This review provides an overview of the most relevant findings on prostate cancer (PCa) presented at the 2006 annual meetings of the European Association of Urology, American Urological Association, and the American Society of Clinical Oncology, which were discussed during the “New Horizons in Urology” closed meeting in Marbella, Spain, in October 2006.
Experts in the field of PCa selected and discussed the most relevant new studies. In addition, the participants’ opinion on two representative case studies was assessed by interactive voting, and results were commented on by the PCa experts.
With regard to the early detection of PCa, it was shown that there is no real PSA threshold. In addition, studies on active surveillance indicated that this is a feasible strategy for carefully selected patients, but that those patients with a PSA doubling time <12 mo are at elevated risk for PCa-associated progression and death. Furthermore, it was demonstrated that, besides histopathologic data of radical prostatectomy (RP) specimens, Partin tables also are not 100% reliable. Regarding localised disease, interim analysis at 67-mo follow-up showed that radiation therapy is comparable to RP in terms of survival and disease progression. High-intensity focused ultrasound is associated with low morbidity. Finally, intermittent hormonal therapy for advanced disease might be an option for regular practice. Zoledronic acid was found to prevent bone complications in patients on androgen-deprivation therapy.
Relevant new data on PCa presented at the major 2006 urologic/oncologic meetings have potential to improve screening, detection, and management of this disease.
Keywords: Bone mineral density, Brachytherapy, Chemotherapy, High-intensity focused ultrasound (HIFU), Hormone therapy, Prostate cancer, PSA, PSADT, Prostatectomy, Zoledronic acid.
Global cancer incidence rates show that prostate cancer (PCa), with more than 670,000 new diagnoses each year, has become the second most common cancer in men after lung cancer . The highest incidence rates are found in industrial countries, whereas China and India have the lowest incidence rates. Despite this obvious discrepancy between countries, substantial increases in incidence have been reported in recent years for many countries around the world . Although this increase has been suggested to result from the improved detection of PCa following transurethral resection of the prostate (TURP) and, more recently, from the advanced screening method based on detection of prostate-specific antigen (PSA), longer life expectancy and increased disease prevalence resulting from environmental carcinogens may also contribute to the increased incidence . Whether or not the observed increase is “real,” the number of cases is expected to keep on rising as the population at risk (older men) expands because of increasing life expectancy.
In recent years, stage distribution data have shown that 91% of men are diagnosed with PCa while the cancer is still confined to the primary site or after the cancer has spread to regional lymph nodes (localised or regional PCa), while only 5% are diagnosed after the cancer has metastasized (distant stage). In the latter case, the 5-yr survival is only 33.3%, whereas patients diagnosed with localised or regional PCa have a 5-yr survival rate of 100% (www.seer.cancer.gov). These substantial differences in survival rate emphasise the importance of early detection of PCa and the ongoing necessity to optimise and further improve the management of PCa.
Recent developments in the detection and management of PCa were presented in 2006 at the annual meetings from the European Association of Urology (EAU), the American Urological Association (AUA), and the American Society of Clinical Oncology (ASCO). A selection of interesting studies in PCa presented at these congresses was discussed during the “New Horizons in Urology” meeting in Marbella, Spain. Furthermore, participants to this meeting were asked to express their opinion on representative clinical case studies, illustrative of the chosen studies, by means of interactive voting. The results from this voting procedure were commented on by experts in the field of PCa.
2. Screening and detection
The introduction of PSA as a screening tool has profoundly altered the aspects of PCa detection in the past few decades. Although no universal PSA threshold is accepted, a PSA level >4
3. Natural history
Active surveillance or watchful waiting is a treatment strategy especially for men with favourable tumour characteristics and includes an active standpoint to postpone treatment until evidence of disease progression . At the AUA 2006 annual meeting, a study was presented that evaluated the clinical profiles and outcomes of men with PCa who were initially managed with active surveillance . A total of 240 patients were selected for active surveillance, of whom 140 met all of the following inclusion criteria: PSA
Besides providing a good basis for active surveillance, monitoring PSA values over time may also form the basis to calculate the PSA doubling time (PSADT). This tool is mainly used to predict outcomes such as time to progression and PCa-specific mortality . At the EAU 2006 annual meeting, Collette and colleagues  assessed the prognostic value of PSADT as predictor of objective progression or death. One hundred forty eligible patients retrieved from the watchful waiting arm of the European Organisation for Research and Treatment of Cancer (EORTC) trial 30891 were assigned to this study because they had a baseline PSA value between 8 and 50
The role of the pathologist has proven essential, not only in diagnosing PCa but also in planning therapeutic and management strategies . Pathologic data depend on an individual's interpretation of histologic source material and therefore should be treated with caution. With respect to this issue, van der Kwast and colleagues  presented data on their critical pathologic review of prostatectomy specimens. This study was part of the EORTC trial 22911 in which 503 patients previously treated with radical prostatectomy (RP) were randomly assigned to the control arm and 502 patients to immediate postoperative radiotherapy. A total of 552 prostatectomy specimens (280 control arm, 272 test arm) obtained in 12 major centres were reviewed by a single pathologist for stage, margin status, and Gleason score. Results demonstrated that there was a high agreement between local pathologists and the review pathologist with regard to seminal vesicle involvement (κ
Hence, it was emphasised at the closed meeting in Marbella that pathology results are a piece of information within a global set of parameters that should all be taken into account before a decision is made regarding therapy.
5. Predictive value of Partin tables
Partin tables were developed to estimate the pathologic stage of PCa on the basis of PSA level, Gleason score, and clinical stage; they have become an important tool in guiding decisions about effective treatment of PCa  and . A study presented at the EAU 2006 annual meeting evaluated the predictive value of the Partin tables in assessing the risk of lymph node involvement in patients undergoing RP for clinically localised PCa . Seven hundred forty-eight patients with cT1c PCa, a preoperative PSA
6. Treatment of localised disease
6.1. Laparoscopic radical prostatectomy
In the past several years, laparoscopic RP (LRP) has become an accepted alternative to open surgery. For both open and LRP, the presence of positive surgical margins (PSMs) is associated with an increased risk for biochemical and local recurrence . It has been shown that a PSM
6.2. Radiation therapy
Radiation therapy, comprising external beam radiation therapy (EBRT), brachytherapy, or a combination of both, is an established treatment strategy for patients with localised or locally advanced PCa. Still, there are no randomised studies available comparing either of these radiation treatment options with RP . At the EAU 2006 annual meeting, however, results were presented on the first multicentre, prospective, randomised trial comparing EBRT with retropubic RP by Di Stasi and colleagues . Between January 1997 and September 2001, 137 patients with clinically localised newly diagnosed PCa were randomised to either RP (N
In recent years, brachytherapy has become an accepted and standard means of therapy and is now an important therapeutic option available to radiation oncologists and urologists worldwide . At the AUA 2006 annual meeting, the long-term biochemical (PSA) freedom from failure (bFFF) of brachytherapy was investigated in 1562 men diagnosed with T1–3 PCa . Between 1990 and 2002, 54.7% of the patients were treated with radioactive iodine (125I), whereas 12.5% and 32.8% were treated with palladium (103Pd) or 103Pd combined with EBRT, respectively. Of these patients, 43.2% were regarded as low-risk patients, whereas 25.1% and 31.7% were categorised into intermediate- and high-risk patients, respectively. The median follow-up of the study was 5 yr (range: 2–15). The bFFF rate of the entire cohort was 84% at 12 yr with 88%, 90%, and 73% in low-, intermediate, and high-risk patients, respectively. Furthermore, 125I, 103Pd, or the combination therapy was associated with a bFFF rate of 86%, 75%, and 87% respectively. From these results, it was concluded that brachytherapy results in a low-level biochemical recurrence if patients are carefully selected .
6.3. High-intensity focused ultrasound (HIFU) as alternative treatment strategy
HIFU involves the emission of focused ultrasound waves inducing tissue damage by the conversion of mechanical energy into heat and by cavitation . Although HIFU is a technique that is not associated with the invasive character of surgical intervention, patients treated with HIFU are likely to experience significant posttreatment discomfort attributable to HIFU-related side-effects . At the EAU 2006 annual meeting, Thueroff and colleagues  analysed the side-effects resulting from >1300 HIFUs that were performed in a prospective single cohort study in men with localised PCa between April 1996 and November 2005. During follow-up, side-effects were documented and categorised into five main groups: systemic, micturition, infection, sexual, and rectum/pelvis problems. A total of 2745 events were registered, of which 42% were judged to be “therapy related”; the most frequent ones are summarised in Table 1. These results indicate that HIFU is associated with low morbidity; however, side-effects tend to increase with the number of local pretreatments.
|Side-effects||Primary HIFU mono||Second HIFU||HIFU salvage after multiple local pretreatments|
|Catheter time (median days)||5||4||4|
|Erectile dysfunction (%)||55||75||100|
|Urinary tract infection (%)||9.5||15.2||18.3|
|Stress incontinence (>3 mo) (%)||1.7||2.2||39|
|TURP after (%)||5||2||5|
|Rectourethral fistula (after 1999) (N)||2||1||5|
7. Treatment of advanced disease
7.1. Hormonal therapy
Hormonal therapy aims at depriving androgens, either through the suppression of androgen secretion by means of surgical or medical castration or through inhibition of the action of circulating androgens by using antiandrogens. Alternatively, these two approaches can be combined to achieve maximal androgen blockade (MAB). Although MAB has been proven to result in a small advantage in overall survival compared with castration alone, it is associated with increased adverse events and reduced QoL . In this respect, intermittent hormonal therapy might be a good alternative because of its potential to preserve the patient's QoL during the off-therapy periods. A randomised, phase 3 study  presented at the ASCO 2006 annual meeting compared intermittent versus continuous hormonal therapy. After an initial induction period of 3 mo with 200
7.2. Bone complications
Although androgen-deprivation therapy (ADT) is an effective treatment strategy for patients with PCa, it is associated with accelerated bone loss, osteoporosis, and an increased risk for fractures, even in patients without bone metastases . At the EAU 2006 annual meeting, Casey and colleagues  presented results from an open-label, controlled, multi-centre study that investigated whether zoledronic acid (ZA), known to be effective against skeletal complications in patients with bone metastases, can prevent bone loss in PCa patients without bone metastases on ADT therapy. Over a 12-mo period, 200 hormone-naïve men with locally advanced PCa were randomised at a 1:1 ratio to a control group receiving goserelin acetate alone or to a treatment group receiving ZA (4
8. Case studies
During the closed expert meeting “New Horizons in Urology,” held October 2006 in Marbella, the opinion of the participants with respect to two representative cases regarding PCa was assessed by an interactive voting procedure. The results were discussed and commented on by experts in the field of PCa.
8.1. Case 1
A 68-year-old man without lower urinary tract symptoms (LUTS) went to his general practitioner for his checkup. He had a PSA value of 8.2
With this information in mind, the first question posed to the audience was what the risk for biologic progression at 5 yr would be for this patient after curative treatment. The participants were asked to choose from three options. Sixty-five percent of the participants thought that the risk for progression at 5 yr was between 30% to 40%, whereas 27% believed the risk to be 60% to 70% and only 8% thought that the risk was <10%. The experts commented that the majority of the attendees were on the right track because the risk is usually between 40% to 50%.
Next, the participants were asked to choose from six possible treatment options if the patient was N0 M0. The majority choose RP (43%), one third went for EBRT plus LHRH agonist, whereas the reminder was divided between the other four options (Fig. 6). Although the majority choose RP, the patient eventually received radiation therapy combined with LHRH agonists for 3 yr. The experts commented that, because of the age of the patient and the therewith associated probability of his being unfit for surgery, normally one should not opt for RP. However, in recent years the elderly tend to be more fit at advanced age, so that, if carefully selected, these patients could be candidates for RP. It was, however, mentioned by the experts that, in this case, RP alone would probably not be sufficient and should be combined with either radiation or hormonal therapy.
Five years after ending LHRH agonist therapy, a PSA increase was measured: 3.9 to 5.1 to 6.4
8.2. Case 2
The second case was a 66-year-old man with severe LUTS. He had an international prostate symptom score (IPSS) of 24 and a PSA of 3.2
Assessment of the treatment preferences of the participants showed that 65% chose active surveillance, 29% opted for prostatectomy, and HIFU and LHRH agonist each got 3% of the votes. In line with the majority, the patient was actively followed with PSA measurement and DRE every 6 mo. During follow-up, PSA progressed from 1.2
Research on PCa produced numerous new interesting data that were presented at the 2006 key urologic and oncologic meetings. Although there has been a lot of debate on lowering the PSA threshold below 4
RP is still the favoured therapy for patients with localised disease. Although laparoscopic surgery is beneficial for the patient's QoL, it is also associated with an increased risk of PSM. It was, however, shown that patients with a PSM
With regard to advanced disease, it was demonstrated that intermittent hormonal therapy might be an option for clinical practice because it is comparable to continuous hormonal therapy in terms of disease control, but is associated with an improved sexual function. However, this seemingly equal effectiveness of both modalities should be further confirmed in a larger-scale study with a longer follow-up period. Finally, it was found that zoledronic acid is able to prevent bone complications in patients on ADT and, therefore, should perhaps be considered a standard supplementary agent during ADT.
Conflicts of interests
The author has nothing to disclose.
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