Материал: Oxford American Handbook of Urology ( PDFDrive )

78 CHAPTER 3 Bladder outlet obstruction

Medical management of BPH: 5A-reductase inhibitors

5A-reductase inhibitors inhibit the conversion of testosterone to dihydrotestosterone (DHT), the more potent androgen in the prostate. This causes shrinkage of the prostatic epithelium and thus a reduction in prostate volume, thereby reducing the static component of benign prostatic enlargement. This takes some months to occur, so urinary symptoms will not improve initially.

Finasteride is a competitive inhibitor of the enzyme 5A-reductase (type II isoenzyme), which converts testosterone to DHT. Finasteride therefore lowers serum and intraprostatic DHT levels.

Dutasteride is a dual inhibitor (type I and II isoenzyme) of 5A-reductase. Whether it has any clinically significant advantages over finasteride in the treatment of BPH remains to be established.

Efficacy

A number of large studies have shown symptom improvement over placebo on the order of 2–3 points on the IPSS and improvements in flow rate on the order of 1–2 mL/s (SCARP1 [Scandinavian BPH Study Group], PROSPECT2 [Proscar Safety Plus Efficacy Canadian Two-year Study], PROWESS [Proscar Worldwide Efficacy and Safety Study] Group,3 and, more recently, PLESS4 [Proscar Long-term Efficacy and Safety Study]). The PLESS data also show a small reduction in the risk of urinary retention.

Side effects

Generally speaking, these are fairly mild. Principally they center on sexual problems (e.g., loss of libido, 5%; impotence, 5%; reduced volume of ejaculate in a few percent of patients).

5D-reductase inhibitors and risk of urinary retention

The PLESS data4 have been widely publicized as showing a substantial reduction in the risk of urinary retention. In this 4-year follow-up study, 42 of 1471 men on finasteride went into urinary retention (3%), while 99 of 1404 on placebo experienced an episode of retention (7%). This represents an impressive 43% relative reduction in risk in those taking finasteride.

However, the absolute risk reduction over a 4-year period is a less impressive 4%. So, finasteride does reduce the risk of retention, but it is reducing the risk of an event that is actually quite rare, as suggested by the fact that 93% of men on placebo in this study did not experience retention over a 4-year period. Put another way, to prevent 1 episode of retention, 25 men would have to continue treatment with finasteride for 4 years.

5D-reductase inhibitors for hematuria due to BPH

Shrinking large vascular prostates probably helps reduce the frequency of hematuria in men with BPH.5

MEDICAL MANAGEMENT OF BPH: 5A-REDUCTASE INHIBITORS 79

Further reading

Debruyne FM, Jardin A, Colloi D, et al. (1998). Sustained-release alfuzosin, finasteride and the combination of both in the treatment of benign prostatic hyperplasia. Eur Urol 34:169–175.

Kirby RS, Roerborn C, Boyle P, et al. (2003). Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology 61:119–126.

Lepor H, Williford WO, Barry MJ, et al. (1996). The efficacy of terazosin, finasteride, or both in benign prostatic hypertrophy. N Engl J Med 335:533–539.

McConnell JD, Roehrborn CG, Bautista OM, et al. (2003). The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. New Engl J Med 349:2387–2398.

1 Andersen JT, Ekman P, Wolf H, et al. (1995). Can finasteride reverse the progress of benign prostatic hyperplasia? A two-year placebo-controlled study. The Scandinavian BPH Study Group. Urology 46:631–637.

2 Nickel J, Fradet Y, Boake RC, et al. (1996). Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomised controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian Two Year Study. Can Med Assoc J 155:1251–1259.

3 Marberger MJ (1998). Long-term effects of finasteride in patients with benign prostatic hyperplasia: a double-blind, placebo-controlled, multicenter study. PROWESS Study Group. Urology 51:677–686.

4 McConnell JD, Bruskewitz R, Walsh PC, et al. (1998). The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study (PLESS) Group. N Engl J Med 338:557–563.

5 Foley SJ, Soloman LZ, Wedderburn AW, et al. (2000). Finasteride for haematuria due to BPH. A prospective study of the natural history of hematuria associated with BPH and the effect of finasteride. J Urol 163:496–498.

80 CHAPTER 3 Bladder outlet obstruction

Medical management of BPH: combination therapy

A combination of an A-blocker and a 5A-reductase inhibitor can be used to manage BPH. The relevant studies are as follows:

•MTOPS study1 (Medical Therapy of Prostatic Symptoms): This combination prevented progression of BPH (progression being defined as a worsening of symptom score by 4 or more, or the development of complications such as UTI or acute urinary retention).

•Veterans Affairs Combination Therapy Study2: 1200 men were randomized to placebo, finasteride, terazosin, or a combination of terazosin and finasteride. At 1-year follow-up, relative to placebo, finasteride had reduced the symptom score by an average of 3 points, whereas terazosin alone or in combination with finasteride had reduced the symptom score by an average of 6 points.

•PREDICT study3 (Prospective European Doxazosin and Combination Therapy): randomized over 1000 men to placebo, finasteride, doxazosin, or a combination of finasteride and doxazosin. The differences in symptom score at baseline and at 1-year follow-up were –5.7 and –6.6 for placebo and finasteride, and –8.3 and –8.5 for doxazosin and combination therapy.

•ALFIN study4 (ALFuzosin, FINasteride, and combination in the treatment of BPH): 1000 men were randomized to alfuzosin, finasteride, or a combination. At 6 months, the improvement in the IPSS was not significantly different in the alfuzosin vs. the combination group.

•CombAT study4,5 (tamsulosin, dutasteride, and combination in the treatment of BPH): 4844 men were randomized to tamsulosin, dutesteride, or a combination. At 24 months, the improvement in the IPSS was significantly different in the tamsulosin vs. the combination group. Combination therapy was better in patients with a large prostate than monotherapy with the A-blocker or 5A-reductase inhibitor alone.

Thus, in two large studies (CombAT and MTOPS), combination therapy was more useful than monotherapy with either an A-blocker or 5Areductase inhibitor alone. Currently, dual therapy with an A-blocker and a 5A-reductase inhibitor is usually reserved for patients who are symptomatic with a large prostate (>40 g or a PSA >1.5 ng/mL).

In addition, 5A-reductase inhibitor therapy has been studied in patients with prostate cancer (Prostate Cancer Prevention Trial).6 Over 18,000 men were randomized to finasteride or placebo over a 7-year period. Those in the finasteride group had a 25% lower prevalence of prostate cancer detected on prostate biopsy. However, higher-grade tumors, which are biologically more aggressive than low-grade cancers, were more common in the finasteride group. Further research in this area has suggested that prostate reduced in size by finasteride may have made higher-grade disease easier to biopsy and find.

MEDICAL MANAGEMENT OF BPH: COMBINATION THERAPY 81

The REDUCE trial enrolled over 8000 men to study the effect of dutasteride on prostate cancer prevention. This international 4-year study examined patients with intermediate risk for the development of prostate cancer. In order to enroll in the study, patients were required to have a 10 core prostate biopsy on entry and at years 2 and 4. Results showed a 23% reduction in the development of prostate cancer, and those that did develop cancer did not have higher-grade disease.7

1 McConnell JD, Roehrborn CG, Bautista OM, et al. (2003). The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 349:2387–2398.

2 Lepor H, Williford WO, Barry MJ, et al. (1996). The efficacy of terazosin, finasteride, or both in benign prostatic hypertrophy. N Engl J Med 335:533–539.

3 Kirby RS, Roerborn C, Boyle P, et al. (2003). Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology 61:119–126.

4 Debruyne FM, Jardin A, Colloi D, et al. (1998). Sustained-release alfuzosin, finasteride and the combination of both in the treatment of benign prostatic hyperplasia. Eur Urol 34:169–175.

5 Barkin J, Roehrborn CG, Siami P, et al. (2009). CombAT Study Group. Effect of dutasteride, tamsulosin and the combination on patient-reported quality of life and treatment satisfaction in men with moderate-to-severe benign prostatic hyperplasia: 2-year data from the CombAT trial. BJU Int 103(7):919–926.

6 Thompson IM, Goodman PJ, Tangen CM, et al. (2003). The influence of finasteride on the development of prostate cancer. N Engl J Med 349:215–224.

7 Andriole GL, Bostwick D, Brawley O, et al. (2010). The influence of dutasteride on the risk of biopsy-detectable prostate cancer: outcomes of the REduction by DUtasteride of Prostate Cancer Events (REDUCE) study. N Engl J Med 362:1192–1202.