Combined Drug Therapy Prevents Progression of Prostate Enlargement Helps Men at High Risk Avoid Surgery

A combination of drugs is significantly more effective than either drug alone for preventing progression of benign prostatic hyperplasia (BPH), especially in men at high risk for disease progression, according to a study appearing in the New England Journal of Medicine tomorrow.

The Medical Therapy of Prostatic Symptoms (MTOPS) Trial tested whether finasteride (Proscar), doxazosin (Cardura) or a combination of the drugs could prevent progression of BPH and the need for surgery or other invasive treatments. Treatments were compared to placebo.

Physicians at 17 MTOPS medical centers treated 3,047 randomized men with BPH for an average of 4.5 years, much longer than previous studies. Vital signs, urinary symptoms, urinary flow, side effects and medication use were checked every 3 months and digital rectal exams, serum PSA and urine was checked yearly. Prostate size was measured at the beginning and end of the study by ultrasound. Progression of disease was defined by one of the following: a 4-point rise in the American Urological Association's symptom severity score, urinary retention (inability to urinate), recurrent urinary tract infection or urinary incontinence.

Finasteride, a 5 alpha-reductase inhibitor, and doxazosin, an alpha-1 receptor blocker, together reduced the overall risk of BPH progression by 66 percent compared to placebo. The combined drugs also provided the greatest symptom relief and improvement in urinary flow rate. Doxazosin alone reduced overall risk of progression by 39 percent and finasteride alone by 34 percent relative to placebo. The combination treatment and finasteride alone also significantly reduced the risk of invasive therapy by 67 percent and 64 percent, respectively. Doxazosin did not reduce the long-term risk of invasive therapy. Most invasive treatments in MTOPS were transurethral or open surgeries to remove prostate tissue. Other invasive therapy includes transurethral incision, microwave or laser therapy to reduce prostate size and prostatic stents, devices that widen the urethra.

MTOPS found that combination therapy was especially effective in men at highest risk for BPH progression �� those with prostates larger than 40 ml (30 percent of participants) or serum PSAs above 4 ng/milliliter (20 percent of participants).

The combination therapy offers dramatically greater and longer-lasting relief from symptoms and, over time, the finasteride shrinks the prostate and actually prevents growth so that fewer men at highest risk for progressive disease need surgery," said John D. McConnell, M.D., lead author of the paper. McConnell is a professor of urology and executive vice president at the University of Texas Southwestern Medical Center in Dallas.

For the first time, MTOPS has given us benchmarks to identify men who are probably headed for surgery and may benefit most from combination therapy, said Leroy M. Nyberg Jr., Ph.D., M.D., director of urology research at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Men who are bothered by lower urinary tract symptoms and BPH should see their doctor about combination treatment and whether it's right for them.

BPH progressed in only 5 percent (49 men) of men on the two drugs, in 10 percent (85 men) on doxazosin, in 10 percent (89 men) on finasteride, and in 17 percent (128 men) on placebo. The events signaling disease progression were mostly worsening symptoms (78 percent), but also included acute urinary retention (12 percent) and incontinence (9 percent).

The risk of urinary retention was reduced 81 percent by combination therapy, 68 percent by finasteride alone. Doxazosin alone did not reduce the risk of urinary retention. The risk of incontinence was reduced 65 percent by combination therapy. Only 5 men developed urinary tract or blood infections. No patients developed impaired kidney function related to BPH.

MTOPS should help alleviate the concern that medical treatment for BPH might initially relieve symptoms but mask problems related to continuing prostate growth, Nyberg said.

Twenty-seven percent of men on doxazosin, 24 percent of men on finasteride, and 18 percent of men on combination therapy stopped treatments early, primarily due to side effects. The most common side effects included sexual dysfunction in men treated with finasteride and dizziness and tiredness in men treated with doxazosin.

NIDDK funded the MTOPS Trial, with support from the National Center on Minority Health and Health Disparities; both are part of the National Institutes of Health. Pfizer, Inc., of New York City and Merck & Co. of Whitehouse Station, New Jersey, donated active drugs, placebos and funds for patient recruitment and retention.

A list of MTOPS Centers is available at http://www.niddk.nih.gov/patient/mtops/mtopscenters.htm.

Learn more about BPH at http://kidney.niddk.nih.gov/kudiseases/pubs/prostateenlargement/index.htm.

A list of Questions and Answers is available at http://www.niddk.nih.gov/patient/mtops/mtops-q&a.htm.

To interview Dr. McConnell or Dr. Claus Roehrborn, second and corresponding author on the paper, call Rachel Horton at (214) 648-3404.