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Comparative effectiveness ­research
in localized prostate ­cancer
­treatment
Prostate-specific antigen testing has dramatically increased the incidence of
localized prostate cancer. Most men with localized cancer attempt curative
therapy, usually with surgery or radiation. However, there is uncertainty about
whether and how to best treat these cancers. No published controlled trials have
directly compared surgery against radiation or either treatment against active
surveillance. Given the indolent nature of prostate cancer and the substantial risks
of treatment-related harms, the effects of cancer and treatment on quality of life
are important patient-centered outcomes. Comparative effectiveness research,
using observational cohorts, claims data and simulation models, enables
comparisons of treatments that have not been studied in controlled trials and
captures real-world outcomes data to better support informed decision-making.
KEYWORDS: cohort studies n comparative effectiveness research n decision-making
decision support techniques n prostatectomy n prostatic neoplasms n quality of life
n radiotherapy
n
Treating localized prostate cancer
Richard M Hoffman*1,2,
David F Penson3,4, Anthony L Zietman5,6
& Michael J Barry5,7
Department of Medicine, University of New
Mexico, Albuquerque, NM, USA
2
Medicine Service, New Mexico VA Health Care
System, Albuquerque, NM, USA
3
Department of Urological Surgery, Vanderbilt
University, Nashville, TN, USA
4
GRECC, VA Tennessee Healthcare System, Nashville,
TN, USA
5
Harvard Medical School, Boston, MA, USA
6
Massachusetts General Hospital, Boston, MA, USA
7
Informed Medical Decisions Foundation, Boston,
MA, USA
*Author for correspondence:
[email protected]
1
The Institute of Medicine designated prostate cancer treatment for localized (earlystage) disease as one of the 25 most important areas for comparative effectiveness
research (Box 1) [101]. The advent of prostate-specific antigen (PSA) testing in the late
1980s has led to an epidemic of prostate cancer – an estimated 1.3 million additional
cases [1] – with the lifetime risk of being diagnosed increasing from 9 to 16% [102].
Because PSA testing can detect cancers 5–10 years before clinical presentation [2],
approximately 80% of PSA-detected cancers are diagnosed at localized stage [102].
Between 70 and 90% of men with localized prostate cancer attempt curative therapy
with either surgery or radiation therapy [3–5]. However, PSA testing is associated with
overdiagnosis; a modeling study suggests that 23–42% of cancers detected by screening would never have caused clinical problems during a man’s lifetime [2]. This implies
that treatment might be unnecessary for some men and that men with low-risk cancers
should consider observation.
While population data can characterize the risk for overdiagnosis, we lack sufficiently accurate tumor markers to confidently determine the risk for an individual
patient. Consequently, active surveillance has recently emerged as a treatment option
for mitigating the harms of overdiagnosis and unnecessary treatment. With active
surveillance, men with low-risk cancers (defined by PSA <10 ng/ml, Gleason <7 and
minimal tumor volume on biopsy) defer active treatment and undergo close monitoring with serial PSA testing and biopsies to determine whether cancer is progressing
and requires treatment [6]. However, there is no consensus on the optimal criteria for
selecting patients for active surveillance, the appropriate monitoring strategies or the
best measures of progression [7].
Treatment selection is further complicated because the optimal therapy for men
with potentially clinically important cancers is unknown – no adequately sized randomized trials have directly compared survival benefits between surgery and radiation therapy. However, we do have convincing data from observational and clinical
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2(6), 583–593 (2013)
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Box 1. Treatment options for localized prostate cancer.
Radical surgery
■■ Open radical prostatectomy
■■ Robotic-assisted laparoscopic radical prostatectomy
■■ Laparoscopic radical prostatectomy
■■ Focal therapy
■■ Cryosurgery
■■ High-intensity focused ultrasound
■■ Radiotherapy
■■ External beam (conformal 3D, intensity-modulated radiation therapy,
proton beam, stereotactic), which can be combined with androgen
deprivation therapy for high-risk cancers
■■ Interstitial (brachytherapy)
■■ Active surveillance
■■ Watchful waiting
■■
trials, which used validated health-related quality
of life (HRQOL) measures [8], documenting the
frequent occurrence of treatment complications
that adversely affect sexual, urinary and bowel
function [9–11]. Indeed, treatment decisions are
influenced by concerns over complication risks
[12]. While newer surgical and radiation modalities, including robot-assisted laparoscopic prostatectomy, stereotactic radiation, intensity-modulated radiation therapy (IMRT) and proton-beam
therapy, are considered to be safer and more effective than older ­modalities, supporting data are
quite limited.
Thus, in 2013 there is uncertainty about
whether, when and how to treat localized prostate
cancers. Although specialists have been shown to
believe that the treatment that they offer is superior to alternative therapies [13], treatment selection for localized prostate cancer is recognized
as a preference sensitive decision [14]. The goal
for physicians should be to inform their patients
about the potential benefits and harms of treatment options and help them to select a treatment
that is concordant with their values. However,
finding the body of evidence on patient-centered
outcomes, such as survival and prostate cancer
quality of life, is challenging. This review will
address the importance of comparative effectiveness research for supporting decision-making and
critically appraise the strengths and limitations of
current data from randomized controlled trials
and observational studies.
Randomized controlled trials
■■ Comparisons of different treatment
modalities
Treatment decisions for localized prostate cancer
should ideally be guided by randomized controlled
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trial data comparing different modalities. However, few such studies have been reported in the
literature. A 2011 evidence synthesis document
prepared for the Agency for Healthcare Research
and Quality identified only four randomized trials reporting either all-cause or prostate cancerspecific mortality or harms associated with treatment compared with watchful waiting or active
surveillance [103].
Several studies attempting to compare surgery
and radiation therapy have closed due to poor
enrollment, including the SPIRIT trial [15] and
the START trial [104]. The START trial was comparing early treatment (surgery, external beam
radiotherapy and brachytherapy) with active surveillance. The only ongoing randomized trial of
different modalities is the ProtecT study from the
UK [16]. ProtecT is a multicenter trial that has
enrolled over 3000 men, aged 50–69 years with
PSA-detected localized cancer. The study aims to
compare radical prostatectomy against conformal
radiation therapy and active surveillance (Box 2).
ProtecT closed to accrual in 2011 and quality
of life and survival results are expected in 2015
when median follow-up will be approximately
10 years.
■■ Comparisons of surgery & watchful waiting
Several randomized trials have compared surgery
versus watchful waiting for men with localized
prostate cancer. Watchful waiting is a palliative
approach where men will only be offered treatment to relieve symptoms of disease progression
and not for cure. The Veterans Administration
Cooperative Urological Research Group randomized 142 patients diagnosed with localized cancer between 1967 and 1975 [17]. After a
median follow-up of 23 years, investigators found
no survival difference. However, the study was
underpowered owing to the small sample size
and substantial losses to follow-up. Furthermore,
results are not applicable to current practice given
advances in staging, grading and treatment.
The SPCG-4 randomly assigned 695 men
with localized prostate cancer, mean age of
65 years, to either surgery or watchful waiting
[18–21]. During a median 12.8 years of followup, men under­going radical prostatectomy
were significantly less likely to die from prostate cancer than men in the watchful waiting
group, with cumulative mortalities of 14.6 versus
20.7%, respectively [20]. The absolute prostate
cancer mortality difference was 6.1 percentage
points (95% CI: 0.2–12.0), providing a number
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Localized prostate ­cancer treatment review
Box 2. ProtecT study.
ProtecT is a multicenter UK trial that has enrolled over 3000 men aged 50–69 years with
prostate-specific antigen-detected localized cancer. The study is the only large randomized
trial comparing multiple modalities – assigning men to either radical prostatectomy, conformal
radiotherapy or an active monitoring arm. ProtecT closed to accrual in 2011 and quality of
life and survival results are expected in 2015, when median follow-up will be approximately
10 years [16].
needed to treat of 15. However, the survival benefit was only observed among men younger than
65 years of age at diagnosis. Men in the radical
prostatectomy group also had a reduced cumulative incidence of death (6.6 percentage points;
95% CI: -1.3–14.5) and distant metastasis (11.7
percentage points; 95% CI: 4.8–18.6). However, the majority of cancers in SPCG-4 were
clinically detected (only 5.2% were detected
by screening) so these results were not readily
translated to US populations where most cancers are being detected through screening. PSA
testing introduces both a lengthy lead-time and
a considerable risk for overdiag­nosis, which
would increase the number needed to treat over
a specific time frame [2].
The PIVOT trial randomly assigned 731 veterans with localized cancer, mean age of 67 years,
to either surgery or watchful waiting (Box 3)
[22]. In contrast to the SPCG-4, PIVOT was
conducted in the era of PSA testing. Approximately 50% of the men enrolled in PIVOT had
nonpalpable stage T1c cancer, indicating PSA
detection, while approximately 75% of men in
SPCG-4 had stage 2 (palpable) tumors. During
a median follow-up of 10 years, 48.4% of the
men died; the risk of dying from prostate cancer or treatment was 7.1% overall and there was
no benefit for surgery. Planned post hoc analyses
suggested that surgery could reduce the risks of
dying from prostate cancer and developing bone
metastases for men with more aggressive cancers, defined by PSA levels >10 ng/ml, Gleason
scores >7 or those in the intermediate or highrisk categories (based on PSA level, Gleason score
and tumor stage). Surgery was associated with a
significantly reduced risk of incident metastases
for men with intermediate and high-risk cancers, and a significantly reduced prostate cancer
mortality for men with PSA levels >10 ng/ml
(absolute risk reduction = 7.2 percentage points;
95% CI: 0.6–14.3). Notably, PIVOT did not
come close to achieving its target enrollment of
2000 men.
While SPCG-4 and PIVOT were rigorously
conducted, the results are less applicable to current practice because the comparison group was
watchful waiting. Watchful waiting is considered to be most appropriate for men with limited life expectancy who are unlikely to live long
enough to benefit from treatment – or to be
healthy enough to endure aggressive treatment.
While this represents a different population than
the men being considered for active surveillance,
watchful waiting is a relevant option given the
substantial number of cancer cases arising from
screening older men with multiple comorbidities
[23,24]. However, even when the harms of treatment are likely to outweigh the benefits, many
men are dissatisfied with being offered a palliative approach for a newly diagnosed cancer [25].
In the decades following the introduction of PSA
testing, many elderly men with localized cancers
who were not candidates for aggressive therapy
opted for primary androgen deprivation therapy
(ADT) [5]. While ADT can extend life in men
Box 3. PIVOT trial.
The trial randomly assigned 731 US veterans, with a median age 67 years, to either surgery
or watchful waiting. This study was conducted during the prostate-specific antigen (PSA) era,
and approximately 50% of study subjects had a nonpalpable stage T1c cancer, indicating PSA
detection. During a median follow-up of 10 years, approximately half of the subjects died,
including 7% who died from prostate cancer. Surgery did not reduce overall or prostate cancer
mortality; however, surgery did reduce prostate cancer mortality for men with high-risk cancers
characterized by PSA >10 ng/ml and/or Gleason score >6. Given concerns about overdiagnosis
with PSA testing, these results support consideration of active surveillance for men with low-risk
cancers [22].
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review Hoffman, Penson, Zietman & Barry
with metastatic cancer [26] or in conjunction
with external beam radiation therapy (EBRT)
for men with a high-risk localized cancer [27,28],
there is no evidence that primary ADT improves
survival in localized cancer [29].
■■ Comparisons of active treatment with active
surveillance
Active surveillance is a newer approach that has
been suggested for healthy men with low-risk
localized prostate cancers [6]. The ProtecT trial
has an active surveillance arm [16] and numerous
cohort studies suggest that active surveillance
can reduce the likelihood of undergoing active
treatment by over 60% [30–33]. Few prostate cancer deaths have been observed among men on
these protocols and there is no certainty that
early active treatment could have prevented
these deaths. A NIH State-of-the-Science Conference concluded that active surveillance has
emerged as a viable option for men with low-risk
cancers [7].
■■ Comparisons of different surgical techniques
Surgical techniques have evolved during the PSA
era, including the refinement of the nerve-sparing
prostatectomy to minimize postoperative erectile
dysfunction [34]. More notably, robotic-assisted
laparoscopic prostatectomy has largely overtaken
open prostatectomy as the most popular treatment approach [35]. While robotic surgery has
been widely publicized, there is little evidence
that the technique provides meaningful benefits
for cancer control or substantially reduces the
risk for treatment complications [36,37]. Again,
there are no published results from controlled
trials comparing robotic surgery with open prostatectomy, although an ongoing Mayo Clinic
study is expected to complete data collection by
May 2016 [105].
■■ Comparisons of external beam radiotherapy
with other modalities
External beam radiotherapy and brachytherapy
are widely used to treat localized prostate cancer.
Radiation therapy techniques have progressed
markedly in recent decades to deliver higher
radiation doses in a more focused manner.
However, there are little data from randomized
controlled studies to determine the effectiveness of radiation therapy compared with other
modalities. Randomized trials have shown an
overall and disease-specific survival benefit for
adding ADT to EBRT for men with higher-risk
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localized prostate cancers [27,38]. A Scandinavian
study of men with locally advanced prostate
cancer also found that adding EBRT to ADT
improved disease-specific survival for the subset
(21%) of men with high-risk localized prostate
cancer [39]. However, recent overviews of randomized controlled trials for clinically localized
prostate cancer found no survival comparisons of
EBRT alone against either brachytherapy alone
or surgery [40,41].
■■ Comparisons of different radiation therapies
A 2011 systematic review that compared different radiation treatments for clinically localized
prostate cancer only identified ten randomized
trials that reported either clinical or biochemical
outcomes [42]. Seven studies compared doses and
fraction sizes of EBRT, two compared EBRT
and brachytherapy against EBRT alone, and
one compared different forms of low dose rate
radiation therapy. Increased EBRT doses were
associated with greater freedom from biochemical failure, but studies either found no significant
survival differences or did not report survival
data. None of the studies compared different
EBRT technologies, including 3D conformal
therapy, IMRT, proton beam and the more
recently introduced stereotactic techniques. An
ongoing National Cancer Institute Phase III trial
is evaluating proton therapy versus IMRT for
men with low or low–intermediate risk prostate
cancers (T1c–2b), with the primary outcome of
disease-specific quality of life (bowel function)
and secondary outcomes that include urinary
and sexual function, cost–effectiveness, and
overall and disease-specific survival [106].
■■ Comparisons of radiation therapy with
watchful waiting
Recent systematic reviews did not identify any
eligible studies comparing radiation therapy
with no treatment or no initial treatment [41,42].
A Scandinavian trial that randomized men
with localized disease to either 3D conformal
radiotherapy or watchful waiting has reported
quality of life outcome data [9], but only published survival data in an abstract [107]. The study
enrolled 214 patients between 1986 and 1997;
after a minimum of 16 years of follow-up, men
receiving EBRT had a reduced risk for distant
progression but no overall or disease-specific
survival benefit.
Conducting randomized treatment trials
is challenging. Because PSA testing is often
future science group
Localized prostate ­cancer treatment detecting microscopic cancers, follow-up of
10–15 years is needed to assess survival outcomes. Even then, interpreting results is problematic because selection criteria and treatments
change over time. Biomarkers with better prognostic value than PSA progression could be
useful surrogate end points for evaluating new
treatments. While the importance of measuring
patient-centered outcomes is now well acknowledged, few controlled trials have reported on
prospectively collected HRQOL data.
Observational studies
In the absence of relevant randomized controlled
trials, comparative effectiveness of treatments
for localized prostate cancer is being addressed
by retrospective analyses of databases, prospective cohort studies and simulation models.
Each approach has important strengths and
limitations.
■■ Surveillance Epidemiology & End
Results–Medicare data set
One of the most widely used resources for conducting comparative effectiveness research has
been the Surveillance Epidemiology and End
Results (SEER)–Medicare data set, which links
national tumor registry data with Medicare
enrollment and claims. SEER collects information about demographics, cancer site, stage,
histology and treatment for persons newly diagnosed with cancer in one of the SEER geographic
areas. The data set provides claims data on covered healthcare services for Medicare beneficiaries in SEER that can be used to characterize
treatments and comorbidity. SEER–Medicare
data have been used to compare different treatment modalities for localized prostate cancer,
including the examples shown in Box 4.
The advantages of using SEER–Medicare are
the large national sample with many years of
follow-up and extensive data on demographics
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and comorbidity. However, coding may be
imprecise, for example, the study of minimally
invasive radical prostatectomy could not identify
robot-assisted laparoscopic procedures [43], and
there may be limited data on the duration of
hormonal therapy or on radiation dose delivered,
both of which may affect survival. Comorbidity measures based on claims data, which were
developed to predict relatively short-term mortality, are less applicable for modeling long-term
survival in men with localized prostate cancer.
Additionally, the occurrence and severity of
complications that adversely affect HRQOL
cannot be readily captured through claims data.
■■ Cohort studies
Prospective observational studies enable investigators to assemble large patient cohorts and
obtain comprehensive outcome data that facilitates comparisons across treatment modalities. By
surveying or interviewing patients, investigators
can obtain data on patient-centered outcomes
such as general and disease-specific HRQOL.
Cohort studies enable comparisons of treatment
options, such as surgery versus radiotherapy, that
have not successfully been evaluated in randomized controlled trials. Cohort studies also allow
timely evaluations of newer treatment options,
including robotic-assisted laparoscopic prostatectomy, proton-beam radiotherapy, stereotactic radiotherapy or cryotherapy, which have not
yet been evaluated in randomized trials. Cohort
studies can provide longer-term outcomes data
for larger patient samples, particularly through
linkages with the National Death Index, than
can be obtained in randomized trials. Multisite
observational cohort studies can evaluate the
effects of practice variation on outcomes across
a wide range of healthcare delivery systems.
Among the large-scale prospective observational studies are PCOS [44], CaPSURE [45] and
CEASAR [46]. The PCOS is a population-based
Box 4. Examples of using Surveillance, Epidemiology and End Results–Medicare data to conductive comparative
effectiveness research on prostate cancer treatment.
Minimally invasive (laparoscopic) radical prostatectomy has been shown to be associated with shorter hospital length of stay,
similar rates of secondary cancer therapy, but more genitourinary complications compared with open radical prostatectomy [43]
■■ Older men with localized cancer who underwent active treatment had an overall survival advantage relative to observation [54]
■■ Men with high-risk cancer undergoing radiotherapy had a more favorable disease-specific survival relative to observation [70]
■■ Men undergoing radical prostatectomy had a lower cancer-specific mortality risk than men undergoing radiotherapy, particularly
for high-risk cancers [71]
■■ Intensity-modulated radiation therapy, proton therapy and conformal radiotherapy were shown to have differing side effect
profiles in treating men with localized cancer [72]
■■
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review Hoffman, Penson, Zietman & Barry
study that enrolled over 3500 men newly diagnosed with prostate cancer in the mid-1990s
at six SEER tumor registries (Box 5). Investigators reviewed medical records to obtain data
on cancer diagnosis, tumor characteristics and
treatment. Participants periodically completed
mailed surveys beginning at 6 months until
approximately 15 years after diagnosis. Surveys
captured demographic, comorbidity, clinical
and HRQOL data. Investigators have used
propensity score methods to compare HRQOL
outcomes for men with localized prostate cancer. PCOS analyses have shown that surgery
is associated with substantially more impaired
urinary and sexual function within 5 years of
diagnosis than radiation therapy [47], although
differences diminish with long-term follow-up
[10]. Elderly men undergoing active treatment
have greater functional impairment relative
to those receiving conservative management
[48], and primary ADT is also associated with
greater functional impairment than watchful
waiting [49]. Men undergoing radical prostatectomy had significantly lower overall and prostate cancer mortality at 15-year follow-up than
men undergoing radiation therapy [50]. The
most recent PCOS publication showed high
other-cause mortality risks for men with low- or
intermediate­-risk prostate cancer and multiple
major comorbidities [51].
CaPSURE is a multisite longitudinal observational study that has been following prostate cancer patients since 1995 [45]. Enrolling urologists
provide clinical data and patients periodically
complete questionnaires on HRQOL, resource
utilization and satisfaction with care. CaPSURE
investigators have shown that men undergoing
radical prostatectomy, particularly those with
higher risk cancers, have a substantially reduced
risk for prostate cancer mortality compared with
those receiving radiotherapy or primary ADT [52].
CEASAR used SEER tumor registries to enroll
men under 80 years of age with a PSA <50 ng/
ml diagnosed with clinically localized disease in
2011–2012. CEASAR also included a small convenience sample of men from CaPSURE to accrue
approximately 3600 men onto the study. Similarly to PCOS, participants completed surveys at
baseline, 6 and 12 months after enrollment and
investigators performed a detailed medical record
review 1 year after diagnosis. CEASAR differs
from PCOS in several ways. First, the majority
of the patients were enrolled before receiving
treatment, generating a more accurate portrayal
of baseline function. Second, the patient surveys
included a number of nontraditional scales (such
as participatory decision-making style and healthcare distrust) and a more detailed comorbidity
scale (the total illness burden index for prostate
cancer) that should allow for better risk adjustment [53]. Finally, CEASAR measured quality of
care indicators, enabling analyses to adjust for differences in the quality of interventions, a rarely
addressed factor in comparative effectiveness
research. Data collection is ongoing in CEASAR,
with planned follow-up through 5 years.
■■ Selection bias
Cohort studies, particularly those using population-based sampling, may be more generalizable to real-world practice than randomized
trials. However, treatment comparisons are
highly susceptible to selection bias, where characteristics associated with treatment selection
are also associated with clinical outcomes. For
example, radical prostatectomy is more likely
to be offered to younger, healthier men than
radiation therapy, while radiation therapy will
be more readily offered to men with high-risk
or even potentially regionally advanced cancer.
Healthy elderly men are more likely to undergo
active treatment than observation. The SEER–
Medicare study showing a survival benefit with
active treatment for elderly men found a 13 percentage point absolute risk reduction for overall
mortality, although only a 0.6 percentage point
reduction in prostate cancer mortality [53]. The
survival benefit thus seems more likely due to
Box 5. The PCOS study.
The PCOS is a landmark US population-based observational study designed to investigate how prostate cancer and treatment
affect quality of life. Investigators at Surveillance, Epidemiology, and End Results (SEER) Cancer registries in six geographic regions
enrolled approximately 3500 men newly diagnosed with prostate cancer between October 1994 and October 1995. Investigators
abstracted medical records to obtain data about diagnostic evaluations, tumor characteristics and treatments. The centerpiece of
the study was a survey that collected information about urinary, sexual and bowel function, as well as general health-related quality
of life data shortly after diagnosis and again after 12 months, 24 months, 5 years and 15 years. Results have described practice
patterns and outcomes, including quality of life and survival following diagnosis of localized cancer [44].
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Localized prostate ­cancer treatment residual confounding in assessing comorbidity
than a treatment effect [55]. Selection bias can be
addressed through stat­istical techniques, including propensity scores and instrumental variables.
Propensity score methods use regression models of relevant baseline characteristics to determine a patient’s propensity for receiving a specific
treatment [56]. This derived propensity score facilitates comparing outcomes across treatments by
balancing patient characteristics. The propensity
score can be used as a covariate in multivariable
models, for stratified analyses of patients based
on propensity scores, or for matching patients
with identical propensity scores. These analyses
are still subject to residual confounding because
they can adjust only for measured confounding
covariates.
Instrumental variable analysis uses an exogenous
variable (instrument) that is hypothesized to affect
treatment choice but not be related to outcomes.
Variations in the instrument that are associated
with variations in treatment are considered to be
a random effect that addresses both measured and
unmeasured confounding. A modeling study used
SEER–Medicare data of treatment outcomes for
localized prostate cancer to compare results from
propensity score analysis with instrumental variable analysis [57]. The authors found that results
from instrumental variable analyses, which were
in the opposite direction of the propensity score
analyses, actually more closely approximated clinical trial results. However, selecting an appropriate
instrument can be challenging.
■■ Simulation models
Another approach to comparative effectiveness
research for treating localized prostate cancer has
been the use of simulation models. The Cancer
Intervention and Surveillance Modeling Network
prostate cancer working group, an international
consortium of investigators, uses statistical models to evaluate prostate cancer progression, detection and prognosis. Models incorporate data from
randomized trials and observational data, including SEER, to enable investigators to estimate outcome probabilities for events that might not occur
for decades – well beyond the follow-up period of
randomized trials. Although numerous prostate
cancer screening and treatment trials have over
a decade of follow-up [20,22,58,59], this duration is
insufficient to address the lifetime risks faced by
a 50-year-old man with a screen-detected cancer.
Models for screening have estimated that the
number needed to screen to prevent one death
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from prostate cancer decreases from over 1000
to less than 100 when projected over 25 years of
follow-up, although results are sensitive to screening strategies and the harms of treating overdiagnosed cancers [60,61]. A Cancer Intervention and
Surveillance Modeling Network modeling study
has shown that failing to treat screen-detected
cancers can be harmful for younger men and
those with high Gleason scores [62]. Another
modeling study demonstrated that active surveillance was associated with greater quality-adjusted
life expectancy than surgery, radiotherapy or
brachytherapy for men with low-risk, clinically
localized cancers [63]. The same investigators also
showed that observation (active surveillance or
watchful waiting) was more effective and less
costly than initial treatment, with watchful waiting consistently being the most effective and least
expensive strategy [64]. Modeling may also allow
tailoring of results to individual patient groups
defined by their cancer risk. A major limitation
for simulation modeling is the dearth of relevant
comparative treatment data for outcome assumptions, either because there are no data from randomized trials, data are limited to specific patient
characteristics defined by age or race, or data are
based on outmoded treatment strategies.
Comparative effectiveness research is also
needed to evaluate decision-making. Treatment
selection for localized prostate cancer is recognized as a preference sensitive decision because
there is uncertainty about whether and how to
optimally treat prostate cancer and treatment
options have differing risk profiles [14]. Unfortunately, studies suggest that decision processes for
selecting treatment are often poorly informed,
emotionally laden and occur under unwarranted
perceptions of urgency [12,65]. Providing decision
support tools, such as decision aids, is recognized
as an effective strategy for improving decision
quality [66]. Decision aids, which can be written,
video or web-based, have been shown to increase
knowledge and engagement in decision-making,
reduce decisional conflict and decrease interest in
aggressive treatments. However, few randomized
studies have evaluated decision aids for prostate
cancer treatment [66,67]. None of these studies
used decision aids that provided information
about active surveillance as an option for men
with low-risk cancers. Evaluating whether receiving up-to-date decision aids for prostate cancer
treatment affects treatment decisions and quality
of life is an important agenda for comparative
effectiveness research [68].
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Conclusion
PSA testing has led to an epidemic of localized
prostate cancer. While there is no certainty about
how, or even whether, to treat men with screendetected cancers, most undergo curative therapy.
We have little guidance from randomized trials,
because there have been no published head-tohead comparisons with different active treatment modalities. We do know that most deaths
among men enrolled in clinical trials are due to
causes other than prostate cancer and the chance
of dying from prostate cancer within 10 years
of a screening diagnosis is quite low. Men with
high-risk localized cancers seem most likely to
benefit from aggressive treatment, either radical
prostatectomy or the combination of EBRT and
ADT. Active treatment seems to provide little
benefit for men with low-risk cancers.
However, definitively determining the optimal active treatment for a localized cancer is
difficult because the lengthy time required
for observing survival differences means that
treatments will evolve and the applicability of
survival results can always be challenged – particularly by proponents of the apparently less
successful treatment. Complicating the issue
is the emergence of active surveillance as an
option for men with low-risk cancers. While
the ProtecT trial will provide some guidance
for treatment decisions, there will still be
uncertainty as to the optimal selection criteria,
monitoring strategies and the most clinically
relevant outcomes. Furthermore, given that the
risk of dying from a screen-detected cancer over
a decade is relatively small, treatment decisions
will be weighted heavily on complications and
their adverse effects on quality of life, although
there is also a need for better prognostic biomarkers to use for surrogate clinical end points.
Given the practical limitations of cost, time and
ability to enroll adequate sample sizes for conducting randomized trials to compare different
treatment modalities, observational studies will
be the most efficient strategy for conducting the
comparative effectiveness research needed to
support informed decision-making.
Future perspective
Prostate cancer will probably remain one of
the most frequently diagnosed cancers in
American men. Screen-detected cancers are
often indolent, making it challenging to conduct efficacy trials. The emergence of new and
expensive treatment technologies also means
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that current practice is a moving target. Results
from comparative effectiveness research, using
observational cohorts, claims data and modeling will have an increasingly important role
in guiding treatment decisions. This research
can efficiently address patient-centered outcomes, including HRQOL, across a spectrum
of established and novel active treatments and
active surveillance. Comparative effectiveness research can also evaluate the decisionmaking processes, suggesting strategies for
better supporting informed decision-making.
Another important role should be to evaluate
the cost–effectiveness of new technologies [69].
Expensive treatments, including robot-assisted
laparoscopic radical prostatectomy, IMRT and
proton therapy, have been rapidly and widely
disseminated into practice in the absence of
compelling evidence for better cancer control
or fewer side effects. Often decisions to introduce these technologies are driven by financial
considerations that drive up the costs of healthcare without ensuring a commensurate quality improvement. Comparative effectiveness
and cost–effectiveness analyses can be used to
inform policy decisions outlining indications
for using and reimbursing the new technologies.
Disclaimer
The views expressed in this article are those of the authors
and do not necessarily reflect the position or policy of the
Department of Veterans Affairs.
Financial & competing interests disclosure
RM Hoffman receives partial salary support for editing a
prostate cancer treatment decision aid from the Informed
Medical Decisions Foundation, a not-for-profit (501 [c]3)
private foundation. He is supported by the Department of
Veterans Affairs. MJ Barry receives salary support as president of the Informed Medical Decisions Foundation. The
Foundation develops content for patient education programs, including programs on prostate cancer screening and
treatment. The Foundation has an arrangement with a
for-profit company, Health Dialog, to coproduce these programs. The programs are used as part of the decision support
and disease management services Health Dialog provides
to consumers through healthcare organizations and employers. The authors have no other relevant affiliations or financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript apart from
those disclosed.
No writing assistance was utilized in the production of
this manuscript.
future science group
Localized prostate ­cancer treatment review
Executive summary
Treating localized prostate cancer
■■ Prostate-specific antigen testing has led to a dramatic increase in the incidence of localized prostate cancer, although a
substantial proportion of screen-detected cancers are considered to be overdiagnosed.
■■ Most men who are diagnosed with localized prostate cancer attempt curative therapy with surgery or radiation, although
observation may be appropriate for men with low-risk cancers or limited life expectancy.
Randomized controlled trials
■■ Controlled trials suggest a survival benefit for treating men with high-risk screen-detected cancers with either radical
prostatectomy or external beam radiotherapy combined with androgen deprivation. No controlled trials have published results
comparing different treatment modalities, including comparisons of active treatment versus active surveillance.
Observational studies
■■ Comparative effectiveness research based on observational cohort studies, retrospective claims analyses and simulation models
allows investigators to efficiently compare treatments that have not been studied in controlled trials and capture real-world
patient-centered outcomes.
Conclusion
■■ Results from comparative effectiveness research can better support patient decision-making on whether and how to treat
localized prostate cancer, as well as support policy decisions about disseminating and reimbursing new technologies.
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