EURURO Vol. 72 No. 6

900 1030

1. Introduction
Prostate cancer (PCa) screening reduces advanced disease
and PCa-specific death , but also leads to “overdiagno-
sis” and overtreatment of indolent tumors . Conserva-
tive management is increasingly utilized for favorable-risk
PCa to delay or avoid aggressive treatment and potential
side effects Prior comparative-effectiveness models
have confirmed that this is a valid strategy for certain
patients , with improved quality of life (QOL) and
reduced initial resource utilization .
Despite agreement on the importance of conservative
management to preserve screening benefits and reduce
overtreatment , there is no consensus what to do next
Conservative management encompasses two very
different strategies: “watchful waiting” (WW) without
curative intent and “active surveillance” (AS) with serial
testing for “ disease progression” to offer selective delayed
treatment with curative intent. No randomized trials have
compared benefits and harms between WW and contem-
porary AS. Furthermore, for patients choosing AS, there is no
consensus on the type, frequency, or sequence of follow-up
tests to monitor for disease progression . Thus, the
objective of this clinical decision analysis is to compare life
expectancy and quality-adjusted life expectancy between
WW and different AS protocols for US men 50 yr.
2. Patients and methods
We developed a state-transition Markov model to compare different
strategies of conservative management for a cohort of US men diagnosed
with clinically localized PCa who chose conservative management.
Markov models represent a hypothetical cohort moving among pre-
defined health states that are mutually exclusive and collectively
exhaustive . Our model starts when the patient is diagnosed with
PCa and begins conservative management. We used this model to
evaluate two different outcomes: life years (LYs) and quality-adjusted life
years (QALYs), which put quality and quantity of life into the same metric
by multiplying the predicted duration of each health state by the utility
(QOL weight) for living in that state. The model was analyzed and reported
according to ISPOR/SMDM international recommendations .
The base case analyses compare WW (follow without further testing
until the development of advanced PCa or death from other causes) with
AS with prostate-specific antigen (PSA) every 6 mo and yearly biopsy
(based on the Johns Hopkins AS protocol ). We also examined an AS
strategy with more frequent PSAs (quarterly) with biopsies at years 1, 3,
7, and 10, and then every 5 yr, similar to Prostate Cancer Research
International Active Surveillance (PRIAS) and an exploratory
strategy including PSA every 6 mo and magnetic resonance imaging
(MRI) yearly where biopsy is performed only if MRI is abnormal. Finally,
we evaluated an exploratory strategy with PSA every 6 mo and biopsy
every 5 yr. For all strategies, biopsies were discontinued at age 75 yr in
the main analysis, as in the Johns Hopkins program
We used a state-transition cohort model to obtain estimates for
specific populations of interest determined a priori, based on clinical
features. For the main analysis, the cohort started at age 50 yr, and the
model was rerun for cohorts starting at age 40, 65, 70, and 75 yr.
shows a schematic of the model. At the start, men have been diagnosed
with PCa and they have chosen conservative management. Some were
classified accurately with Gleason 6 (grade group 1), while others were
misclassified and have undetected higher-grade disease. During each
model cycle, individuals can remain on conservative management,
undergo treatment for reclassification (then into a post-treatment state),
develop metastases, or die. We used a cycle length of 1 mo and a lifelong
time horizon due to the long natural history of PCa. Depending on the
approach to conservative management, some cycles may include
rebiopsy. Overall mortality data were obtained from US life tables, with
a priori adjustment by a multiplier of 0.45 to account for the highly
selected healthier population affected by localized PCa Our model
considered the following potential harms: biopsy complications, short-
and long-term complications of PCa treatment (aggregate measure
including sexual, urinary, and bowel dysfunction), and development of
metastasis. Since our objective was to examine efficacy, we assumed
100% compliance with protocol-recommended biopsies and that all men
found to have disease reclassification (increases in tumor grade)
underwent treatment.
shows the model inputs (see Supplementary material for
details). Transition probabilities between states were estimated from the
literature. Previously published “utilities” (ie, QOL weights re flecting
quantitative health preferences) were used to quantify QOL implications
for each disease state
One- and two-way deterministic sensitivity analyses were performed to
assess the implications of uncertainty for key variables. Tornado diagrams
were used to summarize results of one-way sensitivity analysis. Since
previous studies showed an impact of time preference on PCa treatment
selection, we also performed sensitivity analysis using discounting (ie,
assigning lower weights to future events) We also estimated the risk of
radical treatment, metastasis, and PCa death. Model validation was
performed based on ISPOR–SMDM recommendations and comprised the
following: (1) expert consensus on face validity of model inputs, structure,
and results; (2) verification through extensive sensitivity and extreme value
analysis; (3) cross validation to previous models; and (4) blinded external
validation to partially dependent and independent published studies with
>5 yr follow-up . All analyses were performed using TreeAge Pro version
2014 (TreeAge Software, Inc., Williamstown, MA, USA).
3. Results
3.1. Main base case analysis
shows the base case results of the decision analysis.
In a cohort of men starting at age 50 with low-risk PCa
undergoing conservative management, AS using the Johns
Hopkins strategy yielded more LYs compared with WW
(35.21 vs 34.55 LYs, or a difference of 0.66 life-years;
). Lifetime risks of PCa death and metastasis were,
respectively, 5.42% and 6.40% with AS versus 8.72% and
10.30% with WW. Men on AS had a 50% lifetime risk of
undergoing radical treatment.
Using the outcome of quality-adjusted life expectancy,
AS yielded more QALYs (33.89) than WW (33.36 QALYs, an
expected difference of 0.53 life-years).
For a cohort starting at age 40 yr ), AS yielded
more LYs and QALYs compared with WW. By contrast,
among men aged 65 yr, WW had more QALYs than AS
. Supplementary shows LYs and QALYs for
men with very low–risk PCa.
3.2. Alternative AS protocols
In men aged 50 yr, using PRIAS, MRI-based, and 5-yr
biopsy strategies yielded 35.12, 35.20, and 34.99 LYs,
respectively. Lifetime risks of PCa death and metastasis
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