign “Well there aren’t any physical symptoms in the sense that I am like a child, when I want to go, I want to go all of a sudden, and that doesn’t even give me a chance half the time to reach the toilet” [GA,Post,019]

“I don’t find that there is a symptom, the urgency, no it doesn’t, because I don’t soak myself.”[GA,Post,017]

Attitudes towards healthcare use “I tell myself ‘why are you going to the doctors?’ I don’t want to see any more doctors, you know, I am sick off the doctors.”[GA,Post,011]

“It’s waiting in hospitals, waiting to get help in some way, I think that’s one of the reasons[…] I don’t feel myself sitting in waiting rooms like, you know, because that’s how the situation now is, just wait, and sit in waiting rooms for ages”[GA,Post,013]

Costs (financial and social) “…you hardly ever find a gynaecologist who isn’t going to charge you.[…] plus there’s a lot of people that can’t afford it[…] I’ve got no money these days. I put a lot of money for my reconstruction and it’s really set me back a lot, you know”[GA,Post,013]

“The cost and the issue around taking antibiotics and the cost of consultation and prescription potentially must be quite high if this is just a side effect of taking, of being on this medication”[GT,Post,06]

Embarrassment “Always confidential, I live with 45 other women but I don’t tell them, you know, no one knows that I have this problem.” [GA,Post,016]

“Maybe a bit embarrassed” [GT,Pre,05]

“I guess it is very personal. Not easy for a lot of people to discuss.”[GA,Post,015]

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VIII Recruitment Sheet Study II

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IX Recruitment Process Study II

PEGASUS - Women’s experiences of genitourinary symptoms study ELIGIBILITY CRITERIA

To be eligible to participate in the study, women must: ! Be post-menopausal* at diagnosis ! Early breast cancer (Stages IA, IB, IIA and IIB) ! Oestrogen receptor positive tumours ! Prior to start adjuvant endocrine therapy (tamoxifen or aromatase inhibitors) ! Be aged between ≥18 and ≤75 years ! Be able to complete questionnaires written in English

* Post-menopausal status is defined as cessation of menses for more than 1 year.

EXCLUSION CRITERIA

· Women with recurrent cancer or metastatic disease · Women with abnormal bleeding · Women currently using HRT** (including vaginal oestrogen)

** Women on hormonal replacement therapy (HRT) while being diagnosed with breast cancer should have stopped therapy for at least 1 month prior to the start of this study.

Recruitment Process dated 11/07/2012, version 1 Page 1 of 2

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RECRUITMENT PROCESS

Establish eligibility (see criteria)

Invite women before they start endocrine therapy (tamoxifen or aromatase inhibitors)

(i.e. shortly after surgery, post-operative consultation, during chemotherapy or radiotherapy)

Woman is interested in participating: · Complete Recruitment Sheet

Woman declines participation: · Complete ‘decliners’ section of Recruitment Sheet (optional)

Fax Recruitment Sheet to study co-ordinator:

Fax: 02[Insert] 9385 0033

Recruitment Process dated 11/07/2012, version 1 Page 2 of 2

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X Recruitment Script Study II

PEGASUS – Women’s experiences of genitourinary symptoms study

RECRUITMENT SCRIPT

Background Information for Breast Care Nurses (BCNs) & Oncologists This is a prospective multi-site study to investigate the prevalence and severity of genitourinary symptoms in post-menopausal women receiving adjuvant endocrine therapy for early breast cancer. We want to compare the results before women start receiving endocrine therapy and during. We also want to determine whether there is an association between genitourinary symptoms and sexual functioning and overall impact on quality of life in this group of women. As part of the study, women will be asked to complete four brief questionnaires over a 24 months period. If a woman agrees to take part, she will have to provide her postal address or e-mail (depending on how she wants to be contacted), apart from her name and telephone number to the BCN or to her treating oncologist to fax this information to the research co- ordinator.

Script (for inviting woman to study) “We are involved in a research study investigating how commonly genitourinary symptoms occur and how bothersome they can be in post-menopausal women taking hormonal therapy for early breast cancer. Many women on this therapy report genitourinary symptoms such as urinary frequency, urgency, burning, incontinence, pelvic organ prolapse and vaginal dryness but they often find it difficult to talk about their symptoms. In view of this we don’t know how commonly they occur and how much they affect day to day living. We believe that this study may contribute to better outcomes for women diagnosed with breast cancer and experiencing genitourinary symptoms in the future.

Taking part in this study would involve completing four brief questionnaires over a period of 24 months. Participation is completely voluntary and whether you say yes or no won’t affect your medical care in any way. If you would like to be involved or you would like to have more information about the study to help you decide whether or not to participate, I will give your name and phone number to the study co- ordinator. I will also need to know if you prefer to receive the study material and the first questionnaire via postal address or e-mail. The research co-ordinator will then phone to tell you more about the study and answer any questions you might have. Would you like to participate?”

If YES Obtain contact details If NO Thank you for your time and complete the decliners section of Recruitment Sheet (optional)

CONTACT DETAILS (Insert details on the Recruitment Sheet)

Obtain contact details and preferred contact method and time to be telephoned by the research co-ordinator.

BCNs/ Oncologists: “How do you prefer to receive informational materials about the study: via e-mail or mail? If it’s ok I will now take your name, phone number and address/e-mail to send to the research co-ordinator to contact you. What would be a convenient time for her to call?”

Recruitment Script dated 15Feb2013, version 3 Page 1 of 1

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XI Invitation Letter for Study II

[LETTERHEAD]

Dear < Name>, I am writing to invite you to take part in a study, which is being conducted by researchers from the Prince of Wales Hospital, Sydney into possible genitourinary side effects of hormone therapy, such as tamoxifen, arimidex, femara or aromasin.

Many women who experience genitourinary symptoms such as urinary frequency, urgency, burning, incontinence and pelvic organ prolapse often find it difficult to talk about their symptoms. In view of this we don’t know how commonly they occur and how much they affect day to day living.

The study aims to better understand the genitourinary side effects of hormonal therapy for early breast cancer and their effect on quality of life and to research what can be done to treat or possibly prevent the symptoms.

You are invited to this study because you have previously been diagnosed with early breast cancer and hormone receptor positive tumour.

Participation in the study would involve completing four brief questionnaires over a period of two years, each of which takes 20-30 minutes to complete. You can choose to receive the questionnaires as hard copies or to complete them online. Your responses will be completely confidential and their content will not be shared with your doctor.

The enclosed Participant Information Pamphlet provides detailed information about the study. If, after having read the Participant Information Pamphlet you do wish to participate in the study, please:

1. Sign the study Consent Form, enclosed 2. Complete the 1st questionnaire, enclosed 3. Return the Consent Form and the questionnaire to me using the reply-paid envelope provided, within the next 5 days if possible.

I will then contact you to tell you more about the study, answer any questions you might have regarding the study, and organise proceedings from there. If you have any questions about the study, please call me on 1800 814 403 (free of charge) and leave a message.

Participation in this study is completely voluntary. It is up to you whether or not you participate. If you do not wish to participate, please leave a message on the free call number and we will not contact you again in relation to the study.

Your participation in this study would be invaluable and allow us to understand the frequency and importance of the genitourinary side effects of hormone therapy. Many thanks for considering our request.

Yours sincerely,

Study Co-ordinator

Letter of Invitation1_ version 2_dated 20 May 2013 Page 1 of 1

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XII Consent Form Study II

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XIII Patient Information Pamphlet Study II

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XIV Baseline questionnaire (Q1) Study II has been removed due to Copyright restrictions

XV Follow-up Questionnaire (Q2-Q4) Study II has been removed due to

Copyright restrictions

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