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.

82 CHAPTER 3 Bladder outlet obstruction

Medical management of BPH: alternative drug therapy

Anticholinergics

For a man with frequency, urgency, and urge incontinence—symptoms suggestive of an overactive bladder—consider prescribing an anticholinergic (e.g., oxybutynin, tolterodine, trospium chloride, or flavoxate). There is the concern that these drugs could precipitate urinary retention in men with BOO (because they block parasympathetic/cholinergic mediated contraction of the detrusor), but the risk of this occurring is probably very low, even in men with urodynamically proven BOO.1

Phytotherapy

An alternative drug treatment for BPH symptoms, and one that is widely used in Europe and increasingly in North America, is phytotherapy. Half of all medications consumed for BPH symptoms are phytotherapeutic ones.2 These agents are derived from plants and include the African plum (Pygeum africanum), purple coneflower (Echinacea purpurea), South African star grass (Hipoxis rooperi), and saw palmetto berry (Seronoa Repens, Permixon).

Saw palmetto contains an anti-inflammatory, antiproliferative, estrogenic drug with 5A-reductase inhibitory activity, derived from the American dwarf palm. It has been compared with finasteride in a large double-blind, randomized trial, and equivalent (40%) reductions in symptom score were found with both agents over a 6-month period. A meta-analysis of 18 randomized controlled trials of almost 3000 men has suggested that Seronoa repens produces similar improvements in symptoms and flow rates to those produced by finasteride.3

A recent New England Journal of Medicine study found saw palmetto no better than placebo in relieving BPH symptoms.4

South African star grass (Hipoxis rooperi, marketed as Harzol) contains B-sitosterol, which may induce apoptosis in prostate stromal cells by causing elevated levels of TGF-B1. In a double-blind, randomized control trial, symptom improvement was 5 points over that with placebo.

For other agents (e.g., Urtica dioica—stinging nettle; the African plum) the studies have not been placebo controlled and lack sufficient statistical power to prove conclusively that they work.2

1 Reynard J (2004). Does anticholinergic medication have a role for men with lower urinary tract symptoms/benign prostatic hyperplasia either alone or in combination with other agents? Curr Opin Urol 14:13–16.

2 Lowe FC, Fagelman E (1999). Phytotherapy in the treatment of benign prostatic hyperplasia: an update. Urology 53:671–678.

3 Wilt JW, Ishani A, Stark G, et al. (1998). Saw palmetto extracts for treatment of benign prostatic hyperplasia: a systematic review. JAMA 280:1604–1608.

4 Bent S, et al. (2006) Saw palmetto extracts for treatment of benign prostatic hyperplasia. N Engl J Med 354:557–566.

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