Download Patient-reported outcome measures in metastatic prostate cancer

PROSTATE DISEASE
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Patient-reported outcome measures
in metastatic prostate cancer
LAURA SELLERS, AYLIN NUHOGLU SAVAS, REENA DAVDA, KATE RICKETTS AND HEATHER PAYNE
P
Survival remains a primary aim of treatment in prostate
cancer, but quality of life is also an essential benefit of any
therapy. Patient-reported outcome measures, which record
quality of life as perceived by the patient, are now widely
used in cancer trials and, as discussed in this article, have a
place in everyday practice.
rostate cancer is the most common
male cancer in the UK. In 2012, 43 400
men were diagnosed with and 10 800 men
died from this cancer in the UK.1 It has
been estimated that approximately 10%
of men diagnosed with prostate cancer
present with advanced or metastatic
disease. In addition, other men relapse
and progress to develop advanced disease
after initial radical treatment for localised
or locally advanced disease. Advanced
prostate cancer can be associated
with debilitating symptoms, including
metastatic bone pain, fracture and spinal
cord compression, in addition to local
symptoms from the primary tumour.
Initial treatment for advanced prostate
cancer is with androgen deprivation
therapy (ADT), which is achieved by
either orchiectomy or, more commonly,
by chemical castration using luteinising
hormone-releasing hormone agonists
(LHRHa). In the majority of patients, ADT
achieves remission and delays disease
progression. However, disease-related
symptoms, in addition to toxicities from
ADT and the psychological impact of living
Figure 1. EPIC is a well-established PROM questionnaire developed to monitor HR-QOL
outcomes in prostate cancer survivors (http://medicine.umich.edu/dept/urology/research/epic)
www.trendsinmenshealth.com
Laura Sellers, Clinical Research Fellow,
University College London Hospital; Aylin
Nuhoglu Savas, PhD student, Department
of Medical Physics and Bioengineering,
University College London; Reena Davda,
Clinical Oncologist, University College London
Hospital; Kate Ricketts, Lecturer, Department
of Medical Physics and Bioengineering,
University College London; Heather Payne,
Consultant Clinical Oncologist, University
College London Hospital
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with an ‘incurable’ cancer, can have a
significant impact on health-related quality
of life (HR-QOL).
Following the initial benefits of ADT, men
invariably progress with resistant disease
(castration-resistant prostate cancer –
CRPC). Historically, further treatment
modalities have been limited, but this
has changed over the last decade as a
number of new and exciting chemotherapy,
bone-targeted and novel hormonal agents
have demonstrated significant increases
in overall survival (OS) for men with
progressive metastatic CRPC.2-4
The optimal management and sequencing
of these drugs is an increasingly complex
process, involving many different
disciplines in primary, secondary and
palliative care and, most importantly, the
specific needs, views and circumstances of
each individual patient and consideration
of how therapy will affect their HR-QOL.
Survival remains a primary measure of
treatment effect, but HR-QOL is also
an essential component of the overall
benefit of any therapy. Patient-reported
outcome measures (PROMs) instruments,
collecting information on HR-QOL as
perceived by the patient himself, are
now widely used in cancer treatment trials
and have future implications for
our everyday practice.
WHAT ARE PROMS?
Questionnaires may be self-administered or
administered at point of care. A large number
of validated questionnaires assessing HR-QOL
for specific diseases have been developed
by different groups and disciplines. Diseasespecific PROMs are often used in randomised
control trials to assess a range of relevant
health domains and to monitor real-life
consequences of treatment.
The most frequently used PROMs for
metastatic prostate cancer are discussed in
this review, including EPIC, FACT-P, EORTC
QLQ-C30 and EQ-5D PROMs.5
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Expanded prostate cancer index
composite (EPIC)
EPIC is a well-established PROM questionnaire
developed to monitor HR-QOL outcomes in
prostate cancer survivors (Figure 1). EPIC has
been shortened and refined in recent years
to make it easier for patients to complete.
The EPIC-50 was derived from the UCLA
Prostate Cancer Index and contains 50
items assessing five prostate cancer-specific
domains: urinary incontinence; urinary
irritation/obstructive symptoms; bowels;
sexual; and vitality/hormonal.6
The original version was time–consuming
to complete, which limited its use outside
of clinical trials. A shorter version, the
EPIC-26, was therefore designed. This
evaluates the same five symptom domains
as the EPIC-50, but consists of only 26
questions and takes between 10 and 15
minutes to complete, scoring from worst
(0) to best (100). EPIC-26 is a useful tool to
monitor domain-specific changes in HR-QOL
among prostate cancer survivors over time,
and can quantify changes resulting from the
introduction of new treatments.7 A working
group for the International Consortium
for Health and Outcome Measurements
(ICHOM) has recently recommended EPIC-26
as a valuable tool for the standardised
collection of data across different centres to
allow internationally comparable collection
of PROMs after treatment for localised
prostate cancer.8
The Expanded Prostate Cancer Index
Composite for Clinical Practice (EPIC-CP)
was developed for routine clinical care
of patients with prostate cancer. Shorter
and more practical for community and
academic purposes, it is a one-page,
16-item questionnaire, which aims to
improve the collection and management
of patient-reported outcomes outside of
clinical trials and may be used or adapted
to collect data in the clinic setting.9
BROADER PROMS TOOLS
Men diagnosed with metastatic disease
frequently experience symptoms outside
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urinary, bowel and sexual domains that
have an impact on their QOL. These include
mood symptoms/psychological changes
and pain. Tools addressing general HR-QOL
for advanced disease include the FACT-G,
EORTC-QLQ-C30 and EQ-5D, which have
been validated specifically in patients with
cancer and used in trials in metastatic
prostate cancer.10,11
The Functional Assessment of Cancer
Therapy – Prostate Scales (FACT-P)
The Functional Assessment of Cancer
Therapy – General (FACT-G) was
developed in the USA and, since 1989,
has been widely utilised in cancer studies
for the assessment of HR-QOL. FACT-G
requires 8–10 minutes to complete, and
includes 39 questions involving four
domains: physical, functional, social and
emotional. Multiple subscales have been
added for different tumour types. FACT-P
is a well-validated, self-administered
questionnaire used specifically in prostate
cancer, which includes the FACT-G scale
and a prostate cancer subscale (PCS)
(Figure 2). The PCS addresses issues
related to sexuality, bowel/bladder function
and pain. Higher scores indicate higher
HR-QOL, and an increase of greater
than five points indicates significant
improvement in HR-QOL.11
The FACT-P tool is validated in all stages
of prostate cancer. Patients with advanced
prostate cancer consistently score lower
on FACT-P compared with patients with
localised disease, reflecting the physical
and psychological effects of increased
disease burden and perhaps the toxicities
of additional therapies. FACT-P was also
found to be sensitive to changes in other
indicators of treatment efficacy, including
performance status and PSA levels.11
The European Organisation for
Research and Treatment of Cancer
QLQ-C30 (EORTC-QLQ-C30)
The EORTC-QLQ-C30 is another commonly
used questionnaire. Designed to assess
the QOL of all cancer patients participating
www.trendsinmenshealth.com
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advanced prostate cancer, the BPI score
demonstrates stability over time and
corresponds with other aspects of patientreported health and clinical outcomes.15
The Present Pain Intensity score (PPI)
is a single question of the McGill Pain
Questionnaire, which asks patients to
characterise their present pain using
descriptors from 0 (no pain) to 5
(excruciating). There is little literature
comparing the psychometric performance
of these pain scales in prostate cancer.
However, the BPI pain intensity and
FACT-P pain scales may be better than
the PPI question at capturing the pain
experience among patients with advanced
prostate cancer.16
Figure 2. The prostate cancer subscale from FACT-P (Version 4) addresses issues related to
sexuality, bowel/bladder function and pain. Questionnaires are subject to copyright and
permission must be obtained before use (www.facit.org)
in clinical trials and widely used in
prostate cancer research, it includes nine
multi-item scales: five scales include
physical, role, cognitive, emotional and
social; three scales focus on symptoms
(fatigue, pain, nausea and vomiting);
and there is a single global health and
QOL scale.13,14
In advanced prostate cancer trials where
the EQ-5D has not been measured, models
have been developed to ‘translate’ prostate
cancer-specific HR-QOL using results from
FACT-P and EORTC-QLC-C30 scores, in
order to obtain a single index value for
EQ-5D. EQ-5D can also be used to evaluate
cost-effectiveness.10
EuroQol (EQ-5D)
In response to the vast number of QOL
measures available, the EuroQol Group
created the EQ-5D questionnaire. This
has been designed as an international,
standardised, generic instrument for
describing and evaluating HR-QOL, to
allow comparison of QOL measures
between different studies and diseases.
It is non-disease specific and includes six
dimensions of health mobility, self-care,
usual activities, pain/discomfort, and
anxiety/depression, with one question
per domain. It is short, self-administered
and developed for ease of use outside of
clinical trials.
ANALGESIC SCORES
Pain is one of the most common symptoms
in advanced prostate cancer and several
pain assessment questionnaires are
routinely used in prostate cancer trials.
www.trendsinmenshealth.com
The Brief Pain Inventory (BPI) was
initially developed to assess pain
related to cancer. The BPI pain intensity
scale has four questions to capture the
variability of pain over time. A visual
analogue scale is used, with a range of
0–10 (where 0 equals no pain and 10 is
pain as bad as you can imagine). Pain is
rated when it is at its worst, least, average
and right now (Figure 3). In patients with
Many patients with advanced prostate
cancer use analgesic medications
for their pain. The World Health
Organization Analgesic Treatment
Ladder has been used to quantify
analgesic medication use among patients
with advanced cancer in several trials.
The Analgesic Quantification Assessment
(AQA) represents a sensitive measure of
analgesic use and may better determine
whether changes in pain assessments in
clinical trials are due to the intervention
or changes in analgesic use.
To determine the initial AQA score
each patient is scored by the World
Health Organization Analgesic Ladder.
The score is then converted into a daily
Oral Morphine Equivalent (OME). The
results score on the 8-point AQA scale
corresponds to no analgesic use,
non-opioid analgesics, weak opioids
and strong opioids (Table 1).17
Changes in pain scores can be a good
indicator of the efficacy of both the
analgesic used and specific cancer drugs in
reducing the burden of metastatic disease.
PROMS IN RECENT TRIALS IN CRPC
Overall survival and progression-free
survival are relevant and important primary
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reported benefits in the delay in median
time to opiate use, from 23.4 months
for prednisolone to 33.4 months in the
abiraterone and prednisolone combination.2
Figure 3. A question from the Brief Pain Inventory (BPI) (short form). The BPI is useful in
demonstrating the stability of pain over time in prostate cancer
endpoints in many randomised controlled
trials in metastatic CRPC. However, they
do not provide a comprehensive picture
of overall treatment effects. The QOL for
each individual patient will be different,
as each person has different expectations
and goals in life that cannot be predicted
by clinicians. The increasing importance
of PROMs as a clinical endpoint is now
widely recognised, with several recent
trials evaluating the effectiveness of
drugs in CRPC collecting QOL measures as
secondary endpoints.2,3,18
An example of the incorporation of
PROMs in a clinical trial is the COU 302
study, where 1088 asymptomatic or
mildly symptomatic men with progressive
CRPC without prior chemotherapy were
randomised to receive the novel hormonal
agent abiraterone (Zytiga) 1000mg/day
plus low-dose prednisolone (10mg daily)
or placebo plus prednisolone. The final
analysis of this trial, after a median
follow-up of 49.2 months, showed a
significant improvement in median OS in
favour of abiraterone and prednisolone
compared to prednisolone alone (34.7
months versus 30.3 months; HR 0.81,
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p=0.0033). Abiraterone also demonstrated
significant improvements in important
secondary endpoints, including time to
the initiation of cytotoxic chemotherapy
(10 months), time to first skeletal-related
event, time to PSA progression and rate of
decline of PSA.
The study utilised the FACT-P questionnaire
to assess the benefits in preservation of
QOL and time to deterioration in QOL.
There was a significant delay in reduction
of FACT-P total scores, from 12.7 months
in those men treated with abiraterone and
prednisolone to 8.3 months in the placebo
and prednisolone group. The study also
A WIDER ROLE FOR PROMS
There are a large number of PROMs tools
available, and differences between them
can make it difficult to directly compare
outcomes in different trials. However,
standardised PROMs in advanced disease
enable the collection of meaningful and
internationally comparable outcomes
on QOL, which can inform clinical
decision-making and funding. Recently,
the ICHOM panel of experts identified
relevant measures of HR-QOL to form
recommendations for a standard set
of patient-centred outcomes in APC. It
recommended two questionnaires, as it
felt no single tool sufficiently covered
all relevant domains: a prostate cancerspecific questionnaire, EPIC, to assess
sexual, urinary, and hormonal and bowel
function, and an overall QOL questionnaire,
the EORTC QLQ-C30 instrument, for
cancer-related QOL.19
Doctors frequently underestimate the
effects of disease and its treatment on
patients’ QOL.20 PROMs facilitate the
collection of comprehensive information
regarding HR-QOL, which better enables
doctors to consider not only overall
and progression-free survival, but
how treatments affect an individual
patient in daily life. The QOL changes
documented may result from changes in
AQA Score
Description
0
1
2
3
4
5
6
7
No analgesic
Non-opioid analgesic
Weak opioids*
Strong opioids ≤75mg OME per day
Strong opioids >75–150mg OME per day
Strong opioids >150–300mg OME per day
Strong opioids >300–600mg OME per day
Strong opioids >600mg OME per day
Table 1. Analgesic Quantification Algorithm scoring system (AQA, Analgesic Quantification
Algorithm; OME, oral morphine equivalent)
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www.trendsinmenshealth.com
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burden of disease, treatment toxicity and
psychological factors.
Although PROMs questionnaires are now
widely used in clinical trials, they are not
widely used in routine clinical practice.
Some tools are multi-dimensional and
difficult to administer, which limits their use
to clinical trials. The development of less
time-consuming and easier to administer
questionnaires should encourage the wider
use of these tools and may improve everyday
practice. Additionally, smartphones and
wider access to the internet may improve the
distribution of PROMs tools, allowing for the
real-time collection of HR-QOL data, resulting
in better shared decision-making between
doctors and their patients.
CONCLUSION
Metastatic prostate cancer is an incurable
disease and patient QOL is of the upmost
importance. Historically, the collection of
data on patients’ own perspectives on their
QOL was poor. However, the incorporation
of tools in both clinical trials and routine
practice in the clinic setting can provide
valuable QOL information. Thanks to the
development of PROMs, patients now
have a voice in the development and
assessment of new therapeutic strategies
in metastatic prostate cancer.
Declaration of interests
Heather Payne has attended and received
honoraria for advisory boards, travel
expenses to medical meetings and served
as a consultant for AstraZeneca, Astellas,
Janssen, Sanofi Aventis, Takeda, Amgen,
Ipsen, Ferring and Novartis. Her work was
supported by the UCLH/UCL Comprehensive
Biomedical Research Centre.
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