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A Relevant Therapeutic Target for Patients with Benign Prostatic Hyperplasia
Improving Survival in Follicular Lymphoma

The Evolution of 5-alpha Reductase Inhibition in Benign Prostatic Hyperplasia and Prostate Cancer Prevention

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.

101st Annual Meeting of the American Urological Association

Atlanta, Georgia / May 20-25, 2006

The PCPT (Prostate Cancer Prevention Trial) involved 19,000 men 55 years or older with a normal digital rectal exam and prostate-specific antigen (PSA) level £3 ng/mL (Thompson et al. N Engl J Med 2003;349(3):215-24). They were randomized to the 5-alpha reductase inhibitor finasteride or placebo and followed for a maximum of seven years. The trial was stopped early when an interim analysis revealed a statistically significant 24.8% reduction in prostate cancer incidence in the active treatment group. If applied to the entire US population of men over the age of 50, the reduction would translate into 262,567 person-years of life saved over a 10-year period (Unger et al. Urol Oncol 2004;22(4):362-8).

“A Nobel laureate has come to the conclusion that a person-year of life saved in the US is worth about $200,000,” Dr. Ian M. Thompson, Chair and Professor, University of Texas Health Sciences Center, San Antonio, told delegates. “You can do the math and see that this is no trivial matter.”

Enthusiasm for the PCPT findings was tempered by the observation that actively-treated patients had a 6.4% prevalence of high-grade cancer (Gleason score 7-10), compared to 5.1% in the placebo group. Although small, the difference was statistically significant and evoked concern that the 5-alpha reductase inhibitor might have induced high-grade cancer, explained Dr. Thompson.

New Analyses of PCPT Data

Since publication of the PCPT findings, new analyses of data from this trial as well as other sources have dispelled the concern that finasteride induced high-grade cancer. The first piece of evidence emerged from the observation that the difference in high-grade cancer did not increase over time, a point noted in at least one letter to the editor written in response to the PCPT’s published results (Roehrborn CG. N Engl J Med 2003;349(16):1569-72). The increase in high-grade cancer occurred only in men who had the shortest exposure to finasteride (less than seven years). Among those who received the 5-alpha reductase inhibitor for a full seven years, the prevalence of high-grade cancer did not differ from the placebo group. If the agent had induced high-grade cancer, the difference from the placebo group would have been expected to increase over time with increased exposure. In the Breast Cancer Prevention Trial, for example, the difference in endometrial cancer risk increased over time with longer duration of exposure to tamoxifen (Fisher et al. J Natl Cancer Inst 1998;90(18):1371-88).

At the AUA meeting, Dr. Thompson presented a new analysis of PCPT data, showing that a difference in PSA performance characteristics between finasteride and placebo explained, at least in part, the difference in high-grade cancer. The analysis involved 9700 men who had a biopsy and PSA measurement within one year of biopsy. The data provided the basis for calculating the sensitivity and receiver operating characteristic curve for cancer detection. For detection of any cancer, detection of Gleason 7+ cancer and detection of Gleason 8+ cancer, the area under the curve (AUC) was greater with the 5-alpha reductase inhibitor, reflecting greater sensitivity for cancer detection. “Finasteride significantly improves the operating characteristics of PSA for the early detection of cancer,” indicated Dr. Thompson. “Said otherwise, for any given value of specificity, sensitivity for cancer detection is improved and detection of high-grade cancer also is improved.”

Another key piece of evidence was the recognition that patients in the PCPT active treatment arm had prostates that were 25% smaller than those of men in the placebo arm. The finding led to speculation that the reduction in gland size with the compound increased the proportion of the gland sampled with the sextant biopsy technique used in the PCPT. Investigators at the University of Toronto-Princess Margaret Hospital have reported evidence to corroborate that speculation. In a review of 369 cases of prostate cancer treated with radical prostatectomy, the likelihood that high-grade cancer was not detected on biopsy increased with gland volume (Kulkarni et al. J Urol 2006;175(2):505-9).

Prostate Volume and Cancer Detection

Additional evidence of the relationship between prostate volume and prostate cancer detection was evaluated by an international research group that included Drs. Luc Valiquette and Pierre Karakiewicz, Cancer Prognostics and Outcomes Unit, Université de Montréal, Quebec, in a study that involved 3412 patients who underwent radical prostatectomy. PSA ranged from 0.12 to 50 (median 6.7) and clinical stages were T1c in 66.6% of patients, T2 in 32.4% and T3 in 1%. Gleason scores at biopsy were £6 in 68.9% of patients, 7 in 28% and 8-10 in 3.1%, while prostate volume ranged from 11 to 214 cc (median 44 cc).

The association between clinical predictors (PSA, clinical stage, Gleason score at biopsy, prostate volume) and high-grade prostate cancer (pathological Gleason score 7) were tested by univariate and multivariate logistic regression models, where high-grade prostate cancer was found in 1806 (52.4%) of the radical prostatectomy cohort. Researchers also reported that the prevalence of high-grade prostate cancer decreased significantly with increased prostate volume in the univariate analysis (Q1: prostate volume <34 cc, 56.7%; Q2: 34-44 cc, 56.8%; Q3: 45-58 cc, 53.2%; and Q4: 59cc, 42.3%). In addition to prostate volume, Gleason scores at biopsy, PSA and clinical stage were also found to be significant predictors of high-grade prostate cancer (P<0.005). In the multivariate analysis, all four predictors remained statistically significant (P<0.001).

According to investigators, this analysis demonstrated that prostate volume confers a protective effect on high-grade prostate cancer, findings that are corroborated with those of the PCPT. Based on this analysis, researchers deemed it safe to assume that the increased rate of high-grade prostate cancer in small glands was gland volume-related in the PCPT.

More evidence of a sampling differential has emerged from an as-yet unpublished pathology study involving the PCPT. Prostatectomy specimens from men who developed cancer during the trial were evaluated by a panel of urologic pathologists. Comparing biopsy and prostatectomy findings, the panel found that high-grade cancer was missed on biopsy more often in the placebo group; more tumours were upgraded at prostatectomy in the placebo group and more were downgraded in the finasteride group; and high-grade cancer identified at prostatectomy was missed on 50% of biopsies in the placebo group, compared to 29% in the finasteride-treated group.

Summarizing the clinical implications of the new findings, Dr. Thompson concluded, “These data would suggest that this intervention [finasteride] should be seriously considered as a public health approach with minimal morbidity, other genitourinary benefits and one with clear-cut evidence of a reduction in disease. Against a backdrop of very few clinical trials establishing proof of efficacy in prostate cancer, it is an exciting advance in control of the disease.”

Changing Opinions

The data that have emerged since publication of the PCPT findings have already begun to influence the thinking of opinion leaders in urology. Dr. Claus Roehrborn, Professor and Chair, Department of Urology, University of Texas Southwestern Medical Center, Dallas, noted that an editorial accompanying the original PCPT report emphasized the increased prevalence of high-grade cancer and concluded that “finasteride does not seem to be attractive for the chemoprevention of prostate cancer” (Scardino PT. N Engl J Med 2003;349(3):297-9). Two years later, the same editorialist came to the following conclusion: “Chemoprevention of prostate cancer is at hand. The implications for management are profound... Life-saving radical surgery and therapy for prostate cancer will persist but the need is likely to fall substantially as chemoprevention is established and embraced” (Scardino PT. Nat Clin Pract Urol 2005;2(8):355).

An ongoing clinical trial aims to determine the impact of 5-alpha reductase inhibition therapy on prostate cancer in men at high risk for the disease. In contrast to the PCPT patient population, the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial involves men who are deemed at risk for prostate cancer because of a need for prostate biopsy determined by clinical evaluation (elevated PSA value or abnormal digital rectal exam). Although clinical implications of the REDUCE trial are still a few years away, “Five-alpha reductase inhibitors provide a promising new option for the chemoprevention of prostate cancer,” Dr. Roehrborn concluded.

Renaissance in Benign Prostatic Hyperplasia Management

Advances in the management of BPH have included recognition of new factors involved in disease progression, clarification of the roles of various options for medical treatment (including combination therapy) and examination of relationships among BPH, lower urinary tract symptoms (LUTS) and male sexual dysfunction.

The MTOPS (Medical Therapy of Prostatic Symptoms) trial provided some of the first evidence that inflammation plays a role in BPH progression, according to Dr. Steven Kaplan, Chief, Institute for Bladder and Prostate Health, Weill Medical College, Cornell University, New York. A recent analysis of MTOPS data showed that evidence of chronic inflammation was significantly associated (P=0.003) with progression to acute urinary retention and with a trend toward overall progression (Roehrborn et al. AUA 2005 Annual Meeting, Abstract 1277).

Other evidence of a role for inflammation has come from a study showing that increased levels of pro-inflammatory C-reactive protein were associated with an increased likelihood that a man would have three or more symptoms of LUTS. Study findings from the literature (Novara et al. Eur Urol Suppl 2005;5:401-9) and as presented by researchers here at the AUA (Hrachowitz et al., Abstract 1448; Penna et al., Abstract 1451) also have shown that BPH can induce and sustain a chronic autoimmune inflammatory process; moreover, BPH may be closely associated with the pro-inflammatory cytokine interleukin-17 and may promote a cascade of pro-inflammatory molecules. “This information is intriguing, but I think the concept and the role that inflammation plays in BPH remains to be determined,” Dr. Kaplan cautioned.

Another as yet undefined association involves BPH and apoptosis or programmed cell death. BPH has been shown to be associated with a reduced rate of apoptosis, noted Dr. Kaplan. Studies have shown that 5-alpha reductase inhibitors have pro-apoptotic effects, but whether these observations have clinical relevance remains to be seen, he observed.

Emerging Influences in BPH

Obesity has emerged as another factor in the development and progression of BPH. Data from the Baltimore Longitudinal Study of Aging demonstrated a significant association (P<0.01) between body mass index (BMI), severity of BPH symptoms and prostate volume (Parsons et al. AUA 2005 Annual Meeting, Abstract 1278). Another recent study showed that waist circumference >90 cm had a significant (P=0.037) association with BPH risk and that BMI ³25 and central obesity significantly increased (P=0.008) the risk of BPH (Lee et al. Obesity (Silver Spring) 2006;14(1):172-9). “The relationships between obesity and BPH and BPH symptoms are absolutely stunning,” commented Dr. Kaplan. “The emerging data on this issue are fascinating, and I think the data present urologists with a great opportunity to look at, understand and modulate what appears to be a very important factor in BPH.”

The prevalence of both BPH/LUTS and sexual dysfunction increases with age. This common feature of the two conditions has led a growing number of urology experts to take a closer look at the relationships between BPH/LUTS and sexual dysfunction in men. “Impaired sexual performance remains an undesirable side effect of BPH and treatment often produces significant clinical improvement and symptom reduction,” Dr. Kaplan confirmed.

Available data suggest that sympathetic activity may mediate LUTS and erectile dysfunction. Given that potential common etiology, a therapeutic strategy that addresses both conditions may be advantageous. Dr. Kaplan has reported that treatment with an alpha-blocker improves sexual quality of life in men with BPH/LUTS (Uckert et al. J Urol 2001;166(6):2484-90). Moreover, the type 5 phosphodiesterase (PDE5) inhibitor sildenafil has been found to improve urinary scores (Kaplan SA. Urology 2004;63(3):428-34, Sairam et al. BJU Int 2002;90(9):836-9). Several studies presented here during the scientific sessions provided additional evidence of the efficacy of PDE5 inhibition in the treatment of men with LUTS and sexual dysfunction. “If you put all the data together, the connection between sexual dysfunction and LUTS is more than just an age-related phenomenon,” stated Dr. Kaplan.

Clarifying Management

The MTOPS trial offered insight into the roles of various options for medical treatment of BPH/LUTS. In particular, the trial provided strong evidence that the combination of a 5-alpha reductase inhibitor and an alpha-blocker offers the greatest protection against BPH progression. Clarification of the role of individual compounds has continued to evolve since the results of the trial were announced.

Continued analysis of the MTOPS data have shown that alpha-blockers’ ability to prevent BPH progression is limited to men with small prostates, noted Dr. Kaplan. In contrast, 5-alpha reductase inhibitors offer protection against progression across the spectrum of prostate volumes, with benefits to patients with a prostate volume >25 cc.

Emerging data on the therapeutic role of 5-alpha reductase inhibitors have shown that long-term treatment results in clinically meaningful symptomatic improvement. Serum testosterone has been shown to be a key influence on prostate volume and BPH symptoms. Treatment with a 5-alpha reductase inhibitor reduces BPH symptoms to a similar degree across the range of baseline testosterone levels (Marberger et al. J Clin Endocrinol Metab 2006;91(4):1323-8). Moreover, men with the most severe symptoms at baseline derive the greatest benefit from long-term treatment with a 5-alpha reductase inhibitor (Roehrborn et al. AUA 2005 Annual Meeting, Abstract 1646).

Summary

The changing landscape of BPH/LUTS management, including the association with sexual dysfunction and other factors such as obesity, indicates a need for change in urologists’ clinical perspective, Dr. Kaplan suggested. The growing body of evidence linking different conditions suggests that “male pelvic dysfunction” might be a more appropriate term to describe the clinical picture that men present. He added that urologists should take the lead in making the perceptual and clinical transformation to ensure that their patients receive the best possible care for their symptoms.

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