Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

61st Annual Meeting of the Canadian Urological Association

Halifax, Nova Scotia / June 25-28, 2006

According to Dr. John Fitzpatrick, Professor and Chair, Department of Surgery, University College Dublin, Ireland, and Editor-in-Chief, British Journal International, benign prostatic hyperplasia (BPH) therapy trials used to look for improvements in static variables such as symptom score, flow rates or post-void residual urines. “Now, mainly because of the MTOPS [Medical Therapy of Prostatic Symptoms] study, we are looking at something that is much more important to the patient—the risk that he will progress to the need to have surgery or acute urinary retention [AUR]. These are dynamic variables,” he told delegates.

Dr. Fitzpatrick noted that in the MTOPS trial, BPH progression was almost entirely due to a symptom score of four points or greater. Prostate volumes were moderate, at a median of 31 mL, and patients who reached an end point were dropped from the study. The ALTESS (Alfuzosin Long-term Safety and Efficacy Study), on the other hand, continued to observe patients after they reached an end point, and patients had a higher symptom score and prostate size than in MTOPS. But like doxazosin in MTOPS, alfuzosin in ALTESS improved symptoms in the short term, but did not prevent symptom progression or AUR over the long term (Roehrborn et al. BJU Int 2006;97(4):734-41).

Given the present state of knowledge, what therapies should urologists use to treat BPH? “Alpha blockers seem very good for quick symptom relief,” Dr. Fitzpatrick summarized. He added that they do not seem to prevent AUR or the need for surgery and that in moderate to large prostates, “you would certainly be looking at using 5-alpha reductase inhibitors.” Dr. Fitzpatrick noted that a prostate-specific antigen (PSA) of >1.3 is probably a good starting point as a proxy for the appropriate-sized gland to treat. He concluded that combination therapy definitely has a role to play, particularly in men at risk for progression, with larger prostates, higher PSA levels and lower flow rates.

Impact of MTOPS

“The MTOPS trial has impacted more on BPH than anything else over the last decade,” according to Dr. Curtis Nickel, Professor of Urology, Queen’s University and Kingston General Hospital, Ontario. MTOPS randomized over 3000 patients to placebo, doxazosin, finasteride or both compounds. Combination therapy was better than either treatment alone in preventing symptom progression, occurrence of AUR or need for surgery.

Patients with larger prostates had a higher risk of BPH progression. Prostates grew about 1 mL/year vs. 3 mL/year for patients in the lowest and highest baseline PSA quartiles, respectively. Nearly half of the total prostate volume variability in patients with “true BPH” was predicted by total serum PSA (Roehrborn et al. AUA 2006 Abstract 1288).

“One of the most exciting findings of MTOPS is the effect of inflammation,” Dr. Nickel stated. “Not one patient who had no inflammation on biopsy went into AUR in the five years, compared to a 6% rate with inflammation. If you put a patient on doxazosin and they do not have inflammation in the prostate gland, you are unlikely to prevent progression of symptoms, AUR and surgery, and that is similar for finasteride. I think that is one of the most important findings. MTOPS has driven the guidelines and our practice patterns,” he summarized. “Now we decide on treatment based on severity of symptoms, bother and the concern about prostate cancer. We know that for a patient with a small prostate gland [<25 cc] and low PSA, there is no benefit of adding a 5-alpha reductase inhibitor unless he has a significant family history of prostate cancer, whereas for a patient with a large prostate and high PSA, certainly a finasteride or combination therapy is the most effective therapy.”

PCPT and Clinical Practice

“The MTOPS story is one half of the story of the use of 5-alpha reductase inhibitors in the management of patients,” indicated Dr. Laurence Klotz, Professor of Surgery, University of Toronto and Chief of Urology, Sunnybrook Health Sciences Centre, Ontario. “The other half is the PCPT [Prostate Cancer Prevention Trial], perhaps the most important trial in the last generation, certainly in the prostate cancer field.” The trial randomized over 18,000 men between the ages of 55 and 70 to finasteride or placebo. The end point was a biopsy at the end of seven years or earlier. There was a 25% reduction in the rate of prostate cancer diagnosis in the finasteride group compared to placebo, but the proportion of high-grade cancers was increased. Recent evidence shows that that the higher-grade cancer was not caused by a histologic artifact, Dr. Klotz explained. Rather, it was partly due to improved PSA testing with finasteride and to more accurate sampling of the gland as a result of volume reduction.

According to Dr. Klotz, the take-home messages from the PCPT trial are “Prostate cancer is preventable—a huge observation. The upgrading was an artifact of size reduction of the prostate and improved performance of PSA; there is powerful evidence to support this and no evidence to support the alternative. In fact, the level of evidence of the benefit of prevention of prostate cancer is greater than for screening and aggressive attempts at a cure.”

The patient’s choice is to have an annual PSA with a 40% to 50% risk of a prostate biopsy and an 18% to 20% risk of being diagnosed with prostate cancer and with uncertain evidence that life will be prolonged, or he can take a pill that reduces risk of prostate cancer by 25% and also reduces risk of urinary retention and transurethral resection of the prostate, and treats BPH symptoms. “I think we have a responsibility to offer prevention strategies to patients who have concerns about prostate cancer risk,” he summarized.

Consensus Statement on the Use of 5-alpha Reductase Inhibitors

The Canadian Consensus Statement on the use of 5-alpha reductase inhibitors in BPH and prostate cancer prevention was a result of a meeting organized by the Canadian Urology Research Consortium (CURC) and the Canadian Uro-Oncology Group (CUOG), reported Dr. Fred Saad, Professor of Surgery, CHUM-Hôpital Notre-Dame, Montreal, Quebec. A group of experts in the field gathered to address clinical practice issues raised by new data from the PCPT and MTOPS trials and concluded that MTOPS demonstrated that 5-alpha reductase inhibitors are appropriate and effective treatment for patients with lower urinary tract symptoms (LUTS) associated with demonstrated prostatic enlargement (>30 cc), and in patients without prostate cancer, a PSA level of >1.5 is a useful marker for prostatic enlargement.

The Consensus key points are: “The overall results from PCPT and MTOPS are of significant importance. Prostate management guidelines should be updated to include results from both the MTOPS and PCPT studies. In men who have large prostates and LUTS, 5-alpha reductase inhibitors should be considered, both for treatment of BPH and prostate cancer risk reduction. For men who are concerned about prostate cancer, it is appropriate to discuss chemoprevention with finasteride. Prostate cancer risk reduction has been demonstrated in PCPT with finasteride. A class effect with respect to dutasteride has not yet been established. Urologists are encouraged to disseminate these recommendations.”

Summary

Dr. Klotz explained that urologists are interventionalists by training who traditionally diagnose and treat diseases rather than prevent them, but that is now changing. In response to a case scenario, half of the audience supported the use of 5-alpha reductase inhibitors for prevention in patients in whom that was the only indication. “It is a lot like the statin story. You have got to identify patients who are at risk, and in them it makes sense. It does not mean everyone should get it, but to make a long story short, the drug works.”