2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

PROSTATE CANCER RISK REDUCTION
men were followed for 14 years, screening would avert the
death of five of nine men destined to die of prostate cancer
while leading to the diagnosis of prostate cancer in 120 men.
In addition to the considerable laboratory expenses associated
with PSA screening, the anxiety associated with
abnormal PSA test results and the known significant side
effects of prostate biopsy—including sepsis and hospitalization—represent
significant “costs” of prostate cancer overdiagnosis.
Indeed, the largest cost associated with prostate
cancer overdiagnosis is overtreatment. In a Scandinavian
study, Fall and colleagues showed that during the first week
following the diagnosis of prostate cancer, patients experienced
a 2.8-fold (95% CI: 2.5–3.2) increased relative risk of a
major cardiovascular event and a 8.4-fold (95% CI: 1.9–22.7)
increased risk of suicide. 19 In PLCO, more than 90%
of screen-detected cancers have received aggressive therapy.
4 Certainly, earlier detection and treatment of prostate
cancer in the PSA era have contributed to the decreasing
mortality of this disease. Nonetheless, the significant human
and economic burden of prostate cancer overtreatment
presents a considerable challenge to current PSA-based
screening efforts.
Agents to Reduce Overdiagnosis of Prostate Cancer
Plausible approaches to prostate cancer risk reduction
include a variety of agents. The 5-alpha reductase inhibitors
and vitamin E and selenium have been the best studied.
SELECT evaluated vitamin E and selenium and failed to
show any reduction in the diagnosis of prostate cancer. 20 A
more recent analysis of the data suggested that vitamin E
may actually increase the detection of prostate cancer. 21
Five-alpha reductase inhibitors are a group of drugs with
antiandrogenic activity, commonly used in the treatment of
BPH. These agents exert their antiandrogenic effect by
blocking the conversion of testosterone to the active form
dihydrotestosterone (DHT); the latter acts as a potent cellular
androgen that promotes prostate growth. Two isoenzymes
of 5-alpha reductase are found in the human genome,
Type 1 and Type 2. Type 2 appears to be the more important
isoform in the pathophysiology of BPH, whereas both Types
1 and 2 are expressed in cancer and cancer-related (PIN)
tissue. Finasteride is a selective inhibitor of 5-alpha reductase
Type 2, while dutasteride is an inhibitor of both isoenzymes.
Both drugs have been linked to decreased sexual
KEY POINTS
● Prostate-specific antigen (PSA)-based screening is
associated with overdiagnosis of prostate cancer.
● Most prostate cancers detected in the United States
are treated aggressively.
● Five-alpha reductase inhibitors decrease the detection
of low-risk prostate cancers during PSA screening.
● It is uncertain whether 5-alpha reductase inhibitors
used in this setting promote aggressive prostate cancer.
● Five-alpha reductase inhibitors improve the performance
of PSA as a diagnostic test for aggressive
prostate cancer.
Table 1. Comparison of PCPT and REDUCE
PCPT REDUCE
Design
Duration (yr) 7 4
Number of patients 18,882 8,251
Location United States International
Age � 55 50–80
Entry PSA � 3 2.5–10
5-� reductase inhibition Type 2 only Types 1 and 2
Negative baseline biopsy No Yes
Follow-up biopsy 7 yr � FC 2yrand4yr� FC
Cores per study biopsy 6 10
Baseline Characteristics
Median age 63 63
Median PSA 1.1 5.7
Prostate Cancer Results
Placebo 24.4% 21.1%
Treated 18.4% 16.3%
Abbreviations: FC, for cause; PSA, prostate-specific antigen; yr, years.
function and libido as well as gynecomastia in a small subset
of men. In general, men apt to experience these side effects
do so during the first year; thereafter, rates are similar
between placebo and treated men. Most side effects are
reversible if the drug is stopped.
Five-alpha reductase inhibitors have been studied in two
large prospective randomized trials, both of which have
demonstrated a reduced incidence of prostate cancer diagnosis
(see Table 1). PCPT evaluated men age 55 or older with
serum PSA values of � 3 who were randomly selected to
receive placebo or 5 mg per day of finasteride and underwent
“for cause” and end-of-study biopsies at 7 years. 22 This trial
showed a 25% (95% CI: 18.6–30.6, p � 0.001) statistically
significant risk reduction in the diagnosis of prostate cancer
in men treated with finasteride. However, this study has
been criticized for three main reasons. First, there was a
very high detection rate for prostate cancer over the 7-year
course of the trial. This “low-risk” group of men in the
placebo arm (who had a normal rectal exam and a PSA � 3)
had a 24.4% chance of a prostate cancer diagnosis after 7
years of follow-up. In contrast, average U.S. men have a 17%
lifetime risk of prostate cancer. Second, there were fewer
“for cause” biopsies in the finasteride arm. If the biopsy rates
had been equal between the two arms, the difference in
overall prostate cancer detection rates would have been
narrowed. Finally, a major concern of PCPT was the finding
on biopsy of more prostate cancers with a Gleason score of 7
or higher in the finasteride arm. This excess of Gleason score
7 to 10 cancer has been attributed to biases induced by
finasteride—the major ones being the increased sensitivity
of PSA and the “volume” bias. The latter reflects the effect of
prostate size on the ability of digital rectal exam and biopsy
to detect prostate cancer. Four independent groups have
adjusted the original data of PCPT for these biases against
finasteride. The 27% excess Gleason score 7 to 10 disease in
the finasteride arm is eliminated. 23-26 It was on the basis of
these findings that ASCO and the American Urological
Association together recommended that men with a PSA of
3 or below who are undergoing screening with PSA should
be encouraged to talk to their physicians about the risks
and benefits of taking a 5-alpha reductase inhibitor. 27 More
recently, the U.S. Food and Drug Administration (FDA)
used other models to adjust for bias in PCPT. One of these
models showed a persistent 1.51 (95% CI: 1.01 to 2.26)
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