Current prospects for the chemoprevention of prostate cancer ROGER KIRBY, TOM MCNICHOLAS AND JOHN FITZPATRICK
Unlike other areas of medicine, such as These data provide compelling evidence
has often been slow to embrace strategies
capable of significantly reducing a man’s
no significant difference in the rates of
for risk reduction. Currently, urologists
risk of prostate cancer. Indeed, the slight
acceptance of biopsy in the two groups.
prefer to treat the disease at the stage they
encounter it, rather than approaching the
vitamin E is of concern. The mild increase
in risk of diabetes with selenium has been
Thompson et al.7 found that ‘ finasteride significantly enhanced
supplements in the absence of large-scale
the ability of PSA level to detect
prostate cancer in the USA is estimated at
both prostate cancer and high-
Another landmark study of chemoprevention
grade prostate cancer
of prostate cancer is the Prostate Cancer
progress, potentially it provides a prime
Prevention Trial (PCPT).6 In the PCPT, an
’
abnormal digital rectal examination (DRE)
and half by PSA level. The mean PSA level
The first chemopreventative strategy to be
evaluated in a randomised controlled trial
analysis, prostate cancer was confirmed in
Cancer Prevention Trial (SELECT) study.
803/4368 (18.4 per cent) of the finasteride
reduction was 24.8 per cent (p<0.001).
placebo arm. Participants who temporarily
• Hazard ratios and 99 per cent confidence
cancer were 1.04 for selenium (CI 0.87–
prostate-specific antigen (PSA) level, prostate
1.24), 1.13 for vitamin E (0.95–1.35) and
taking the study drug, were still eligible for
the end-of-study biopsy. The annual rate of
differed slightly between study groups. This article was originally published in
• There were no significant differences in
BJU Int 2010;106:751–3.
2122/9423 (22.5 per cent) in the finasteride
• There was a statistically non-significant
Professor R. Kirby, MA, MD, FRCS(Urol), FEBU, Director, The Prostate Centre, London; Professor T.A. McNicholas, MB BS, FRCS, FEBU, Consultant Urologist, The Lister Hospital,
• There was a statistically non-significant
Stevenage, Hertfordshire; Professor J.M. Fitzpatrick, MB BCh, FRCSI, MCh, FRCS, FC Urol(SA), FRCS(Glas), Professor of Surgery, Mater Misericordiae Hospital, Dublin, Ireland TRENDS IN UROLOGY & MEN’S HEALTH JANUARY/FEBRUARY 2011 www.trendsinurology.com
beyond those dictated by the protocol. The
finasteride/placebo) in the first year to 3.6
per cent (4.8 per cent high grade) in the
per cent and 3.4 per cent in the fifth year.
temporary discontinuation, which occurred
and a statistically non-significant 14 per
men in the dutasteride group, as compared
in 18.3 per cent in the finasteride group
cent increase in high-grade disease. When
prostatectomy (understanding that ‘true’
Gleason grade is best determined at radical
cent (95 per cent CI 15.2–29.8) over the
24.8 per cent reduction in risk of cancer
is available for analysis rather than the
overall, there was a small increased risk,
biopsy that is affected by sampling error)
Overall, in the first year through to the
both absolute and relative, of high-grade
was incorporated, the analysis found that
disease. Gleason 7–10 tumours constituted
the true rates of high-grade disease in the
underwent a needle biopsy, there were 220
and 6.0 per cent in the finasteride group, a
27 per cent risk reduction (p=0.02). Pinsky
cent). This excess of 43 cancers could be
et al.9 from the National Cancer Institute,
seen to be primarily caused by the excess
using a different analysis methodology and
(p=0.81). Dutasteride therapy, as compared
with placebo, resulted in a reduction in the
arrived at a similar conclusion that the rate
rate of acute urinary retention (1.6 per cent
end-of-study biopsies (excess of three).
versus 6.7 per cent, a 77.3 per cent relative
The cause for this has been the subject of
reduction). The incidence of adverse events
much debate, but it is now widely accepted
was similar to that in studies of dutasteride
finasteride affected the PSA detection rate
of prostate cancer. Studying 5112 and 4579
men in the placebo and finasteride groups,
multicentre, international study; subjects
were randomised to receive either the dual
category of cardiac failure was higher in
biopsy and associated PSA level, Thompson
the dutasteride group than in the placebo
et al.7 found that finasteride significantly
period of four years. Eligibility criteria
group (0.7 per cent [30 men] versus 0.4 per
enhanced the ability of PSA level to detect
include PSA level between 2.5 and 10ng/ml
that over the course of the four-year study
period, dutasteride reduced the risk ofincident prostate cancer detected onbiopsy and improved the outcomes related
Over the course of the four-year study period [of the ‘REDUCE trial], dutasteride reduced the risk of incident In a recent editorial, Dr Patrick Walsh10 prostate cancer detected on biopsy and improved the outcomes related to BPH
reduction of cancer diagnosed based on a biopsy driven by PSA level rises or
’
analysis, taking into account those factors
prostate on palpation was more clinically
that affected cancer detection in the two
study entry prostate biopsy, an advantage
biopsy rate in the finasteride group as well
‘for-cause’ prostate biopsies performed
as the group of factors related to cancer
detection. Examining only biopsy itself, the
affected differentially by 5ARIs), there were
bias-adjusted rates of prostate cancer in
few additional PSA level-prompted biopsies
impact of 5ARIs on the risk of developing
www.trendsinurology.com TRENDS IN UROLOGY & MEN’S HEALTH JANUARY/FEBRUARY 2011 Recent developments in molecular genetics are beginning to ‘ allow us to identify a subgroup of patients with an especially
regimen. Because this class of drug is welldocumented as having a significant impact
high risk of developing prostate cancer, who might be
on the sensitivity and specificity of both
expected to benefit from effective chemoprevention ’
diagnosis, any trial relying on PSA level or DRE-triggered biopsies would fail
The follow-up protocol was also considerably
et al. Chemoprevention of prostate cancer.
>70 per cent of patients in both the active
treatment and placebo completing the biopsy
Lippman SM, Klein EA, Goodman PJ, et al.
protocol, which adds credibility to the results.
Effect of selenium and vitamin E on risk of
Walsh also questions the relevance of the
score cancers, which possess a much lower
authorities will doubtless come to their own
Stranges S, Marshall JR, Natarajan R, et al.
conclusions about the safety and efficacy of
Effects of long-term selenium supplementation
dutasteride as a chemopreventative agent
on the incidence of type 2 diabetes: a randomized
in prostate cancer, and will do so in view
trial. Ann Intern Med 2007;147:217– 23.
decide whether active treatment or active
than is possible simply from a review of the
et al. The influence of finasteride on the
surveillance is the best treatment strategy,
publication in the New England Journal of
Medicine,1 which is inevitably a summary
uncertainty. In addition, it may be the case
of a very large volume of material. In the
7 Thompson IM, Chi C, Ankerst DP, et al.
Effect of finasteride on the sensitivity of
Gleason 6 tumours identified in the study
PSA for detecting prostate cancer. J Natl
advisability of the use of these agents in a
al. Finasteride does not increase the risk of
beginning to allow us to identify a subgroup
high-grade prostate cancer: a bias-adjusted
of patients with an especially high risk of
modeling approach. Cancer Prev Res (Phila
developing prostate cancer.13 These highly
cancers. However, this is at variance with
Pinsky P, Parnes H, Ford L. Estimating rates
publications,11,12 which suggests that both
of true high-grade disease in the Prostate
finasteride and dutasteride in fact improve
benefit from effective chemoprevention for
the sensitivity and specificity of PSA level
this disease. In the interim, clinicians must
most likely to benefit from these medications.
cancer. N Engl J Med 2010;362:1237–8.
prostate cancer risk, namely the incidence
Declaration of interests
et al. Finasteride improves the sensitivity of
cancer detection. J Urol 2007;177:1749–52.
12 Andriole GL, Bostwick D, Brawley O, et al. REFERENCES
The utility of PSA for detection of prostate
It is relevant in this context to compare the
et al. Effect of dutasteride on the risk of
results from the REduction by DUtasteride
trial. The key differences lie in the patient
of prostate Cancer Events (REDUCE) study.
13 Kirby RS, Eeles RA, Kote-Jarai Z, et al.
developing prostate cancer and arguably a
more clinically relevant group to evaluate. TRENDS IN UROLOGY & MEN’S HEALTH JANUARY/FEBRUARY 2011 www.trendsinurology.com
8945d_043-044 6/18/03 11:21 AM Page 43 mac85 Mac 85:1st shift: 1268_tm:8945d: SENDING A SIGNAL THROUGH A GAS For decades scientists have tried to understand how cells work together in tis-sues, as well as in whole organisms. By the 1980s, the identity of many signal-ing molecules, the cellular responses they evoked, and many aspects of intracellu-lar signaling pathways were understood. All t
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