Comment chemoprevention_layout

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
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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.
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