Year : 2011 | Volume
: 27 | Issue : 1 | Page : 153--155
Role of 5-alpha reductase inhibitors in the prevention of prostate cancer
Bhupendra P Singh, SN Sankhwar, Apul Goel
Department of Urology, Chhatrapati Shahuji Maharaj Medical University (King George Medical University), Lucknow, Uttar Pradesh, India
Bhupendra P Singh
Department of Urology, Chhatrapati Shahuji Maharaj Medical University (King George Medical University), Lucknow, Uttar Pradesh
|How to cite this article:|
Singh BP, Sankhwar S N, Goel A. Role of 5-alpha reductase inhibitors in the prevention of prostate cancer.Indian J Urol 2011;27:153-155
|How to cite this URL:|
Singh BP, Sankhwar S N, Goel A. Role of 5-alpha reductase inhibitors in the prevention of prostate cancer. Indian J Urol [serial online] 2011 [cited 2020 Jul 4 ];27:153-155
Available from: http://www.indianjurol.com/text.asp?2011/27/1/153/78407
In this 4-year, multicenter, randomized, double-blind, placebo-controlled trial, authors compared the dutasteride (0.5 mg daily) with the placebo. Inclusion criteria were men of 50-75 years of age with a prostate-specific antigen (PSA) level of 2.5-10.0 ng/ml, who had one negative prostate biopsy (6-12 cores) within 6 months before enrollment. Subjects underwent protocol biopsies: 10-core transrectal ultrasound-guided biopsies as part of the protocol at 2 and 4 years; biopsies were performed independently of the protocol when they were clinically indicated. Among 6729 men who underwent a biopsy or prostate surgery, cancer detection rate was 659/3305 in the dutasteride group, as compared with 858/3424 in the placebo group, with a relative risk reduction of 22.8% with dutasteride over the 4-year study period (P<0.001). In years 1 through 4, among the 6706 men who underwent a needle biopsy, there were 220 tumors with a Gleason score of 7 to 10 among 3299 men in the dutasteride group and 233 among 3407 men in the placebo group (P=0.81). Although during first 2 years of trial, there were 141 more tumors with a Gleason score of 5 to 7 in placebo group than in dutasteride group (558 among 3346 participants vs. 417 among 3239 participants), number of tumors with a Gleason score of 8 to 10 was similar in two groups (18 and 17, respectively). During 3rd and 4th years, there were 12 tumors with a Gleason score of 8-10 in dutasteride group, as compared with only 1 in placebo group (P=0.003). With dutasteride therapy, the need for surgery for BPH, risk of UTI, and acute urinary retention were reduced by 73%, 40.7%, and 77.3% respectively. Authors concluded that dutasteride reduced the risk of incidental prostate cancers detected on biopsy over the 4 years and improved the outcomes related to benign prostatic hyperplasia.
Prostate cancer prevention trial found a 6.4% reduction in low-grade tumors with 1.3% increase in high-grade tumors (Gleason score: 7-10) in finasteride group. This higher incidence of high-grade tumors was restricted to those undergoing for cause biopsy (prompted by PSA rise). The debate for this increase in high-grade tumors by finasteride prompted three possible causes: reduction in prostate size along with better PSA sensitivity and specificity, changes in prostatic epithelium causing Gleason misinterpretation, or an actual increase in de novo high-grade cancers by biological changes. However, later analyses suggested that reduced size of the prostate and better PSA sensitivity by fiansteride may be responsible for better detection of high-grade tumors, rather than actual increase in their incidence. Similarly REDUCE trial has shown an overall 5.2% decrease in incidence of tumors by dutasteride with higher incidence of high-grade cancers (8-10) in dutasteride group in 3rd and 4th years (12 vs. 1). Cause for more high-grade tumors in dutasteride group may be either early exit of higher number of low-grade tumor patients from trial in placebo group in first 2 years (many of which otherwise would have upgraded to higher grade tumors in next 2 years) or dutasteride therapy itself (by reducing prostate size, better DRE and PSA sensitivity - similar to finasteride). Both studies had about four times higher positive biopsy rates (24.4% in PCPT and 25.1% in REDUCE trial) in placebo group than 6% assumption based on SEER data, suggesting that many of the tumors were likely to be clinically insignificant. In both studies, incidence of cancer in patients on drug was almost similar (18.4% in PCPT and 19.9% in REDUCE trial).
Prostate cancer detection in a biopsy specimen depends on tumor volume, prostate volume, and the number of cores in sample. Serfling et al. predicted an 11-17% increase in biopsy-detected cancer among men treated with dutasteride (vs. those receiving placebo), assuming that dutasteride did not reduce tumor volume and reduced the prostate volume by 25%. In REDUCE study, the decrease in prostate volume was 30.4±0.79% at year 2 and 37.1±0.93% at year 4 (P<0.001). The reduction in prostate volume with dutasteride and increase in prostate volume with placebo could have accounted for an increase in the number of biopsy-detected prostate cancers in dutasteride group, but the actual result was a 23% relative reduction in prostate cancer, a finding in support for tumor shrinkage with dutasteride. Although authors mention that there was no difference in incidence of 7-10 Gleason score cancers over 1-4 years and 8-10 Gleason score cancers in first 2 years, give possible explanations for more 8-10 Gleason tumors in last 2 years of trial, and even claim that dutasteride decreases the incidence of high-grade tumors (if mathematical model similar to finasteride is applied) , the very fact that dutasteride was associated with much higher number of 8-10 Gleason score tumors (19 in placebo vs. 29 in dutastride group over 4 years) is similar to that for finasteride in PCPT; incidence of 6 Gleason score tumors reduced, no effect on 7 Gleason score tumors, and increased incidence of 8 Gleason score tumors.
Any significance of a new finding among side-effects (a higher incidence of composite event of cardiac failure in dutasteride group) is yet to be established and refined as a composite event termed "cardiac failure," included many conditions such as congestive heart failure, cardiac failure, acute cardiac failure, ventricular failure, cardiopulmonary failure, and congestive cardiomyopathy.
As prostate cancer is found at autopsy in almost half of older men who die without knowing they had the cancer, a decrease in cancer incidence (by dutasteride) detected on random biopsies may not be useful for predicting the ultimate impact on cancer-related morbidity or mortality. In REDUCE study, of the biopsies performed for cause outside the protocol, 16.6% in dutasteride group, and 16.7% in placebo group were positive. Similarly with finasteride, no difference in cancer incidence have been shown if biopsy was done for a clinical indication, i.e., an abnormal examination or PSA level corrected for the effect of finasteride (cancer detected in 26.5% of those taking finasteride and 29.5% receiving placebo, a 10% reduction that was not statistically significant).  A study from the Finnish Prostate Cancer Trial showed no significant decrease in the incidence of prostate cancer by finasteride. 
The really important tumors, which presented with high grade or were to progress to a higher grade, could not be prevented by dutasteride. This is in contrary to some previous studies that showed that there may be increased level of 5-alpha reductase type 1 in these tumors.  In the random biopsies performed at the end of the PCPT also, there was no decrease in high-grade disease.  In patients on finasteride, risk of high-grade disease has been shown to be increased because of PSA suppression. ,
Hence dutasteride and finasteride both are in same boat in terms of results of the trial, positive biopsy rate, and perhaps do not yield promising results for prostate cancer prevention. Although many mathematical models may suggested benefit of finasteride/dutasteride (of course they are associated with much more statistical assumptions and biases) and the American Society of Clinical Oncology (ASCO) and the American Urological association (AUA) jointly recommended the use of both dutasteride and finasteride in asymptomatic men to reduce the risk for cancer in new guidelines (issued in 2009), they are still not widely used for the purpose. Moreover the concerns raised by Patrick Walsh,  i.e., only temporary shrinkage of low-grade tumors, false sense of security to patients and no effect in actual clinical setting may be important in addition to long-term cost of drug, side-effects, and cost of treatment of sexual side effects. Although Gleason score 5-6 cancers are clinically significant to the patients, how much biologically significant they are in causing mortality when diagnosed in asymptomatic men is still debatable. Today when secondary prevention in the form of cancer prostate screening have failed to affect the mortality, decreasing the incidence of trial overdiagnosed asymptomatic low-grade cancers by these 5-alpha reductase inhibitors (as primary prevention) may not have any actual impact on cancer mortality. Are we really interested in primary prevention of cancers of which biological significance is not clear? And that too, by the drugs with definite side effects and associated cost of therapy for them? Aim of any preventive strategy whether primary or secondary should be to reduce mortality and not to produce morbidity. Concerns of overdiagnosing and overtreating insignificant prostate cancers are genuine considering the natural history of the disease. Till their role is further defined, physicians and patients should be clear in their minds not to use these drugs for such purpose. This stands true at least in Indian scenario where 2.5-10 PSA with negative biopsy is quite often seen (one of the situations where Andriole et al. suggest dutasteride use) and incidence and burden of clinical prostate cancer seems to be lower, further questioning their utility in decreasing cancer-related mortality and morbidity.
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