The impact of medication side effects on adherence and persistence to hormone therapy in breast cancer survivors: A qualitative systematic review and thematic synthesis

Background Hormone Therapy (HT) reduces the risk of breast cancer recurrence and mortality in women with breast cancer. Despite these clinical benefits, rates of HT non-adherence and non-persistence are high. Research suggests this may be due to the impact of HT side effects. However, little research has explored the individual contribution of side effects to non-adherence and non-persistence behaviours, thereby hindering the implementation of targeted intervention strategies. Our aim is to review the published literature on breast cancer survivors’ lived experiences of HT side effects and explore how these may be related to non-adherence and non-persistence behaviour. Methods Electronic searches were conducted from inception to May 2020, utilising Cochrane CENTRAL, Medline, Embase, Web of Science and PsycINFO databases. Searches included a combination of terms related to breast cancer, adherence, hormone therapy and side effects. Results Sixteen eligible papers were identified, and study quality was high. Data were thematically synthesised into four analytical themes, which encompassed 13 descriptive sub-themes: ‘Daily impact of side-effects’, ‘Role of Health Care Professionals’, ‘Managing HT side-effects’, and ‘Weighing up the pros and cons’. Conclusions HT side effects significantly impact breast cancer survivor's quality of life. A lack of support from healthcare providers leads to self-management strategies, which negatively affects adherence and persistence behaviour.


Introduction
Breast cancer is the most common cancer in the UK, accounting for 15% of all new cases and is the third most common cause of cancer-related deaths [1]. Hormone Therapy (HT), is a treatment that suppresses hormone production or that interferes with hormone receptor signalling in order to prevent tumour growth, is prescribed to breast cancer survivors for up to ten years following diagnosis. Around three quarters of breast cancers are hormonereceptor-positive and are treatable with HT. The most commonly prescribed HTs are Selective Estrogen Receptor Modulators (SERMS) (e.g. Tamoxifen) and Aromatase Inhibitors (AI) (e.g. Letrozole, Anastrozole and Exemestane) [2]. When taken as prescribed, HT reduces the risk of breast cancer recurrence by 40% and mortality by a third [3]. However, despite its clinical efficacy for recurrence prevention, many cancer survivors do not take their HT as prescribed. Approximately 50% of women take less than 80% of the prescribed dosage [4] and up to 50% discontinue their treatment by the fifth year of prescription [5]. This pattern of poor persistence and non-adherence is associated with increased odds of breast cancer recurrence and mortality [6]. Adherence to and persistence with hormone therapy is therefore considered a key determinant of disease-free survival.
Adherence is defined as the degree to which an individual's behaviour corresponds with agreed treatment recommendations in terms of dose, timing and frequency, whereas persistence refers to the duration of treatment from initiation to discontinuation [7]. Recent research has begun to explore the mechanisms that impact upon adherence and persistence behaviour and has identified sociodemographic, clinical and psychosocial characteristics as potential risk factors [8,9]. Sociodemographic variables such as age, socioeconomic status, ethnicity, education and out of pocket costs of medications have been shown to negatively impact HT adherence and persistence [10e12]. Similarly, clinical characteristics such as switching between treatments (e.g. from Tamoxifen to Letrozole) is also negatively associated with adherence and persistence [12]. Whilst the identification of sociodemographic and clinical risk factors facilitate our understanding of those individuals most likely to be non-adherent and non-persistent, they have limited value when considering strategies to promote positive behaviour change. However, identifying psychosocial characteristics that increase the risk of non-adherence and non-persistence to HT does provide a potential pathway to behaviour change interventions to promote adherence and persistence.
In a recent review of barriers and facilitators of HT adherence and persistence [9], several factors were identified as possible intervention targets due to their impact on adherence and persistence behaviour. One of these factors was categorised as 'side effects from HT' and included cognitive, gynaecological, musculoskeletal and sleep/fatigue-related symptoms. Similarly, numerous studies have found that patients' experience of HT side effects (joint pain, hot flushes, night sweats, fatigue), affect adherence and rates of treatment discontinuation [8,13,14], potentially because the adverse effects of treatment outweigh the perceived benefits [15]. Therefore, unlike sociodemographic and clinical factors that are not amenable to change, side effects are suggested intervention targets because their effective management has the potential to increase long-term HT adherence and reduce rates of treatment discontinuation. However, the contribution of specific side effects to HT non-adherence and non-persistence is poorly understood, making the development and prioritisation of targeted intervention strategies difficult. Many studies prefer instead to utilise quantitative questionnaire-based methodologies to report an overall side effect profile where presence/absence of side effects are reported as a single yes/no variable [16e18]. In addition, a lack of consistency in published terminology (e.g. adherence, compliance, persistence, continuance), definitions (e.g. medication possession ratio (MPR) of 80% or discontinuation before 5 years), data measurements and sources (e.g. medical records, clinician checklists, self-report questionnaires) make cross-study comparison challenging [19]. Therefore, greater consistency and qualitative understanding of the impact of individual side effects would help to identify and quantify the specific psychosocial determinants of non-adherence and non-persistence that are modifiable through intervention.
Two recent reviews of qualitative research in this area [19,20] have identified that adherence to HT is negatively impacted by the presence and severity of side effects. However, these reviews were broad in scope, considering multiple patient-related factors (e.g. quality of life, self-efficacy, patient beliefs, side effects) that influenced adherence and persistence. Therefore, whilst these studies provide valuable insight into the lived experience of taking HT, further qualitative work must explore the primary motivations for non-adherence and non-persistence if tailored approaches for managing side effects are to improve adherence and persistence behaviour in breast cancer survivors. Therefore, the aims of this review are to (i) synthesise breast cancer survivors' lived experiences of HT side effects and (ii) conduct an in-depth exploration of how these experiences may influence adherence and persistence behaviour. By synthesising experiences of side effects and how they are perceived to influence adherence and persistence behaviour, potential facilitators and barriers to adherence and persistence will be identified. This will inform the implementation of targeted evidence-based interventions to improve adherence to HT and reduce rates of recurrence and mortality.

Method
This review has followed the ENTREQ statement [21] and has adopted Thomas and Harden's (2008) [22] approach to thematic synthesis.

Search strategy
A comprehensive search strategy was developed and adapted from   [9]. A combination of search terms related to 1) breast cancer, 2) adherence and persistence 3) hormone therapy and 4) side effects were included. A full copy of the search strategy is included as a supplementary file. Electronic searches were performed from inception to May 2020 using the following databases: Cochrane CENTRAL, Medline, Embase, Web of Science, and PsycINFO. The review protocol was registered on the PROS-PERO database on August 13, 2020 (CRD42020192481). As outlined in the protocol, we originally planned to conduct a mixed-methods review of the literature on the impact of HT side effects on adherence and persistence. However, the initial search generated such a significant volume of quantitative and qualitative studies that it was decided to be more valuable to publish two separate reviews.

Inclusion criteria
Studies were included if they utilised a qualitative methodology to investigate the impact of HT side effects on adherence and/or persistence in adult, female breast cancer survivors. No exclusion criteria were applied to year of publication. Papers were excluded if they were not available in English. Full details of the inclusion/ exclusion criteria are presented in Table 1.

Study selection
Search results were uploaded to 'Covidence' (Melbourne, Australia), an online tool used to manage systematic review screening and data extraction. After the removal of duplicates, titles and abstracts were independently screened by two authors (NP & SA) using a pre-defined screening tool based on the inclusion/ exclusion criteria. If an abstract did not provide sufficient exclusion information, then the article was obtained for full text screening. Full text screening was conducted independently by the same two authors. Screening conflicts were resolved through discussion with a third reviewer (LF). Efforts were made to contact authors of papers where the full text was unavailable and to obtain full reports from conference abstracts.

Data extraction
Data were extracted from the method sections of included papers to obtain details of the study purpose, sample size, participant characteristics, study design and method of analysis. Data extraction was conducted by two authors (NP & SA) and all text labelled as 'results' or 'findings' were extracted to permit synthesis of all relevant data [22].

Quality appraisal
Selected studies were assessed for quality using the Joanna Briggs Institute Critical Appraisal Checklist for Qualitative Research [23]. Two authors (NP & SA) independently assessed the quality of the included studies by scoring each article against the checklist criteria of "met", "not met", "unclear" and "not applicable". The quality criteria included domains related to method and methodology, data analysis, interpretation of results and reflexivity. An additional item was added to the quality assessment tool to assess whether the included studies had provided a clear description of adherence and persistence. This additional item was scored using the same checklist criteria. Any disagreements were resolved by consulting a third author (LF). In this review no study was eliminated based on quality assessment.

Data analysis
Data were analysed according to the thematic synthesis approach developed by Thomas & Harden [22]. This approach is influenced by both meta-ethnography and grounded theory [24]. The first stage of this approach is inductive, coding results line-byline, then re-examining codes across studies to identify similarities. Following Thomas and Harden's [22] use of axial coding, codes were then re-assessed to ensure they accurately captured the data and additional levels of code were assigned when the text could be more appropriately represented. Descriptive themes were then developed by organising codes together into logical groups. The initial coding was conducted by SA, with NP contributing to the final interpretative stage. Analytical themes were developed from the data to explore women's lived experience of taking HT and the influence of HT side effects on adherence and persistence behaviour. Table 1 Inclusion and exclusion criteria.

Study characteristics
A total of 5107 articles were identified. After removing quantitative studies, duplicates and screening titles and abstracts, 456 full-text articles were screened. Sixteen articles were included in the review. Full details of the search results and reasons for exclusion are shown in the PRISMA diagram (Fig. 1). The included studies were published between 2013 and 2019. Studies were published in 7 countries, with almost half (n ¼ 7) originating from the USA. Sample sizes ranged from 12 to 54 participants: the total number of participants interviewed was 445 (excluding Mao et al. (2013) as this study included messages posted on a website) [25]. For full study characteristics information, see Table 2.

Quality assessment
Overall, the methodological quality of the included studies was judged to be high. However, only 50% of studies provided a clear description of adherence and persistence. Details of the quality assessment can be seen in Table 4.

Thematic synthesis
Four analytical themes were derived from the data. The first, 'Daily impact of HT side effects', relates to the influence of HT on all aspects of functioning, including work, relationships, social life and physical and mental health. The second theme, 'Role of Health Care Professionals (HCPs)', highlights the important role that HCPs play in a patient's HT adherence behaviour. Third, 'Managing HT side effects' summarises the strategies used by patients to reduce HT side effects. Finally, 'Weighing up the pros and cons' highlights the key aspects involved in HT adherence and persistence decision making. For each of these analytical themes, several descriptive themes were identified, which are detailed in Table 5 below.

Daily impact of HT side effects
Many women reported experiencing intense side effects from HT, describing them as "violent" and "excruciating" [37]. Side effects were reported to significantly impact on women's quality of life, which as a result impacted upon their mental wellbeing. This created a heavy emotional burden which led women to question their identity and to experience depressive and suicidal states [30,32,33,36,38]. Physical side effects such as joint pain had a debilitating effect, leaving one individual reliant on a cane for walking [32]. Several participants experienced pain throughout the whole body, severely restricting their movement. This limited their ability to perform household chores, personal care and even simple tasks like getting out of bed in the morning [30,32]. Ability to perform physical tasks at work was also affected [31]. As well as restricting physical capability at work, cognitive side effects of hormone therapy (including difficulty concentrating and memory loss) made it difficult for women to focus on tasks [41]. Women also described themselves as more forgetful, which was exacerbated by the interruption of sleep due to hot flushes, night sweats and joint pain [31,34,35,37]. This loss of sleep was related to lack of energy for social activities and professional responsibilities [31]. Professional confidence was also affected by body image concerns due to weight gain [38]. In addition to debilitating physical side effects, the "disabling" effect [36] of adjuvant HT treatment had severe emotional implications. Women became socially withdrawn and avoided typical daily activities due to fear of embarrassment from unpredictable side effects and losing trust in their own bodies [37]. A loss of sexual desire and menopausal symptoms such as hot flashes and vaginal dryness put strain on romantic relationships [33,38], which was distressing for several participants [36,38]. Women also reported that side effects impacted on other interpersonal relationships, such as relationships with family members and friends, as they felt that they were unable to interact with them as they had done previously [38], or that they could not talk to them about the side effects they were experiencing [31]. Menopausal symptoms also impacted women's sense of identity, as symptoms such as musculoskeletal pain, loose teeth, vaginal dryness and alopecia created a sense of premature ageing, leading one individual to describe feeling "like a 90-year-old woman" [34].

Role of Health Care Professionals (HCPs)
A lack of pre-emptive information about the nature and severity of HT side effects was highlighted consistently in the literature, with women reporting feeling unprepared for what they experienced. Participants explained that they had been informed of the side effects of primary treatment such as chemotherapy [27], but expressed the desire to be forewarned about the potential side effects of hormone treatment [26]. Some had been prepared for side effects but were surprised by the range and intensity of the menopausal symptoms [34]. Women stated that this lack of information was a significant issue, as informed expectations would about how Adjuvant Hormone Therapy-related symptoms might be better managed.
Wells et al. have helped them to cope better and potentially, to adhere more closely to their prescription [27,30]. Many struggled to identify whether menopausal symptoms were due to HT, normal ageing or pre-existing conditions [38] and this confusion was linked to delaying seeking help, which led to worsening of side effects and in some cases, discontinuation of treatment [40]. Although some women recalled having initial conversations about the purpose of adjuvant treatment, they struggled to describe these conversations, and many were sure they had received little warning about potential side effects [31]. Many were informed of adjuvant treatment during their first cancer treatment consultation and had been too "bombarded" [27] with information to fully comprehend or remember what information they had been given. The transition from "receiving" primary treatment (chemotherapy, surgery and radiotherapy) [38] to being largely responsible for their own medication use, marked a significant change for breast cancer survivors. Participants described "falling through the gaps" [27] of the healthcare system after finishing primary treatment, with some feeling that their primary care practitioner did not possess sufficient specialist knowledge to support them with adjuvant HT [26,33] and that other Health Care Professionals (HCPs) (such as breast cancer nurses and oncologists) [29,31] were too busy supporting patients in primary therapy to answer their questions. This resulted in women feeling unsupported and left to Table 4 Results of the quality assessment of included studies. Table 3 Reported side effects. manage side effects on their own [37]. Women who did discuss side effects with their HCPs were often not satisfied with the outcome of the consultation. They expressed a desire for more personalised advice, describing the guidance they received as "repetitive and too general" [26]. Some described having their concerns minimised and perceived HCPs as uncaring about their suffering [30,31]. Women stated there is a need for more psychological support with side effects [30,36,37], and more monitoring of side effects to support them in taking the medication. One individual stated that more encouragement from her HCP to persist with medication would  have made her reconsider her decision to discontinue [37]. Having trust in HCP's good intentions and expertise was linked to willingness to follow their advice [26,27,35], therefore, a supportive relationship with HCPs could potentially improve adherence to medication. This was highlighted by one participant explaining they discontinued adjuvant treatment without consulting a doctor because they felt "nobody was interested" [38].

Managing HT side effects
Many women were proactive in their self-management of side effects, conducting their own research (largely online) to deepen their understanding of their medication and identify ways to reduce side effects. Strategies included: dietary changes, increased exercise, wearing thinner clothes, taking breaks during household chores, and minimising activity in swollen limbs [27,28,38]. This online research led some to reconsider their decision to continue taking HT [40], as they realised their symptoms were caused by their medication.
Online breast cancer survivor communities were commonly utilised as a source of information [26,29,40]. Women valued experiential support from others who had taken HT and could provide support on how to manage side effects [26]. These communities were also a significant source of social and emotional support, as women felt a sense of relief upon realising, "I'm not the only one that's going through this" [40]. Women also valued the social support they received from their personal networks, who helped to support them with side effects and encouraged persistence when their motivation waned [37]. HCPs could play a particular role in this, as HCPs who listened to women's experiences and did not minimize their side effects [26], were considered more supportive and encouraging of adherence and persistence.
Some participants made considered decisions not to adhere to their prescriptions or to discontinue their prescriptions completely to get relief from the side effects of HT [38]. Participants took "medication holidays" to alleviate side effects including hot flushes, night sweats (disrupting sleep), joint pain and depressive symptoms, and nausea [29,34,35]. One study [29] stated that women who were advised to take medication breaks by their HCPs were more likely to resume their treatment, compared to those women who took medication breaks on their own initiative. This highlights the need for HCPs to actively support women experiencing side effects in order to facilitate HT adherence.

Weighing up the pros and cons
The influence of side effects on quality of life led to many women reconsidering their decision to persist with treatment. This decision was influenced by many factors including side effect severity, fear of cancer recurrence and perceived risk of recurrence.
Side effect severity appears to influence an individual's decision of whether to persist or discontinue HT. Some women coped relatively well with HT side effects [29], whereas some described the treatment as "potentially worse than the disease" and "unbearable" [37]. The intensity of side effects was a key factor in the decision to discontinue therapy, as many reached a stage where they felt the advantages of the drugs were outweighed by the burden of side effects [31,33,34,37]. This was prominent in older women, who explained they would prioritise quality of life in their remaining years over minimising the risk of recurrence due to wanting to "enjoy the life you have left". Similarly, many expressed a desire to move on from cancer treatment and resume normality, which they felt HT was inhibiting [40].
The advantages of HT were well-understood by the majority of breast cancer survivors. Adjuvant treatment was considered a "security blanket" [37], giving women hope for remaining cancerfree in the future [36]. This was a powerful motivator, as women expressed a constant fear of cancer recurrence, characterising this worry as, "a sword dangling above your head" [30]. Awareness of potential recurrence was a factor in anticipated regret. Women expressed wanting to know that they had "done all the right things" [36] to prevent recurrence. A recurring sentiment among survivors was that adjuvant treatment was not optional, and they were obliged to persist due to family responsibilities [27,36] and a duty to the people who had supported them through treatment [35]. Managing the side effects from HT was described as a "small price to pay" [30] for the potential benefits.
Although HT gave some a sense of security against recurrence, this was often dependent on how much women perceived themselves to be at risk. Some women were confident in their decision to discontinue or persist due to specific characteristics (age, cancer sensitivity, and cancer hormone receptor status) [35], whereas some felt oncologists had not been able to give them a clear indicator of their risk of recurrence [27]. Some were sceptical of the benefits of HT due to the lack of tangible efficacy, and confusion regarding its influence on risk of recurrence [37]. This demonstrates an opportunity for HCPs to facilitate adherence, by reminding women of the purpose of HT treatment, normalising their experience of side effects [35], and encouraging them to persist [27].

Discussion
This qualitative review aimed to identify how side effects of hormone therapy (HT) can influence breast cancer survivors adherence to and persistence with their medication. Identifying the impact of side effects on adherence to and persistence with HT for breast cancer survivors is critical for reducing risk of recurrence and reducing mortality. Four analytical themes were identified as having a significant influence on HT adherence and persistence behaviour. These themes were: "Daily impact of HT side effects", "Role of Health Care professionals (HCPs)", "Managing HT Side effects", and "Weighing up the pros and cons".  (19), who both identified that side effects had a considerable impact on quality of life and consequently adherence and persistence, and that there is a need for more follow-up care and support from health care professionals. The current review progresses previous reviews through its detailed examination of the specific relationship between side effects and adherence and persistence with HT, whereas earlier reviews of the qualitative literature simply aimed to identify studies which examined adherence and persistence.
There is strong evidence that the presence and severity of side effects can impact on adherence and persistence behaviour [41]. The current review revealed that HT side effects had wide-ranging impacts on breast cancer survivors' daily life. Musculoskeletal pain limited mobility and impacted on sleep, which then impacted cognitive functioning (i.e. concentration and memory), thus reducing women's ability to work. HT side effects also affected women's ability to socialise and enjoy fulfilling sexual relationships. Symptom-specific interventions have been trialled, with some evidence suggesting that use of medications can reduce the severity of side effects [42]. However, some side effects (i.e. sleep disturbance, fatigue) cannot be resolved through medical interventions, as pharmacological treatments are not recommended for long term use [43]. Therefore, psychological interventions such as mindfulness and/or cognitive behavioural therapy, and lifestyle interventions such as physical activity, which are effective at improving sleep and fatigue in a variety of clinical populations [44,45], also need to be trialled with breast cancer survivors to assess whether reducing these side effects promotes HT adherence and persistence.
The impact of side effects can result in woman choosing between a reduction in cancer risk and maintaining their quality of life. This evaluation process appears to be pivotal to the decision to adhere and persist with adjuvant hormone therapy, as survivors appear to actively decide if the benefits of treatment outweigh the detrimental impact side effects have on their quality of life [33,34]. The findings of this review also emphasised how women often felt unprepared for the side effects of HT. If women are to persist with HT, then they require adequate information about the benefits of treatment and the risk of recurrence that is tailored to their needs [46]. Previous research has suggested that informing women with breast cancer about HT and potential side effects can be a successful strategy to enhance adherence [47]. However, providing information alone is not sufficient for improving adherence and persistence [48]. Adequate health care provider support and communication needs to be provided to support long term adherence and persistence.
The results of this review also highlighted the significance of the important role healthcare professionals play in supporting women to manage HT side effects and encouraging adherence and persistence behaviour. This review has identified that breast cancer patients who receive HT often receive this treatment whilst in a transitional period from primary to secondary care, and a result patients often feel they are no longer a priority or find that they are not able to receive the specialist care that they require. This lack of support indicates a missed opportunity for early intervention and promotion of the benefits of persisting with adjuvant HT, as some woman reported that more encouragement and support from healthcare professionals would help them to cope better with their side effects [19].
A lack of support from healthcare providers leads to survivors developing their own self-management strategies for dealing with medication side effects, which in some cases results in nonadherence [29,34]. Patient-centred communication is a positive predictor of adherence [49], with evidence suggesting that better communication improves patient outcomes and reduces the burden of symptoms [50]. Communication with healthcare providers and individually tailored approaches are therefore needed for effective treatment planning [19]. Comprehensive follow-up care should be provided for women who are prescribed adjuvant HT so that those experiencing adverse effects can be identified and supported to continue with their medication as prescribed.
Studies included within this review tended to combine all types of HT rather than consider any differences between different treatment approaches. Clinical observations suggest that different treatments (i.e. Tamoxifen and AI) have different side effect profiles, albeit with some overlap. This review was not able to disentangle if there were any differences between the impact of side effects based on treatment type, and whether this had any impact on adherence and persistence. This highlights a limitation of the literature, as evidence indicates that side effect burden impacts on the decision to persist with treatment. Therefore, being able to identify if one treatment option is less impactful may help to promote adherence and persistence, and would be clinically meaningful for both patients and practitioners.
A limitation of this review is that it focuses specifically on women with breast cancer and their experience of HT side effects. Approximately 350 men are diagnosed with breast cancer annually in the UK [51], and whilst this is considerably less than the number of women, it is still an important issue that should be considered in future research. Men with breast cancer can also be treated with HT such as tamoxifen, however they may experience different side effects. However, there is a lack of research on men with breast cancers experience of taking HT and they may experience different side effects or have other barriers to adherence. Another limitation of this review was that it was not possible to determine the impact of prior treatment on adherence and persistence, or the impact of age or ethnicity, which may impact the side effects experienced. Due to the qualitative nature of the included studies and the lack of distinctions made in the original studies it is difficult to draw any conclusions. However, the authors are currently completing a review that focuses on the quantitative literature related to this topic and are hoping to unpick the impact of prior treatment, age and ethnicity differences further in that review.

Conclusion
This paper aimed to explore how side effects influence adherence and persistence to HT. This review has identified key areas for developing interventions to improve HT adherence and persistence in clinical practice. By identifying the precise ways in which side effects contribute to non-adherence and treatment discontinuation, interventions can be offered which reduce the impact of side effects and remove some of the barriers to breast cancer survivors taking their medication as prescribed.

Declaration of competing interest
There are no competing interests to declare.