Review Articles

Prostate Specific Antigen Kinetics

in the Management of Prostate Cancer
Shomik Sengupta,* Christopher Amling,† Anthony V. D’Amico* and Michael L. Blute*,‡
From the Department of Urology, Mayo Clinic, Rochester, Minnesota (SS, MLB), Department of Urology, University of Alabama,
Birmingham, Alabama (CA), and Department of Radiation Oncology, Brigham and Women’s Hospital, and the Dana Farber Cancer
Institute, Harvard Medical School, Boston, Massachusetts (AVD)

Purpose: We review the usefulness of prostate specific antigen kinetics (ie prostate specific antigen velocity and doubling
time) in the treatment of patients with prostate cancer.
Materials and Methods: The MEDLINE database was searched to identify studies investigating prostate specific antigen
kinetics in patients with prostate cancer.
Results: Various techniques are available for estimating prostate specific antigen kinetics, but to minimize the impact of prostate
specific antigen variability on such calculations at least a 90-day period and preferably more than 2 measurements should be used.
There is little to suggest which measure of prostate specific antigen kinetics may be superior since both appear to provide useful
prognostic information. Prostate specific antigen velocity is easier to calculate but prostate specific antigen doubling time may have
greater biological justification. Retrospective studies show that before treatment prostate specific antigen kinetics provide
prognostic information regarding the risk of treatment failure and subsequent death from cancer. Additionally, in patients treated
surgically preoperative prostate specific antigen kinetics predict the risk of adverse pathology, while in those undergoing
conservative treatment prostate specific antigen kinetics are associated with the risk of progression and need for intervention. In
patients with biochemical failure after therapy prostate specific antigen kinetics predict the risk and potential site of clinical
recurrence, the likely response to salvage therapy, and the risk of death from cancer. Preliminary assessments also suggest that
prostate specific antigen kinetics may serve as a surrogate end point to replace cancer specific mortality.
Conclusions: Although prospective studies are lacking, the current literature suggests that prostate specific antigen kinetics
provide valuable prognostic information, and should be further evaluated in clinical decision making and as a surrogate end
point for future trials.

Key Words: prostatic neoplasms, prostate-specific antigen, prostatectomy, radiotherapy, survival

ince its advent in clinical practice in the 1980s, PSA with time. PSAV was originally described by Carter et al based

S has had a significant impact on the management of

prostate cancer. Most notably, by allowing the early
detection of asymptomatic disease it has been responsible
for the stage migration of prostate cancer during the last 2
decades. Additionally, serum PSA has become indispensable
for prognostication and surveillance.
However, PSA remains an imperfect test. In the diagnos-
tic setting noncancerous causes of PSA increase such as
benign hypertrophy or inflammation of the prostate fre-
quently confound the clinical picture. Prostate cancers of
widely disparate biology may present with comparable
PSAs, thus, undermining the prognostic reliability of a sin-
gle PSA measurement. Given the prolonged natural history
of prostate cancer, the implications of changes in serum PSA
after therapy are often unclear on short-term followup.
A way to overcome some of the limitations of PSA testing
has been to examine PSA kinetics or the rate of PSA change
Submitted for publication April 22, 2007.
* Nothing to disclose.
† Financial interest and/or other relationship with Johnson &
Johnson, TAP Pharmaceuticals and Sanofi-Aventis.
‡ Correspondence: Department of Urology, Mayo Clinic, 200 First
St. SW, Rochester, Minnesota 55905 (telephone: 507-284-3987;
FAX: 507-284-4987; e-mail: Blute.Michael@mayo.edu).
on the Baltimore Longitudinal Study of Aging.1 Subsequently
PSADT was described by Schmid et al and was studied exten-
sively in patients treated with radiotherapy for prostate can-
cer.2 An increasing body of work suggests that these 2 mea-
sures of PSA kinetics may be useful in managing prostate
cancer. We review the available data related to PSAV and
PSADT in various clinical settings. It is notable that the liter-
ature on PSA kinetics is largely retrospective, resulting from
the fact that PSA kinetic data are easier to interpret after a
number of measurements have been collected. In contrast, as
new PSA readings are obtained in clinical practice, it may be
difficult to discern changes reflecting cancer behavior from
those reflecting confounding processes such as inflammation.
PSA KINETIC
PARAMETERS: ESTIMATION AND ERROR
Because PSAV and PSADT are measures of the rate of PSA
change with time, their estimation relies on the statistical
Editor’s Note: This article is the first of 5 published in
this issue for which category 1 CME credits can be
earned. Instructions for obtaining credits are given
with the questions on pages 1208 and 1209.

0022-5347/08/1793-0821/0 821 Vol. 179, 821-826, March 2008

THE JOURNAL OF UROLOGY® Printed in U.S.A.
Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.10.023
822 PROSTATE SPECIFIC ANTIGEN KINETICS AND PROSTATE CANCER
technique of regression. The calculation of PSAV is based
on the assumption that PSA increases in a linear fashion with
time and, therefore, uses linear regression analysis. In practice
this translates into a fairly simple slope calculation of the
formula, PSAV ⫽ change in PSA/time between measurements.
If more than 2 PSA readings are available PSAV may simply
be averaged. For example, for 3 PSA measurements, PSAV ⫽
[{(PSA2 – PSA1)/interval1} ⫹ {(PSA3 – PSA2)/interval2}]/2.
In contrast, PSADT assumes an exponential increase in
PSA and, therefore, requires a somewhat more complex
analysis for estimation. Regression techniques for the esti-
mation of PSADT require the logarithmic transformation of
available PSA values by the somewhat daunting formula,
PSADT ⫽ t ⫻ natural log2/natural log (ratio of PSAs). In
practice the calculation of PSADT requires the use of statis-
tical software or online algorithms, although a recently pub-
lished graphical tool allows the estimation of PSADT in
practice settings without electronic resources.3
The measurement of serum PSA is susceptible to error
from several sources, most notably from interassay and bi-
ological variations, and a number of precautions are re-
quired to minimize the impact of such errors on estimates of
PSA kinetics. Thus, sequential PSA readings should ideally
be obtained from the same laboratory using a well calibrated
assay. Furthermore, the greater the number of PSA mea-
surements used and the longer the interval during which
they are obtained, the more likely it is that the resulting
estimate of PSA kinetics truly reflects cancer growth.
However, the need for expedient decision making and the
costs of repeat PSA testing usually place practical limits on
the number and spacing of available PSA measurements.
Additionally, since cancer biology may evolve, leading to
variation in PSA kinetics with time, it seems prudent to
restrict PSA kinetic assessments to a maximum of 12 to 24
months.4 Two PSA readings separated by at least 3 months
appear to provide a reasonably accurate estimate of PSADT,
but a minimum of 3 readings during at least 6 months
should be obtained when possible.
PSA KINETICS AND
CONSERVATIVE MANAGEMENT
Men with prostate cancer may be treated conservatively with
planned delayed intervention with curative AS or palliative
WW intent. Although serial PSA data are usually available for
men undergoing such conservative treatment, published re-
ports are few and somewhat difficult to interpret. Many studies
are retrospective, and include patients with a broad spectrum
of disease pathologies treated with AS and WW. While elderly
TABLE 1. Relationship of PSA kinetics to clinical features, risk of progression and need for intervention in patients
with prostate cancer treated conservatively
Hardie et al5 Stephenson et al6
No. pts 80 94
PSA kinetic PSADT PSADT
p Value:
Age NS NS
PSA 0.039 NS
T stage 0.036* 0.04
Biopsy grade NS NR
Progression DRE 0.019, biopsy 0.03
Time to treatment
* Multivariate analysis.
or frail patients treated conservatively because of limited life
expectancy may have intermediate to high risk tumors,
younger patients placed on AS protocols are usually selected on
the basis of low risk features. Not surprisingly, PSA is found to
increase relatively slowly in most of these patients with
PSADT longer than 10 years in the majority.
The rate of PSA increase appears to be related to the
aggressiveness of the prostate cancer as indicated by an
association with clinical stage, biopsy grade and initial
PSA,5,6 although these findings vary somewhat among se-
ries (table 1).7,8 Another difficulty in interpreting the pre-
dictive value of PSA kinetics in this setting is that since an
increase in PSA is often a trigger for intervention, men with
rapid PSA kinetics are over represented in the treated sub-
group, thus leading to selection bias. In fact, some active
surveillance protocols explicitly incorporate PSA kinetic
measures as criteria for intervention. For example, Choo et
al offer curative surgery to men under active surveillance
with a PSADT of less than 3 years.7
However, a number of other studies that did not formally
use PSA kinetics for decisions on intervention have reported
a significant association between PSA kinetics and the need
for intervention or time to intervention, thus providing sup-
port for this concept.9 –11 Furthermore, PSADT has been
shown to correlate with other measures of progression such
as DRE, repeat biopsy or bone scan.6,9 Finally, PSA kinetic
measures appear to be associated with the risk of death from
prostate cancer in men treated conservatively.12,13
Despite these findings doubts remain regarding the use-
fulness of PSA kinetic measures in an individual patient
given the wide variation and significant overlap.6 – 8 Addi-
tionally, variability in PSA kinetics with time is pronounced,
further complicating the application of these measures in
decision making during the conservative management of
prostate cancer. 4,8 Currently it seems sensible to incorpo-
rate PSA kinetics along with other criteria in AS and WW
protocols, although individualized rather than universal
cutoff points may be preferable.5
PSA KINETICS AND RADICAL PROSTATECTOMY
As serial PSA testing becomes more common, preoperative
PSA kinetic data are increasingly available for patients
treated surgically. Preoperative PSA kinetic measures are
associated with aggressive pathological features at prosta-
tectomy, including local and nodal stage, specimen Gleason
score, and involvement of surgical margins. Although early
studies suggested that preoperative PSA kinetics were not
predictive of postoperative outcomes, they were likely lim-
Choo et al7 Gerber et al8 McLaren et al9
134 49 113
PSADT PSAV PSADT
NS NS
NS NS
NS NS
NS NS
DRE ⬍0.01, clinical ⬍0.0001
⬍0.0001
 PROSTATE SPECIFIC ANTIGEN KINETICS AND PROSTATE CANCER 823

TABLE 2. Relationship of preoperative PSA kinetics with pathologic findings and survival in surgically treated patients
D’Amico et al14 Sengupta et al15 Patel et al16

No. pts 1,069 2,290 202

PSA kinetic PSAV PSAV ⫹ PSADT PSAV
p Value:
Stage ⬍0.05 ⬍0.0001 0.007
Grade ⬍0.05 ⬍0.0001 0.04
Pos surgical margin PSAV ⬍0.0001, PSADT NS 0.01
Survival* CSS ⬍0.001, OS ⬍0.01 CSS ⬍0.0001 RFS 0.03
* Multivariate analysis.

ited in power, and more recent series have confirmed preop-
erative PSA kinetics to be predictive of the risk of progres-
sion and death after radical prostatectomy (table 2).
D’Amico et al analyzed a cohort of 1,069 men who had
undergone serial PSA testing at the same laboratory before
surgery, and PSAV greater than 2.0 ng/ml per year was
associated with a significantly increased risk of death from
prostate cancer and from all causes.14 Sengupta et al com-
pared preoperative PSAV and PSADT, and reported that
PSADT was a stronger predictor of clinical recurrence or
death from cancer.15 Preoperative PSA kinetics do not ap-
pear to simply be surrogate markers for conventional clini-
cal or histological indicators of aggressive disease, since the
prognostic value of PSA kinetics persists on multivariate
analysis.14 –16 The inclusion of PSA kinetics causes preoper-
ative PSA to drop out of multivariate models, suggesting
that the rate of increase may be more important prognosti-
cally than the absolute PSA value.15
In the postoperative setting, since all PSA producing
tissue has been removed, serum PSA is expected to be un-
detectable. Although a detectable PSA is taken to be pre-
sumptive evidence of cancer recurrence, only about a third of
these patients have clinically evident recurrence. Defining
recurrence by biochemical criteria remains controversial,
with various cut points used in the literature. It has been
reported that a PSA increase of less than 0.4 ng/ml was
rarely associated with further subsequent increases, sug-
gesting that this threshold is most appropriate. Stephenson
et al also found a PSA cutoff of 0.4 ng/ml to be associated
with subsequent PSADT and risk of metastasis.17
Even in patients with biochemical recurrence a subgroup
can be identified with slowly increasing PSA, delayed and
infrequent clinical recurrence, and low risk of death from
cancer who may be best treated conservatively.18 When clin-
ical recurrence is local, that is at the site of resection, salvage
therapy may be considered. When recurrence is systemic, pal-
liative hormonal therapy becomes most appropriate. PSADT
after recurrence is predicted by preoperative risk factors,
pathological findings and time to biochemical failure,19 and
these factors may help delineate the risk of metastatic vs local
recurrence.20 –23
Early studies suggested that the likely site of recurrence
may be predicted based on PSAV24 or PSADT25 after bio-
chemical recurrence. Subsequent reports have confirmed a
clear association between rapid PSA kinetics and the subse-
quent risk of metastatic recurrence (table 3). Recently an
association between PSA kinetics after recurrence and sur-
vival has been established, with a 5-year cancer specific
mortality of 31% vs 1% for patients with PSADT less than 3
months vs 3 months or greater,26 suggesting that PSADT
may be useful as a surrogate end point for cancer death.27
Notably, prostate cancer predominates as a cause of death in
men with PSA recurrence after surgery, even up to a PSADT
of 15 months.28 Additionally, in patients receiving salvage
radiotherapy PSA kinetics before radiation appear to be an
important prognostic factor,29 while high risk patients
treated with adjuvant hormonal therapy are most likely to
benefit if they have a rapid PSADT.30 Furthermore, in the
face of an increasing PSA while on hormonal therapy after
initial local therapy, PSA kinetic measures predict subse-
quent survival and may have some use in decision making
regarding additional therapy.31
PSA KINETICS AND RADIOTHERAPY
Data on PSA kinetics in patients treated with external or
interstitial radiation largely parallel those described in sur-
gically treated patients (table 4). Thus, Hanks et al found
the pretreatment PSADT and the radiation dose to be sig-
nificant multivariate predictors of biochemical recurrence-
free survival.32 Recently D’Amico et al reported that pre-
treatment PSAV greater than 2.0 ng/ml per year was
associated with an increased risk of biochemical recurrence,
death from cancer and death from any cause after external
beam radiation regardless of the risk group.33 Eggener et al
observed that a pretreatment PSAV cutoff of 2.0 ng/ml per
year is also predictive of biochemical outcomes after brachy-
therapy.34 D’Amico et al further reported that patients with

TABLE 3. Relationship of post-recurrence PSA kinetics and survival in surgically treated patients
Dotan et al20 Pound et al22 Roberts et al23 Zhou et al26

No. pts 1,997 2,809 NS

No. PSA recurrence 239 315 879 (587 with PSADT) 498
PSA kinetic PSAV PSADT PSADT PSADT
Association with survival (p value) Systemic PFS (⬍0.001) Systemic PFS (⬍0.001),
PFS (⬍0.001)*
Comments Bone metastasis PSADT less than 6 mos PSADT less than 3 mos predicts
(OR 0.93, p ⬍0.003)* predicts systemic prostate cancer specific
progression mortality (HR 54.9)
* Multivariate analysis.
824 PROSTATE SPECIFIC ANTIGEN KINETICS AND PROSTATE CANCER

TABLE 4. Relationship of pretreatment PSA kinetics with survival in patients treated with radiotherapy
Hanks et al32 D’Amico et al33 Eggener et al34 Eggener et al34

No. pts 99 358 83 47

Treatment External beam (dose NS) External beam (77 Gy) External beam (dose NR) Brachytherapy
PSA kinetic PSADT PSAV PSAV (greater than PSAV (greater than
2 ng/ml/yr) 2 ng/ml/yr)
Association with survival bRFS bRFS, CSS ⫹ OS (each p ⬍0.01) bRFS bRFS
Comments 50% bRFS at 18 mos in pts with Low risk ⫹ high risk groups 80% Vs 55% at 6 yrs 88% Vs 65% at 6 yrs
PSADT less than 12 mos

a rapid pretreatment PSAV benefit from the addition of
androgen deprivation to external beam radiation.35
PSA kinetics after radiation are confounded by the con-
tinuing production of PSA by the prostate, which is suscep-
tible to a number of influences. Thus, the concomitant use of
androgen deprivation and radiation often causes a with-
drawal effect, leading to more rapid PSA increases, which may
lead to misclassification of biochemical failure.36,37 In fact,
during the initial period after external beam radiotherapy,
PSA decreases and the negative PSA kinetics as well as the
PSA nadir appear to be prognostic of overall survival.38 After
interstitial seed placement the phenomenon of PSA bounce
may occur and cause confusion with early biochemical relapse.
In fact, the PSA kinetics for the 2 events appear to be similar,
and the time from therapy may be the most reliable distin-
guishing characteristic with bounces typically occurring earlier
than recurrence.39 PSADT after recurrence may also be useful
in classifying the likely site of recurrence in patients treated
with radiotherapy, with those with local relapse amenable to
salvage therapies.40 The success rate of salvage cryotherapy in
this setting also depends on PSADT before salvage.41
Zagars and Pollack,42 and Lee et al43 reported that
PSADT less than 8 months after relapse is associated with
the risk of metastatic disease and death from all causes in
patients treated with external beam radiotherapy alone42 or
in combination with androgen deprivation (table 5).43 Using
3-dimensional conformal intensity modulated radiation
therapy Zelefsky et al observed a similar relationship between
PSADT and metastatic recurrence.44 Cancer specific mortality
after external beam radiation for prostate cancer is strongly
associated with PSADT after recurrence, and is 75% vs 15% for
PSADT less than 3 months vs 3 months or greater in patients
with Gleason score greater than 7, and 35% vs 4%, respec-
tively, in those with Gleason score 7 or less.26 Similarly, for
patients treated with interstitial seed placement 10-year CSS
is 30% for patients with a PSADT of 6 months or less vs 98% for
those with a PSADT of more than 10 months.45
CLINICAL USE AND FUTURE DIRECTIONS
The application of PSA kinetic measures in clinical practice
is really no more than a formalization of serial PSA testing.
While regular PSA measurements for surveillance after
treatment have long been routine, it has recently become
more common in other clinical settings. Thus, many patients
now undergo repeat PSA screening before prostate cancer
diagnosis. The indication for prostatic biopsy in these patients
is typically an increase in PSA beyond a threshold level. How-
ever, controversy persists regarding the optimal PSA cutoff,
with emerging data indicating that the risk of prostate cancer
remains significant even with a nominally normal PSA.
It remains uncertain whether PSA kinetic measures are
likely to be helpful in this setting. In the prospective Pros-
tate Cancer Prevention Trial PSAV based on at least 2 PSAs
in 3 years was not a significant predictor of a positive end of
study biopsy.46 In contrast, short-term PSAV more than 2
months before biopsy was associated with the presence of
malignancy in patients with an abnormal PSA.47 It is also
notable that data from the Baltimore Longitudinal Study of
Aging revealed differences in PSAV years before prostate
cancer diagnosis.1 A problem with retrospective analyses of
the diagnostic value of PSA kinetics is that not all men
undergo biopsy, resulting in assignment bias.48 Further pro-
spective study of this issue is awaited, but in younger men
rapid unexplained increases in PSA, even in the normal
range, need to be viewed with concern.
For patients with a prostate cancer diagnosis PSA kinet-
ics appear to convey prognostic information that should be
considered with conventional prognostic factors such as ab-
solute PSA, clinical stage and biopsy grade. Although PSA
kinetics are of the greatest relevance immediately before
diagnosis, PSA velocity can provide prognostic information
years ahead.13 PSA kinetics are likely to be useful not only
in counseling patients regarding likely outcomes after treat-
ment, but also in suggesting experimental multimodal ther-

TABLE 5. Relationship of post-recurrence PSA kinetics with survival in patients treated with radiotherapy
Zagars and Pollack42 Lee et al43 Zelefsky et al44 Sartor et al40 Zhou et al26 Stock et al45

No. pts 841 621 1,650 399 NS 1,561

Treatment 60–78 Gy 76 Gy ⫹ ADT 64–81 Gy ⫾ ADT 70 Gy External beam, Brachytherapy ⫾
dose NS external beam ⫾ ADT
No. relapse 263 75 381 234 (increasing PSA) 661 131
PSA kinetic PSADT less than 8 mos PSADT PSADT PSADT PSADT PSADT
Association with sRFS Clinical RFS p ⬍0.001, sRFS ⫹ OS sRFS, local RFS CSS CSS
survival OS p ⫽ 0.015
Comments 93% Vs 46% at 7 yrs PSADT less than 6 Site of recurrence
mos vs greater
than 12 mos, HR
greater than 6.6
 PROSTATE SPECIFIC ANTIGEN KINETICS AND PROSTATE CANCER
apy protocols for those with aggressive disease. Finally, in
the context of AS protocols, PSA kinetic measures may be
crucial criteria for intervention, although precise cutoff lev-
els require further investigation.
Biochemical recurrence after treatment leads inevitably
to consideration of PSA kinetics in clinical decision making.
In this context, along with known pretreatment and post-
treatment prognostic factors, PSA kinetics may allow an
assessment of the probability of relapse and the likely site,
thereby facilitating rational decisions regarding the need for
and type of salvage therapy. For instance, it appears that for
men with biochemical recurrence after radical prostatec-
tomy or external beam radiation and a PSADT of less than
3 months, earlier initiation of hormonal therapy delays the
development of bony metastases, thereby improving quality
of life even if survival is not prolonged.27 This group of men
may also be usefully studied in randomized trials of systemic
chemotherapy such as docetaxel. Similarly for men with
metastatic prostate cancer PSA kinetic measures may be
used to guide the initiation of hormonal therapy and second-
ary intervention during the hormone refractory phase.49
In these clinical situations either measure of PSA kinet-
ics may be applied. There is empirical evidence that prostate
cancer biology does in fact conform to an exponential model
and, therefore, PSADT may be more accurate.2,50 This is
partially supported by the results of a large retrospective
study of PSA kinetics before prostatectomy.15 However, dur-
ing short intervals the linear and exponential curves closely
approximate each other and, therefore, PSAV provides a
satisfactory alternative that is usually easier to calculate.
Finally, it should be noted that PSAV and PSADT are re-
lated to each other and to serum PSA by the formula, PSAV ⬁
PSA/PSADT. In a linear model (constant PSAV) PSADT is
assumed to vary with PSA, and vice versa in an exponential
model (constant PSADT). In reality, for a particular cancer
in a particular man the exact pattern of PSA increase with
time may not conform exactly to either model, and which-
ever model is used ends up being an approximation.
Abbreviations and Acronyms
ADT ⫽ androgen deprivation therapy
AS ⫽ active surveillance
bRFS ⫽ biochemical RFS
CSS ⫽ cancer specific survival
DRE ⫽ digital rectal examination
NS ⫽ not statistically significant
NR ⫽ not reported
OS ⫽ overall survival
PFS ⫽ progression-free survival
PSA ⫽ prostate specific antigen
PSADT ⫽ PSA doubling time
PSAV ⫽ PSA velocity
RFS ⫽ recurrence-free survival
sRFS ⫽ systemic RFS
WW ⫽ watchful waiting
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