Introduction
Prostate cancer is the most common cancer in men in Europe [
1]. Approximately 17–34% of men in the UK diagnosed with prostate cancer have a metastatic form of the disease at diagnosis [
1]. The androgen receptor is involved in the growth and spread of prostate cancer and can initially be treated hormonally using androgen deprivation therapy (ADT). Men with metastatic prostate cancer who have not been previously treated with ADT or who are still sensitive to ADT and not castration resistant are defined as having mHSPC.
Evidence from recent studies has highlighted that administration of docetaxel (chemotherapy) plus ADT among men with mHSPC can prolong overall survival, particularly among those men with ‘high-risk’ forms of the disease and generally poorer prognosis [
2‐
7]. Accordingly, the most recent European Association of Urology (EAU) and European Society for Medical Oncology (ESMO) guidelines recommend that docetaxel combined with ADT should be considered the standard of care for men with metastases at first presentation, provided they are fit enough to receive the drug [
8,
9]. To date, however, there has been little exploration of the experiences and perspectives of men with mHSPC receiving docetaxel, particularly in terms of treatment satisfaction and Health-Related Quality of Life (HRQoL). The aim of this study, therefore, was to explore the perspectives of men and carers of men with mHSPC who had received docetaxel using qualitative and quantitative research methods.
Methods
Design
A cross-sectional, multinational mixed methods study was conducted in two phases. Phase 1 (qualitative stage) involved the conduct of semi-structured interviews among men with mHSPC and who had experience of docetaxel and informal (unpaid) carers of friends or relatives with mHSPC and who had been treated with docetaxel. Phase 2 comprised a quantitative survey among men with mHSPC and carers of men with mHSPC to quantify experiences with docetaxel.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all participants for each stage of the study and ethical approval was granted by Freiburger Ethik-Kommission International (study code: 22894, FEKI code 016/1630).
Participants
Participants for both phases of the research were recruited from five European countries (France, Germany, UK, Italy and Spain) between October 2016 and January 2017 (qualitative phase 1) and September 2017 and March 2018 (quantitative phase 2).
To be eligible for participation in either phase of the study, men with mHSPC were required to: have a formal diagnosis of mHSPC; have metastases outside of the pelvis and have received at least two cycles of docetaxel within the past 6 months. During the qualitative phase, a small number of men with mHSPC (n = 5) who had refused docetaxel following discussions with their healthcare professional were also included.
Only primary carers of men with mHSPC were eligible for participation in the study. For the purposes of this study, primary carers were defined as friends or relatives that visited at least twice weekly, carried out tasks to help the patient on a regular basis and/or attended several meetings where the patient had met their health care professional. Formal (paid) carers were excluded from participation.
Phase 1: Qualitative Interviews
Semi-structured qualitative interviews were conducted with men with mHSPC (n = 31) and carers of men with mHSPC (n = 14) to elicit in-depth data concerning their experiences of docetaxel. Initially men were asked to talk openly about their experience of mHSPC and their medical history. The next section of the interview focused on the men’s experience of previous treatments, treatment expectations and their journey from diagnosis to the current day. To support discussion of the treatment journey, participants were provided with a blank depiction of a timeline on which they were asked to draw a line depicting their highs and lows, which were to be defined in any way that the participant saw relevant. The final part of the interview asked patients to reflect on the impact that their diagnosis and treatment had on daily life. The carer interview was similar in structure. All interviews were conducted in the local language by trained qualitative interviewers.
In addition to the interviews, a subset of the men recruited to participate in the interview (n = 18) were also asked to complete a diary for a period of 7 days to probe on their experiences and how they were feeling each day.
Data from the semi-structured interviews and diaries were analysed using thematic analysis techniques centered upon the grouping of verbatim quotes.
Phase 2: Quantitative Stage
Eligible participants completed a 30-min online survey at home. The content of the survey was informed by the findings from the phase 1 qualitative interviews. At the beginning of the survey, participants were asked to provide background demographic and clinical information as well as answer a series of screening questions to determine eligibility. Participants were then asked to complete a series of disease-specific and generic patient-reported outcome (PRO) questionnaires designed to collect information concerning treatment satisfaction and HRQoL:
-
Cancer Therapy Satisfaction Questionnaire (CTSQ): The CTSQ is a patient-completed questionnaire developed and validated for use in various cancers to evaluate satisfaction with intravenous and/or oral chemotherapy, biological and hormonal therapies. The CTSQ comprises 16 items measuring 3 domains; expectations of therapy (ET), feelings about side effects (FSE) and satisfaction with therapy (SWT). Each domain is scored from 0 to 100 with higher scores representing greater satisfaction [
10].
-
The Brief Fatigue Inventory (BFI): The BFI comprises nine items used to assess the severity and impact of cancer-related fatigue. All items are rated on a scale from 0 (no fatigue/does not interfere) to 10 (fatigue as bad as you can imagine/completely interferes). Eight of the nine items use a recall period of the ‘past 24 h’ and one item assesses fatigue ‘right now’. A global fatigue score can be calculated as an average of all item responses [
11].
-
Functional Assessment of Cancer Therapy-Prostate (FACT-P): The FACT-P is a multidimensional, self-report QoL instrument specifically designed for use with prostate cancer patients. The questionnaire consists of 27 core items assessing four domains, including physical well-being (PWB), social/family well-being (S/FWB), emotional well-being (EWB) and functional well-being (FWB), and a prostate cancer-specific (PCS) subscale (12 items). Each item is rated on a 0–4 Likert type scale ranging from ‘not at all’ to ‘very much’. Item scores are summed to produce domain scores for which the range varies by domain. Higher scores represent better health and HRQoL [
12].
-
EuroQol-5-Dimensions 5-Levels (EQ-5D-5L): The EQ-5D-5L is a standardized questionnaire applicable to a wide range of health conditions and treatments and requires respondents to rate their health status in terms of “Mobility”, “Self-Care”, “Usual Activities”, “Pain/Discomfort” and “Anxiety/Depression” on a 5-point response continuum (1—no problem to 5—extreme problem/unable to do) with lower scores representing better health. A ‘utility index score’ can be calculated for each patient ranging from − 0.59 to 1.00 with 1.00 indicating ‘full health’. In addition, respondents rate their health status on a 100-mm visual analogue scale [
13].
Carers were also asked to provide demographic and clinical information about themselves and the patient they care for and asked to complete the Burden Scale for Family Caregivers (BSFC). The BSFC comprises 28 items designed to assess the impact on emotional and physical health of family caregivers. All items are rated on a 4-point Likert scale with response options ranging from 0 (strongly disagree) to 3 (strongly agree) [
14].
The data from participants were entered into a database for analysis. The database was developed with quality control functionalities in place (e.g., validation alerts when out-of-range values are entered, auto-tabbing, spell checking, shortcut keys, data entry status flags). Participant scores per item and summary scores for each questionnaire were calculated in accordance with developer instructions. For men with mHSPC, the relationship between PRO scores was explored via the calculation of Pearson correlation coefficients.
Discussion
The management of metastatic prostate cancer is a rapid and continuously evolving field. One of the most notable developments in recent years has been the adoption of docetaxel in combination with hormonal therapy as a first-line treatment for mHSPC. Traditionally reserved for advanced prostate cancer that is no longer responsive to hormonal therapy (i.e., castration-resistant prostate cancer), the use of a cytotoxic therapy among men with newly diagnosed mHSPC represents a significant shift in the treatment paradigm. Driving this shift has been evidence from clinical studies highlighting a survival benefit associated with the use of docetaxel among men with mHSPC [
2‐
7]. While improving survival is a key goal of cancer therapy, there is increasing recognition that the ‘quality of survival’ (in terms of how patients feel and function) is also important [
16].
Docetaxel is a cytotoxic chemotherapy and evidence from clinical studies highlights that, in addition to severe adverse events (e.g., neutropenia) that can lead to discontinuation of therapy, docetaxel in combination with ADT is also associated with a worsening of cancer-related symptoms such as fatigue and deficits in quality of life, which may be evident for up to 12 months following commencement of treatment [
2‐
7]. Qualitative feedback from participants in the current study highlighted fatigue as a prominent problem among men who had received docetaxel for the treatment of mHSPC. This was further highlighted by BFI data collected during the quantitative phase, with most participants reporting feeling unusually tired or fatigued in the past week and experiencing moderate to severe fatigue. It is recognized that fatigue is a symptom with a complex aetiology than can be attributed to cancer itself, its treatment and/or a broad range of physical and psychological comorbidities [
17,
18]. However, levels of fatigue reported in this study are greater than those reported at baseline and post-treatment time points in other studies among men with mHSPC. For example, in the LATITUDE study (phase III study comparing ADT with abiraterone acetate plus prednisone against ADT plus placebo) mean worst fatigue and mean average fatigue in the past 24 h as measured by the BFI were 2.2 and 1.8, respectively, at the study baseline; compared with 5.1 and 4.6 in the current study [
19].
Strong correlations were observed between BFI-Total and FACT-P Total scores, suggesting that fatigue is a significant driver of quality of life among men receiving docetaxel for the treatment of mHSPC. Prior investigations of docetaxel in combination with ADT (CHAARTED) have evaluated HRQoL using FACT-P. By comparison, levels of HRQoL reported by participants in the current study are considerably lower than baseline and post-treatment evaluations in the CHAARTED study, with this finding consistent across FACT-P scores/domains. For example, mean FACT-P Total scores in the current study were 92.4 compared with 116.6–119.4 in the CHAARTED study [
6].
These findings may reflect the inherent challenges of translating clinical trial data into real-world practice. Indeed, there are several confounding factors that may contribute to the observed disparities between studies including study design, sampling (e.g., presence of comorbidities), therapeutic implementation and healthcare context [
20]. However, levels of HRQoL observed in this study are also lower than those observed among other real-world observations of men with mHSPC. For example, in a cross-sectional survey of 203 men with mHSPC conducted in 2014, mean EQ-5D utility index scores were reported to be 0.84 (compared with 0.70 in the current study). Similarly, higher FACT-P total scores (102.1 vs. 92.4) and physical well-being (21.0 vs. 17.6), emotional well-being (15.8 vs. 15.0) and social well-being (18.6 vs. 13.8) domain scores, which are reflective of better quality of life, were also observed in this study compared with the current study [
21].
In this context, findings from the current study suggest that existing data from clinical trials may underestimate the HRQoL impact associated with use of docetaxel among men with mHSPC in a real-world setting. While there are some men with mHSPC who are functioning well on docetaxel and are generally satisfied with therapy, equally there are men who are doing less well and who are dissatisfied with therapy. Current treatment guidelines recommend that men with mHSPC be treated with ADT plus docetaxel ‘provided the patient is fit enough’. Interviews with docetaxel refusers conducted as part of this study provided some insights into why men may not consider themselves suitable to receive docetaxel. However, there would appear to be little evidence available regarding the proportion of men with mHSPC who may be deemed unsuitable to receive docetaxel or indeed the parameters by which judgements regarding ‘suitability’ are to be made. The population of men with mHSPC is diverse in terms of both clinical and demographic characteristics. Although there is some preliminary evidence from clinical studies regarding factors that may predict both success and acceptability of docetaxel in men with mHSPC (e.g., those with high-risk disease), further research in a real-world setting is required to inform treatment decisions in practice.
Patient experience data such as those collected during this study are considered increasingly important for informing decisions in clinical development and research [
22] as well as clinical practice [
23]. The combination of qualitative and quantitative research techniques employed as part of a mixed methods approach and the exploration of multiple stakeholder perspectives (i.e., patients and carers) are key strengths of the current research. However, in considering the implications of findings from this study, it is necessary to acknowledge limitations that apply to this research. First, as a cross-sectional study, it is not possible to directly evaluate how docetaxel may have impacted outcomes among men with mHSPC in terms of experience of side effects and deficits in HRQoL. Further prospective observational research in which patient experiences are evaluated over time from the outset of treatment is required to better understand the consequences of docetaxel and to elucidate disparities between the experiences of men with mHSPC using docetaxel in a real-world versus a clinical trial setting. Furthermore, the sample size of the current study conforms to what is typically appropriate for qualitative research studies and for exploration of simple relationships in cross-sectional studies [
24]. However, this sample size is not sufficient to explore between-group differences (based on clinical and demographic subgroups) and identification of predictors of negative or positive outcomes associated with docetaxel use. Based on the findings of this study, these are topics for further investigation.
Acknowledgements
The authors would like to extend our thanks to all the men with mHSPC and carers of men with mHSPC who participated in this study.
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