Download The quality of life of men with locally advanced prostate cancer

Original Article
QoL OF MEN WITH LOCALLY ADVANCED PROSTATE CANCER DURING NEOADJUVANT HORMONE THERAPY
STEPHENS
et al.
The quality of life of men with locally advanced
prostate cancer during neoadjuvant hormone therapy:
data from the Medical Research Council RT01 trial
(ISRCTN 47772397)
Richard J. Stephens, David P. Dearnaley*, Richard Cowan†, Matthew Sydes,
Sharon Naylor and Lesley Fallowfield‡; on behalf of all the RT01 collaborators
Cancer Group, MRC Clinical Trials Unit, London, *Institute of Cancer Research, Academic Radiotherapy, Sutton, Surrey,
†Department of Clinical Oncology, Christie Hospital, Manchester, and ‡Psychosocial Oncology Group, Brighton and
Sussex Medical School, Cancer Research UK, Brighton, UK
Accepted for publication 17 August 2006
OBJECTIVE
To explore patients’ quality of life (QoL) during
neoadjuvant hormone therapy (HT) using data
from the Medical Research Council RT01 trial
of standard- (64 Gy/32-fraction) and high(74 Gy/37-fraction) dose radiotherapy (RT,
both given conformally).
PATIENTS AND METHODS
Of the 843 patients randomized to the RT01
trial, 316 completed the Functional
Assessment Of Cancer Therapy core
questionnaire with its additional prostate
subscale, and the Short Form-36 Health
Survey questionnaire with the University of
INTRODUCTION
Worldwide, more than half a million men are
diagnosed with prostate cancer every year,
the recent increases in incidence being mainly
due to the widespread use of PSA testing. This
has resulted in dramatic increases in the UK in
last decade, from ≈14 000 new cases in 1994
to an estimated 27 000 new cases in 2002,
echoing similar increases in North America in
the previous decade, when the incidence
increased from ≈110 000 in 1982 to 280 000
in 1992 [1]. This changing pattern has resulted
in a decrease in the average age at diagnosis,
a decline in the proportion of advanced-stage
tumours, and an increase in the proportion of
moderately differentiated tumours, and
consequently changing patterns of care [2].
Although most men diagnosed as a result of
PSA testing will have very early disease, for
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California-Los Angeles Prostate Cancer Index
before HT and again before starting RT. Three
predefined QoL hypotheses were generated to
focus the analyses.
and patients indicated an improvement in
attitude and satisfaction with treatment.
RESULTS
In this group of men, many of whom reported
reduced sexual functioning before treatment,
the additional decline during HT seemed to be
generally accepted as the price to pay for an
appropriate cancer treatment. Nevertheless,
these changes need to be discussed with
patients before HT is commenced.
For the three primary QoL analyses there was
evidence that sexual functioning deteriorated,
urinary function did not change, and there
was a slight decline in physical well-being
after ≥3 months of HT. Sensitivity analyses
confirmed these findings. Exploratory
analyses also suggested that role functioning
deteriorated, sleep was more disturbed, and
there was an increase in fatigue. However,
overall QoL was not reported to be affected
whom active surveillance (or ‘watchful
waiting’) might be an option for those
with a good prognosis [3,4], there will still
be substantial numbers of men with more
advanced localized disease for whom
radical radiotherapy (RT) remains the most
commonly used curative method.
Although RT is effective in most cases,
local failure is associated with an increased
rate of metastatic disease [5], and whilst
increasing the dose of RT might reduce
the proportion of local recurrences, this
will be at the expense of more side-effects.
However, the use of conformal RT allows
the same dose to be delivered to the
tumour with no increase in toxicity; e.g. a
UK study [6] reported less radiation-induced
proctitis and bleeding with conformal 64 Gy/
32-fraction RT than with conventional 64 Gy/
32-fraction RT.
CONCLUSIONS
KEYWORDS
hormone therapy, quality of life, prostate
cancer
The aim of the MRC RT01 trial was to
investigate whether the conformal RT dose
could be safely increased. Thus men were
randomized to either standard conformal RT
(64 Gy in 32 daily fractions) or high-dose
conformal RT (74 Gy in 37 daily fractions).
The primary outcome measure was tumour
control rate, but quality of life (QoL) was an
important secondary endpoint, patients
completing the Functional Assessment of
Cancer Therapy (FACT-P) core questionnaire
with its additional prostate subscale [7], the
Short Form-36 Health Survey questionnaire
(SF-36 [8]), and the University of CaliforniaLos Angeles Prostate Cancer Index (UCLA-PCI)
[9] questionnaire at regular intervals before,
during and after RT.
In the UK, many patients routinely receive
≥3 months of hormone therapy (HT,
androgen suppression or androgen
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deprivation) before RT. Phase III trials [10–12]
showed the benefits of this policy in
biochemical disease control, metastases-free
and overall survival, and a reduction in size of
the prostate gland and prostate tumour,
allowing a reduction of the RT volume
required [13–16]. In the RT01 trial, all patients
received 3–6 months of HT before RT.
Little is known about the patients’ QoL during
this period of neoadjuvant HT, but the MRC
RT01 trial provided the opportunity to
investigate this, as patients completed QoL
questionnaires before starting HT and again
before starting RT. We here describe the
changes reported in patients’ QoL by
comparing the responses to the
questionnaires at these two times.
PATIENTS AND METHODS
Detailed information on the trial design was
published elsewhere [17] and therefore only a
summary is given here. Patients were eligible
for the trial if they fulfilled the following
criteria: histologically confirmed carcinoma of
the prostate, clinical disease stage T1b-T3a,
N0, M0, a PSA level of <50 ng/mL, a WHO
performance status of 0 or 1, a normal blood
count, no previous pelvic RT, radical
prostatectomy or androgen deprivation, and
no previous or concomitant medical history
that made radical RT inappropriate. Local
ethical approval and individual patient
consent were required.
seminal vesicle involvement [18]. The PSA
level and DRE results were reported after 6
and 12 weeks of HT and before starting RT
clinicians reported on the patients’ urinary
and bowel symptoms, and erectile potency.
At registration (before starting HT whenever
possible) and at randomization (before RT),
patients completed the FACT-P questionnaire,
comprising the FACT core questionnaire (29
questions) with its additional prostate
subscale (12 questions), the SF-36, and the
UCLA-PCI (21 questions). The individual items
from all of these questionnaires can be
combined into different domains or subscales,
as detailed in Table 1.
The primary outcome measure of the trial was
tumour control rate. The estimated local
disease control rate with standard-dose
conformal RT at 5 years was 80%, and the
target sample size of 800 men was sufficient
to reliably detect an improvement of 10% (to
90%) with high-dose conformal RT (twosided P < 0.05, and 97.5% power).
TABLE 1 The domains and subscales of the QoL
questionnaires
Questionnaire/Domain
FACT-P
Physical well-being
Social well-being
Relationship with doctor
Emotional well-being
Functional well-being
Additional concerns
SF-36
Physical
Role
Bodily pain
General health
Vitality
Social functioning
Role emotional
Mental health
Health transition
UCL A-PCI
Urinary function
Bowel habits
Sexual function
Satisfaction with
treatment
Items
Possible
response
scores
7
7
2
6
7
12
0–28
0–28
0–8
0–24
0–28
0–48
10
4
2
5
4
2
3
5
1
10–30
4–8
1–6
5–25
4–24
2–10
3–6
5–30
1–5
6
5
9
1
6–26
5–25
9–42
1–5
To focus the QoL aspect of the trial, before the
analyses, the two clinicians on the QoL
subcommittee of the RT01 trial (D.P.D.
and R.C.) were asked to generate hypotheses
relating to the expected changes over time,
and the differences between the regimens. In
all, six hypotheses were generated: (i) HT will
cause a deterioration in sexual functioning;
(ii) HT will improve overall urinary function;
(iii) HT will cause a deterioration in physical
well-being; (iv) RT will cause transient bowel
side-effects; (v) RT will improve medium-term
urinary functioning; (vi) RT will cause a
deterioration in long-term bowel functioning.
The present study reports on the first three
hypotheses, which relate to the period when
HT was given.
big a problem has your urinary function been
for you during the last 4 weeks?’ was used.
The 5-point response ranged from ‘no
problem’ (score 1) to ‘big problem’ (score 5). It
was assumed that, before HT 30% of patients
would report a problem with urinary
functioning (score 3–5), and so to reliably
detect a reduction of 15% (to 15%) before RT
required a total of 322 patients, using a chisquare test (two-sided, 90% power, 5%
significance level).
Ideally, patients were registered onto the trial
before HT and only randomized to receive
either standard or high-dose conformal RT
after ≥3 months of androgen suppression.
However, it was permissible to register
patients after starting HT, to include patients
who had already started on HT before referral
to an oncologist.
To address the first hypothesis, the data from
the UCLA-PCI question 20 ‘Overall, how big a
problem has your sexual function been for
you during the last 4 weeks?’ was used. The
responses to this question range from ‘no
problem’ (score 1) to ‘big problem’ (score 5). It
was assumed that, before HT, half the patients
would report a ‘small’ to ‘big’ problem (score
3–5), and so to reliably detect an increase of
15% (to 65%) before RT required a total of
453 patients, using a chi-square test (twosided, 90% power, 5% significance level).
Finally, to address the third hypothesis, the
data from the FACT-P physical well-being
subscale was used, which combines seven
questions, all answered on 5-point scales
(0–4), to give a subscale score of 0–28. It was
assumed that before HT 10% of patients
would report a physical problem (score >7 on
the subscale), and so to reliably detect an
increase of 15% (to 25%) before RT required a
total of 266 patients, using a chi-square test
(two-sided, 90% power, 5% significance
level).
Before starting HT patients were defined as
having either a low or moderate risk of
To address the second hypothesis, the data
from the UCLA-PCI question 6 ‘Overall, how
The following criteria were defined to
ensure that the data analysed reflected the
Neoadjuvant androgen suppression was
achieved using LHRH agonists at 4-weekly
intervals in conjunction with initial
antiandrogens (e.g. cyproterone acetate),
to prevent ‘flare’ phenomenon. The
antiandrogens were given 1 week before the
first LHRH agonist injection and for 3–4 weeks
in total. The LHRH agonists were given for
3–6 months before starting RT, and were
continued throughout RT.
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QoL OF MEN WITH LOCALLY ADVANCED PROSTATE CANCER DURING NEOADJUVANT HORMONE THERAPY
result of ≥ 3 months of HT: The pre-HT QoL
questionnaires had to be completed within
14 days (before or after) of the start of
hormones; the pre-RT QoL questionnaires had
to be completed before the start of RT; there
had to be ≥3 months between completing the
pre-HT and pre-RT questionnaires.
Supplementary exploratory analyses were
also performed to investigate the change in:
(a) domain scores; (b) individual QoL
questionnaire items; and (c) the Trial Outcome
Index (TOI) of the FACT-P questionnaire. The
TOI is composed of the sum of the scores of
the physical, functional and prostate cancer
subscales, and thus reflects the overall QoL
experienced.
RESULTS
Between January 1998 and September 2001,
862 patients were registered, and 843 of these
were randomized from 25 centres in the UK,
New Zealand and Australia. As shown in
Fig. 1, of the 843 patients randomized, only
290, 319 and 290, respectively had data
available for testing the three hypotheses, as
most patients had been started on HT before
being registered for the trial, and so did not
complete the pre-HT QoL questionnaires.
Tables 2 and 3 compare the baseline (before
HT) clinical characteristics and clinicians’
assessment of the patients’ baseline urinary,
bowel and sexual symptoms of the 321
patients with QoL data available, and the
remaining 522. There were no obvious
differences in bowel or sexual functioning
between the groups, but somewhat more of
the men not in the QoL group had frequency
or nocturia at baseline. One explanation for
this might be that referring urologists tended
to start symptomatic patients on HT as soon
as possible.
Hypothesis (i) was that sexual functioning
would become an increasingly significant
problem. Of the 290 patients with QoL data,
47% had a score of 3–5 before HT and this
increased by 13%, to 60% before RT (chisquare P = 0.004), as indicated by the shift
to the right in Fig. 2A. In all, 57 patients
improved, 108 stayed the same and 125
worsened. The mean score worsened from
2.64 to 3.24, and thus there was evidence that
sexual functioning became an increasing
problem during this period on HT.
©
Hypothesis (ii) was that overall urinary
function would improve. Of the 319 patients
with QoL data, 75 (24%) reported a score
of 3–5 (small to big problem) before HT
compared to 76 (24%) before RT (P = 1.00;
Fig. 2B). In all, 74 patients reported an
improvement, 76 a deterioration and the
remaining 169 no change. The mean score
changed from 1.87 to 1.91. Thus there was no
evidence that overall urinary function
improved during this period.
Hypothesis (iii) was that patients’ physical
well-being would deteriorate. Of the 290
patients with QoL data, 19 (7%) had a score
of >7 on the FACT-P physical well-being
subscale before HT, indicating some
impairment of physical well-being; this
increased to 35 (12%) before RT (P = 0.03). In
all, 71 patients improved, 56 stayed the same
and 163 worsened (Fig. 2C). The mean score
worsened from 2.60 before HT to 3.55 before
RT, and thus there was some evidence of a
slight decline in physical well being.
As the number of patients with QoL data was
only just adequate for two of the hypotheses,
and well below the calculated sample size
required for the third, the criteria for inclusion
in these analyses were relaxed to increase the
sample sizes. Thus, there was an additional
140 patients who either completed a
questionnaire (a) at 14–21 days (before or
after) starting HT, (b) within 7 days after
starting RT, or (c) between 10 weeks and
3 months apart, giving 461 available patients.
Of these, 419, 456 and 427 patients had
adequate data for the three hypotheses,
respectively. All the above analyses were
repeated using this extended group, but
when compared to the results obtained with
the original group of patients, they were
consistent with the original results (data not
shown).
To explore whether there was any indication
that any subgroup of patients reported more
or less change in their sexual, urinary or
physical functioning during HT, subgroups of
patients defined by those baseline (before HT)
characteristics that the chief investigator of
the RT01 trial (D.P.D.) suggested might be
important, were investigated. Although, as
would be expected, patients with different
baseline characteristics reported different
levels of baseline functioning (e.g. those with
different levels of erectile potency reported
different levels of sexual functioning, and
those with different levels of nocturia
reported different levels of urinary
functioning), there were no clear indications
that any subgroup reported more or fewer
changes after HT (data not shown).
All the domains from the three questionnaires
(Table 1) were explored for changes during HT,
but as there are multiple analyses and as they
were not listed in the original hypotheses,
these results should only be considered as
hypothesis-generating. The patients included
in these exploratory analyses were those with
the original, stricter criteria, and for clarity
and consistency, all the scores were
standardized (converted to a 0–100 range).
Figure 3A shows the mean scores for the
nine SF-36 domains pre-HT and pre-RT. ‘Role
functioning’ (whether patients experienced
problems with work or other regular daily
activities as a result of their physical
health) showed the greatest decline, whereas
‘health transition’ (how patients felt now
compared to a year ago) showed a clear
improvement.
Figure 3B shows the changes in the four
UCLA-PCI domains, with the low baseline level
of ‘sexual functioning’ decreasing even
further, although ‘satisfaction with treatment’
increased slightly. Each of the 10 individual
items of the UCLA-PCI sexual functioning
domain were much reduced on HT (Fig. 3C).
Figure 3D shows the six subscales of the
FACT-P questionnaire, indicating only
marginal changes, but assessing in detail the
12 items in the additional concerns domain
(Fig. 3E) the ability to keep an erection
showed the greatest decline.
All 98 individual items from the three QoL
questionnaires were examined for evidence of
change in scores from before HT to before RT.
Osoba et al. [19] suggested that a change of
≥20 points on a standardized scale (i.e. with a
range of 0–100) represents a clinically large
change, and changes of 10–20 and 5–10
points, moderate and small clinical changes,
respectively. Nine of the 11 sexual functioning
items (eight of the nine items of the UCLA-PCI
sexual domain, and the item relating to
erection on the FACT-P) showed a change of
≥20 standardized points, the exceptions being
Q15 on the FACT-P (‘Have you been sexually
active?’) and Q20 on the UCLA-PCI (‘Overall,
how big a problem has your sexual function
been for you?’), which changed by 17.7 and
15.0 points, respectively. Five further items
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S T E P H E N S ET AL.
FIG. 1. The QoL data available.
Total number of patients
randomized – 843
Was RT received?
Yes
831 patients
No
12 patients
QL questionnaire completed
within 14 days of start of
hormones?
Yes
509 patients
No
322 patients
QL questionnaire completed
prior to start of RT?
Yes
458 patients
No
51 patients
QL questionnaires completed
at least 3 months apart
304
Yes
321 patients
No
137 patients
Data available for
hypothesis 1?
Data available for
hypothesis 2?
Data available for
hypothesis 3?
Yes
290 patients
Yes
319 patients
Yes
290 patients
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QoL OF MEN WITH LOCALLY ADVANCED PROSTATE CANCER DURING NEOADJUVANT HORMONE THERAPY
Variable
With QoL data
Number of patients
321
Median (interquartile) age
67 (63–71)
at registration, years
Risk group, n (%)
Low
113 (35)
Medium
208 (65)
Median (interquartile)
110 (74–158)
days from diagnosis
to registration
Clinical tumour stage, n (%)
T1
91 (30)
T2
170 (56)
T3
43 (14)
No data
17
Type of biopsy
Transrectal
278 (87)
TURP
37 (12)
Other
5 (2)
No data
1
Differentiation
Well
37 (12)
Moderately
242 (75)
Poorly
42 (13)
No data
0
Median (interquartile) biochemical*
PSA level, ng/mL
11.8 (8.0–19.0)
Testosterone, nmol/L
13.0 (0.4–41.3)
FSH, IU/L
6.0 (4.0–9.6)
LH, IU/L
5.2 (3.4–7.6)
showed a change of 10–20 points: three of
the four questions on the FACT-P relating to
role functioning, indicating that patients were
more limited in their work and other regular
activities after HT (the other question in this
subgroup showed a change of 9 points), and
FACT-P questions 31 (relating to sleeping,
patients indicating they were sleeping less
well after hormones) and 41 (patients
reporting they were less ‘able to feel like a
man’ after hormones). A small clinical change
was indicated in a further 12 questions,
suggesting an increase in fatigue but an
improvement in attitude, less nervousness,
more satisfaction with their treatment and
less concern that health would get worse.
Although these analyses were exploratory and
might have been random findings, the
consistent pattern in all of the questions
relating to decreased role functioning needs
consideration.
The TOI of the FACT-P was calculated by
adding the scores of the physical well-being
subscale (seven items), the functional well-
©
No QoL data
522
67 (63–70)
TABLE 2
The patients’ baseline
clinical characteristics
(before HT)
162 (31)
360 (69)
126 (89–169)
112 (23)
278 (58)
87 (18)
45
437 (85)
65 (13)
14 (3)
6
69 (13)
391 (76)
57 (11)
5
13.4 (8.1–20.8)
13.2 (0.4–40.1)
5.7 (4.0–9.0)
4.5 (3.0–7.1)
*PSA based on 321 and 516
patients, testosterone on
239 and 276, FSH on 244
and 259, and LH on 240 and
255.
being subscale (seven items) and the
additional prostate cancer concerns subscale
(12 items) giving a total 26 items with a
response range of 0–104. In all, 218 patients
had complete data and the mean score
increased from 16.2 before HT to 20.2 before
RT, indicating a small deterioration in overall
QoL. A change of 5–8 points on the 27-item
TOI of the FACT-BRM [20] is considered the
minimally important difference. In the present
data, 103 (47%) patients deteriorated by ≥5
points, and 48 (22%) by ≥9 points, although
30 (14%) reported improvements of
≥5 points (nine patients by ≥9 points).
DISCUSSION
The RT01 trial was one of the largest
randomized treatment trials of prostate
cancer, and therefore offers the opportunity
to investigate various issues relating to men’s
experience of their treatment. The present
study reviews the QoL experienced during the
period of neoadjuvant HT, which was received
by all the patients in this trial before standard
or high-dose conformal RT.
Neoadjuvant HT is used, especially in the UK,
to reduce the size of the tumour prior to RT,
and is generally reported to be associated
with minimal morbidity [21], although
clinician-reported side-effects include high
levels of erectile dysfunction [22]. However,
clinicians and patients differ in how they
report QoL, symptoms and side-effects, and
Litwin et al. [23] suggested that clinicians
report significantly lower levels of fatigue and
pain, and less impairment of physical, urinary,
bowel and sexual functioning than do
patients. Therefore it is important to take
account of patient-assessed outcomes.
As all patients received neoadjuvant HT in the
present study, and there was no comparable
untreated group, we are unable to distinguish
between the effect of HT and the effects of
the disease over time. Indeed, other studies
that have examined ‘watch and wait’ policies
in similar groups of men have reported
decreasing physical and sexual function over
5 years [24]. However, given the relatively
short period considered here (3 months) the
assumption must be that most changes seen
in the present patients was directly related to
the HT.
In the current trial the expected effect of
hormones on sexual functioning was clear,
and there was a strong indication that
role functioning (whether patients have
experienced problems with work or other
regular daily activities as a result of their
physical health) was adversely affected.
Patients also reported increased levels of
fatigue but it appeared that they had a
positive attitude to their disease and
treatment, which might explain why overall
QoL did not seem to change. Interestingly no
effect on urinary symptoms was observed
during this period, although it might be
because the symptoms reported before HT
were unrelated to the prostate cancer.
Importantly, we were not able to reliably
identify any subgroups of patients who
appeared to be affected more or less
during HT.
In addition to the way LHRH agonists were
used in this trial (before RT for patients with
locally advanced disease), they might be given
as conservative treatment for localized
disease, as adjuvant treatment after RT or
surgery, or as primary treatment for patients
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Variable
Clinician report, n or n (%)
Number of patients
Urinary symptoms
Average daytime frequency, /h
>2
2
1–2 (no treatment)
1–2 (simple outpatient
management)
<1
No data
Nocturia, times
0–1
2–3
4–5
6–8
>8
No data
Incontinence
None
Occasional
Frequent, requiring pads
No data
Bowel symptoms
Frequency, times
1–2
3–4 (no medical treatment)
3–4 (simple outpatient
management)
>4
No data
Rectal bleeding
None
Occasional
Moderate
Severe
No data
Erectile potency
Normal
Decreased
Absent
No data
FIG. 2. Quality of Life reported pre-HT (red bars) and
pre-RT (green bars).
No QoL data
321
522
214 (68)
66 (21)
30 (9)
3 (1)
290 (57)
143 (28)
54 (11)
11 (2)
200
4 (1)
4
9 (2)
15
50
178 (56)
110 (34)
27 (8)
3 (1)
1 (<1)
2
244 (48)
208 (41)
50 (10)
6 (1)
2 (<1)
12
285 (89)
32 (10)
2 (1)
2
448 (88)
54 (11)
5 (1)
15
299 (94)
18 (6)
1 (<1)
485 (96)
17 (3)
2 (<1)
0 (0)
3
0 (0)
18
299 (93)
19 (6)
2 (1)
0 (0)
1
477 (94)
30 (6)
3 (1)
0 (0)
12
134 (44)
92 (30)
82 (27)
13
241 (50)
123 (26)
115 (24)
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with advanced or metastatic disease. The
effect of hormones on patients’ QoL in some
of these settings has been reported and
reviewed [25], and can provide useful
comparison data to the findings of the
current study.
Studies reporting the experience of a group of
men receiving LHRH treatment generally
confirm decreased sexual functioning as the
only major side-effect. For example, using
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TABLE 3
Baseline symptoms (before
HT) as reported by the
clinician
With QoL data
A. Overall sexual function (UCLA-PCI) question
20 ‘Overall how big a problem has your sexual
function been for you during the last 4 weeks?’
150
100
0
1
2
3
4
5
B. Overall urinary function (UCLA-PCI) question
6 ‘Overall how big a problem has your urinary
function been for you during the last 4 weeks?’
200
150
100
50
0
1
2
3
4
5
C. Physical well-being subscale (FACT-P items
1–7)
200
150
100
50
0
0–2
3–7
15–21
15–21
22–28
Litwin et al. [27] reported on 63 patients with
metastatic prostate cancer who were assessed
at baseline (before orchidectomy, 16) or
before leuprolide treatment (47) and then
regularly for 2 years. Using the SF-36 and
UCLA-PCI questionnaires, improvements were
reported in 12 of the 14 domains from
baseline to 1 year, and only the mean scores
for sexual functioning and sexual bother
worsened.
data from the Cancer of the Prostate Strategic
Urologic Research Endeavour database, which
collects data on all patients in the USA
irrespective of disease stage or treatment,
Lubeck et al. [26] reported on 67 men who
completed the SF-36 and UCLA-PCI
questionnaires before and after HT. No
significant changes were observed in any
domains, except the UCLA-PCI sexual function
scale, which decreased from a mean
standardized score of 24.9 to 14.7.
Finally, Stone et al. [28] reported a significant
increase in the self-reported levels of severe
fatigue after androgen suppression in 62 men
receiving hormones as either neoadjuvant or
primary treatment. Results from a battery of
questionnaires also indicated declines in
virility and potency, and a slight increase in
nausea and vomiting, but a reduction in pain
and improvement in urinary difficulties. These
changes did not appear to affect the patients’
functional ability or overall QoL.
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QoL OF MEN WITH LOCALLY ADVANCED PROSTATE CANCER DURING NEOADJUVANT HORMONE THERAPY
FIG. 3. Exploratory analyses comparing the standardized mean scores before HT (red) and RT (green).
A. SF-36 Domains
100
B. UCLA-PCI Domains
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©
Herr and O’Sullivan [31] evaluated the
longitudinal QoL of 144 men with
asymptomatic locally advanced prostate
cancer choosing no therapy (65) or HT with
orchidectomy, leuprolide or leuprolide +
flutamide (79). Patients completed the
European Organisation for Research and
Treatment of Cancer prostate cancer QLQ [32],
the intrusion subscale of the Impact of Event
Scale [33], and Selby’s QoL uniscale [34] at
baseline, 6 and 12 months. Compared with
the ‘no treatment’ group, the HT group, and
especially the men on medical HT, reported
increased psychological distress, fatigue and
sexual problems, and decreased physical
functioning and overall QoL.
Herr et al. [35] also reported on 35 men with
metastatic prostate cancer (16 of whom
chose HT and 19 no immediate treatment)
using the same set of questionnaires
administered at 1, 2 and 6 months after
diagnosis. At 1 and 2 months the HT group
reported more sexual problems, and at
6 months more fatigue, sexual problems and
physical symptoms.
W
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ith qu ng
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n
Generally, studies comparing a group of
men who chose or were prescribed or
randomized to receive LHRH, and a group
who did not, indicate, in addition to the
decline in sexual functioning, some increase
in symptoms and side-effects with HT. For
example, Lamb et al. [16], within a randomized
three-arm trial of 818 patients with locally
advanced prostate cancer of 0, 3 and
6 months of neoadjuvant maximal androgen
deprivation (MAD) reported that patients on
MAD (completing a questionnaire designed
for Australasian patients) had a slight
worsening of bowel function but some
improvement of urinary symptoms. In
addition, most of the 36% of patients who
The Prostate Cancer Outcomes Study
collected data on men with newly diagnosed
prostate cancer who were recorded on six
USA registries, and Potosky et al. [30]
compared those receiving androgendeprivation therapy with those receiving no
therapy. Self-reported data using the SF-36
and a prostate-specific questionnaire were
collected at 6 and 12 months after diagnosis,
and men were asked about their baseline
status, retrospectively. Compared with the
416 men on no therapy, the 245 men on
androgen-deprivation therapy reported
decreased potency and vitality, and increased
physical discomfort, but increased
satisfaction with treatment.
were sexually active before any treatment
became inactive while on MAD. However,
at 1 year after treatment there were no
differences between those men who had
had RT alone and those who received RT and
3–6 months of HT.
In 91 patients with asymptomatic lymph
node-positive prostate cancer, most of whom
were randomized between immediate and
deferred HT, Van Andel and Kurth [29]
reported that, using standard QoL
instruments, the men on immediate HT
reported worse sexual, emotional and physical
functioning, and a worse overall QoL, than
men receiving no HT.
Finally, Fowler et al. [36] identified 1089 men
who had had a radical prostatectomy 7–8
years previously and divided the group into
those who had been androgen-deprived and
those who had not. Using a trial-specific
questionnaire, they reported that the HT
group had significantly worse scores on all
seven measures.
Studies comparing surgical castration, LHRH
and antiandrogens suggest higher levels of
sexual dysfunction but perhaps better overall
QoL with LHRH. For example, Cassileth et al.
[37] compared the QoL of 115 men with
advanced stage prostate cancer who chose
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S T E P H E N S ET AL.
orchidectomy with 32 who chose injections
with the LHRH agonist goserelin. At 3 months
the LHRH group reported more sexual
dysfunction (as measured on a trial-specific
questionnaire) but better psychological status
(as measured on the Profile of Mood States
[38]) and QoL (as measured on the Functional
Living Index-Cancer [39]) than the
orchidectomy group. However, at 6 months,
whereas the levels of sexual dysfunction were
similar, the LHRH group reported a sustained
improvement in QoL.
In a randomized trial of 486 men, comparing
antiandrogens with castration, Chodak et al.
[40] found that at 6 months sexual function
had declined from pretreatment levels in the
castrated group but was maintained in the
group receiving bicalutamide.
Comparing the two methods of HT (132
orchidectomy patients, 299 on LHRH
agonists) using data from the Prostate Cancer
Outcomes Study, no significant differences
were reported [41], although all patients
reported decreased sexual interest and
activity, and the LHRH group reported more
physical discomfort, worry about cancer, and
worse overall health than the orchidectomy
group. Nevertheless, >90% in each group said
they would choose the same treatment again.
There are several potential limitations in some
of the studies cited; results might be
confounded by a mixture of disease groups
and/or other treatments; most included only a
small sample of patients; some used nonstandard questionnaires; there is a lack of
clarity as to how missing data were treated;
retrospectively collected data might be
inaccurate [42]; as a result of attrition, some
studies compared different groups of patients
at different times; comparisons where
patients choose their own treatment might
be biased; and some of the more common
androgen deprivation symptoms (hot flashes,
breast swelling and tenderness) were not
specifically assessed.
Nevertheless, the results from these studies
generally support the findings reported in the
RT01 trial. Most indicate that during HT there
is a clear reduction in sexual functioning, with
some suggestion of increased fatigue and
decreased physical functioning, and some
improvements in psychological status, which
overall do not seem to affect significantly
the overall QoL. This contrasts with studies
suggesting that sexual problems are a source
308
of psychosocial distress [43] and cause a
decline in general health-related QoL [44]. If
this was a general pattern then consideration
might have to be given to ways of alleviating
sexual dysfunction, but while some papers
report that erectile aids might reduce these
problems [45], others report that they do
not [46].
It is likely that, in this group of generally
elderly men, sexual activity is already
reduced, as shown by the low level of sexual
functioning before HT and the low proportion
of men who say they were bothered by this
[27,47]. Supporting evidence for this comes
from a cross-sectional survey of 113 patients
with metastatic prostate cancer who were
either in remission and receiving a LHRH
agonist (60 men) or had disease progression
(53 men) [48]. Using the eight domains of the
SF-36, those men in remission had a similar
profile to a socio-demographically matched
group of the USA general population. In
addition, evidence from a study in which men
without prostate cancer were asked whether
they would choose a LHRH agonist or a
nonsteroidal antiandrogen suggest that the
method of administration (3-monthly
injection vs oral tablet) and increased risk of
fractures and loss of physical strength, are of
greater concern than sexually related
symptoms [49].
The conclusion might be that there is an
acceptance that a decrease in sexual
functioning is the price to pay for an
appropriate cancer treatment, although this
topic obviously merits appropriate discussion
with patients before starting treatment.
ACKNOWLEDGEMENTS
Full acknowledgements of the clinicians,
radiographers, physicists, local research staff,
and trials unit staff involved in this trial are
given elsewhere [17]. In addition, we thank
the subsequent CTU Trials Managers, James
Latham and Jacqui Nuttall.
CONFLICT OF INTEREST
None declared.
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Correspondence: Richard J Stephens, Cancer
Group, MRC Clinical Trials Unit, 222 Euston
Road, London NW1 2DA, UK.
e-mail: [email protected]
Abbreviations: RT, radiotherapy; HT, hormone
therapy; QoL, quality of life; FACT-P,
Functional Assessment of Cancer Therapyprostate subscale; SF-36, Short Form-36
Health Survey; UCLA-PCI, University of
California-Los Angeles Prostate Cancer Index;
TOI, Trial Outcome Index; MAD, maximal
androgen deprivation.
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JOURNAL COMPILATION
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2006 BJU INTERNATIONAL