© The Canadian Journal of Urology™; 19(Supplement 1); October 2012
RehsiaAND Shayegan
30
or a control group. Men in the screening group were
invited for screening every 2 years until they reached
the study’s upper age limit (median 69 years, range
67-71
years), and only men with elevated PSA levels
were offered additional tests such as DRE and prostate
biopsies. The primary study endpoint was prostate-
cancer-specific mortality, analyzed according to the
intention-to-screen principle. Men with a PSA at or
above a certain threshold were invited for further
urologic work up; the threshold was 3.4 ng/mL from
1995-1998, 2.9
ng/mL from 1999-2004, and 2.5 ng/mL
from 2005 onward. At 14 years of followup, to prevent
one death from prostate cancer, the NNS was 293 and
the NNTwas 12. There are several reasons why results
from this study differed from those in the ERSPC
and PLCO studies. Patients were generally younger
(
average age 54 years) with a lower PSA threshold for
biopsy (originally 3.4 ng/mL, whichwas later lowered
to 2.5 ng/mL) and with less PSA pre-screening (3%).
1
In addition, this trial included 14 years of follow up
data, which provides mature, long term results.
The current Canadian Urological Association
guidelines
1
recommend that the risks and benefits of
prostate cancer screening must be discussed with the
patient, so that a shared decision can be made about
screening. Screening should be offered to all men 50
years old with at least a 10 year life expectancy. In
addition, men at higher risk of prostate cancer (such
as those of African descent or with a family history of
prostate cancer) should be offered earlier screening
at age 40.
PSA measurement
The usefulness of PSA as a screening tool to detect
and diagnose prostate cancer is subject to a number
of challenges. As previously mentioned, a number of
physiologic states besides prostate cancer may affect
the absolute level of serum PSA, and it is difficult
to determine a specific cutoff level above which a
prostate biopsy is necessary. The usefulness of PSAas
a diagnostic tool may be improved by using adjunctive
approaches, such as also measuring free PSA, PSA
density, PSA velocity, and age-adjusted PSA, or by
using 5-alpha reductase inhibitors (5-ARIs).
Adjusting PSA cutoffs according to age helps to
detect more cancers in younger patients and fewer
cancers in older men. Using a cutoff PSA velocity of
greater than 0.75 ng/mL/year when a patient’s PSAis
above 4 ng/mLmay improve the sensitivity of cancer
detection.
11
PSAdensity allows for adjustment of PSA
level according to prostate volume. A PSA density
greater than 0.15 ng/mL may be associated with an
increased risk of prostate cancer.
12
However, a PSA
density assessment is not as convenient as a simple
PSA test, since it requires transrectal ultrasonography
to accuratelymeasure the prostate volume. The use of a
ratio of free PSAto total PSAimproves PSAspecificity.
1
Men with higher ratios are more likely to have benign
disease.
5-
ARIs are known to decrease serumPSAlevels and
improve PSA kinetics.
13
The decrease in PSA levels by
5-
ARIs must be taken into account when judging the
significance of a PSA measurement. In the Prostate
Cancer Prevention Trial (PCPT), finasteride lowered the
PSA by 50% after 12 months of therapy, and therefore,
a multiplier of 2 was used as a criterion for biopsy.
14
Preliminary analyses of the Reduction by Dutasteride
of Prostate Cancer Events (REDUCE) trial also suggest
that dutasteride enhances the performance of PSA as a
diagnostic test for prostate cancer.
15
Anumber of nomograms can be used to help assess
the risk of prostate cancer. These risk assessment tools
take into account variables such as DRE, PSA, PSA
velocity, PSA isoforms, age, race, family history of
prostate cancer, and genetic data to determine a man’s
risk of prostate cancer and the risk of biologically
significant disease.
16,17
Using such a multivariate
model better predicts the risk of prostate cancer when
compared to PSA alone.
Prostate cancer chemoprevention trials
ThePCPTandREDUCE trials are twokey, contemporary
chemoprevention studies. The PCPT trial randomized
18,882
men aged 55 years or older to finasteride 5
mg po daily versus placebo, and the primary study
endpoint was the incidence of prostate cancer over the
study period. The study reported a 24.8% reduction
in diagnosed prostate cancer in the treated cohort.
However, while most of this was due to a decrease in
lowgrade tumors, the prevalence of high grade tumors
(
Gleason grade 7 to 10) was slightly higher in the
finasteride group than in the placebo group (6.4%versus
5.1%).
The potential induction of high grade disease by
finasteride has been the subject of much controversy. In
general, it is felt that the drug does not cause the high
grade cancer, but rather, a reduction in the volume of
the prostate gland caused by finasteride may render
randombiopsiesmore effective in detecting foci of high
grade disease.
14
Nonetheless, this finding has resulted
in a general tendency to avoid the use of finasteride for
chemoprevention of prostate cancer.
The REDUCE trial randomized 8,231 patients to
either treatment with dutasteride 0.5 mg po daily or a
placebo. The study participants were men aged 50 to 75
years old, withPSAscores from2.5 ng/mLto 10 ng/mL,
