In 2006, prostate cancer accounted for approximately 20% of all noncutaneous cancers detected in European men, placing it at the top of the list of diagnosed cancers . Incidence rates of prostate cancer have risen dramatically across Europe in the last 2 decades but still vary by a factor of up to 4 in the different European countries (Fig 1 and Fig 2). This difference is clearly due to the variable use of early detection approaches, particularly prostate-specific antigen (PSA) screening, in asymptomatic patients. Surprisingly, although higher prostate cancer incidence has always been accompanied by profound stage and grade shifts , mortality rates across Europe do not reflect this variability (Fig. 1). This becomes even more apparent when adding the corresponding figures from the United States, with incidence and mortality rates of 173.8 and 30.3, respectively, per 100
2. Prostate cancer 2008
The incidence and mortality figures appear to suggest that a multitude of screen-detected cancers are clinically irrelevant within the lifetime of the patient. Consequently, population-based PSA screening is generally discouraged . Mortality figures in geographic and ecologic studies, however, are also heavily affected by patient selection, data procurement, and therapeutic strategies, so caution is advised when comparing these studies directly . Analyses of trends in prostate cancer mortality are more conclusive, and these are beginning to show a gradual reduction in prostate cancer mortality in relation to the intensity of PSA screening , , , and . Ultimately, assessment of the value of population-based prostate cancer screening will have to come from the large prospective randomised trials presently under way. Nevertheless, in today's clinical practice, “opportunistic” PSA screening is a fact and is probably here to stay.
As a result, urologists are seeing more prostate cancer of lower volume and with less progressive potential in younger patients. Many of these tumours have the histologic characteristics of autopsy tumours, which have been documented in up to 55% of men aged 50–60 yr who died of unrelated causes . If detected in patients, there is a high chance that such tumours would never cause symptoms during the patient's lifetime. Termed indolent or clinically insignificant cancers, they probably need not be diagnosed or even treated. The definition of clinically insignificant cancers varies, but the Epstein criteria  are most commonly applied: no Gleason grade 4/5 in lesion, tumour volume <0.5
Even when defined as clinically significant, low-volume, low-grade prostate cancers tend to progress slowly. If untreated, they affect survival curves only beyond a life expectancy of at least 10 yr  and . Consequently, active surveillance has become an accepted management strategy for tumours of this category . Prostate cancer incidence increases at a logarithmic scale with age. In Austria, the prevalence of opportunistic PSA screening is 55.8% in men aged 40–79 yr . Although the incidence in younger men is rising, more than one-third of localised cancers are still detected in men aged >70 yr  (Table 1), who have limited life expectancy and higher comorbidity. Public awareness campaigns make it difficult to exclude older men from early detection programmes, even if they will gain no benefit from such detection.
|n||Per 100 000||n||Per 100 000||n||Per 100 000|
Unfortunately, prostate cancer tends to be heterogeneous, and adverse histologic criteria may be missed at biopsy. In clinical practice, indolent cancers are difficult to separate from cancers with aggressive potential that are detected early and need therapy – the key target in patients who profit from early diagnosis. In a study by Epstein et al  of 103 patients with biopsy criteria suggestive of clinically insignificant cancers, 26% had Gleason grade >4, 29% had tumour volumes >0.5
The complexity of the issue was compounded by the unexpected results of a routine sextant biopsy in 2950 men with serum PSA <4
The dilemma the urologist faces today is that although prostate cancer is still a killing cancer, early detection approaches increase the detection of indolent cancers with the risk of overdiagnosis and overtreatment, and dangerous tumours are missed. Present evaluation of the aggressive potential and prognosis of individual cancers remains problematic.
3. Identifying clinically relevant cancer
Identifying clinically relevant prostate cancer pivots around the decision to biopsy. In the absence of abnormal clinical findings, the driving factor is PSA, which is still considered to be the best routinely available biomarker  and . There is no consensus on upper cut-off points of “normal” PSA levels, especially in view of the PCPT data, but at <1
The biopsy technique also plays a crucial role. In the European Prostate Cancer Detection Study, patients with PSA in the range of 4–10
Ruling out low-volume, high-grade cancer by biopsy remains unreliable. Even with ex vivo saturation biopsies averaging 44 cores from radical prostatectomy specimens, clinically significant cancers were missed in 11.4% of the specimens . In addition to Gleason pattern, the amount of cancer in a systematic biopsy specimen and clinical data such as PSA and stage reflect the aggressive potential of the tumour. Logistic regression based on large clinical series was used to develop models for predicting the presence of indolent cancers  and . The resulting nomograms provide the best tool presently available in this context, but the dissemination (area under the receiver operator characteristic [ROC] curve) is still <0.80 in most models. In clinical practice, this may mean an incorrect decision in approximately one out of five patients.
In essence, the individual decision as to whether the cancer detected is threatening and needs treatment is still heavily influenced by subjective factors, such as the patient's and the doctor's preferences. More specific biomarkers to assist in this decision are sorely needed. They are now on the horizon, as Dr J. Schalken presents in this issue.
4. Preventing prostate cancer
Given the slow progression of many prostate cancers, as reflected by issues of lead-time bias, overdiagnosis, and active surveillance, attempts to decelerate progression by active intervention before tumours become clinically relevant appear attractive. Evolving concepts of the mechanisms involved in carcinogenesis of prostate cancer suggest an early phase of initiating events causing genome damage by injury from exposure to oxidants and carcinogens  (Fig. 3). Inflammatory responses, possibly as a reaction to exogenous infection, appear to be key initiating events . Proliferative inflammatory atrophy is the morphologic sign of rapidly dividing epithelial cells under stress that do not fully differentiate  and . Their close proximity to lesions of prostatic intraepithelial neoplasia (PIN) and prostate cancer is well documented . Men with genetic variants of genes important for host response to inflammation, such as RNASEL at chromosome 1q24-25 and MSRI at chromosome 8p22-23, appear to be at higher risk because of impaired protective mechanisms. With somatic fusions between the androgen-regulated gene TMPRSSZ and genes encoding ETS family transcription factors, the initiation phase of carcinogenesis changes to the promotion phase, in which malignant progression appears to be directly driven by androgenic hormone signalling .
Interference with this complex chain of events can theoretically prevent prostate cancer. By definition, this would be primary prevention if malignant cell development is avoided and secondary prevention if the transformation of occult to clinically relevant cancer is interrupted. For late-life manifestations of prostate cancers, even just delaying oncogenesis may have the same clinical effect.
Evidence that environmental factors can affect this chain of events comes from ecologic epidemiology. Prostate cancer incidence varies greatly in different regions of the world, and migrants from regions of low cancer-death rates to regions of high mortality experience a dramatic increase in prostate cancer risk within their lifetime . Case-control studies identified a number of environmental, mainly dietary, risk factors as possible explanations for this phenomenon. Consequently, dietary modifications reducing assumed risk factors and/or adding antioxidants have been widely propagated. Unfortunately, epidemiologic studies of this type must be viewed with caution, and only adequately powered prospective randomised trials can be considered conclusive. This is illustrated by the Southern Finland/ATBC Study (FIN-ATB) of cancer prevention . Case control studies from the Finnish cancer registry had suggested that high dietary β-carotene reduces prostate cancer risk significantly, but a prospective randomised study of almost 30
Direct medical intervention in specific phases of oncogenesis or chemoprevention appears to be a more logical approach. A plausible target for this strategy would be early control of inflammatory processes. In the absence of known causes of inflammation, targeting the reactive cells with cyclooxygenase-2 (COX-2) inhibitors appeared to be a compelling approach. Unfortunately, phase 3 studies had to be terminated prematurely due to unacceptably high numbers of adverse events . The lesson learned is that a successful prevention strategy for prostate cancer would currently need to have essentially no toxicity.
Later intervention in carcinogenesis by interfering with androgen signalling appears to be a more targeted and, therefore, more cost-effective approach. The risk–benefit ratio is favourably altered by 5α-reductase inhibitors, which also have a proven beneficial effect on benign prostatic hyperplasia (BPH)  and . The key for wider acceptance of these chemopreventive strategies will be targeting higher risk patients for whom the treatment numbers needed to prevent clinically significant cancer can be reduced to ratios that are acceptable in clinical practice . These issues are covered in detail in Dr V. Ravery's article in this issue.
5. Improving endocrine therapy
Depending on the intensity of early detection programmes, one out of 2.5–6 patients with prostate cancer ultimately dies from the disease. Endocrine therapy is the mainstay of therapy for progressive prostate cancer and will usually be received by all patients in this category; a fatal outcome reflects its failure.
Data from the USA show that the use of hormonal therapy in prostate cancer has increased despite the stage or grade shift to lower risk cancers . Improvements in prostate cancer mortality are most pronounced in patients >70 yr of age (Table 1). Early hormonal intervention that delays death from prostate cancer long enough for the patient to die of unrelated causes has been postulated as a possible explanation , but more recent data refute this hypothesis of a positive effect of primary androgen deprivation in localised  or early advanced disease . Combining androgen deprivation with an antiandrogen (total androgen blockade) improves cancer-specific survival only marginally but increases adverse effects significantly . As detailed in the article by Dr L. Martinez-Pineiro in this issue, the focus on endocrine therapy has shifted more towards identifying subgroups of patients that profit from early hormonal therapy to improve treatment efficacy and to reduce the burden of adverse effects.
Recent studies have shown that cancers that do not respond to traditional androgen deprivation still show androgen-receptor signalling, high intratumoural androgens, and overexpression of enzymes that are key to androgen synthesis  and . Obviously, this activity is driven by nongonadal androgen sources . The definition of hormone-refractory prostate cancer has therefore been changed to castration-refractory prostate cancer, implying that other hormonal manipulations may still be able to affect the tumour cell . Traditional attempts to control nongonadal androgen synthesis with, for example, adrenalectomy, glucocorticoids, or ketoconazole have shown only modest benefits. Blockade of the microsomal enzyme CYP17 interrupts both androgen and oestrogen biosynthesis but leaves corticosterone synthesis unaffected. Abitarone acetate is a highly selective and irreversible CYP17 inhibitor which can be administered orally at low toxicity. Initial clinical studies suggest that it has significant benefits as second-line hormonal therapy , but further studies are needed to confirm this.
6. Integrating molecular oncology
The pivotal TAX 327 and Southwest Oncology Group (SWOG) 99-16 trials demonstrated improvement in overall survival of patients with castration-refractory metastatic prostate cancer who were treated with docetaxel-based chemotherapy. Since then, this treatment has become the mainstay of therapy for these patients. A recent update on survival analysis for TAX 327 confirmed that the benefits observed with the 3-weekly docetaxel protocol are sustained after a total of 3 yr . Multivariate analysis showed that baseline PSA and PSA kinetics are independent prognostic factors for survival, together with pain and measurable disease . Although an important step, the impact of docetaxel overall was modest, with only several months of survival advantage gained at the cost of considerable morbidity. Recent research has concentrated on efforts to improve the risk–benefit ratio by identifying patients who respond well, to better define criteria of treatment response, and to assess individual prognosis. Ensuring a sufficient window of drug exposure, even with initially deteriorating symptoms and PSA, and modelling length and dosage of therapy to response have proven to be significant challenges  and . Controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and preventing or delaying expected disease manifestations are now considered to be more useful end points than strict survival data or PSA kinetics .
The true frontier of development in the field comes from exploring novel approaches with other traditional cytotoxic agents, with or without docetaxel, and/or novel molecules targeting specific molecular pathways in tumour biology. A multitude of phase 2 and 3 studies are presently under way, investigating either primary or second-line therapy of castrate-resistant prostate cancer. In the final article of this issue, Dr K. Fizazi will cover potential targets for this approach, currently available data from phase 2 and 3 clinical studies, and an overview of where this field may be heading.
Urologists have come a long way in battling the most malignant disease of men. The advances in earlier diagnosis, better evaluation of the progressive potential of individual tumours, and better and less morbid curative therapy are beginning to result in reduced mortality statistics. Consequently, the majority of prostate cancers diagnosed today are low-risk, low-volume cancers, and decisions on whether treatment is required or can be postponed to a later point in case of progression and how active surveillance is safely monitored have become new challenges. Improved understanding of prostate cancer oncogenesis with identification of preclinical forms is also shifting interest to the new field of early medical intervention in the preclinical stage to prevent clinical prostate cancer. Unfortunately, despite these success stories, prostate cancer still tops cancer mortality statistics for men. Present management strategies for disseminated prostate cancer appear disappointingly insufficient. Treatment options that are more effective, less morbid, and adapted to the individual patient are urgently needed.
Conflicts of interest
Michael Marberger is a consultant with Merck & Co., GlaxoSmithKline, Richard Wolf, GP Pharm, and Vantas.
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© 2008 European Association of Urology, Published by Elsevier B.V.