Review

Keywords

Castration-resistantprostate cancer

Symptoms

HRQoL

Patient’sperspective

Heather Payne, MBBS,FRCP, FRCRDepartment ofOncology, UCLH NHSFoundation Trust, 250Euston Road, London,NW1 2PG, UK

Richard Pearcy, MD,FRCSDepartment of Urology,Plymouth Hospitals,Plymouth, UK

E-mail:heather_payne@blueyonder.co.uk

Online 20 January 2012

� 2011 WPMH GmbH. Publish

ed

Symptoms andhealth-related quality oflife in castration-resistantprostate cancer:the patient’s perspective

Heather Payne and Richard Pearcy

Abstract

Castration-resistant prostate cancer (CRPC) is associated with multiple symptoms that have a significant

impact on patients’ health-related quality of life (HRQoL). We were interested to establish the extent to

which disease and treatment-related symptoms affect the HRQoL of patients with CRPC from the patients’

perspective, so we undertook a review of current literature and also obtained feedback at an international

meeting. Our review of evidence from the literature found that the majority of patients with CRPC are

significantly affected by a number of disease- and treatment-related symptoms that have a negative impact

on their HRQoL. These findings highlighted the need for treatment decisions to be based on an assessment

of quality as well as quantity of life for this patient population. We also established that there are substantial

differences in the perception of HRQoL between patients and their physicians. Physicians remain the most

direct influence on patient choice, therefore they have a responsibility to fully inform patients about their

disease stage, the available treatment options and potential impact on HRQoL. Despite advances in the

treatment and management of CRPC, further improvements in HRQoL are necessary. As a consequence, all

future treatment approaches for CRPC should take into account both survival benefit and the impact on

HRQoL. Furthermore, patients, their partners andphysicians should all be involved in the treatment decision-

making process. This should include an assessment of HRQoL to ensure potential impact and benefit is fully

understood. � 2011 WPMH GmbH. Published by Elsevier Ireland Ltd.

Introduction

Castration-resistant prostate cancer (CRPC) can

be associated with multiple symptoms, arising

both from the disease itself and also as a con-

sequence of treatment, which can have a sig-

nificant impact on patients’ health-related

quality of life (HRQoL) [1], both physically and

mentally [2]. Treatment decisions for patients

with CRPC should therefore be based both on

quality as well as quantity of life [3–5], in addi-

tion to the costs and efficacy of the treatment [6].

Androgen-deprivation therapy (ADT) is the

mainstay of treatment for advanced prostate

by Elsevier Ireland Ltd.

cancer. Although the majority of men initially

respond to this treatment, it is associated with

side effects that can significantly impact

HRQoL, and progression to CRPC eventually

occurs in almost all patients. Although patients

may respond to secondary hormonal manipula-

tions, many may become symptomatic and ulti-

mately require chemotherapy. Docetaxel (and

recently cabazitaxel) is approved in the US for

patients with metastatic CRPC. Although it pro-

longs survival, docetaxel is associated with sig-

nificant toxicities [7] and its impact on HRQoL is

variable and dependent on symptom load [8]. It

is hoped that agents currently in development

Vol. 9, No. 1, pp. 9–16, March 2012 9

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10 Vol. 9, No. 1, pp

will demonstrate both better survival and

improvements in HRQoL for this often elderly

population with extensive comorbidities [9].

Strategic approaches need to be tailored care-

fully to manage and care effectively for these

patients who may indeed be willing to sacrifice

some degree of life expectancy to avoid treat-

ment-related side effects [10].

This review will examine, with the assistance

of a number of case studies, the significant

HRQoL issues confronting patients with CRPC.

Potential disconnects between patients and

their physicians with regards to the relative

importance of these issues will be addressed,

and the information needs of patients in rela-

tion to their disease will be assessed.

Urological symptoms

Urinary, bowel and sexual dysfunction may

occur with radiation therapy and/or surgery

for patients with localized or locally advanced

prostate cancer [11]; however, evidence that

these symptoms can be exacerbated in patients

with CRPC is limited. One qualitative survey

has highlighted that the true impact of such

dysfunctions may not be revealed with generic

QoL measures, because they are not perceived

as health problems per se [12]. In a survey of

men following radical prostatectomy, urinary

dysfunction (i.e. incontinence) was found to be

the most bothersome factor, although sexual

dysfunction was the most prevalent factor

affecting HRQoL [13]. With progression to

advanced disease and long-term castration-

based therapy, most men are resigned to a loss

of erectile function; however, the reduction in

libido can make this less of an issue [12].

Pain

As prostate cancer has a propensity to metasta-

size to bone, many patients will experience

some degree of discomfort, and pain manage-

ment is a significant problem [14]. Pain and the

side effects of pain medication, e.g. opiate-based

therapy, precipitate a number of HRQoL issues

for patients. A recent study confirmed the

importance, to patients and healthcare profes-

sionals alike, of pain and its impact on physical/

role functioning to the HRQoL of patients with

prostate cancer and bone metastases [15]. The

. 9–16, March 2012

balance between the toxicities of further hor-

mone therapies and/or chemotherapy or local

radiation treatment, which may improve pain-

ful symptoms by reducing the cancer burden,

need to be carefully balanced with the toxicities

of opiate analgesia if left untreated.

Case study 1 highlights the issue of pain

control and illustrates the impact that side

effects of treatment have on HRQoL for the

patient. The case study also highlights how

these factors influence treatment decisions

and disease course.

Psychological issues

Anxiety and depression are major barriers to

effective treatment. A survey in 2008 high-

lighted psychological distress as one of the

greatest supportive care needs of men with

prostate cancer [16]. Results from a longitudi-

nal study of men with prostate cancer found

that psychological distress (anxiety and depres-

sion) was greatest at diagnosis, with younger

patients especially being affected by anxiety

[17]. It is important to note that the anxieties

experienced by patients with CRPC vary greatly

depending on the individual circumstances.

Case study 2 highlights some of the fears

and emotions that patients face regarding

their disease and the side effects of treatment.

A recent study highlighted the importance

of anxiety as a target for decision making.

Despite physicians rating it as relatively unim-

portant, anxiety may result in earlier and

potentially unnecessary initiation of ADT in

patients with biochemical recurrence [18]. In

addition, anxiety related to PSA levels and the

results of PSA testing has also been revealed as

a substantial problem in patients with prostate

cancer. In a questionnaire-based study of

patients with metastatic prostate cancer, half

of the patients surveyed also believed that if

PSA measurements ceased, it would suggest

their doctor was giving up on them [19]. In

addition, 76% of patients reported some level

of anxiety and 15% reported extreme anxiety

before receiving PSA test results. Physicians

should counsel patients with CRPC against

making treatment decisions based on PSA cri-

teria alone: PSA is only one component of

decision making, with clinical and radiogra-

phical findings being equally (if not more)

important [20].

Review

Case study 1: A patient with prostate cancer who has significant anxiety and pain issues but whosetreatment is limited by side effects

Mr B is a 53-year-old white man who was diagnosed with metastatic prostate cancer 3 years

ago. Initially, he was treated with a single agent luteinizing-hormone releasing hormone

(LHRH) agonist; he was subsequently briefly treated with bicalutamide, but discontinued due

to abnormal liver function tests. When he developed symptomatic progressive bone disease he

received docetaxel and prednisone for a total of 3 months before further disease progression.

Whilst receiving his chemotherapy he expressed concerns about his change in appearance,

including hair loss and the development of Cushingoid features. He also expressed frustration

about the hot flushes, but did not tolerate agents such as selective serotonin reuptake

inhibitors (SSRIs) or gabapentin to manage these symptoms.

Mr B then underwent radiotherapy to his left hip and lumbar spine; as he lived some distance

from the medical centre, he received this treatment in one 800 cGY fraction. As a consequence he

developed nausea and vomiting, which made him hesitant to pursue further palliative radio-

therapy for pain control. Due to his concerns about the chemotherapy-induced toxicities, Mr B

was treated with ketoconazole and prednisone, however, this treatment was discontinued after

1 month, again due to nausea and vomiting. Mr B was subsequently treated with mitoxantrone

but discontinued this due to progressive disease and significant fatigue. He continued to

struggle with the pain but took opiates only intermittently to avoid constipation and sedation.

As Mr B developed worsening back pain and lower extremity weakness he underwent an

MRI scan that revealed an epidural mass from L2–L4. Mr B declined hospital admission to

begin radiotherapy, citing personal issues, and dexamethasone therapy was initiated (4 mg

every 6 hours). Subsequently, he started radiotherapy at a local centre; however, he developed

significant mood lability, suicidal ideations and significant anxiety, which was attributed, in

part, to dexamethasone. He declined further medical management due to concerns regarding

side effects, but fortunately his mood stabilized as dexamethasone was decreased. Mr B

enrolled at a home hospice after completing his radiotherapy.

Case study 2: A patient with prostate cancer who is a carer for his disabled wife and has anxietyabout treatment and its impact on his life

Mr G is a fit 78-year-old man who is the main carer for his severely disabled wife. He was

diagnosed with locally advanced prostate cancer in June 1996 at a peripheral clinic approxi-

mately 20 miles from the Cancer Centre. Mr G was treated with radical radiotherapy and had a

good initial clinical and prostate-specific antigen (PSA) response. However, in May 2005 he had a

biochemical relapse and was treated with hormone therapy (initiated when PSA measured 11.6

ng/ml). Over the next 3 years he was successfully managed for disease progression and bone

metastases at home and in the local clinic. Initially, he was treated with goserelin, then

bicalutamide was added to achieve step-up combined androgen blockade, and finally stilboes-

trol was added to the goserelin. Despite this, Mr G subsequently developed symptomatic

progression and further increases in PSA (doubling time <3 months). He was offered che-

motherapy but refused as it involved travelling to the Cancer Centre and he could not leave his

wife. He was initially treated with low-dose steroids (dexamethasone 0.5 mg daily) but a few

weeks later developed sudden severe pain which necessitated an emergency admission to the

Cancer Centre for analgesic control. As an inpatient, Mr G accepted a cycle of docetaxel/

prednisolone. He admitted being terrified of travelling as he felt responsible for his wife, was

scared of the word ‘chemotherapy’ and he did not want to admit to himself that his disease was

progressing. Currently, his pain is well controlled after four cycles of chemotherapy, and his

PSA is stable. Mr G has accepted a ‘care package’ to help with daily living needs for him and his

wife. He still feels anxious about travelling to the Cancer Centre but feels there are physical

benefits for which he will accept the reduction in other aspects of HRQoL.

Vol. 9, No. 1, pp. 9–16, March 2012 11

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Treatment-related symptoms

Symptoms related directly to treatment can

have a significant impact on HRQoL. Many

patients with CRPC have been receiving long-

term ADT, which can be associated with both

short- and long-term sequelae including erectile

dysfunction, hot flashes, fatigue, and psycholo-

gical effects [21]. Long-term consequences

include accelerated bone loss, muscle wasting

and increased cardiovascular risk [22]. In addi-

tion, patients with metastatic disease may

develop toxicities (e.g. neutropenia, fatigue,

nausea and vomiting) associated with che-

motherapy. Patients may also experience anxi-

ety relating to their preconceptions of

chemotherapy and its impact. While the goal

of palliative chemotherapy in any disease set-

ting is to improve symptoms, it is likely that in

many patients it can worsen HRQoL for at least

part of each treatment cycle. A study comparing

docetaxel plus prednisone with mitoxantrone

plus prednisone reported a significant improve-

ment in overall survival in patients receiving

docetaxel every 3 weeks. HRQoL measures,

including sexuality, urinary incontinence,

bowel or rectal function and reductions in pain,

were also improved [7]. In contrast, a study

comparing prednisone in combination with

cabazitaxel or mitoxantrone chemotherapy

demonstrated no significant difference in pain

response rates or time to pain progression

between the two treatment groups [23]. Patients

with metastatic CRPC who progressed after

treatment with docetaxel-containing che-

motherapy and who received the targeted

agent abiraterone acetate plus prednisone

had a significant improvement in pain relief

and delay of pain recurrence, as well as an

improved overall survival, versus those who

received placebo plus prednisone [24], indicat-

ing that treatments beyond chemotherapy may

improve patients’ HRQoL at an advanced stage

of the disease.

Differences in HRQoL may occur in patients

who present with metastatic CRPC compared

with those who have progressed to develop

metastatic disease following radical primary

therapy that they received because they were

high risk at disease presentation. For example,

urinary symptoms following radical prosta-

tectomy and bowel dysfunction following radi-

cal radiotherapy can occur at a later date and

will have an adverse effect on HRQoL. However,

. 9–16, March 2012

in a study of patients with locally advanced or

high-risk local prostate cancer, the addition of

local radiotherapy to ADT halved the 10-year

prostate-cancer specific mortality compared

with ADT alone, but only slightly increased

urinary, rectal and sexual problems [25]. These

data could provide a rationale to help patients

decide on a more radical treatment approach

upon presentation, which might also reduce

the need for lifelong ADT and associated side

effects.

Co-morbid medical conditions

Many patients with metastatic CRPC are likely

to be of advanced age and be burdened with

other age-related co-morbidities, which may

influence their HRQoL. For example, a 4-year

follow-up study of patients with prostate can-

cer showed that those with cardiovascular

disease had a worse physical and sexual HRQoL

before and after treatment, compared with a

matched sample without cardiovascular dis-

ease [26]. Therefore, treatment decisions

should be made in the context of the indivi-

dual patient’s other co-morbidities. Case study

3 highlights some of the issues facing patients

with a range of co-morbidities and the clini-

cians treating them.

Patient perceptions of HRQoL

Patients’ attributes and decisions relating to the

HRQoL issues are influenced by their individual

circumstances. For example, younger men diag-

nosed with prostate cancer will have different

issues to those diagnosed later in life, as they are

often still working and have financial depen-

dants. Some may delay chemotherapy because

it possibly results in time off work and time

away from their families (as highlighted in Case

study 2). Other patients may feel that the side

effects of treatment outweigh the potential

benefits (see Case study 1); while older patients

may find their treatment options limited by co-

morbidities (Case study 3).

A significant decline in HRQoL has been

reported during the final year of life in

patients with metastatic CRPC. However, it is

not clear which specific patient characteristics

are associated with more rapid declines [27,28].

It has long been recognized that patients will

Review

Case study 3: A patient with prostate cancer who has significant co-morbidity issues that impacttreatment decisions

Mr A is an 82-year-old man who 13 years previously had undergone definitive radiotherapy for

Gleason 7 prostate cancer. Three years later his PSA levels were rising and he was treated with

cryotherapy. Once his PSA began to rise again he was prescribed a LHRH agonist and his PSA

levels remained under control until a year ago, when bicalutamide was added. He was referred

to a medical oncologist after having diffuse pain for a month, which was most severe in his

shoulders and ribs. Because of his symptoms, he required assistance with bathing and

dressing. He had a poor appetite and lost 15 lbs in weight but he was feeling well prior to

the onset of these symptoms and his other co-morbidities (high blood pressure and high

cholesterol) were controlled.

Mr A’s physical examination was unremarkable except for point tenderness over the ribs

and shoulders. At presentation, his PSA was 117 ng/ml and rose to 305 ng/ml 6 weeks

following discontinuation of bicalutamide. A subsequent complete blood count, and chem-

istry assessment (including liver function tests) were all within normal limits and his

testosterone levels remained suppressed. However, a bone scan showed diffuse metastatic

disease, although a CT scan was negative for visceral metastatic disease. He was offered several

treatment options, including docetaxel plus prednisone, ketoconazole plus prednisone, and

palliative radiotherapy, and because of the rapid onset of his symptoms and otherwise good

health he elected to proceed with chemotherapy. He had a rapid improvement in his appetite

and energy levels and a decrease in his narcotic requirements. He had an unusually long

period of disease control on chemotherapy and was treated with intermittent therapy which

allowed him to return home during treatment breaks; he eventually developed progressive

disease. His treatment options were limited due to his other medical problems, which had

arisen during the course of his illness, and included atrial fibrillation, congestive heart failure

and mild dementia. He was deemed not to be a candidate for further aggressive treatment and

he passed away after 6 months whilst under the care of a home hospice team, approximately 4

years after starting docetaxel.

understate their experience of side effects

when talking to their physician; equally, phy-

sicians may not fully explain potential issues

associated with the treatment they provide.

There is also evidence suggesting that the

partners of patients with prostate cancer are

affected by sexual dysfunction and psycholo-

gical distress. Indeed, a survey of patients with

prostate cancer and their partners found that

both had greater levels of depression than the

general population [29]. When persistent,

these can also result in a decline in the part-

ner’s QoL [30–33].

Differences in patient and physicianperceptions of HRQoL

Substantial differences in reported HRQoL

have been documented between patients with

prostate cancer and their physicians, which

appear to persist over time [34,35]. Physicians

may concentrate on the presence or absence of

particular symptoms, rather than the HRQoL

impact on the patient. In a study examining

the agreement between healthcare profes-

sional evaluations of HRQoL issues with that

of patients with bone metastases, psychosocial

issues were emphasized by the patients with a

particular focus on ‘worry’ about loss of mobi-

lity, depression about death, loss of income,

dependence on others and disease progression,

whereas healthcare professionals rated ‘symp-

tom’ issues as more important [15]. While

urologists tend to focus on particular symp-

toms (such as pain), they have been shown to

be much less proficient than the patient’s

partner at accurately quantifying subjective

HRQoL [36]. This highlights (1) the importance

of partners’ roles in decision making and

patient care and (2) that physicians should

treat each patient individually to determine

the factors that are most important to the

patient and their relatives and to help them

make informed decisions based on their per-

ceived HRQoL.

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14 Vol. 9, No. 1, pp

Patient information needs

Although encouraging progress has been

made in most aspects of patients’ experiences

of cancer services, there is evidence that

patients with prostate cancer may be continu-

ing to have a relatively worse experience than

those with other cancers [37]. That report

showed that a fifth of UK patients had either

not discussed, or not fully understood, poten-

tial pain and/or side effects associated with

treatment, potential impact on HRQoL and

possible alternative or complementary treat-

ments [37]. This may be because the decision-

making process for prostate cancer is very

complex and without doubt leads to additional

anxiety and difficulty comprehending choices

especially at diagnosis.

Research undertaken in the US in 2008

suggested that relatively little is known about

prostate cancer patients’ information seeking

after diagnosis, how they use such information

in making a treatment decision, or what role

information plays in adjusting to HRQoL issues

post treatment [38]. That survey highlighted

that although respondents felt reasonably

informed about prostate cancer, over a third

of them reported being less than informed.

Similarly, many respondents were generally

satisfied with their communication with phy-

sicians, however, approximately 40% of them

reported being less than satisfied.

A review of the literature on information

needs and sources of information among can-

cer patients undertaken in the US found that

the most frequent information need was treat-

ment related and the most frequent informa-

tion source was their healthcare professionals

[39]. Although healthcare professionals

emerge as important sources of health infor-

mation, the Internet is also becoming an

increasingly used resource. Yet despite the

increase in available information about pros-

tate cancer, patients are generally not well

informed about CRPC. This may be due to

the uncertain and rapidly evolving treatment

landscape for CRPC, but also because many

websites and information sources do not dis-

cuss treatment options beyond relapse after

first-line hormone therapy. This causes signifi-

cant anxiety for men when they are diagnosed

with the condition, as it implies a lack of

therapy options beyond this stage and a poor

long-term prognosis. Experiences of patients

. 9–16, March 2012

with prostate cancer and their partners,

assessed using semi-structured interviews,

showed that patients’ and partners’ informa-

tion needs were often not identified or met,

and the preferred roles patients may wish for

in decision making were not being explored

[40].

These findings emphasise the importance to

patients of the appropriate communication of

information on the prognosis of their disease

and its treatment. For example, one study

found that men with prostate cancer preferred

verbal information given by a consultant to

written information, although leaflets were

rated above information on television and

other media [41]. The communication style

of clinicians was also shown to influence men’s

evaluation of the information.

Physician involvement in decisionmaking

The physician remains the single most direct

influencer for patients in the decision-making

process and so has a responsibility to not only

explain the potential benefits of treatments (in

terms of disease control), but also the negative

impact that treatments can have on HRQoL.

This process should be undertaken with the

support of a multidisciplinary team, including

specialist nurses, to aid patient decision mak-

ing. An extensive literature review of the psy-

chosocial consequences of prostate cancer

concluded that physicians should consider

the increased need for information and emo-

tional support requested by men with prostate

cancer [42]. However, a Canadian survey of

men with prostate cancer revealed that only

51% agreed that their primary care physician

was part of their treatment team [43]. In

response to an open-ended question about

the impact of the disease and treatment on

their HRQoL, while many of the men reported

physical symptoms, only a minority reported

having received adequate help from their

healthcare providers. Systemic barriers, such

as the discomfort of healthcare professionals

in discussing sexual dysfunction and the lack

of time in busy clinical practices to deal with

sensitive issues, were suggested to have been

contributory factors. To address this in the UK,

the National Institute for Clinical Excellence

(NICE) has highlighted the need for dedicated

Review

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Conflict of interest

The authors declare that they have no compet-

ing interests.

Authors’ contributions

Heather Payne conceived the idea for this

article based on findings from a session held

at an international meeting looking at the

challenges in the management of patients

with CRPC. Both authors provided input on

the manuscript draft and have approved the

final draft for submission. Heather Payne pro-

vided the case studies included in the paper.

Acknowledgements

We thank Yu-Ning Wong, MD from Fox Chase

Cancer Center, Philadelphia, USA for provision

of one of the case studies included in this

review. We also thank Dr Juliet Fawcett from

Mudskipper Bioscience who provided editorial

assistance funded by AstraZeneca.

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