D o O l d e r M e n... P r o s t a t e C a...

D o O l d e r M e n B e n e fi t F r o m C u r a t i v e T h e r a p y o f L o c a l i z e d
Prostate Cancer?
By Shabbir M.H. Alibhai, Gary Naglie, Robert Nam, John Trachtenberg, and Murray D. Krahn
prolonged LE up to age 75 years but did not improve QALE
at any age. For moderately differentiated cancers, potentially curative therapy resulted in LE and QALE gains up to
age 75 years. For poorly differentiated disease, potentially
curative therapy resulted in LE and QALE gains up to age 80
years. Benefits of potentially curative therapy were restricted to men with no worse than mild comorbidity. When
cohort and pooled case series data were used, RP was
preferred over EBRT in all groups but was comparable to
modern radiotherapy.
Conclusion: Potentially curative therapy results in significantly improved LE and QALE for older men with few
comorbidities and moderately or poorly differentiated localized prostate cancer. Age should not be a barrier to
treatment in this group.
J Clin Oncol 21:3318-3327. © 2003 by American
Society of Clinical Oncology.
REATMENT DECISION making in localized prostate cancer is complex. With a recent notable exception,1 there are
no randomized clinical trials that have demonstrated a survival
advantage of potentially curative therapy (radical prostatectomy
[RP] or radiotherapy) over watchful waiting (WW). Expert
guidelines were developed prior to the aforementioned trial to
identify patients most likely to benefit from treatment.2,3 Key
factors to consider are tumor grade,4,5 prostate-specific antigen
level,6,7 and the patient’s remaining life expectancy,8-10 which
declines with increasing age and comorbid illnesses.11,12 Some
researchers have attempted to simplify treatment decisions by
using nomograms incorporating tumor variables.13,14
The role of age in decision making is particularly problematic.
Published data suggest that otherwise healthy older men with
higher-grade cancers may not be receiving potentially lifeprolonging treatment, as a result of the perception that they are
unlikely to benefit from these therapies.8 Rates of RP use decline
sharply in patients older than 70 years.15-18 Men younger than 60
years who have clinically localized disease are 25 times more
likely to receive RP than men age 70 years or older.17 A similar
but less dramatic pattern is seen in radiotherapy.15-18 In contrast,
decreased rates of potentially curative therapy do not seem to be
influenced by tumor grade or comorbidity,15,17 indicating that a
patient’s chronological age alone may be inappropriately influencing treatment decisions.19
In an effort to identify which patients should be offered
potentially curative treatment, two decision analyses have been
published.20,21 Both models demonstrated no gain in qualityadjusted life expectancy (QALE) with RP as compared to WW
for patients older than 70 years, regardless of tumor grade.20,21
Several features of these models have been criticized.10,22
First, the studies used to estimate treatment efficacy may be
outdated and were subject to selection bias. The former may be
particularly true for radiotherapy with which improvements in
radiation-delivery techniques have led to significant improvements in biochemical outcomes.23-26 Second, pretreatment potency and continence status were not consistently considered.
This may be particularly important for older men, who may be
less concerned by long-term treatment-related toxicities because
of pre-existing impotence and incontinence. Finally, the utilities
used in the models were not obtained from men with prostate
cancer, which may have led to unrealistically harsh valuations of
treatment-related complications. Thus, published models may
not adequately inform current clinical decision making.
T
From the Division of General Internal Medicine & Clinical Epidemiology,
University Health Network; Geriatric Program, Toronto Rehabilitation
Institute; and Departments of Medicine, Health Policy, Management and
Evaluation, and Surgery, University of Toronto, Toronto, Canada.
Submitted September 4, 2002; accepted June 9, 2003.
Supported in part by the Department of Medicine, University of Toronto;
the Queen Elizabeth Hospital Research Foundation, Toronto; and the
Toronto Rehabilitation Institute (S.M.H.A.), by the Mary Trimmer Chair in
Geriatric Medicine Research at the University of Toronto (G.N.), and by an
Investigator Award (M.D.K.) from the Canadian Institutes for Health
Research.
Address reprint requests to S.M.H. Alibhai, MD, University Health
Network, Room ENG-233, 200 Elizabeth St, Toronto, Ontario, Canada M5G
2C4; e-mail: [email protected]
© 2003 by American Society of Clinical Oncology.
0732-183X/03/2117-3318/$20.00
3318
Journal of Clinical Oncology, Vol 21, No 17 (September 1), 2003: pp 3318-3327
DOI: 10.1200/JCO.2003.09.034
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Copyright © 2003 American Society of Clinical Oncology. All rights reserved.
Purpose: Prior decision-analytic models are based on
outdated or suboptimal efficacy, patient preference, and
comorbidity data. We estimated life expectancy (LE) and
quality-adjusted life expectancy (QALE) associated with
available treatments for localized prostate cancer in men
aged > 65 years, adjusting for Gleason score, patient preferences, and comorbidity.
Methods: We evaluated three treatments, using a decision-analytic Markov model: radical prostatectomy (RP),
external beam radiotherapy (EBRT), and watchful waiting
(WW). Rates of treatment complications and pretreatment
incontinence and impotence were derived from published
studies. We estimated treatment efficacy using three data
sources: cancer registry cohort data, pooled case series, and
modern radiotherapy studies. Utilities were obtained from
141 prostate cancer patients and from published studies.
Results: For men with well-differentiated tumors and
few comorbidities, potentially curative therapy (RP or EBRT)
3319
OPTIMAL TREATMENT OF LOCALIZED PROSTATE CANCER
The recently published randomized trial of RP versus WW
demonstrated a statistically significant and clinically important
improvement in disease-specific mortality in the RP arm after a
median of 6.2 years of follow-up.1 Although RP seems to be
superior to WW, this study leaves several important questions
unanswered: Does surgery lead to improved overall survival
compared with WW? What is the role of radiotherapy? What is
the optimal treatment of patients with Gleason stage 8 to 10
tumors, all of whom were excluded from the Scandinavian trial?
How should age, comorbidity, and patient preferences influence
treatment choice?
We have constructed a decision model that integrates patientspecific data (age and comorbidity), tumor-specific data (grade),
and patient-preference data, and that addresses the limitations of
previous analyses to identify which older patients may benefit
from potentially curative therapy of localized prostate cancer.
METHODS
Model Design
We developed a Markov state transition model to compare life expectancy
(LE) and QALE associated with treatment of localized prostate cancer (Fig
1 ). The model simulates the natural history of hypothetical cohorts of men
with newly diagnosed cancer of varying grades.27 Three treatment strategies
were considered: RP, external-beam radiotherapy (EBRT), and, WW. Three
grades of disease were considered: well-differentiated (grade 1, Gleason
score 2 to 428), moderately-differentiated (grade 2, Gleason score 5 to 7), and
poorly differentiated (grade 3, Gleason score 8 to 10) prostate cancer.
Patients receiving either RP or EBRT have a small risk of treatmentrelated mortality. Survivors of RP and EBRT, along with all WW patients,
enter one of eight health states, which are combinations of the posttreatment
state with or without incontinence, impotence, chronic bowel injury, or a
combination of the three (Fig 1). Incontinence, impotence, or both could
predate the diagnosis of prostate cancer, result from treatment-associated
complications, or develop as a function of age, independent of treatment.
Each year, patients could remain in their current health state; could
develop age-associated incontinence, impotence, or both; or could develop
metastatic disease. We assumed that patients who develop metastatic disease
are administered hormonal therapy.29 In each subsequent year, their disease
might remain stable or become hormone-resistant (resulting in death from
prostate cancer). Within each year, patients might also die as a result of other
causes. Actuarial life-tables for men were used to estimate the age-specific
annual risk of dying from other causes.30
Data Sources
We performed a computerized search using the MEDLINE database from
January 1966 to November 2000. Combinations of the following medical
subject headings and text words or phrases were employed: prostatic
neoplasms, follow-up studies, treatment outcome, prostatectomy, radiotherapy, and watchful waiting. Citations were restricted to the English language.
We also cross-referenced prostatic neoplasms with the text word “utilities”
and the headings “decision making” or “quality-adjusted life years” in order
to identify all published studies in which utilities for prostate cancer
outcomes were measured. Reference lists from identified studies, published
meta-analyses, decision analyses, selected review articles, book chapters, and
our own files were also examined. Content experts in urology, radiation
oncology, incontinence, and impotence were contacted to ensure that no
important studies were overlooked.
Treatment Efficacy
We chose to examine disease-specific survival as our primary efficacy
outcome because this outcome is clinically important to patients and
clinicians. Moreover, it avoids the pitfalls associated with intermediate end
points, such as biochemical relapse (ie, increasing prostate-specific antigen
level), which do not always have a consistent relationship with outcomes
such as survival or development of metastases.31,32
We used three sets of data to estimate treatment efficacy. In our baseline
analysis, we used grade-stratified, 10-year, disease-specific survival data
from the only large, population-based data set (n ⫽ 59,876) of prostate
cancer patients stratified by grade and treatment.33 We used the annual
probability of dying from progressive metastatic prostate cancer reported in
a systematic overview of randomized trials of androgen blockade in
metastatic prostate cancer (Table 1).34 We imputed the probability of
developing metastatic disease using disease-specific survival rates and the
mortality risk associated with metastatic disease. We chose to impute rates of
developing metastases rather than directly obtain them from the literature
because of systematic differences in clinical, biochemical, and radiographic
follow-up of patients in published studies. We then assumed that once
patients developed metastatic disease, the annual probability of dying from
prostate cancer was independent of initial treatment.
We attempted to validate our estimates of disease efficacy using a second
data set. We used grade-stratified disease-specific mortality rates obtained
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Copyright © 2003 American Society of Clinical Oncology. All rights reserved.
Fig 1. Key healthcare states and
transitions in Markov model, radical
prostatectomy branch. After undergoing
treatment, patients entered one of eight
post-treatment healthcare states. In
each cycle, patients could remain stable,
die as a result of other causes, or develop hormone-responsive metastases.
Patients with metastases could either
remain stable, die as a result of other
causes, or die as a result of advanced
prostate cancer.
3320
ALIBHAI ET AL
Table 1.
Model Probabilities and Utilities
Description
P
Range
Variable*
.224
.023-.26
NA
.00297
.0091
.00148-.0048
.00297-.0205
.0172
.0306
.0123-.0205
.0233-.0384
.0123
.0205
.0107-.0172
.0139-.0312
.0139
.0330
.0107-.0172
.0240-.0447
.0447
.0349
.0388-.0510
.0277-.0389
.0407
.0205
.0368-.0468
.0123-.0330
.0407
.0388
.0330-.0510
.0223-.0644
.0992
.0644
.0847-.119
.0529-.0744
.130
.170
.112-.151
.105-.292
Variable*
Variable*
.228
.168
NA
.0045-.0459
.579-.798
.126-.253
.154-.524
NA
.002
Variable*
.128
.116
.016
0-.006
.294-.431
.064-.506
.053-.333
.008-.131
Variable*
Variable*
.0609
.156-.643
.116-.236
50-200%
.91
.94
.92
.99
.84
.58
1.0
.97
.92
.88
.67
.67
.69-1.0
.92-1.0
.57-1.0
.45-1.0
.42-1.0
.05-0.58
.72-1.0
—
—
—
.50-1.0
.50-1.0
NOTE. Includes all major probabilities and utilities in model. Annual probabilities of developing metastatic disease for each treatment modality obtained from both cohort
data33 and multi-institutional case series.5,35,36 Unless specified otherwise, grade 1 ⫽ Gleason score 2-4; grade 2 ⫽ Gleason score 5-7; grade 3 ⫽ Gleason score, 8-10.
Abbreviations: RP, radical prostatectomy; EBRT, external-beam radiotherapy; WW, watchful waiting; RTOG, Radiation Therapy Oncology Group; ICED, Index of
Coexistent Disease; NA, not applicable.
*Dependent on patient age.
†For EBRT, grade 2 ⫽ Gleason score 5-6; grade 3 ⫽ Gleason score 7-10.
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Copyright © 2003 American Society of Clinical Oncology. All rights reserved.
Overall probabilities
Annual probability of non–prostate cancer death30
Annual probability of death from metastatic prostate cancer34
Grade-specific progression rates
Grade 1
RP
Cohort data33
Case series35
EBRT
Cohort data33
Case series36
WW
Cohort data33
Case series5
Grade 2
RP
Cohort data33
Case series35
EBRT
Cohort data33
Case series†36
WW
Cohort data33
Case series5
Grade 3
RP
Cohort data33
Case series35
EBRT
Cohort data33
Case series†36
WW
Cohort data33
Case series5
Radical prostatectomy branch
30-day mortality37,38
Long-term impotence39
Long-term urinary symptoms39,40
Severe symptoms: all urinary symptoms, RTOG grade 3 equivalent39,40
Long-term bowel symptoms
External Beam Radiotherapy Branch
30-day mortality41,42
Long-term impotence43
Long-term urinary symptoms24,25,44-52
Severe symptoms: all urinary symptoms, RTOG grade 3 equivalent24,25,44,52
Long-term bowel symptoms, RTOG grade 3 equivalent24,25,44-47,50-57
Pretreatment probabilities
Age-associated impotence39,58
Age-associated urinary symptoms39,59
Severe symptoms: all urinary symptoms,39 RTOG grade 3 equivalent
Utilities
Long-term impotence21,60
Long-term urinary symptoms, nonsevere61
Long-term urinary symptoms, severe21,60
Long-term bowel complications60,62
Hormone-responsive metastases21,63
Hormone-resistant metastases63,64
Watchful waiting, assumed
Comorbidity ICED level 165
Comorbidity ICED level 266
Comorbidity ICED level 365
Short-term utility of surgery, estimated
Short-term utility of radiotherapy, estimated
3321
OPTIMAL TREATMENT OF LOCALIZED PROSTATE CANCER
Treatment Complications
The probability of age-stratified 30-day mortality after RP was obtained
from a large cohort study of Medicare patients.37 For 30-day mortality data
after EBRT, we used unstratified case series mortality data.41,42 To examine
long-term treatment-related complications, we included all studies that
featured patient-reported complication rates at least 1 year after treatment.
Studies that did not include pretreatment incontinence and impotence rates
were excluded to avoid labeling a pre-existing condition as a treatment side
effect. For incontinence, we calculated the proportion of patients with
incontinence that reported severe (equivalent to at least grade 3 Radiation
Therapy Oncology Group toxicity53) and nonsevere incontinence directly
from studies that provided this information. For impotence, studies were
excluded if age-stratified rates were not reported. Severe bowel injury was
defined as equivalent to at least grade 3 toxicity. Pooled rates were obtained for
each complication, weighted by the inverse of the study estimate’s variance.
We estimated the age-stratified prevalence of incontinence and impotence
before treatment, as well as the distribution of incontinence severity (severe
v nonsevere) from a recently published prospective treatment study of 1,291
men with prostate cancer.39 For men older than age 80 years, incontinence
and impotence rates were obtained from large, population-based studies.58,59
Annual incidence rates of incontinence and impotence were derived from the
studies used for prevalence data.39,58,59
Utilities
Utilities for long-term complications were primarily derived from Krahn et
al.72 For each complication (incontinence, impotence, and bowel injury), a
disutility rating was obtained by finding the difference in mean self-reported
utility rating between patients in the highest and lowest quintiles of symptom
severity on the Prostate Cancer Index73 (Table 1). The disutility of nonsevere
incontinence was obtained from couples attending a general medicine
clinic.61 Utilities related to metastatic disease were obtained from Bennett et
al.63 Plausible ranges for sensitivity analyses were obtained from other
published studies21,52-79 (Table 1).
Utilities for acute treatment-related morbidity and disability for RP and
EBRT were modeled as a single value for a period of 13 weeks for RP and
8 weeks for EBRT (Table 1). The duration of symptoms and associated
utility were estimated on the basis of published descriptions of typical
treatment-related morbidity experienced by patients immediately after treatment.80,81 We did not explicitly assign a disutility to WW but examined this
assumption in sensitivity analyses.
Comorbidity Adjustment
In our model, we assumed that comorbidity modifies short-term and
long-term outcomes as well as quality of life. To model the influence of
comorbidity on annual mortality rates, we obtained hazard rates from the
only published study that stratified mortality rates for prostate cancer by
comorbidity.82 The study used the Index of Coexistent Disease (ICED)83 to
stratify patients into four levels of comorbidity (0 ⫽ no disease or
asymptomatic disease, 3 ⫽ severely disabling or life-threatening disease).
The ICED rates both severity of illness (across 11 organ systems) and
functional limitations.83 The hazard ratio for each comorbidity level, relative
to no comorbidity, was then multiplied by the age-stratified annual probability of dying from other diseases.30
We also adjusted the risk of 30-day mortality after RP for comorbidity.
Descriptions of health states representing different ICED levels were used to
assign scores using a commonly employed perioperative risk index.84 This
allowed us to obtain an odds ratio of the increased risk of mortality caused
by comorbidity, which was used to adjust the age-stratified 30-day mortality
risk after RP.
A utility rating for each level of comorbidity was derived by determining
a severity of angina rating corresponding to each ICED level. We chose
angina as a proxy for cardiovascular disease, the most common cause of
morbidity and mortality in an older cohort.85,86 Utility ratings for each ICED
level were then obtained from two studies of patients with varying severities
of angina.65,66 The resultant utility was multiplied by other utilities for each
hypothetical patient in each branch of the model.
Sensitivity Analyses
To examine the stability of the results of our model to variation in the
base-case estimates, we performed extensive sensitivity analyses on all
variables in our model. We chose age 75 years for our base-case, given that
most patients 75 years or older do not receive potentially curative therapy.15
For probabilities related to treatment efficacy, upper and lower bounds of the
95% confidence interval (CI) of published 10-year disease-specific survival
were used (Table 1). For long-term complication probabilities, the plausible
range was obtained from published estimates (Table 1). A similar strategy
was used for utilities (Table 1).
Discounting
We examined differences in LE and QALE until death or age 100 years
with no discounting.
RESULTS
Our analyses incorporated information on age, comorbidity,
and tumor grade using three complementary treatment-efficacy
data sources. To provide results that are most clinically relevant,
we have organized our results for men who have no comorbidity
by histologic grade. To maximize the transparency of our
findings for clinicians, our results are also summarized for
different age and tumor-grade combinations in a look-up table
(Fig 2). The influence of comorbidity on treatment choice is
discussed separately.
Grade 1 (Gleason score 2 to 4) Disease
When cohort treatment-efficacy data are used for a 65-yearold otherwise well man with grade 1 disease, RP results in LE
gains that exceed those of other treatments (LE for RP, EBRT,
and WW is 14.48, 13.36, and 13.77 years, respectively; Table 2).
Small LE gains are present even in older men (eg, 0.17 years for
a 75-year-old man). However, these LE gains are offset by
quality-of-life effects associated with treatment complications
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from published multi-institutional pooled case series of treatment (Table
1)5,35,36 and calculated the annual risk of metastatic disease using the method
described in the previous paragraph. Case series data for EBRT were
extrapolated to 10 years because the median follow-up time was only 4.1
years.36 We also validated our model’s findings with those of the recently
published randomized trial of RP versus WW1 by reproducing the distribution of Gleason scores of the trial participants and calculating 5-year and
8-year disease-specific mortality for the RP and WW arms.
Finally, we had initially planned to include in our analyses only those
studies that reported grade-stratified disease-specific mortality. However,
major changes have taken place in the delivery of radiotherapy during the last
decade.23 Newer therapeutic modalities, such as escalated-dose, conformal
and intensity-modulated radiotherapy, have led to impressive results in
intermediate outcomes such as biochemical relapse.25,67,68 To date, however,
few published studies have reported disease-specific survival. To estimate
the impact of newer radiotherapeutic techniques on outcomes, we identified
studies that reported grade-stratified biochemical relapse rates after conformal radiotherapy.24,67,69,70 We obtained grade-stratified progression rates
after biochemical relapse from a study of patients treated with radiotherapy
and observed from biochemical relapse to death.71 We then derived progression rates from biochemical relapse to metastatic disease, on the basis of our
previously employed method, assuming the same progression rate from
metastatic disease to death as described. These data were substituted into our
model and compared with results from RP, WW, and EBRT.
3322
ALIBHAI ET AL
Grade 3 (Gleason score 8 to 10) Disease
Impact of Comorbidity
Fig 2. Look-up table identifying patients who will gain in quality-adjusted life
expectancy from potentially curative therapy, stratified by age and tumor grade.
The figure illustrates gains from potentially curative therapy (higher of radical
prostatectomy or modern radiotherapy), radical prostatectomy, and modern
radiotherapy compared to watchful waiting. Gains are stratified into three levels
of benefit, which are stratified by tumor grade. Units are in quality-adjusted life
years.
(Table 3). Thus, WW is preferred (ie, has the greatest QALE) for
men aged 65 years and older. EBRT does not seem to have any
advantage over WW in either LE or QALE. Substituting caseseries– efficacy estimates did not substantially alter the preferred
strategy. Incorporating modern radiotherapy data led to higher
LE and QALE estimates than for EBRT, but WW was still
preferred for men 65 years and older.
Grade 2 (Gleason score 5 to 7) Disease
For men with grade 2 tumors, RP results in LE gains up to age
80 years when compared with other treatments using cohort data
(LE for RP, EBRT, and WW at age 80 is 6.23, 6.13, and 6.19
years, respectively). When quality-of-life effects are considered,
RP has a higher QALE than other treatment strategies up to age
75 years, after which WW has the highest QALE. EBRT does
not seem to have any advantage over WW in either LE or QALE.
If case-series data are employed, WW is preferred in terms of LE
and QALE for men 65 years and older. Results with modern
radiotherapy indicate that WW is the preferred option in terms of
LE and QALE up to age 85 years, although gains are small at age
85 years (LE gain of 0.17 years compared with both RP and WW).
In general, overall LE and QALE decreased as comorbidity
increased across all tumor grades (results for QALE are shown in
Table 3). For patients with low-grade disease, potentially curative therapy did not result in clinically significant QALE gains as
compared with WW for patients aged 65 years or older,
regardless of comorbidity. For grade 2 tumors, RP (but not
EBRT) resulted in higher QALE than WW for patients with mild
or moderate comorbidity up to age 75 and 65 years, respectively.
For high-grade disease, potentially curative therapy resulted in
higher QALE than WW for men even with moderate comorbidity up to age 75 years (QALE for a 75-year-old man with
moderate comorbidity of 3.57, 3.42, and 3.39 years for RP,
EBRT, and WW, respectively).
External Validation
Our model’s results were compared to the 5- and 8-year
disease-specific mortality from the randomized trial by Holmberg et al.1 Our model predicted a 3.3% and 6.4% 5- and 8-year
disease-specific mortality for the RP arm, respectively, compared to 2.6% (95% confidence interval [CI], 0.7% to 4.6%) and
7.1% (95% CI, 3.3% to 11.0%) in the trial. For WW, our model
predicted a 6.8% and 14.8% 5- and 8-year disease-specific
mortality, respectively; the corresponding figures from the trial
were 4.6% (95% CI, 2.1% to 7.2%) and 13.6% (95% CI, 7.9%
to 19.7%). Thus, our model’s predictions were similar to those
observed in the trial.
Sensitivity Analyses
For a 75-year-old man with grade 1 cancer, the preference for
potentially curative therapy versus WW changes depending on
the value of three variables (Table 4). The most influential
variable was the utility associated with WW. WW was preferred
in the baseline analysis, but if the utility of WW was less than
0.99, RP became the preferred strategy. EBRT was preferred to
WW if the utility of WW was less than 0.96. Other key variables
included the disease-specific survival associated with WW and
the utility of impotence. For grade 2 tumors, the preferred
treatment option was influenced only by the utility of impotence.
For grade 3 cancers, potentially curative therapy was preferred
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For otherwise healthy men with grade 3 tumors, potentially
curative therapy (RP or EBRT) results in improved LE and
QALE compared with WW up to the age of 85 years, regardless
of treatment efficacy data. Relatively large gains in both LE and
QALE (ie, greater than 1 year87) are seen in men who undergo
potentially curative therapy up to age 75 years, when compared
with WW (LE gains for RP and EBRT compared to WW of 1.40
years and 0.40 years, respectively, for a 75-year-old man).
Although surgery generally results in greater gains than EBRT in
LE and QALE when cohort or case-series data are used, results
are comparable when modern radiotherapy data are examined
(LE at age 75 of 7.86 and 7.78 years for RP and modern
radiotherapy, respectively).
3323
OPTIMAL TREATMENT OF LOCALIZED PROSTATE CANCER
Table 2.
Life Expectancy for Each Treatment Strategy, Stratified by Age, Grade, and Efficacy Data Source
Age (years)
Age 65
Strategy
CS
13.77
M
CO
CS
13.15
11.07
0.71
0.81
⫺0.41
⫺0.71
11.85
Age 75
CO
CS
10.68
8.65
0.40
0.48
⫺0.26
⫺0.45
13.15
9.86
1.73
0.89
⫺0.25
⫺0.98
8.49
Age 80
CO
CS
8.43
6.55
0.17
0.22
⫺0.15
⫺0.27
10.68
7.95
1.06
⫺0.59
⫺0.17
⫺0.62
7.66
7.53
3.31
4.25
0.83
2.97
0.41
2.24
2.96
M
Age 85
CO
CS
6.44
4.74
4.69
⫺0.17
⫺0.15
⫺0.17
⫺0.15
⫺0.08
⫺0.14
⫺0.04
⫺0.06
8.43
6.19
6.44
4.58
4.69
0.57
⫺0.39
0.04
⫺0.45
⫺0.07
⫺0.28
⫺0.11
⫺0.37
⫺0.06
⫺0.20
⫺0.03
⫺0.09
6.91
6.46
6.03
5.34
5.06
4.19
4.04
2.27
2.96
1.40
1.88
0.56
0.86
0.18
0.34
0.60
2.13
0.40
1.42
0.24
0.85
0.11
0.42
0.25
1.40
2.06
M
0.14
0.80
1.32
M
0.07
0.41
0.75
M
0.02
0.17
0.35
NOTE. Results are shown in years of LE. Utilities were not considered in the analyses. Total LE is shown for watchful waiting, whereas incremental LE is shown for both radical
prostatectomy and radiotherapy compared with watchful waiting from the same column. Results are shown separately for cohort data33 (column CO), pooled case series for
radical prostatectomy,35 external beam radiotherapy,36 watchful waiting,5 (column CS) and modern radiotherapy data78 (column M). Incremental LE from modern
radiotherapy was calculated compared with watchful waiting from cohort data.
Abbreviations: CO, cohort data; CS, case series data; M, modern radiotherapy data; LE, life expectancy.
*Incremental life expectancy results are shown relative to watchful waiting.
over WW across the plausible range of all probabilities and
utilities for a 75-year-old man.
DISCUSSION
The results of our decision analysis indicate that potentially
curative therapy (surgery or radiotherapy) may lead to significant
Table 3.
gains in health outcomes for men up to at least age 75 or 80 years
with moderately or poorly differentiated localized prostate cancer, respectively. This contrasts with current practice, in which a
significant proportion of men older than age 70 years with
moderate or poorly differentiated disease are neither offered88,89
nor undergo15-17 potentially curative therapy. For example,
Impact of Comorbidity on QALE for Different Grades of Disease
Age (years)
65
Strategy
Grade 1
RP
EBRT
WW
Grade 2
RP
EBRT
WW
Grade 3
RP
EBRT
WW
75
85
0*
1
2
3
0
1
2
3
0
1
2
3
12.99
12.24
13.01
10.99
10.50
11.13
7.12
7.02
7.41
2.06
2.17
2.32
7.91
7.69
8.00
6.48
6.37
6.62
3.78
3.83
3.98
0.74
0.83
0.87
4.06
4.25
4.40
3.23
3.44
3.56
1.63
1.86
1.92
0.20
0.41
0.41
12.14
10.53
11.08
10.37
9.21
9.67
6.85
6.43
6.75
2.05
2.13
2.27
7.61
7.04
7.29
6.27
5.92
6.12
3.72
3.68
3.81
0.74
0.83
0.87
4.00
4.10
4.23
3.18
3.34
3.45
1.62
1.83
1.89
0.20
0.41
0.41
10.46
8.32
7.71
9.11
7.47
7.00
6.29
5.55
5.36
2.01
2.05
2.13
6.98
6.08
5.80
5.84
5.22
5.04
3.57
3.42
3.39
0.74
0.82
0.86
3.86
3.83
3.79
3.09
3.15
3.14
1.60
1.78
1.81
0.20
0.41
0.41
Abbreviations: QALE, Quality-adjusted life expectancy; RP, radical prostatectomy; EBRT, external beam radiotherapy;
WW-watchful waiting.
*Results are shown in quality-adjusted life years for patients of different ages and with four different levels of comorbidity
as measured by the Index of Coexistent Disease,63 ranging from 0 (no or asymptomatic comorbidity) to 3 (severely disabling
or life-threatening). For this analysis, treatment efficacy data were obtained from Lu-Yao et al.33
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Grade 1
Watchful waiting
Incremental LE*
Radical
Prostatectomy
External beam
Radiotherapy
Grade 2
Watchful waiting
Incremental LE*
Radical
Prostatectomy
External beam
Radiotherapy
Grade 3
Watchful waiting
Incremental LE*
Radical
Prostatectomy
External beam
Radiotherapy
CO
Age 70
3324
ALIBHAI ET AL
Table 4.
Sensitivity Analysis for All Tumor Grades for a 75-Year-Old Man, No Comorbidity
Base Case
Plausible Range
Threshold* Grade 1
Threshold* Grade 2
Threshold* Grade 3
Age-associated incontinence
Age-associated impotence
Probability of metastasis after RP
Probability of metastasis after EBRT
Probability of metastasis after WW
Probability of 30-day mortality after RP
Probability of impotence after RP
Probability of urinary symptoms after RP
Probability of 30-day mortality after EBRT
Probability of bowel symptoms after EBRT ⱖ grade 3
Probability of impotence after EBRT
Probability of urinary symptoms after EBRT
Probability of severe urinary symptoms after EBRT
Probability of severe urinary symptoms after RP
Probability of severe urinary symptoms due to age
Probability of new impotence
Probability of new urinary symptoms
Short-term utility associated with RP
Short-term utility associated with EBRT
Utility of bowel complications
Utility of impotence
Utility of urinary symptoms, severe
Utility of urinary symptoms, non-severe
Utility of hormone-responsive metastases
Utility of hormone-resistant metastases
Utility of WW
.136
.514
Variable†
Variable†
Variable†
.0104
.607
.228
.002
.0159
.431
.128
.116
.168
.0609
.053
.020
.67
.67
.99
.91
.92
.94
.84
.58
1.0
50%-200%
50%-150%
Variable†
Variable†
Variable†
50%-200%
50%-150%
0.126-0.253
0-0.006
0-0.131
25%-200%
0.064-0.506
50%-200%
50%-200%
50%-200%
0%-200%
0%-200%
0.50-1.0
0.50-1.0
0.45-1.0
0.69-1.0
0.57-1.0
0.92-1.0
0.42-1.0
0.05-0.58
0.72-1.0
NT
TOR
NT
TOR
0.0158
NT
TOR
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
.96
NT
NT
TOR
NT
0.99
NT
NT
TOR
TOR
TOR
TOR
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
.77
TOR
TOR
NT
NT
NT
NT
NT
TOR
TOR
TOR
TOR
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
TOR
NT
TOR
NT
NT
NT
NOTE. All probabilities are reported as annual probabilities. Thresholds were found outside of the plausible range for grade 1 disease as follows: probability of
age-associated impotence (157% of baseline value); probability of impotence after RP (45% of baseline); probability of metastasis after EBRT (.0056); utility of
hormone-responsive metastases (.38). For grade 2 tumors, thresholds were found outside of the plausible range for probability of metastasis after RP (.0268); probability of
metastasis after EBRT (.0202); probability of metastasis after WW (0.0272); 30-day mortality after RP (499% of baseline); utility of non-severe urinary symptoms (.35); and
utility of severe urinary symptoms (.06). For grade 3 cancers, thresholds were found outside of the plausible range for probability of metastasis after RP (.091); probability
of metastasis after EBRT (0.048); probability of metastasis after WW (.055); 30-day mortality after RP (1568% of baseline); utility of impotence (.51); and utility of non-severe
urinary symptoms (.01).
Abbreviations: NT, no threshold found for this variable; TOR, threshold found outside of range of plausible values; RP, radical prostatectomy; EBRT, external beam
radiotherapy; WW, watchful waiting.
*The threshold refers to the value of a given variable above and below which the preferred strategy changes.
†Base case and plausible range are dependent on tumor grade and are listed in Table 1.
Krahn et al89 found that the odds of a 75-year-old man being
offered RP for a moderately differentiated tumor were only
0.003 times the odds of a 55-year-old man being offered the
same treatment. Thus, our discussion focuses on which groups of
older patients should, on the basis of our findings, be offered
potentially curative therapy.
For patients with low-grade (Gleason score 2 to 4) disease, the
survival advantages of potentially curative therapy are modest.
In this group of patients, the tumor is slow growing, treatment
complications are important, and the risk of dying from competing causes exceeds the risk of cancer death. Moreover, benefits
from potentially curative therapy are restricted to men with no
comorbidity and are conditional on patients’ preferences for
outcomes of treatment. In particular, an individual patient’s level
of discomfort associated with leaving his disease untreated
significantly influences the preferred treatment.90
For patients with moderate-grade (Gleason score 5 to 7)
tumors, there is significant uncertainty. The choice of optimal
treatment is highly dependent on which outcome studies one
accepts. If one believes in long-term outcomes reported in
population-based cohort studies or biochemical outcomes with
modern radiotherapy, potentially curative therapy is beneficial
up to age 75 years for men with either no or mild comorbidity.
If one accepts results from highly selected individuals at specialized tertiary care institutions, the benefits of treating anyone
age 65 years or older with either surgery or radiotherapy are
marginal, regardless of overall health. A key patient preference
that may influence treatment is the patient’s values regarding
preservation of sexual function.
For patients with high-grade (Gleason score 8 to 10) lesions,
the results are most clear. Otherwise healthy men up to age 80
years would experience significant benefits in terms of both
survival and quality-adjusted survival with potentially curative
therapy. Increasing comorbidity leads to decreased benefits, such
that potentially curative therapy is no longer superior to WW for
75-year-old men with moderate comorbidity or 80-year-old men
with even mild comorbidity. Although surgery seems to show
somewhat greater benefit than radiotherapy, variation in preferences among individual patients, along with innovations in
radiotherapeutic techniques in some centers, may make either
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Copyright © 2003 American Society of Clinical Oncology. All rights reserved.
Variable
3325
OPTIMAL TREATMENT OF LOCALIZED PROSTATE CANCER
utilities for various health states used in our model were elicited
from a relatively large cohort of men with prostate cancer, and
are more representative of men with prostate cancer than those
used in previous studies. Quantitatively, better disease-specific
survival with potentially curative therapy and higher utility
ratings for treatment-related complications accounted for much
of the differences between our results and those of Fleming et
al20 and Kattan et al,21 respectively.
The greatest limitation to our analyses is the lack of efficacy
data from randomized trials. The recently published Scandinavian trial1 addresses neither the role of radiotherapy nor the
treatment of Gleason score 8 to 10 tumors. Although another
large randomized trial is underway, results will not be available
for several years, and will only address the question of surgery
versus WW.93
Despite using multiple data sources in our study, observational
data are more prone to bias than are randomized clinical trials. It
is nonetheless reassuring that use of multiple data sources
generally yielded qualitatively similar results that were comparable to those of Holmberg et al.1 In addition, although results for
intermediate outcomes, such as biochemical relapse, in studies
using modern radiotherapeutic techniques seem promising, longterm survival data have yet to be published.25,67,94 Thus, our
results using modern radiotherapy must be viewed with caution
in the absence of mature outcome data. The current quality of
evidence also does not allow us to determine which of the two
potentially curative modalities (surgery or radiotherapy) is superior. Because of limited long-term disease-specific survival
data from published studies, we were also unable to separate
Gleason-score 7 from Gleason score 5 and 6 tumors, which
limits our ability to provide recommendations about the optimal
management of these more aggressive tumors.95-98
What is most clear from our results is that potentially curative
therapy should be seriously considered in reasonably healthy
men up to age 80 years who have high-grade disease. More
generally, clinicians need to consider age, comorbidity, and
patient preferences in addition to tumor grade when considering
treatment options for older men with localized prostate cancer.
ACKNOWLEDGMENT
We thank Drs. Padraig Warde and Mack Roach III for their helpful
comments on previous versions of the manuscript.
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