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.

28th Congress of the Société Internationale d’Urologie

Cape Town, South Africa / November 12-16, 2006

As reported by Dr. Christopher Chapple, Sheffield Hallam University, UK, with regards to hormonal therapy, there is compelling evidence for the benefit of 5-alpha reductase inhibitors in benign prostatic hyperplasia (BPH), especially in the larger-sized prostates of >30 to 40 cc. The efficacy and tolerability of the 5-alpha reductase inhibitors finasteride and dutasteride are similar, with a lesser magnitude of benefit than that seen with alpha-1 adrenoreceptor antagonists. The use of other hormonal alternatives in BPH has shown not to be tolerable or efficacious.

There has been much debate about pharmacological and prostate uroselectivity with alpha-1 adrenoreceptor antagonists but clinical uroselectivity is the most important. The efficacy of these agents in BPH has been demonstrated regardless of prostate size. All the agents in this class have a similar effect on the International Prostate Symptoms Score (IPSS) and urine flow rates, but they differ in terms of side effects, as tamsulosin and alfuzosin appear to have better tolerability than the other agents.

The benefit of preventing progression with combination therapy with the 5-alpha reductase inhibitor finasteride and the alpha-1 adrenoreceptor antagonist doxazosin was demonstrated in the MTOPS (Medical Therapy of Prostate Symptoms) study. Combination therapy is more effective than either agent alone, but there needs to be a balance between costs, efficacy and added side effects. The mechanisms of action and active ingredients in phytotherapy are poorly understood. The preparations differ widely and there are few blinded controlled studies in the literature. There is therefore limited evidence to support their use as a class.

Overactive bladder (OAB) symptoms may occur in bladder outlet obstruction (BOO) and are more bothersome than voiding symptoms; research in this area is ongoing. The use of antimuscarinics as monotherapy for OAB symptoms in the presence of BOO cannot be recommended although combination therapy with an antimuscarinic and an alpha-1 adrenoreceptor antagonist may be effective.

Dr. Anthony J. Costello, Royal Melbourne Hospital, Australia, examined the use of thermotherapy in the treatment of BPH. “As we have tried to minimize side effects of treatment, we have lessened the efficacy. Transurethral resection of the prostate [TURP] remains the treatment modality of choice for significant lower urinary tract symptoms [LUTS].” He concluded, “This is a modestly effective treatment for modest symptoms of BPH and it really does not threaten the gold standard, be it by electrocautery resection or laser resection of the prostate.”

Dr. Peter Gilling, Tauranga Hospital, New Zealand, presented a review of the literature on laser prostatectomy. There are different lasers available, which vary in technique and tissue effect. The treatment options include enucleation, resection, ablation/photoselective vaporization of the prostate (PVP) and coagulation. There are only three small, randomized studies comparing interstitial coagulation (IC) to TURP. IC has prolonged catheter times, significantly lower urine flow rates and more complications compared to TURP. In addition, the retreatment rate is 16% at one year and 40% at three years for IC. There is only a 19.4% reduction in prostate volume and this procedure has largely been abandoned outside the US. Laser ablation/PVP is done using the KTP (Greenlight PVP - 532nm) or the holmium (HoLAP - 2140 nm) laser. Both procedures are essentially equivalent; there is mainly single-centre series and little quality data for either technique. Three-year data for PVP in 139 patients demonstrated a 29% reduction in prostate volume.

Enucleation of the prostate uses a holmium laser and is essentially an endoscopic Millin’s prostatectomy. The technique needs a structured learning curve and techniques for tissue extraction are in their infancy, as more tissue is removed with this procedure. There are eight randomized, controlled trials for laser enucleation of the prostate and four are related to TURP where it has been shown to be more efficacious urodynamically. Laser enucleation was also compared to open prostatectomy in two randomized controlled studies. At 24 months’ efficacy, urodynamics appeared similar (Kuntz RM, Lehrich K. J Urol 2002; 168(4 Pt 1):1465-9, Naspro et al. Eur Urol 2006; 50(3):563-8). The evidence supports enucleation as the best way of using laser energy presently.

Preventing BPH Progression

Dr. Mark J. Speakman, Consultant Urologist and Associate Medical Director, Taunton & Somerset NHS Trust, UK, suggested that BPH is both a progressive and chronic disease. The factors that have been shown to be predictive of BPH progression are symptoms, bother, flow rate, age, prostate volume, prostate-specific antigen (PSA), residual volume and, more recently, inflammation. There is a threefold increased risk of urinary retention if the prostate volume is >40 cc and a ninefold increased risk if the PSA is >1.4 ng/mL (Marberger et al. Eur Urol 2000;38(5):563-8). Treatment with finasteride resulted in a 57% reduced risk of acute urinary retention (McConnell et al. N Engl J Med 1998;338(9) 557-63) and a similar response has been shown with dutasteride (Roehrborn et al. Urology 2002;60(3):434-41). Similar outcomes were seen in both studies with surgery being used as a progression marker.

The MTOPS study showed a 66% risk reduction of progression with the finasteride/doxazosin combination (McConnell et al. N Engl J Med 2003;349(25):2387-98). The cost of combination therapy is an issue, with the MTOPS study showing that 8.4 patients need to be treated to prevent one instance of progression. However, if only high-risk patients are treated (PSA >4 ng/mL or prostate volume >40 cc), then less than five patients need to be treated for one to benefit. Dr. Speakman commented, “Can we afford not to treat BPH progression?” A nomogram, based on the MTOPS data, was developed to help assess a patients’ risk for BPH progression and can be accessed at the following Web site: www.oncovance.com (Slawin KM, Kattan MW. Rev Urol 2004;6(2):89-92). Patients at high risk for BPH progression may benefit from combination therapy.

The Role of PSA in Screening, Diagnosis and Follow-up of Prostate Cancer

According to Dr. Richard D. Williams, Director, Department of Urology, University of Iowa, Iowa City, US prostate cancer incidence and mortality data showed that there has been an initial increase followed by a plateau in the incidence of prostate cancer since the introduction of PSA screening. However, a decrease in prostate cancer mortality is only evident in the past few years. He also stated that a fall in mortality is now being seen in data from the US SEER Registry, Canada and Austria. A fall in prostate cancer mortality is not seen in areas where prostate cancer screening is not performed, such as Mexico. Dr. Williams stated that possible reasons for mortality changes include earlier diagnosis from PSA screening, improved management, lead-time bias, changes in competing causes of death and changes in reporting deaths.

Screening for prostate cancer includes both a digital rectal examination (DRE) and a PSA. PSA has a higher cancer detection rate than DRE, but more effective when combined. PSA has not been ideal as no cut-off is either agreed upon or safe. Methods that have been used to improve the specificity of PSA include PSA velocity, PSA density, age-referenced PSA, per cent-free PSA and complexed PSA. Dr. Williams noted, “A single PSA may not mean very much. You need two or three longitudinal PSAs in general to determine whether the patient really has a high risk, unless their PSA is extremely high. We believe that 0.75 ng/mL/year is appropriate for those patients with 4-10 ng/mL, but there is new data to suggest that if their PSA is 2.5 ng/mL and their PSA velocity is 0.5 ng/mL/year, they may be at risk for having cancer.”

Concerns about PSA screening include costs. In the US, it is estimated that PSA screening will cost $25 billion during the first year alone if men 50-70 years of age are screened. Anxiety associated with prostate biopsy and the morbidity of both the biopsy and treatment are also issues to consider.

The advantages of PSA screening and early detection has been that the incidence of positive lymph nodes has decreased from 25 to 50% to 2 to 3%, and the incidence of organ-confined disease has increased from 40 to 82%. “These will very likely translate into improved long-term survival, but we are not totally there yet,” Dr. Williams told delegates. Whether prostate cancer screening will reduce mortality is currently unknown, but ongoing randomized studies may give us answers.

Dr. Williams concluded that patients at high risk (African-American and/or family history of prostate cancer) with a life expectancy of >10 years are prime candidates for screening at present, individuals whom he would start screening at age 40. Shared decision-making with all patients is Dr. Williams’ recommended approach and low-risk patients should be screened from age 50 if they desire. He remarked, “What we need is a cancer of the prostate progression marker that says you have it and it is likely to progress.”

Chemoprevention in Prostate Cancer

Dr. Claude Schulman, Director of Urology, Erasmus Hospital, Brussels, Belgium, commented that cancer mortality is largely unchanged over the past 30 years, whereas the mortality from heart disease has decreased by 30% in this period, which Dr. Schulman attributed to preventive medicine. Prostate cancer takes many years from genetic alteration to presentation, giving treating physicians time to act. Citing a Scandinavian cancer trial of 44,788 pairs of twins, only in 10% of cancers was genetics a contributing factor (Lichtenstein et al. N Engl J Med 2000; 343(2):78-85). In population migration studies of men from Asia migrating to the US or Europe, their incidence of prostate cancer increases. “Do not blame your genes, blame what is around you,” Dr. Schulman remarked.

Obesity, omega-6 fat, high animal fat and saturated fat diets are bad for prostate cancer. There is some evidence to show that vitamin E, lycopene, carotenoids, soy, phytoestrogens, calcium and selenium are good for prostate cancer, but more definitive information will be gained from the outcomes of the SELECT (Selenium and Vitamin E Cancer Prevention Trial).

The benefits of finasteride were shown in the PCPT (Prostate Cancer Prevention Trial) with a 24.8% decrease in risk of prostate cancer (Thompson et al. N Engl J Med 2003; 349(3):215-24) and there is some evidence that statins may also be beneficial for prostate cancer. Dr. Laurence Klotz, Professor of Surgery, University of Toronto, Ontario, dispelled concerns about high-grade tumours due to finasteride seen in the PCPT. He explained that this was due to decreased prostate volume and increased accuracy of PSA in the finasteride group. In addition, patients from the PCPT trial that went on to have a radical prostatectomy did not have higher-grade tumours.

Repeated Screening for Prostate Cancer

Dr. Judd Moul, Chief of Urology, Duke University Medical Centre, Durham, North Carolina, presented data demonstrating that with serial screening, 72% of prostate cancer is T1c. The rate of organ-confined disease increased from 62% to 77% with serial screening. Serial screening is further driving the stage migration towards earlier-stage disease seen in the US and other developed countries.

Prof. Laurent Boccon-Gibod, Director of Urology, Hôpital Bichat, Paris, France, discussed indications for initial and repeat prostate biopsy. There are clear-cut indications for prostate biopsy, but biopsy indications in a patient with a marginally elevated PSA and a normal DRE depends on biopsy goal. “Is it to detect and treat every prostate cancer or only those that are potentially harmful to the patient?” he asked. To detect every cancer, every man 45 to 75 years of age should be biopsied, the result being a major risk of overtreatment. “We could probably look at it in a more sensible way and try only to diagnose those cancers that would be harmful to the patient, and probably we should seek to biopsy any patients who have any DRE abnormality or a PSA >4 ng/mL,” Prof. Boccon-Gibod suggested. Lowering the PSA threshold to 2.5 increases the number of biopsies performed but there is no documented benefit on prostate cancer-specific mortality.

Repeat biopsy should be done after an initial negative biopsy if the tissue is insufficient. The number of cores should be eight to 12 with a minimum length of 10 mm in each core. Biopsy is also indicated for a persistently elevated or rising PSA (Djavan et al. Eur Urol 2002;42(2):92-103). The incidence of prostate cancer associated with high-grade prostate intraepithelial neoplasia was reduced from 40 to 25% due to more biopsy cores being taken. Follow-up PSA and re-biopsy at one year is recommended. Atypical small acinar proliferation is associated with prostate cancer in ³40% of cases and any suspicious focus on biopsy are also indications for re-biopsy (Epstein JI, Herawi M. J Urol 2006;175(3 Pt 1):820-34). When an initial biopsy shows a micro-focus of cancer, saturation biopsy (32 cores) is suggested and this is negative in 30% of patients (Boccon-Gibod et al. J Urol 2006; 176(3):961-3). Initial and repeat biopsy is based on risk assessment. Adequate sampling, optimal pathological submission and evaluation should reduce doubtful results.

Summary

Prostate disease confers a significant burden on health care resources; BPH and prostate cancer both have significant morbidity. The management of BPH has undergone the trend that is seen widely in medicine of ‘doing more by doing less’ but these treatment modalities must all be compared to the gold standard.

Patients at high risk for the development of prostate cancer must be identified and appropriate preventive strategies implemented. In patients with prostate cancer, there are still challenges to identify those patients with clinically significant disease and thus prevent the morbidity associated with unnecessary treatment.