EditorialThe REDUCE Trial
Introduction
The long-expected final report of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial appeared on April 1, 2010, in the New England Journal of Medicine together with a commentary entitled, “Chemoprevention of prostate cancer,” by Dr Patrick Walsh. Both documents are of clinical importance and warrant discussion.
Section snippets
The REDUCE trial
This trial investigated the value of the dual-action 5α-reductase inhibitor dutasteride (GlaxoSmithKline, Middlesex, UK) in 8231 men with prostate-specific antigen (PSA) values between 2.5 and 10 ng/ml who had undergone previous negative biopsies. Of these men, 6729 had at least one biopsy and were analyzed and presented as what the authors called the “restricted crude rate,” which, at all end points, was taken into consideration. The study resulted in a reduction of positive biopsies over a
Is the risk reduction of positive biopsies after 4 years clinically relevant?
The study addressed a group of men and a PSA range in which biopsies are indicated in routine clinical practice: Most urologists worldwide would carry out periodic biopsies in men presenting with PSA values between 2.5 and 10 ng/ml. The chance of a positive biopsy in this setting was 24.9% in the placebo group and 19.9% in the dutasteride group: a 5% absolute difference. These detection rates are high compared with data of previously biopsied men from the European Randomized Study of Screening
How does dutasteride act in reducing positive biopsies?
The authors and the reviewer, Dr Walsh, agree on this point. The mechanism is not primary prevention, but the reduction in cancer volume and the inhibition of growth of cancers that react to the intracellular reduction of 5α-dihydrotestosterone (DHT) in spite of the simultaneous increase in testosterone (T), which may increase to 40 times higher levels [5]. Considering the commonly applied definitions of secondary and tertiary prevention as the application of preventive measures to high-risk
Can unnecessary biopsies be avoided by use of dutasteride?
A 19.9% positive biopsy rate was seen in the dutasteride arm after 4 yr. This means that 81.1% of all men had negative biopsies. The rate of biopsies is identical in both arms because the elevated PSA at inclusion remained the only protocol biopsy indication. This is an important difference with the PCPT trial [3]. The question of whether the degree of PSA response or the increase of PSA over time relates to cancer detection or to the detection of more aggressive disease after 4 yr is not
The aggressive cancers
As Walsh correctly states, there is no evidence that dutasteride prevents lethal tumors. This is a clear limitation that is inherent to the short duration of the follow-up within the REDUCE trial. In addition, the explanations given for the higher rate of poorly differentiated cases, which might have increased to an even larger difference with a 7-yr follow-up as applied in the PCPT study, remains unsatisfactory. Considering the presented evidence of proper randomization, it must be assumed
Conclusions
In the view of these reviewers, the REDUCE study provides clinically important information. A relative reduction of the detection of small, potentially overdiagnosed cancers of 28.2% (derived from Table 3 of the paper by Andriole et al. [1]) is relevant for men who present with a clinical indication for re-biopsy because of an initially elevated PSA between 2.5 and 10 ng/ml and a previous negative biopsy. Another important aspect, addressed in this review, is that the possibility to save
Conflicts of interest
FH Schröder is an advisor to GlaxoSmithKline, Ferring, and Schering. MJ Roobol is an advisor to GlaxoSmithKline, Beckman, and Genprobe.
References (8)
- et al.
Finasteride improves the sensitivity of digital rectal examination for prostate cancer detection
J Urol
(2007) - et al.
Effect of dutasteride on the risk of prostate cancer
N Eng J Med
(2010) - et al.
A comparison of first and repeat (four years later) prostate cancer screening in a randomized cohort of a symptomatic men aged 55-75 years using a biopsy indication of 3.0 ng/ml (results of ERSPC, Rotterdam)
Prostate
(2006) - et al.
The influence of finasteride on the development of prostate cancer
N Engl J Med
(2003)
Cited by (4)
Next-generation steroidogenesis inhibitors, dutasteride and abiraterone, attenuate but still do not eliminate androgen biosynthesis in 22RV1 cells in vitro
2014, Journal of Steroid Biochemistry and Molecular BiologyCitation Excerpt :It was also found to significantly decrease tumor volume in patients and was found to delay incidence of prostate cancer in high risk individuals as well as progression of prostate cancer development [20–23]. However, it is not typically the drug of choice as a first line hormonal treatment for prostate cancer [24–26]. In this study we investigated the effects of abiraterone and dutasteride alone and in combination to inhibit steroidogenesis.
Re: Fritz H. Schröder, Monique J. Roobol. the reduce trial. Eur Urol 2010;58:253-255
2011, European Urology