EURURO-2517; No of Pages 12
european urology xxx (2008) xxx–xxx
available at www.sciencedirect.com
journal homepage: www.europeanurology.com
Review – Prostate Cancer
Current Applications for Prostate-Specific Antigen Doubling
Time
Michelle L. Ramı́rez, Eric C. Nelson, Ralph W. deVere White,
Primo N. Lara Jr., Christopher P. Evans *
Department of Urology and Cancer Center, University of California at Davis, Sacramento, CA 95817, USA
Article info
Abstract
Article history:
Accepted April 2, 2008
Published online ahead of
print on April 11, 2008
Objective: To review the current status of prostate-specific antigen doubling time (PSADT) as it pertains to the evolution of prostate cancer (PCa),
specifically assessing its role in the following four stages: before diagnosis, prior to definitive treatment, following treatment including
salvage therapy after recurrence, and lastly, after onset of androgeninsensitive PCa.
Methods: We searched PubMed literature for current articles on PSADT
using the key words listed for this review and, where possible, selected
those with significant levels of evidence that were deemed relevant,
seminal, or controversial. We summarized the data regarding PSADT as a
marker for diagnosis and disease characterization, as well as a predictor
of progression, response to treatment, and mortality.
Results: PSADT may offer an advantage in providing a more dynamic
picture of tumor behavior, providing clues regarding the relative aggressiveness of the underlying pathology. Evidence points toward a role for
PSADT in the management of PCa, specifically in active surveillance,
disease recurrence after treatment, and in androgen-independent PCa.
PSADT is an important prognostic factor that may serve as an auxiliary
end point for cancer-specific survival; however, optimal cut-off points
denoting risk remain debatable.
Conclusions: PCa management requires risk stratification with a
combination of variables, PSADT being one of the most reliable predictors. It is now a parameter included in many predictive nomograms and
in treatment guidelines for expectant management and salvage therapy.
Keywords:
Active surveillance
Androgen-independent
prostate cancer
Biochemical recurrence
Biopsy
Expectant management
Prostate cancer
Prostate-specific antigen
doubling time
Prostate-specific antigen
kinetics
Salvage therapy
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# 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Department of Urology, 4860 Y Street, Suite 3500, University of
California, Davis Medical Center, Sacramento, CA 95817, USA. Tel. +1 916 734 7520;
Fax: +1 916 734 8094.
E-mail address: [email protected] (C.P. Evans).
0302-2838/$ – see back matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2008.04.003
Please cite this article in press as: Ramı́rez ML, et al., Current Applications for Prostate-Specific Antigen Doubling Time, Eur Urol
(2008), doi:10.1016/j.eururo.2008.04.003
EURURO-2517; No of Pages 12
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european urology xxx (2008) xxx–xxx
1.
Introduction
Because prostate cancer (PCa) remains a significant
cause of cancer deaths, means of improving detection and management continue to develop in an
effort to overcome inadequacies of current methods.
Specific tumor markers that not only detect PCa but
also differentiate indolent from clinically significant
disease are needed. To more accurately define the
risk of progression and better tailor management
throughout the course of disease, improvements in
biomarkers must be exploited. Current nomograms
using Gleason grade, clinical stage, and prostatespecific antigen (PSA) require modification to provide useful stratification for today’s evolving patient
population.
Among the many disease markers under investigation, PSA doubling time (PSADT) has emerged as
a potentially useful tool. Derived from the same data
as PSA velocity (PSAV), which measures the absolute
rate of change and is calculated as the slope of a
linear regression of PSA measurements over time
(ng/ml yr), PSADT represents the relative rate of
PSA change over time and is defined as the time
needed for the PSA value to double. As opposed to
PSAV, which is related to tumor volume, PSADT
takes into account the exponential nature of
neoplastic growth and requires logarithmic analysis. It is independent of the baseline PSA value and
should therefore be used when comparing different
patient populations [1]. Despite these differences,
the diagnostic and prognostic value of PSADT
compared with PSAV is uncertain, and the relative
merits of these variables deserve further assessment.
Notably, PSADT is still limited by fluctuations in
PSA values, which can be considerable depending on
the timing of measurements. Early determinations
of PSADT in the active surveillance population may
not necessarily be representative of overall PSADT
calculations [2]. Although a question remains as to
the optimal number and timing of measurements, a
currently accepted approach is to use three or more
values separated by at least 3 mo each with a
minimum increase of 0.2 ng/ml [3]. However additional values separated by longer intervals may yield
more reliable results during expectant management
[2]. Furthermore, multiple studies demonstrate
significant discrepancies in PSA measurements
among different detection assays despite current
efforts to standardize PSA assays [4]. The inadequacies in interchangeability between assays may
seriously weaken the reliability of PSADT calculations; thus, PSA values should be measured using
the same assay.
Fig. 1 – Linear regression representation of log PSA over
time where PSADT = (log of 2)/slope. Slope can be
calculated using least squares regression or using two logtransformed PSA values [PSADT = log 2(t2 S t1)/(log
PSA2 S log PSA1)]. PSA = prostate-specific antigen;
PSADT = prostate-specific antigen doubling time.
Multiple methods have been described for calculating PSADT. The simplest involves dividing the
natural log of 2 (0.693) by the slope of the line
described by two log-transformed PSA values, or all
log PSA values may be used to create the best fit line
by least squares regression (Fig. 1). When calculating
PSADT following radiation therapy, subtracting PSA
nadir from subsequent values may increase accuracy [3]. More complex methods involving splines or
quadratic equations to correct for baseline PSA and
benign prostatic hyperplasia have been demonstrated but are not yet commonly applied. Conveniently, online prediction tools that calculate
PSADT are available for use in clinical practice
through, for example, the Memorial Sloan-Kettering
Cancer Center Prostate Nomogram Web site [5].
Using PSADT as opposed to individual or absolute
PSA values may more closely approximate the
biologic behavior of the cancer, that is, tumor
progression. Pruthi et al showed that a short PSADT
following radical prostatectomy (RP) correlated with
the aggressiveness of operative pathology including
capsular penetration, percent Gleason 4–5 disease,
and lymphatic involvement [6]. In the initial paper
suggesting prognostic value to PSADT, D’Amico and
Hanks observed a relationship between shorter
PSADT and more rapid clinical progression in
22 patients with biochemical recurrence following
external-beam radiation therapy (EBRT) [7]. Additional evidence that PSADT reflects tumor biology
derives from the fact that, following initial differences related to therapy, patients with biochemical
relapse after RP compared to EBRT have similar
doubling times [8]. Since then, the possible prog-
Please cite this article in press as: Ramı́rez ML, et al., Current Applications for Prostate-Specific Antigen Doubling Time, Eur Urol
(2008), doi:10.1016/j.eururo.2008.04.003
EURURO-2517; No of Pages 12
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3
Fig. 2 – Overall use of prostate-specific antigen doubling time along the prostate cancer timeline. (1–5) Level of evidence
according to American Society of Clinical Oncology (ASCO) guidelines [9]. Evidence from (1) meta-analysis of multiple,
well-designed, controlled studies or high-powered randomized trials; (2) at least one well-designed, experimental study or
low-powered randomized trials, (3) well-designed, quasi-experimental studies including nonrandomized, controlled,
single-group, cohort, or case-controlled studies; (4) non-experimental studies including descriptive and case studies; and
(5) case reports and clinical examples. PCa = prostate cancer.
nostic value of PSADT has been explored in detail
and expanded significantly.
Here, we summarize existing data to clarify when
during the course of PCa management PSADT is a
reliable biomarker and can therefore be useful in
clinical practice. This review of PSADT will be
organized chronologically around the natural history
of PCa and its treatment. Four sections will be
described: first, the value of PSADT before diagnosis;
second, following diagnosis but prior to definitive
treatment; third, following definitive treatment, and
including salvage therapy, but before androgeninsensitive PCa (AIPCa); and finally, after AIPCa,
including secondary androgen-deprivation therapy
(ADT) and chemotherapy. Fig. 2 presents the possible
uses of PSADT along a PCa timeline and takes into
account the level of evidence according to American
Society of Clinical Oncology (ASCO) guidelines [9].
2.
PSADT before diagnosis
The usefulness of PSADT prior to diagnosis is
probably limited because assessment involves the
binary decision regarding whether or not to perform
biopsy rather than extracting prognostic data. A few
studies have evaluated the diagnostic ability of
PSADT and confer that although PSADT can predict
the presence of disease, it offers little improvement
beyond current methods in determining the need for
initial biopsy.
Raaijmakers et al examined 1689 men undergoing
biopsy in the screening arm of the European
Randomized Study of Screening for Prostate Cancer
[10]. PSADT was significantly different between
those with and without PCa (5.1 vs. 6.1 yr, p =
0.002). However, further analysis revealed PSA
kinetics conveyed little additional data in predicting
biopsy results. PSADT was marginally superior to
PSAV with an area under the curve of 0.573
compared to 0.549, but neither was significant on
multivariate analysis.
Spurgeon et al support these conclusions in a
study examining 1699 men with a PSA level of
<10 ng/ml undergoing biopsy, the majority of which
consisted of only six cores [11]. PSADT of 2–5 yr was
very weakly associated with a positive biopsy and
high-grade PCa (Gleason 7) and was not significant
when other variables were considered. The authors
cite data suggesting that biologic variation of PSA in
the treatment-naı̈ve prostate may reduce the accuracy of PSADT prior to definitive therapy.
On the other hand, PSADT may play a more useful
role following initial negative biopsy. Garzotto et al
Please cite this article in press as: Ramı́rez ML, et al., Current Applications for Prostate-Specific Antigen Doubling Time, Eur Urol
(2008), doi:10.1016/j.eururo.2008.04.003
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na
Yes
No
No
na
Yes
Yes
No
Yes (<12 mo)
No
Yes (36 mo)
No
retrospectively examined 373 patients undergoing
repeat biopsy and found that PSADT was the best
independent predictor for positive results among
other well-characterized predictors. The authors
suggest using PSADT to stratify patients into risk
groups predicting for high-risk disease (Gleason 7),
which should then ascertain the need for repeat
biopsy. Kaplan-Meier analysis demonstrated that
four risk groups could be characterized using PSADT,
PSA density, and the presence or absence of
high-grade prostatic intraepithelial neoplasia (PIN)
[12]. An update of these data with longer follow-up
indicates PSADT (>5 yr, 2–5 yr, and <2 yr) alone is
sufficient to categorize patients into low-, intermediate-, and high-risk groups, respectively [13].
3.
PSADT = prostate-specific antigen doubling time; na = not applicable (no pathologic specimen for evaluation).
Clinical stage (pathologic stage not applicable since treatment was radiotherapy).
b
T1 versus T2–T3.
*
Significance denotes p < 0.05.
a
99
56
62
86
Hanks et al [14]a
Goluboff et al [15]
Egawa et al [16]
Freedland et al [17]
T1–T3NXM0
T1–T2N0MX
T1–T3aN1MX
T1–T2N0MX
3
3
2 (4)
2 (4)
9
25
17
33
(2–48)
(2–83)
(6–74)
(12–98)
No
No
No
No
Noa
Yes
Yesb
No
na
No
No
No
Surgical
margin status
Seminal
vesicle
involvement
Extracapsular
extension
Pathologic
stage
Gleason
score
Median time
between PSA
determinations,
mo (range)
No. of PSA
determinations
per patient
(median)
Clinical
stage
n
Series
Table 1 – Studies examining pretreatment PSADT in predicting outcomes after definitive therapy
PSADT significantly* correlated with
Biochemical
recurrence
european urology xxx (2008) xxx–xxx
Prior to definitive treatment
Prior to definitive treatment, PSADT has been sought
to provide information on the aggressiveness of PCa
in order to predict treatment outcomes and aid in
treatment selection, but data are controversial
and inadequate for supporting its use in patients
requiring definitive therapy. Studies examining
the potential correlation between pretreatment
PSADT and pathologic features have yielded mixed
results regarding Gleason score, extracapsular
extension, and surgical margins status (Table 1)
[14–17]. Although most of these studies support a
correlation between PSADT and pathologic stage,
incorporating pretreatment PSADT into current
methods of clinical staging has not been reported
to increase the accuracy of predictive models.
In addition, investigators have hypothesized that
pretreatment PSADT can predict biochemical recurrence following definitive therapy; however, these
results are also conflicting and cannot confirm that
PSADT is a reliable prognostic factor, most likely
because outcomes are strongly influenced by the
treatment given (Table 1). Unfortunately, these
investigations are limited by their retrospective
nature, small study populations, short follow-up
time, interassay variability, and inconsistency in
operator techniques. Discrepancies in patient populations, progression criteria, and PSADT calculations
may account for varied results.
Alternatively, active surveillance has emerged
as a reasonable option for many patients with
clinically insignificant disease, and PSADT may play
a pivotal role in identifying tumor progression, that
is, an increase in Gleason grade or in the extent of
disease, while these cancers still remain curable.
In an investigation by McLaren et al, a cohort of
113 patients with mostly T1–T2 disease were
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followed with active surveillance for a median of
21 mo [18]. Analysis of PSA progression revealed
that PSADT predicted for clinical progression
( p < 0.0001), stage progression ( p = 0.01), and time
to treatment ( p = 0.0001). In fact, 50% of patients with
a PSADT <18 mo progressed within 6 mo. Overall
survival rates at 2 and 5 yr were 92% and 68%,
respectively, with no recorded cancer-specific
deaths.
In a prospective study conducted by Klotz et al, 299
patients with a PSA level <15 ng/ml, Gleason 3+4,
and T 2b were followed with active surveillance [19].
Selective delayed intervention was initiated if the
cancer progressed clinically, histologically, or by PSA
analysis: PSADT < 2 yr, final PSA > 8 ng/ml, and an
increase in PSA over time yielding p < 0.05 on
regression analysis. At 8 yr, overall survival was
85% and disease-specific survival was 99.3%. Notably,
the two patients who died of PCa did so within 5 yr
and had a PSADT < 2 yr, suggesting the presence of
occult metastasis at the time of diagnosis. Moreover,
of the 24 patients who underwent RP for PSADT < 2
yr, 66% had stage T3 disease.
Although studies conclude PSADT is useful in
determining which patients on active surveillance
are at high risk for progression, the indication for
treatment remains controversial. Definitions of
rapid versus slow doubling times differ among
studies, and PSADT levels can vary considerably
[20]. As opposed to the common 2-yr cut-off,
others, including the European Randomized Study
of Screening for Prostate Cancer, have found
pretreatment PSADT < 4 yr to be associated with
a higher risk of disease progression [21]. Notably, a
recent abstract revealed that although PSADT > 18
mo predicted for 10-yr systemic progression-free
survival in a cohort of 2296 men, it had less
predictive power as Gleason score increased [22].
Moreover, others have revealed that an accurate
PSADT calculation may depend on the number and
timing of PSA measurements and can therefore be
of consequence in obtaining significant results [2].
Despite these uncertainties, the clinical use of
PSADT has become more common [23], and is, to
date, one of the best markers for advancing disease
in the active surveillance population. Certainly, in
weighing options for intervention one must consider the entire picture of progression, as well as
patient preferences and risks associated with treatment. Clinically, National Comprehensive Cancer
Network (NCCN) guidelines for active surveillance,
which suggest PSADT < 3 yr to indicate cancer
progression, can give practitioners additional information for counseling patients and deciding on
further treatment [24].
4.
Following PSA relapse
4.1.
Before salvage therapy
5
Approximately one third of patients who undergo
definitive therapy for PCa will have a detectable
increase in PSA within 10 yr [25]. However, PSA
values vary markedly, as does the rate of clinical
progression, and biochemical recurrence may not
exactly reflect PCa mortality. Recently, PSADT has
been shown to facilitate the evaluation of treatment
modalities, type of tumor relapse, and cancerspecific survival (CSS) by allowing comparison at
an earlier end point than observable disease
manifestation.
In the early 1990s, PSADT was recognized by
numerous authors to correlate with the time to
develop clinical failure [7,14], and subsequent data
described PSADT as a predictor for disease relapse,
as well as type of disease relapse, after definitive
radiotherapy failed [26–28]. Considerable retrospective data reveal that a significantly greater number
patients with PSADT > 6 mo experience local failure
as opposed to metastatic failure, whereas those with
PSADT < 6 mo are more likely to exhibit metastatic
failure. Likewise, multiple large studies have found
PSADT to be a significant risk factor for clinical
progression on multivariate analysis and indicative
of the pattern of clinical recurrence after RP (Table 2)
[29,30]. Furthermore, Okotie et al demonstrated that
men with PSADT < 6 mo were at increased risk of
having a positive bone scan ( p = 0.007) or computed
tomography scan ( p = 0.017) compared to men with
longer PSADT and recommend incorporating PSADT
as a factor determining the need for bone scintigraphy after PSA recurrence [31].
These data suggest those with a shorter PSADT
harbor existing distant metastases best suited to
systemic treatment, whereas a longer PSADT may
represent another source or a slow-growing process
to which delayed or local therapy may be more
appropriate. Recent studies add substantial evidence in favor of this hypothesis [28,32,33]. Pinover
demonstrated that post-EBRT patients treated with
ADT developed distant failure later than untreated
patients if PSADT was <12 mo ( p = 0.02), but in
corresponding treatment groups with longer PSADT
there was no difference in the 5-yr freedom from
distant metastasis rate ( p = 0.74) [28]. Leventis et al
examined predictors of response to salvage EBRT
after RP in 49 men with local recurrence [32]. In
multivariate analysis, they found PSADT to be a
significant independent predictor, with values
<11.8 mo reflecting poor response to radiation
( p = 0.025). In a multicenter analysis of 501 patients,
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(2008), doi:10.1016/j.eururo.2008.04.003
EURURO-2517; No of Pages 12
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0.003
0.012
<0.001
Local
Distant
Local
Distant
Local
Distant
PSADT = prostate-specific antigen doubling time; RP = radical prostatectomy; EBRT = external-beam radiation therapy.
Mean value.
y
Median value.
z
All values taken within a 15-mo period.
*
Every 2 mo (year 1),
every 4 mo (year 2),
semiannually (years 3–5),
and annually thereafter
6–18 (median 12)
5.7 (4–9)y
EBRT
Crook et al [27]
118
>4
3 (0.9–7.3)y
EBRT
Sartor et al [26]
400
2 (1.59/yr)
RP
Roberts et al [30]
879
4.7 (0.5–11)*
Every 3–6 mo
6
<6
6.0–12.0
<6.0
12.6y
5.2y
<0.001
Distant
<10
Every 3 mo (year 1),
semiannually (year 2),
and annually thereafter
Not specifiedz
2
5.3 (0.5–15)*
315
RP
Pound et al [29]
No. of PSA
determinations
per patient
Follow-up, yr
(range)
n
Treatment
type
Series
Table 2 – Posttreatment PSADT as a prognostic factor for clinical failure
Time interval
between PSA
determinations
PSADT, mo
Type of
failure
p
european urology xxx (2008) xxx–xxx
Stephenson et al found similar results using a cutoff of 10 mo; however, some men with rapid PSADT
or high-grade disease (or both), specifically those
with positive surgical margins, benefited from
salvage radiotherapy [33]. In these patients, PSADT
may not directly reflect metastatic disease as in
patients with negative surgical margins, but rather
aggressive residual pelvic disease where early local
salvage therapy may prevent future metastases.
Although it is important to note that not all men
with rapid PSADT will progress, PSADT may be
specific enough to effectively predict patient outcome. Several recent studies have characterized
PSADT < 12 mo as an unfavorable prognostic variable for mortality [34]. Furthermore, stratification of
1064 patients following RP into high-, intermediate-,
and low-risk groups according to PSADT has yielded
significant differences in clinical progression and
mortality among those with PSADTs of <1.0 yr, 1.0–
9.9 yr, and 10 yr [35]. Specifically, those at high risk
had a higher incidence of local and systemic
progression as well as death compared to both the
intermediate- and low-risk groups.
In addition, PSADT was the strongest predictor of
PCa mortality after biochemical failure in a preliminary study of 379 patients by Freedland et al [36].
They established PSADT < 15 mo was significantly
associated with mortality, with PSADT < 3 mo
indicating a very high risk of death, similar to other
data [3]. In a follow-up study of the same cohort,
shorter PSADT remained correlated to cancerspecific and all-cause mortality ( p < 0.001), and
PSADT subdivided risk groups of <3 mo, 3–8.9 mo,
and 9.0–14.9 mo paralleled the prior analysis [37].
After PSADT stratification, 100% of deaths were due
to PCa in those with PSADT < 3 mo, 92% of deaths in
those with PSADT < 9 mo, and 78% of deaths with
PSADT 9.0–14.9 mo, but PCa accounted for only 35%
of deaths in patients with PSADT 15 mo.
Despite the prognostic power of PSADT following
definitive treatment, a question remains as to
whether PSADT is valuable as a surrogate end point
for CSS. Valid assessment, according to Prentice’s
criteria, must meet four specific conditions (Table 3).
Although D’Amico et al claim posttreatment
PSADT < 3 mo satisfies these criteria [3], an analysis
of a phase 3 clinical trial of 1514 men with locally
advanced PCa determined PSADT supports, but is not
completely consistent with, a true end point [38]. In
this investigation Valicenti et al evaluated prospective, randomized data from patients treated with
radiation and ADT and demonstrated that treatment was not prognostic for PSADT < 3 mo. A
possible explanation may be the relatively small
number of patients in this subgroup in whom
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Table 3 – Prentice’s criteria for the use of PSADT as a
surrogate end point
Treatment is prognostic for prostate cancer-specific survival
(true end point)
Treatment is prognostic for PSADT (surrogate end point)
PSADT is prognostic for prostate cancer-specific survival
The full effect of treatment on prostate cancer-specific
survival is explained by PSADT
PSADT = prostate-specific antigen doubling time.
treatment failed; however, it may be that such a
short PSADT is associated with uncompromising
disease, which necessitates more aggressive therapy to detect a significant difference. Nevertheless,
the fact that three criteria were met with PSADTs of
<6 mo, <9 mo, and <12 mo and that the fourth
criteria was not met by only a narrow margin
substantiates the predictive power of PSADT.
Recently, Stephenson et al developed an internally
validated nomogram that may be clinically useful to
predict progression-free survival at 6 yr in patients
undergoing salvage radiotherapy for biochemical
recurrence after RP [39]. Using Cox regression
analysis, they determined significant predictors of
disease progression in a multi-institutional cohort
of 1540 patients and used these parameters (including PSADT < 10 mo) to provide a more accurate
model of cancer relapse (c-index = 0.69). Finally,
NCCN treatment guidelines for salvage radiation
suggest patients with a relapse PSADT of >10 mo are
more likely to benefit from therapy.
4.2.
Following salvage therapy, but before AIPCa
PSADT may also have a role in determining the
timing of hormonal therapy after biochemical
progression. In a large observational study, Moul
et al revealed that there is a delay in the development of clinical metastasis if ADT is initiated early in
patients with high-grade disease (Gleason > 7)
or rapid PSADT (12 mo) following RP [40]. However,
in the overall cohort, early ADT did not affect clinical
outcome suggesting its use for high-risk patients
only. Longer follow-up and a randomized, controlled
study incorporating survival benefit are needed to
substantiate these data.
In patients treated with EBRT and subsequent
short-term ADT, PSADT has been found to be a
significant independent predictor of freedom from
distant metastasis rates, CSS, and overall survival
[41]. Sengupta et al expanded PSA stratification to
463 post-RP patients treated with adjuvant hormonal therapy and identified PSADT as a significant
independent predictor of recurrence-free survival
7
and CSS in both N+ and N0 disease [42]. Stewart et al
demonstrated 72% cancer-specific mortality by 7 yr
in patients with a pre-ADT PSADT of <3 mo and a
post-ADT PSA nadir >0.2 ng/ml, regardless of the
type of prior treatment and the use of ADT [43].
Notably, in a follow-up study of selected patients
with PSADTs of <6 mo, no significant difference in
the estimated time to cancer-specific mortality was
found between PSADTs of <3 mo and 3–6 mo [44].
These high-risk patients may harbor hormoneinsensitive micrometastases and would therefore
be ideal candidates for future therapeutic clinical
trials.
5.
PSADT after AIPCa
In the initial study of PSADT in patients with AIPCa,
Loberg et al found that PSADT had no independent
predictive value in AIPCa. However, the onset of AI
disease significantly shortened PSADT, suggesting
the emergence of more aggressive disease [45].
Subsequent investigations found PSADT may
continue to have predictive value for counseling
patients with AIPCa regarding survival. In a large
retrospective study by Oudard et al, data from
250 patients treated with chemotherapy revealed
stratification by 45 d was a significant predictor of
death on multivariate analysis [46]. Patients with a
PSADT of 45 d had a 26.4-mo median survival
compared to 16.5 mo in those with shorter PSADTs.
Daskivich et al calculated PSADTs at the emergence
of AIPCa and found PSADTs of 12 wk predicted for
decreased overall survival in multivariate analysis
[47]. Multiple articles have confirmed these results
although the optimal cut-off point for PSADT varies
among different patient populations. In addition,
Svatek et al developed a nomogram to estimate the
risk of mortality in patients with AIPCa not yet
exposed to chemotherapy [48]. PSADT is the first
stratifying variable in their model because it was
found to be the strongest prognostic predictor in
their cohort of 129 patients. Most at risk were men
with a PSADT of <6 mo; however, the nomogram
allows for evaluation on a continuous PSADT axis
with additional statistical analysis demonstrating
80.9% accuracy.
PSADT may also predict response to therapy and
therefore serve as a convenient tool for risk
stratification during clinical trial design [49]. Shulman et al studied 36 patients with AIPCa treated
with deferred antiandrogens [49]. Twelve responded
with an average pretreatment PSADT of 12.7 mo
compared to 7.5 mo in non-responders. PSADT was
the only significant predictor of response ( p = 0.037).
Please cite this article in press as: Ramı́rez ML, et al., Current Applications for Prostate-Specific Antigen Doubling Time, Eur Urol
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european urology xxx (2008) xxx–xxx
An analysis by Schmid et al of men with AIPCa
subsequently treated with chemotherapy revealed
significant differences in PSADT between those who
had partial remission or stable disease and those
experiencing progressive disease ( p = 0.002) [50].
Although PSADT did not strictly meet criteria for a
surrogate end point, this study promotes its use as a
potential auxiliary end point until a prospective
trial with survival as a primary end point is
conducted.
6.
Conclusions
Many of the limitations of PSA measurement are due
to the unreliability of a single measurement to
provide useful data. In contrast, PSA kinetics
provides a more dynamic picture of PCa activity.
There is increasing emphasis on using multiple PSA
measurements over time for PCa detection and in
monitoring progression, and NCCN treatment
guidelines for expectant management and salvage
therapy now incorporate PSADT [24].
Before diagnosis, PSADT has not been shown to
be of additional value to current screening and
diagnostic methods. However, it may be helpful in
determining which patients with initial negative
biopsy actually harbor prostate cancer.
Prior to definitive therapy, PSADT usefulness is
limited by the inherent biologic variability of PSA
from the intact prostate. Alternate methods for
calculating PSADT may partially compensate, but
this has yet to be demonstrated. Only until pretreatment PSADT is proven to have a greater
predictive power than PSA alone should it be
implemented in clinical practice. Nevertheless,
accumulating evidence indicates that men who
have a continual rise in PSA are more likely to have
disease progression, and if the rise is rapid, prognosis is more ominous. Therefore, PSADT, in
combination with other variables, may be useful
in risk stratification, although parameters for
observation and intervention are the subject of
controversy.
After definitive therapy, PSADT is an important
determinant of the presence and pattern of disease
recurrence, but optimal thresholds are still to be
established. Certainly those with a short PSADT
represent clinically important disease that should
be treated aggressively, but for the majority of
patients, those with longer doubling times, the
benefits of therapy need to be better defined. Most
likely, levels reflect a continuum of degree of risk
without exact cut-off points. Given the heterogeneity that exists within each stage of PCa,
management should be dictated by a combination
of variables, PSADT being a highly reliable predictor.
Following ADT, PSADT maintains its value as a
significant prognostic indicator and is now being
included in nomograms for this patient subset. It is
possible that PSADT is also a predictor for certain
therapies in the AI setting, as well as a suitable
criterion in selecting patients for new therapeutic
clinical trials.
Finally, the use of PSADT as a surrogate for
CSS has not yet been confirmed, but because
data are promising and other applicable end points
are lacking to evaluate the often extended course
of PCa, many short-term trials are alternatively
using PSADT. Prospective, randomized trials and
meta-analysis to determine optimal cut-off points
in the above-listed categories could improve
validity and bring clarity to conflicting data in
the literature.
Conflicts of interest
The authors have nothing to disclose.
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(2008), doi:10.1016/j.eururo.2008.04.003
EURURO-2517.1; No of Pages 12
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Editorial Comment on: Current Applications for
Prostate-Specific Antigen Doubling Time
Matthew Frank O’Brien
Urologic Oncology, Urology Service,
Department of Surgery, Memorial Sloan-Kettering
Cancer Center, 1275 York Ave, New York,
NY 10065, USA
[email protected]
The search for new and better prostate cancer
biomarkers is ongoing. Prostate-specific antigen
(PSA) remains the best marker for detection,
prognostication, and monitoring of prostate cancer. This report by Ramı́rez et al [1] reviews the
literature pertaining to the use of PSA Doubling
Time (PSADT) across the disease spectrum of
prostate cancer.
PSADT has been demonstrated to be associated
with outcome in the post radical prostatectomy
setting [2] but the role of PSADT in a patient with a
prostate in situ has still to be clarified. The
authors state in their conclusion that ‘‘Only when
pretreatment PSADT has been demonstrated to
add significantly to the predictive ability of PSA
[45]
[46]
[47]
[48]
[49]
[50]
vation therapy in patients with rapidly rising prostatespecific antigen levels after local therapy for prostate
cancer. Cancer 2006;107:514–20.
Loberg RD, Fielhauer JR, Pienta BA, et al. Prostate-specific
antigen doubling time and survival in patients with
advanced metastatic prostate cancer. Urology 2003;
62(Suppl 1):128–33.
Oudard S, Banu E, Scotte F, et al. Prostate-specific antigen
doubling time before onset of chemotherapy as a predictor of survival for hormone-refractory prostate cancer
patients. Ann Oncol 2007;18:1828–33.
Daskivich TJ, Regan MM, Oh WK. Distinct prognostic role
of prostate-specific antigen doubling time and velocity at
emergence of androgen independence in patients treated
with chemotherapy. Urology 2007;70:527–31.
Svatek R, Karakiewicz PI, Shulman M, Karam J, Perrotte
P, Benaim E. Pre-treatment nomogram for disease-specific survival of patients with chemotherapy-naive
androgen independent prostate cancer. Eur Urol 2006;
49:666–74.
Shulman MJ, Karam JA, Benaim EA. Prostate-specific antigen doubling time predicts response to deferred antiandrogen therapy in men with androgen-independent
prostate cancer. Urology 2004;63:732–6.
Schmid H-P, Morant R, Bernhard J, Maibach R. Prostate
specific antigen doubling time as auxiliary end point in
hormone refractory prostatic carcinoma. Eur Urol
2003;43:28–30.
alone should it be incorporated into clinical
practice.’’ This is a very important statement
because only when the prostate has been
removed and there is no contribution of PSA by
benign tissue may PSADT truly have a significant
contribution.
The method of calculation of PSADT remains
controversial, and this paper reports that although
PSADT and PSA velocity are derived from the same
data, PSADT is independent of baseline PSA.
However, Riffenburgh et al [3] demonstrate by
simple mathematics that PSADT is a simple
manipulation of PSA velocity and is dependent on
all PSA measurements used in the calculation.
Hence, the use of PSA kinetics in active surveillance
as a trigger point for intervention is questionable,
unless the absolute PSA value is not also a trigger
point because they both contain the same information. Furthermore, the timing and numbers of PSA
measurements used may affect study results.
The role of PSADT across the spectrum of
prostate cancer has yet to be defined completely.
The take home message from this paper should be
that PSADT may well have a role in predicting
Please cite this article in press as: Ramı́rez ML, et al., Current Applications for Prostate-Specific Antigen Doubling Time, Eur Urol
(2008), doi:10.1016/j.eururo.2008.04.004
EURURO-2517.2; No of Pages 12
european urology xxx (2008) xxx–xxx
outcome. However, PSADT must improve the
predictive ability of a current outcome prediction
model for it to be incorporated into clinical
practice.
References
[1] Ramı́rez ML, Nelson EC, deVere White RW, Lara Jr PN,
Evans CP. Current applications for prostate-specific antigen doubling time. Eur Urol. In press. doi:10.1016/j.
eururo.2008.04.003.
Editorial Comment on: Current Applications for
Prostate-Specific Antigen Doubling Time
Axel Semjonow
Prostate Center, Department of Urology,
University Clinic Münster, Münster, Germany
[email protected]
Ramı́rez et al’s review paper has been well
researched and clearly documents the advantages
and disadvantages of prostate-specific antigen
(PSA) doubling time [1].
Prostate cancer is found in a significant number
of men with PSA levels lower than the traditional
cutoff, which has led to recommendations for
decision points much lower than 4 ng/ml [2]. The
number of indolent cancers found using lower
decision points may increase, but this result could
possibly be avoided with the use of PSA doubling
time or PSA velocity.
It should be considered that a short period of
monitoring for calculation of PSA doubling time or
velocity may not generate reliable information
because of factors such as biological intraindividual variability or differences in the assays used.
Biological variability has been reported to be
approximately 20% if only one PSA measurement
is taken into consideration. In addition, analytical
variability of modern PSA assays accounts for
another 5% of variability [3]. Using different PSA
assays, variation in a sample can be greater than
the reported velocity change for diagnosing prostate cancer of 0.5 or 0.75 ng/ml per year [4,5].
There have been many reports of the active
surveillance of prostate cancer patients that
11
[2] Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after
PSA elevation following radical prostatectomy. JAMA
1999;281:1591–7.
[3] Riffenburgh RH, Amling CL. Use of early PSA velocity to
predict eventual abnormal PSA values in men at risk for
prostate cancer. Prostate Cancer Prostatic Dis 2003;6:
39–44.
DOI: 10.1016/j.eururo.2008.04.004
DOI of original article: 10.1016/j.eururo.2008.04.003
depend on PSA dynamics; therefore, treatment
decisions will be subject to the same issues
mentioned above.
A method is urgently needed to safely identify
patients with prostate cancer who could avoid
radical intervention.
References
[1] Ramı́rez ML, Nelson EC, deVere White RW, Lara PN Jr,
Evans CP. Current applications for prostate-specific antigen doubling time. Eur Urol. In press. doi:10.1016/
j.eururo.2008.04.003.
[2] De Angelis G, Rittenhouse HG, Mikolajczyk SD, Shamel
LB, Semjonow A. Twenty years of PSA: from prostate
antigen to tumor marker. Rev Urol 2007;9:113–23.
[3] Sölétormos G, Semjonow A, Sibley PE, et al. Biological
variation of total prostate-specific antigen: a survey of
published estimates and consequences for clinical practice. Clin Chem 2005;51:1342–51.
[4] Semjonow A, Brandt B, Oberpenning F, Roth S, Hertle L.
Discordance of assay methods creates pitfalls for the
interpretation of prostate-specific antigen values. Prostate Suppl 1996;7:3–16.
[5] Stephan C, Klaas M, Müller C, Schnorr D, Loening SA,
Jung K. Interchangeability of measurements of total and
free prostate specific antigen in serum with 5 frequently
used assay combinations: an update. Clin Chem 2006;
52:59–64.
DOI: 10.1016/j.eururo.2008.04.005
DOI of original article: 10.1016/j.eururo.2008.04.003
Please cite this article in press as: Ramı́rez ML, et al., Current Applications for Prostate-Specific Antigen Doubling Time, Eur Urol
(2008), doi:10.1016/j.eururo.2008.04.005
EURURO-2517.3; No of Pages 12
12
european urology xxx (2008) xxx–xxx
Editorial Comment on: Current Applications for
Prostate-Specific Antigen Doubling Time
Andrea Gallina
Department of Urology, Vita-Salute University,
Milan, Italy
[email protected]
Pierre I. Karakiewicz
Cancer Prognostics and Health Outcomes Unit,
University of Montreal Health Center, Montreal,
QC, Canada
[email protected],
[email protected]
Prostate-specific antigen doubling time (PSADT)
holds great promise for the prediction of cancer
characteristics, such as stage and probability of
progression before the delivery of definitive therapy [1–4]. Similarly, PSADT appears to have the
ability to predict the probability of prostate cancer
(PCa) diagnosis, especially after a previously
negative biopsy. Moreover, PSADT was shown to
predict progression towards lethal PCa phenotypes
after radiation or surgery. Finally, PSADT represents one of the most powerful predictors of
PCa-specific mortality in men with androgeninsensitive prostate cancer (AIPC) [5]. PSADT
calculators are available at several PCa-oriented
Web sites, such as the MSKCC site (www.nomograms.org) or the University of Montreal site
(www.nomogram.org). The PSADT calculators
allow the clinician to define the PSADT value of
the individual patient at a given time. This metric
showed promise as an independent predictor of
cancer outcomes at different stages of the natural
history of treated prostate cancer. Unfortunately,
the current reports which showcase the value of
PSADT might at times be difficult to interpret and
even more difficult to implement. The problem
relates to different PSADT cut-offs that are suggested as ‘‘ideal’’ predictors of unfavorable outcome. As a result, the clinician might not be able to
derive the full benefit of the information contained
within this powerful marker. Svatek et al circumvented the problem related to the interpretation of
various PSADT cut-offs and integrated PSADT
within a prognostic nomogram for men with AIPC
[5]. Of all predictors, PSADT was the most infor-
mative, and accomplished its prognostic role for
prediction of PCa-specific mortality in noncategorized format. Svatek et al demonstrated that this
powerful predictor can result in most accurate
predictions and can yield the best calibration,
when it was combined with three other informative and significant variables [5]. Most importantly,
these researchers proved that PSADT can be used
to provide individualized predictions, which can be
easily interpreted (prognosis expressed as a probability from 0–100% of dying from PCa at different
time points) and can be equally easily accessed by
patients and/or physicians (www.nomogram.org).
Hopefully, more researchers will reexamine their
valuable findings and will attempt to integrate
PSADT within prognostic models capable of providing evidence-based, individualized prognostic
information. Such measures would certainly result
in much wider use of PSADT and would possibly
improve patient care.
References
[1] Ramı́rez ML, Nelson EC, deVere White RW, Primo N, Lara
Jr PN, Evans CP. Current applications for prostatespecific antigen doubling time. Eur Urol. In press.
doi:10.1016/j.eururo.2008.04.003.
[2] Maffezzini M, Bossi A, Collette L. Implications of prostate-specific antigen doubling time as indicator of failure
after surgery or radiation therapy for prostate cancer.
Eur Urol 2007;51:605–13.
[3] Yossepowitch O, Bianco Jr FJ, Eggener SE, Eastham JA,
Scher HI, Scardino PT. The natural history of noncastrate metastatic prostate cancer after radical prostatectomy. Eur Urol 2007;51:940–8.
[4] Studer UE, Collette L, Whelan P, et al. Using PSA to guide
timing of androgen deprivation in patients with T0–4
N0–2 M0 prostate cancer not suitable for local curative
treatment (EORTC 30891). Eur Urol 2008;53:941–9.
[5] Svatek R, Karakiewicz PI, Shulman M, Karam J, Perrotte P,
Benaim E. Pre-treatment nomogram for diseasespecific survival of patients with chemotherapy-naive
androgen independent prostate cancer. Eur Urol 2006;
49:666–74.
DOI: 10.1016/j.eururo.2008.04.006
DOI of original article: 10.1016/j.eururo.2008.04.003
Please cite this article in press as: Ramı́rez ML, et al., Current Applications for Prostate-Specific Antigen Doubling Time, Eur Urol
(2008), doi:10.1016/j.eururo.2008.04.006