Descriptive study on burden and communication of fatigue among castration-resistant prostate cancer patients in Japan

Abstract

Objective

Prostate cancer is a common malignancy and patients may progress to castration-resistant prostate cancer (CRPC). Among patients with CRPC, fatigue is a common symptom associated with current treatments. The aim of this real-world study was to describe patient-reported fatigue in Japanese patients treated with androgen receptor-axis-targeted therapies for CRPC.

Methods

Data of this observational study were collected in a quantitative phase for the description of patient-reported fatigue, and a qualitative phase for elicitation of fatigue perception and barriers to reporting fatigue.

Results

In the quantitative phase (N = 22), fatigue was investigated in two formats: symptoms report and Brief Fatigue Inventory (BFI). In the report of the symptoms, 12 patients reported tiredness, and four moderate-to-severe tiredness during treatment. In the BFI, all patients reported fatigue; eight reported moderate-to-severe fatigue. The most affected BFI domain was mood: five patients reporting moderate-to-severe impact. In interviews (qualitative phase; N = 8), diverse patient experience on fatigue was observed, including apathetic feelings, affected speed and distance during the walk, negative impact on profession, housework, or driving, reduced outgoing activity, and difficulty in enjoying time with grandchildren or travel. Five out of eight patients communicated fatigue to their physicians but received diverse reactions.

Conclusion

Patient interviews highlighted the impact of fatigue on patients’ lives and difficulties in communicating fatigue to physicians. Fatigue frequency after medication may need to be monitored and its burden is considered to provide treatment that meets the needs, wishes, and circumstances of each patient. Further research is needed to elucidate how fatigue affects patients’ lives, and underscore patient-physician communication difficulties.

Keywords:

• Castration-resistant
• prostatic neoplasms
• prostate cancer
• advanced prostate cancer
• fatigue
• physician-patient relations
• reporting fatigue

Introduction

Prostate cancer is the most commonly diagnosed malignancy in men worldwide, with 191,930 estimated new cases in the United States (US) in 2020¹. In Japan, an estimated 78,500 new prostate cancer cases were diagnosed in 2019, according to the National Cancer Center², with an incidence rate of approximately 120 per 100,000 population reported in 2014³. In 2014, for 50–54-year-old males, prostate cancer accounted for approximately 5% of overall cancer incidence, and for patients older than 70 years, prostate cancer accounted for approximately 20% of overall cancer incidence in Japan³.

Castration-resistant prostate cancer (CRPC) is an advanced form of prostate cancer that is characterized by disease progression subsequent to surgical or pharmacological castration (androgen deprivation therapy [ADT]) ⁴. The prognosis for patients with CRPC is poor and survival may be reduced⁴. It has been estimated that 10–20% of patients with prostate cancer will eventually develop CRPC within 5 years; of those with no metastasis at diagnosis of CRPC, 33% could develop metastases within 2 years⁴.

Prostate cancer beyond the localized stage has, for decades, been treated with ADT, while a new chemotherapeutic agent (docetaxel) was introduced at the beginning of the twenty-first century for the treatment of metastatic CRPC⁵. As CRPC remains dependent on a functional androgen receptor (AR) axis and AR-mediated processes⁶, two AR-axis-targeting agents have developed: the androgen biosynthesis inhibitor abiraterone acetate and the second-generation androgen receptor blocker enzalutamide⁷. According to the report of the Advanced Prostate Cancer Consensus Conference (APCCC) in 2019, for treating the majority of nmCRPC patients whose PSA is ≥2 ng/ml and PSA doubling time is ≤10 mo, a combined total of 86% voted for an AR antagonist (apalutamide, darolutamide, or enzalutamide)⁸. In the NCCN guidelines updates: management of prostate cancer 2019, AR antagonist (apalutamide, darolutamide, or enzalutamide) is used for first-line treatment in many patients with Castration-Resistant M0 or later⁹.

Fatigue is one of the most common and detrimental symptoms of cancer patients. The prevalence rate of fatigue has been reported to be over 50% in patients having advanced cancer^10,11 and over 30% in newly diagnosed cancer patients¹² and cancer survivors¹³. Patients receiving anti-cancer treatments such as chemotherapy, radiation therapy, and bone marrow transplants are often known to experience fatigue as a serious side effect of the treatment^14,15. Generally, the terms used to describe fatigue are colloquial and often difficult to translate. The Brief Fatigue Inventory (BFI) was designed to assess fatigue in cancer patients who were found to be difficult¹⁶. It consists of nine numerical scales from 0 to 10 with three items to measure the severity and six items to measure the difficulties in daily life. The three key features of this scale are (1) that it is concise and easy for patients to fill out, (2) that it is easily translated into other languages, and (3) that it consists of intervention items.

Patients with prostate cancer receiving treatment with hormonal therapy often report physical and mental exhaustion leading to a reduced quality of life (QoL) ¹⁷. In men receiving long-term hormonal therapy, fatigue is a common adverse effect for which the loss of muscle mass and a concomitant increase in fat mass along with pain and depression is the most probable underlying mechanism¹⁸. A cross-sectional, multicenter study in patients with CRPC revealed fatigue to be present in 74% of patients, 38.5% of which reported moderate-to-severe fatigue¹⁹.

Treatment options, such as long-term hormonal therapy, for patients with advanced prostate cancer, have increased in recent years and a potentially prolonged life expectancy, with long-term use of hormonal therapy, should be balanced against patients’ QoL in this advanced disease stage²⁰. Thus, evaluation of physical and emotional functioning, as well as pain and fatigue, is essential for treatment decisions in these patients²⁰.

In an observational study in 13 Japanese hospitals, a diagnosis of CRPC was seen to be associated with considerable healthcare resource utilization and increased financial burden on patients³. In an Italian study estimating the cost of disease of metastatic CRPC, the main financial burden was the cost of treatment²¹. The study also showed that the management cost per episode for the adverse event of fatigue was estimated to be approximately 1,236 euros²¹. By further elucidating the overall disease burden on patients, the best evidence-based care can effectively be implemented in actual clinical practice to improve the standard of care for patients with CRPC. In addition, communications between patients and healthcare professionals (HCPs) remain to be improved, to facilitate early symptom reporting thus enhancing disease management that could subsequently improve patients’ QoL²².

In a recent global survey on symptom burden in advanced prostate cancer, regional differences were seen between men from the Asia Pacific region (Japan, Singapore, Taiwan) and those from the United States, with the former being less comfortable discussing their physical well-being²². In a multicenter study in Spain, an association between greater fatigue and reduced QoL was shown in patients with CRPC, irrespectively of the presence or absence of metastases¹⁹.

Surprisingly, there is not enough information on the evaluation of fatigue in Japanese patients with CRPC, and how this symptom is communicated with HCPs in Japan. As described above, patient populations, including Japanese, may be burdened with a sense of potential fatigue without it being known to others. Although the most burdensome side effects of the novel androgen receptor are fatigue, falls and fractures, the risk of fatigue is higher with apalutamide and enzalutamide (27–30%) than with darolutamide (12%)²³. Consequently, understanding fatigue in Japanese patients may lead to more appropriate treatment. A systematic treatment strategy designed for improved fatigue has not yet been established²⁴. Understanding fatigue, which cannot be assessed by standardized PRO scores, may indicate a positive impact for CRPC treatment, including in the Japanese population.

The aim of this real-world study was to describe patient-reported fatigue in Japanese patients who were receiving AR axis-targeted treatment as the first-line therapy except for the first-generation androgen receptor blocker agent for CRPC. Barriers to reporting fatigue and how patients discussed this symptom with HCPs in Japan were also explored.

Methods

Study design

The Fatigue Communication Study was a non-interventional, cross-sectional, observational study conducted in Japan with no study site involvement (no on-site visits occurred). The study was carried out in accordance with Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan. All patients were informed that all shared information was voluntary and under no circumstances was a response to any of the questions mandatory. No additional diagnostic or monitoring process was required for participation or during the study. All patients provided electronic and verbal informed consent before their inclusion in the study.

The data for this study were collected in two phases: a quantitative phase, for the primary study objective to describe patient-reported fatigue; and a qualitative phase, for the secondary objectives of eliciting patient perception to fatigue, identifying barriers to reporting fatigue and how fatigue was discussed with HCPs.

Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials. Any additional data are available upon reasonable request.

Study population

Prior to patients’ inclusion in the study, a screening questionnaire was provided based on which eligibility for participation was to be ensured. Eligible patients consisted of adult males (≥20 years old) diagnosed with CRPC and treated with AR axis-targeted treatment as first-line therapy. Patients with a previous history of docetaxel for CRPC and those receiving abiraterone acetate for mHSPC were not included in the study. Patients participating in an investigational program with interventions outside of routine clinical practice were also excluded from the present study. The study questionnaire was provided separately in Supplementary Table 1.

Sample size

Quantitative phase

Previous studies in countries other than Japan, exploring fatigue in patients with prostate cancer who were treated with ADT and were using the Brief Fatigue Inventory (BFI), samples of 100 and 198 patients were surveyed¹⁷. Considering that 10–20% of patients have been seen to become castrate resistant within 5 years⁴, it was expected that a convenience sample (anticipated n = 40) would suffice for the quantitative phase of the study. Patients were stratified according to the treatment they were receiving.

Qualitative phase

Of the patients who completed the quantitative survey, those whose BFI scores were within the top 25% quartile (respondents reporting to be most affected by fatigue in the study sample) were invited to participate in the qualitative phase. There were no generally agreed upon sample size calculations for concept elicitation from the interviews as adequacy was considered to depend on the completeness of the information obtained from analysis of the transcripts²⁵. The total sample size for the qualitative phase was considered adequate as the objective was to acquire concepts and not necessarily achieve concept saturation, which would be required if a patient-reported outcome instrument were to be subsequently developed. In the qualitative stage, there was no stratification of any nature, as the qualitative component aimed to elicit concepts underscoring the potentially limited communication of their fatigue.

Study phases and variables

Quantitative phase

The quantitative phase consisted of an online web survey that included patients who had passed the screening procedure. In addition to demographic and clinical characteristics, patients answered nine questions using the Japanese version of the BFI (psychometrically and linguistically validated in Japanese patients²⁶).

Quantitative phase variables

Data were collected using self-reported online questionnaires and included demographics, medical history, and medications. Demographic variables included age, marital and employment status, number of children, age of the youngest child, education level, and presence of the primary caregiver. Clinical variables included a year of prostate cancer diagnosis, date of CRPC diagnosis, date of CRPC diagnosis with bone metastasis (if known), last prostate-specific antigen (PSA) test result (if known), and Eastern Cooperative Oncology Group (ECOG) performance (if known).

Symptoms report

Prior to answering questions using the BFI, patients answered questions on certain symptoms they may have experienced (patient-reported symptoms) after administration of oral medication.

BFI

Patient-reported fatigue was further assessed using the BFI with nine validated questions in Japanese; variables were numerically ranging from 0 to 10. An average score between 0 and 10 of the nine questions was used as a global fatigue score. Scores of 1–3, 4–6, and 7–10 were defined as mild, moderate, and severe, respectively. The questions are presented in Table 1.

Table 1. Questions using the Brief Fatigue Inventory assessing severity of fatigue and impact of cancer treatment-related fatigue on daily function.

Item	Question	Description
1	Fatigue right now	Fatigue as currently experienced by the patient, evaluated on a scale from 0 to 10, with 0 meaning ‘no fatigue’ and 10 meaning ‘fatigue at its most severe for you form’.
2	Usual level of fatigue in past 24 h
3	Worst level of fatigue in past 24 h
4	General activity	Interference of fatigue during the past 24 h in the different aspects of the patient’s life, evaluated on a scale from 0 to 10, with zero meaning ‘fatigue does not interfere’ and 10 meaning ‘maximum interference’.
5	Mood
6	Walking ability
7	Normal work
8	Relations with other people
9	Enjoyment of life

Note: A global fatigue score ranging from 0 to 10 was evaluated upon completion of the study.

Qualitative phase

Following the quantitative survey, those patients with BFI scores within the top 25% quartile (respondents reporting to be most affected by fatigue in the study sample) were invited to participate in the qualitative phase. This phase consisted of one-to-one telephone interviews. Consenting patients were enrolled in the qualitative phase of the study and interviewers completed a questionnaire on the patients’ sociodemographic and clinical characteristics. After completion of the questionnaire, the interview started following a semi-structured guide consisting of open-ended questions to allow patients to describe in their own words the burden of fatigue and how this burden was communicated to their treating physicians.

Qualitative phase variables

Key variables of interest included patient perception to fatigue, obstacles, and reasons why patients did not discuss the issue of fatigue with their treating physicians. Concepts derived from the patient interviews included, but were not limited, to: the burden of fatigue as described by patients; how this burden was experienced in terms of symptoms; the impact of fatigue on daily activities; the potential relationship between the grade of fatigue and whether/how this was communicated; and the potential relationship between the grade of fatigue and the patient’s general activity, mood, walking ability, ability to work, ability to build/maintain relations with other people, ability to enjoy life, and whether/how these aspects were communicated to HCPs. The dialogue/expressions used by patients to describe fatigue were also examined to identify barriers to effectively communicating fatigue.

Statistical considerations

Analyses for this study were purely descriptive. No hypothesis was tested. All variables were analyzed descriptively with appropriate statistical methods: categorical variables by frequency tables (absolute and relative frequencies) and continuous variables by sample statistics (i.e. mean, standard deviation, minimum, median, quartiles, and maximum). Continuous variables were described by absolute value. Due to the purposive sampling strategy for the qualitative sample, analysis of the quantitative phase, sufficient to enable recruitment for the qualitative phase, was completed prior to initiating the qualitative phase.

Quantitative phase

BFI scores were described using summary statistics for continuous and categorical variables for each module of the patient questionnaire, as applicable. BFI global scores were captured as continuous variables. The global score was calculated from the nine questions. Scores of 1-2-3, 4-5-6, and 7-8-9-10 were defined as mild, moderate, and severe, respectively. Subscores associated with each of the domains in the BFI were captured and reported separately. Statistical analyses for the quantitative phase were performed using Microsoft Excel.

Results

Patient characteristics

A total of 161 responses to the web survey were identified. Of these, 136 were excluded due to screening failures. Of the remaining 25 responses, the multiple answers were scrutinized, and 22 patients were identified and included in the quantitative phase of the study. Telephone interviews were conducted, resulting in eight patients in the qualitative phase.

At the time of answering the questionnaire, the mean age was 71.1 years, median disease duration was 10 years and 9 months, and median PSA value was 0.05 ng/dL. In this study, all patients received Enzalutamide or Abiraterone acetate, with 33.3% of Enzalutamide and 16.7 of Abiraterone acetate usage are equal to or less than 6 months. Patients were being treated with either enzalutamide or abiraterone acetate and had a treatment history that included leuprorelin, goserelin, degarelix acetate, bicalutamide, and flutamide. Clinical characteristics are presented in Table 2.

Table 2. Clinical characteristics.

Characteristic/Parameter	N = 22
Age (years), mean (min-max)	71.1 (55–85)
Duration of disease, median (min-max)	10 years 9 months (3 months − 21 years and 4 months)
History of androgen deprivation therapy	n	(%)
Surgical orchiectomy	4	18.2
Leuprorelin	9	40.9
Goserelin	5	22.7
Degarelix acetate	8	36.4
Injected (Unknown drug name, per month)	1	4.5
Injected (Unknown drug name, every 3 months)	3	13.6
History of first-generation androgen receptor blockers (Yes)	n	(%)
Bicalutamide	16	72.7
Flutamide	10	45.5
Current treatment by novel androgen receptor blockers (Yes)	n	(%)
Enzalutamide	12	54.5
≤6 months	4	33.3
≤1 year	1	8.3
≥1 year	7	58.3
Abiraterone acetate	10	45.5
≤6 months	2	16.7
≤1 year	3	25.0
≥1 year	5	41.7
Prostate-specific antigen (PSA) level (ng/mL)
At enzalutamide initiation (12 patients)
Mean (SD)	8.09 (6.10)
Median (min, max)	5.60 (0.93, 24)
Interquartile range, 25–75%	2.50–7.80
At abiraterone acetate initiation (10 patients)
Mean (SD)	6.21 (7.20)
Median (min, max)	2.70 (0.15, 23.40)
Interquartile range, 25–75%	1–8.60
At the time of answering the questionnaire (22 patients)
Mean (SD)	1.45 (3.10)
Median (min, max)	0.10 (0, 12)
Interquartile range, 25–75%	0.01–1
Patient-reported metastatic status	n	(%)
No metastasis	9	41
Bone	10	46
Lymph node	6	27

The majority of patients reported a medical history of ADT with leuprorelin (9; 40.9%) and/or degarelix acetate (8; 36.4%); a previous medical history of bicalutamide treatment was reported by 16 (72.7%) patients. Approximately half of the patients reported current treatment with enzalutamide (12; 54.5%) and the other half with abiraterone acetate (10; 45.5%), while most patients (58.3% and 41.7%) reported having been receiving these treatments for more than 1 year. The median PSA values at the beginning of enzalutamide and abiraterone acetate treatment were reported to be 8.09 and 6.21 ng/mL, respectively; the median PSA value at the time of the questionnaire was reported to be 1.45 ng/mL. Half of the patients reported an increase in their PSA values since the last reading.

Of the 22 patients, 13 (59%) reported having either bone or lymph node metastases (or both) (Table 2). Ten (46%) patients reported to have bone metastasis, 6 (27%) patients reported to have lymph node metastasis, while 9 (41%) patients reported ‘no metastasis’. The numbers shown in Table 2 are non-exclusive, as three of the patients reported to have both bone and lymph node metastases. No metastases to other organs were reported.

Quantitative phase analysis

Living conditions

Approximately 60% of patients with fatigue reported they did not work (no reason was provided; Supplementary Table 2). The age among those who reported no employment ranged from 55 to 78; most of these patients had reached the retirement age in Japan. Most patients (16; 73%) reported they did not have a caregiver at home. Ten (45%) patients reported being of financially good or relatively good status. In addition, a medication diary was kept by 16 (73%) of the patients.

Overall health condition

The majority (19; 86%) of patients were able to engage in social activities in a manner similar to that prior to disease onset, without any restrictions. Three (14%) patients reported having mild symptoms restricting manual labor, but activities such as walking, light labor, and sedentary work were reported to be possible. None of the patients reported having difficulties in doing light work or felt the need of constant help to perform daily activities.

Patient-reported symptoms

Prior to answering questions using the BFI, patients answered questions on certain symptoms they may have experienced. Thus, symptoms reported here are not be associated with the BFI scores. Twelve (54.6%; 12/22) of the patients reported symptoms of tiredness ranging from a mild-to-severe intensity; 18.2% (4/22) of the patients reported moderate-to-severe tiredness (Table 3). Other symptoms reported by ≥5% of patients (more than one patient) included back pain, constipation, arthralgia, hypertension, loss of appetite, weight loss, hot flashes, lethargy, foot swelling, palpitations/shortness of breath, and dizziness. There were 10 reports of symptoms of severe intensity including tiredness, back pain, arthralgia, weight loss, hot flashes, and palpitations/shortness of breath. All symptoms reported by the patients are presented in Table 3.

Table 3. Symptoms reported by the patients.

Symptoms	Number of patients who reported symptoms, N = 22
	Mild	Moderate	Severe	Extreme severity
	n (%)	n (%)	n (%)	n (%)
Tiredness	8 (36.4)	3 (13.6)	1 (4.5)	0
Back pain	2 (9.1)	0	1 (4.5)	0
Constipation	5 (22.7)	0	0	0
Arthralgia	6 (27.3)	0	1 (4.5)	0
Hypertension	6 (27.3)	3 (13.6)	0	0
Loss of appetite	4 (18.2)	1 (4.5)	0	0
Weight loss	3 (13.6)	2 (9.1)	1 (4.5)	0
Nausea	1 (4.5)	0	0	0
Hot flashes	7 (31.8)	3 (13.6)	3 (13.6)	1 (4.5)
Lethargy	8 (36.4)	2 (9.1)	0	0
Foot swelling	3 (13.6)	1 (4.5)	0	0
Palpitations/shortness of breath	5 (22.7)	0	0	2 (9.1)
Dizziness	5 (22.7)	0	0	0

Treatment status

Previous and current hormone therapy received by the 22 patients is further presented in Table 4.

Table 4. Previous and current hormone therapies were reported by the patients.

Previous hormone therapy		Current hormone therapy
Hormone therapy	Number of patients (n)	Hormone therapy	Number of patients (n)
Bicalutamide and flutamide	8	enzalutamide	4
		abiraterone acetate	4
Bicalutamide alone	8	enzalutamide	5
		abiraterone acetate	3
Flutamide alone	2	enzalutamide	1
		abiraterone acetate	1
Neither bicalutamide nor flutamide	4	enzalutamide	2
		abiraterone acetate	2

Fatigue

On the BFI, the majority of patients (more than 60% for all questions) reported mild fatigue with BFI scores from 1 to 3 (Table 5). At the time of the questionnaire, 8 (36.4%) patients reported moderate-to-severe fatigue: 7 (31.8%) patients reported moderate fatigue (BFI scores 4–6), and 1 (4.6%) reported severe fatigue (BFI score 7–9). The usual level of fatigue in the 24 h prior to the questionnaire was reported to be moderate by 3 (13.6%) patients and severe by 1 (4.6%) patient. The worst level of fatigue in the 24 h prior to the questionnaire was reported to be moderate or severe, by 7 (31.8%) and 1 (4.6%) patients, respectively. BFI scores showed that 5 (22.7%) patients felt that moderate-to-severe fatigue interfered with their mood. Moderate fatigue was reported to interfere with relations with others, general activity, walking ability, normal work, enjoyment of life, and mood by 1–3 (4.6–13.6%) patients. One (4.6%) patient-reported severe fatigue interfered with general activity, walking ability, normal work, and relations with others, and 2 (9.1%) patients reported severe fatigue interfered with their mood. BFI scores based on patients’ responses are presented in Table 5.

Table 5. Brief Fatigue Inventory scores based on the patients’ responses.

Brief Fatigue Inventory (BFI) items	Number of patients who responded (N = 22)
	BFI score 1–3	BFI score 4–6	BFI score 7–9
	Mild	Moderate	Severe
	n (%)	n (%)	n (%)
Fatigue right NOW	14 (63.6)	7 (31.8)	1 (4.6)
USUAL level of fatigue in past 24 h	18 (81.8)	3 (13.6)	1 (4.56)
WORST level of fatigue in past 24 h	14 (63.6)	7 (31.8)	1 (4.6)
Circle the one number that describes how, during the past 24 h, fatigue has interfered with your:
General activity	19 (86.4)	2 (9.1)	1 (4.6)
Mood	17 (77.3)	3 (13.6)	2 (9.1)
Walking ability	19 (86.4)	2 (9.1)	1 (4.6)
Normal work in the last week	19 (86.4)	2 (9.1)	1 (4.6)
Relations with others	20 (90.9)	1 (4.6)	1 (4.6)
Ability to enjoy life	20 (90.9)	2 (9.1)	0

BFI scores by patient characteristics are shown in Table 6. For patients > 70 years and ≤ 70 years, moderate and severe were 4 of 12 patients and 4 of 10 patients. For the presence or absence of surgical orchiectomy history, 2 of 4 patients (yes) and 6 of 18 patients (no) reported moderate and severe, and other ADTs are listed in Table 6. At the time of the survey, all patients were being treated with either enzalutamide or abiraterone acetate (Table 2).

Table 6. Fatigue right NOW in BFI by patient background stratification.

			BFI score 1–3	BFI score 4–6	BFI score 7–9
			Mild	Moderate	Severe
		N	n (%)	n (%)	n (%)
Age: >70	Yes	12	8 (66.7)	3 (25.0)	1 (8.3)
	No	10	6 (60.0)	4 (20.0)	0 (0.0)
History of surgical orchiectomy	Yes	4	2 (50.0)	2 (50.0)	0 (0.0)
	No	18	12 (66.7)	5 (27.8)	1 (5.6)
History of leuprorelin	Yes	9	7 (77.8)	1 (11.1)	1 (11.1)
	No	13	7 (53.8)	6 (46.2)	0 (0.0)
History of goserelin	Yes	5	4 (80.0)	1 (20.0)	0 (0.0)
	No	17	10 (58.8)	6 (35.3)	1 (5.9)
History of degarelix acetate	Yes	8	6 (75.0)	2 (25.0)	0 (0.0)
	No	14	8 (57.1)	5 (35.7)	1 (7.1)
History of bicalutamide	Yes	16	11 (68.8)	4 (25.0)	1 (6.3)
	No	6	3 (50.0)	3 (50.0)	0 (0.0)
History of flutamide	Yes	10	5 (50.0)	4 (40.0)	1 (10.0)
	No	12	9 (75.0)	3 (25.0)	0 (0.0)

Qualitative phase analysis

Patient characteristics and treatment history

Eight patients were included in the qualitative phase of the study; ages (as reported at the time of the study) ranged from 58 to 76 years, and duration of disease ranged from 4 (prostate cancer diagnosis in 2015) to 16 (prostate cancer diagnosis in 2003) years. Treatment history of surgical orchiectomy was reported by two patients; other treatment histories included leuprorelin acetate (3), goserelin (2), and degarelix acetate (1). The treatment history of the eight patients is summarized in Supplementary Table 3.

Interview survey

During their one-to-one interviews, the eight patients responded to four questions pertaining to the symptom of fatigue, the impact of fatigue on their lives, whether they had been asked to communicate these symptoms to HCPs, and their satisfaction with the treatment received thus far. Verbatim responses in Japanese along with an English translation are presented in Supplementary Table 4.

The patients’ responses were recorded and subsequently analyzed. Based on the responses, fatigue was considered a burden for the patients. Five (out of 8) patients reported fatigue, which had an impact on their daily activities. Notably, they felt they could not perform their daily activities as well or at the same rhythm as prior to the disease. Social activities were also hindered because of fatigue. One patient reported being on the verge of depression due to fatigue; another patient reported a lack of motivation associated with fatigue. Examples of patients’ comments for each BFI domain are provided in Supplementary Table 5. Characteristic responses are listed in Table 7.

Table 7. Healthcare professionals’ responses to patients’ communication of fatigue as reported by patients.

Comments	Patient number
Patients’ comments for each BFI domain
“If it wasn’t for fatigue, I would have been able to continue my job.”	3
“Going out has become troublesome. For example, I have a lot of gatherings like alumni meetings, work activities. I have stopped going to those completely. I don’t even want to go outside anymore”	3
“When fatigue kicks in, I stop the car and make sure I rest, but I think it might be dangerous to drive. That’s how I feel”	4
“I can’t do chores and work at home like gardening. There is a lack of motivation.”	5
Healthcare professional’s response as described by a patient
“I can’t sleep, so I asked about herbal and Chinese medicine because I heard it works. The doctor said there was nothing he (or she) could do.”	1
“I do. I take medications, the doctor said that it cannot be helped.”	3
“I had an honest discussion with my primary care physician back then, this physician was very understanding and wrote me a referral letter to a hospital. The referral was addressed to that doctor.”	4
“The doctor said that drug has such adverse effect (but the discussion doesn’t go as far as to reduce the drug)”	5
“I did tell them. But it didn’t seem like the physician cared.”	8
Communication with HCPs
“It can be difficult to discuss this with the physician, because of the atmosphere. I think that even if I have said anything, they wouldn’t be listening to me. They are always looking at their computer monitor.”	6
Regarding treatment satisfaction
“The doctor might be too busy. I wait for 1 h and only get 3–4 min of time with the doctor. I feel that the cancer center doesn’t give the atmosphere to sit down and discuss calmly.”	5
“The side effects bother me like I have mentioned before. I think due to the side effects it’s a 4.”	2

Regarding communication of fatigue to HCPs, responses varied. Of the eight patients, five reported they discussed their symptoms or the burden of their symptoms with their treating physician. A summary of the treating physicians’ responses as described by the patients is provided in Table 7.

The patients who attempted to communicate their symptoms received diverse responses from their treating physicians, whose reactions ranged from stating that there was nothing to be done, to referring patients to another physician. Of the eight patients, two reported difficulty in discussing their symptoms with HCPs, because they felt the busy atmosphere of the center did not allow HCPs to show the desired interest and allow conversations of this nature to occur. Characteristic responses are listed in Table 7.

Regarding treatment satisfaction on a scale of 1–5 (5 signifying the least satisfaction), six out of eight patients rated their treatment satisfaction with 4 or 5, noting the high disease burden; two patients rated their treatment satisfaction with 1–2. Dissatisfaction with treatment was mainly associated with side effects but also with the lack of communication of their symptoms. Characteristic responses are listed in Table 7.

Discussion

Currently, symptoms such as fatigue, experienced by patients with advanced prostate cancer, are under-recognized. There is a need to develop effective means of communication between patients and HCPs that would encourage early symptom reporting, which may lead to improved disease and treatment management and, therefore, ameliorate patients’ QoL.

In a recent study in chemo-naïve high-risk non-metastatic and metastatic patients with CRPC, fatigue was shown to be present in 74% of all patients who had been receiving traditional hormone therapy, while 38.5% of all patients reported moderate-to-severe fatigue¹⁹. Patients with fatigue showed a worse QoL and poorer functioning as compared to patients who did not report fatigue²⁷. The novelty of this study is the focus on unreported fatigue, which is common in patients with CRPC. In particular, the study described patient-reported fatigue in Japanese patients receiving AR-axis targeted therapy as first-line therapy, excluding first-generation androgen receptor blockers for CRPC.

Our non-interventional cross-sectional study is also a result that dictates the previous study; approximately 55% (12/22) of the patients reported symptoms of tiredness ranging from mild-to-severe intensity; 18.2% (4/22) of the patients reported moderate-to-severe tiredness. In addition, among the 22 patients, there were 10 reports of symptoms of severe intensity including tiredness, back pain, arthralgia, weight loss, hot flashes, and palpitations. Since the Japanese population is known to have high endurance, it is possible that the feeling of fatigue was not shown in the scores because the patients have become accustomed to it. In particular, the target patients in this study have received many treatments in the past because the pathological condition is advanced among prostate cancers.

Beyond the frequency of fatigue, one-to-one interviews during the qualitative phase of the study revealed important patient insights. Five out of eight patients reported fatigue to be a burden on their lives, with an impact on their daily activities including social activities. In response to the question on the effect of fatigue, the patient noted that they reported an impact on employment associated with depressive symptoms, a lack of motivation due to fatigue, and that they do not feel safe to drive. This insight confirms the previous study²⁷.

This study showed that the involvement of HCPs has an important impact; Patients complained that the busy atmosphere made it difficult to discuss their fatigue with the HCP. Or they discussed their fatigue but were told that there was no treatment for these symptoms.

Six of the eight patients reported treatment satisfaction of 4 or 5 (on a scale of 1–5; 5 = least satisfied), emphasizing the high disease burden while dissatisfaction was mainly because of treatment-related side effects, but also due to the lack of communication of the burden of their symptoms.

Similarly to previous studies exploring fatigue in patients with prostate cancer, in this population, fatigue could be associated with various contributing factors including the disease (metastatic or non-metastatic prostate cancer), androgen receptor blocker therapy, age, depression, anxiety, and/or the sleep-disturbing effect of prostatic symptoms²⁷. In addition, it can be difficult to distinguish between fatigue and clinical depression¹⁷. However, this study could not confirm the trend that patient characteristics had given BFI. The factors may have not been reflected in BFI because the patient showed abandonment for continued fatigue in the interview. Eligible patients consisted of adult males (≥20 years old) diagnosed with CRPC and treated with AR axis-targeted treatment as first-line therapy. Patients with a previous history of docetaxel for CRPC and those receiving abiraterone acetate for mHSPC were not included in the study. Patients participating in an investigational program with interventions outside of routine clinical practice were also excluded from the present study. This criterion was strictly selected for the target population whereby few samples could be selected. However, it is known that patients receiving anti-cancer treatments such as chemotherapy, radiation therapy, and bone marrow transplants often experience fatigue as a serious side effect of the treatment^14,15. And thus, it was necessary to eliminate the impact of the interview as much as possible.

These results suggest that fatigue is one of the symptoms that considerably affect patients receiving treatment for CRPC. Therefore, treating physicians may need to monitor patients for fatigue and other symptoms that potentially relate to fatigue (such as lack of motivation, social withdrawal, or depression), and appropriately address the burden of those symptoms by adapting or changing treatment regimens to meet the patient’s individual needs, living conditions, and wishes. Based on package insert²⁸, the first step against fatigue induced by enzalutamide is dose reduction. The enzalutamide starts at 160 mg, allowing for a dose reduction to 120 mg based on physicians’ judgment on fatigue. Adverse events are resolved by dose reduction in almost half of our patients²⁸. In APCCC 2019, a strong consensus (94%) for resistance and aerobic exercise to reduce fatigue of preferred first management option to reduce fatigue in patients receiving systemic therapy for prostate cancer (apart from therapy dose reduction if possible) ⁸.

In addition to monitoring the frequency of fatigue that was investigated in the quantitative phase of the study, the authors considered the patients’ burden in the event of fatigue along with their needs and wishes as revealed in one-to-one interviews. This study has a number of limitations including the cross-sectional design, which captures only a ‘snapshot’ in time; thus, changes in the parameters evaluated may have occurred without having been detected. In the absence of other studies focusing on fatigue in Japanese patients with CRPC, we were not able to validate results against a more robust study/study design. The data collected to evaluate fatigue and its impact on daily life were based on human memory and recollection, which are prone to bias and may degrade with advanced age. However, this effect was accounted for by restricting the recall period to 24 h and 1 week in the quantitative survey. Furthermore, the low number of samples is a limitation of the study. This study had very limited access to patients due to the need to focus on a limited population of Japanese patients receiving AR-axis targeted therapy as first-line therapy, excluding first-generation androgen receptor blockers for CRPC. However, this study was a qualitative study and the respondents' comments covered all the context of CRPC. And, this study was a cross-sectional study, and there is no quantitative data on the fatigue rate prior to starting AR treatment. Therefore, the amount of change in fatigue rate was not available. Future investigations should study unreported fatigue for a wider range of cancer treatments, such as general cancer treatments or patient populations containing first-generation androgen receptor blockers.

Of the 161 responses to the web survey that were originally identified, patients who were cognitively impaired or suffering from extreme fatigue might have been less motivated to complete the survey, thus, resulting in selection bias towards less affected patients who were able to use a computer and complete the web survey. In addition, the self-reporting nature of the questionnaires might have resulted in differences in the interpretation/understanding of the questions, while patients might have perceived fatigue differently depending on the treatment received. In the quantitative analysis, 12 patients were on enzalutamide treatment and 10 on abiraterone acetate, while 18 of the 22 patients had a medical history of bicalutamide or flutamide treatment.

The selection of patients was based solely on their responses with no verification of medical records by HCPs; thus, although patients with mHSPC were to be excluded, such patients may inadvertently have been included and misclassified as patients with CRPC.

Furthermore, patients were recruited via the Oncolo platform (https://oncolo.jp) and potentially via social medial channels or patient advocacy groups. Therefore, there was no specific information pertinent to the patients’ geographical distribution, other than the existing information provided by the Oncolo platform, according to which the geographical location of the website’s visitors is representative across the 47 prefectures of Japan. Another limitation of this study is the small sample size; however, the sample size was not expected to represent a major issue for the analysis, due to the descriptive nature of the study and the fact that no associations were sought to be explored.

Conclusion

In the present study, although the majority of patients reported mild fatigue, the qualitative responses from one-to-one interviews underscored the impact of fatigue in patients’ daily lives and social activities. Additionally, difficulties in communicating symptoms to HCPs were also reported. The frequency of fatigue after medication may need to be monitored and its burden considered to provide treatment that meets the needs, wishes, and circumstances of each patient. Further studies with a more robust study design and larger sample size are warranted for the validation of these results.

Transparency

Declaration of funding

This article is based on an observational study initiated and funded by Bayer Yakuhin Ltd., in Japan.

Declaration of financial/other relationships

Taro Iguchi reports serving as a consultant or advisor, speakers’ bureau participation, and research funding from Bayer; serving as a consultant or advisor and speakers’ bureau participation from Janssen; serving as a consultant or advisor, speakers’ bureau participation and research funding from Astellas; and speakers’ bureau participation from Sanofi. Yusuke Nakamura is an employee of Bayer Yakuhin, Ltd. Takeshi Akiyama, Krishant Chand, and Eric Yu are employees of IQVIA and have received funding from Bayer Yakuhin, Ltd., for work performed on this study. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

The authors provided critical review and revisions to the manuscript drafts, provided final approval of the version to be published, and are accountable for the integrity of the content and for addressing questions.

Acknowledgements

The authors gratefully acknowledge Sayaka Yasuda (Clinical Research Coordinator, Osaka City University) who contributed to the development of the patients’ questionnaire. Writing assistance was provided by Jiju Punnoose and Chrysi Petraki of IQVIA.