Novel Tools to Improve Patient Selection and Monitoring on Active Surveillance for Low-risk Prostate Cancer: A Systematic Review

Context

Active surveillance (AS) is an alternative to initial radical treatment of low-risk prostate cancer (PCa). Current criteria for selection and follow-up incorrectly exclude some patients eligible for AS and misclassify some who actually harbour significant disease. Better prediction of cancer behaviour at diagnosis would allow less strict monitoring and may improve acceptance of AS.

Objective

To review and critically analyse the literature on the value of novel clinical tools for patient selection and monitoring on AS.

Evidence acquisition

A comprehensive search of the PubMed database until July 10, 2013, was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis statement guidelines. Studies assessing novel markers and diagnostics for patient selection for AS and follow-up during AS were included. Studies analysing only classic clinical parameters used in current protocols (prostate-specific antigen, prostate volume, number of (positive) prostate biopsies, percentage malignant tissue, Gleason score) were excluded. This review focuses only on the AS setting and not on predicting insignificant disease in general.

Evidence synthesis

Of 787 studies on AS, 30 were included in this review: 14 on magnetic resonance imaging (MRI), 5 on serum markers, 5 on urinary markers, 4 on histopathology markers, and 2 on germline genetic markers. Several of these markers improve the prediction of tumour volume, tumour grade, or time to active treatment. MRI has a high specificity for low-risk PCa; new serum markers are associated with unfavourable disease. In none of the studies was the new marker used as the primary decision tool. Long-term outcome measures such as mortality were not assessed. The definition of indolent PCa is disputable.

Conclusions

Imaging and serum markers may improve future patient selection for AS and follow-up during AS. Prospective studies should aim to further evaluate the clinical utility of these new markers with respect to longer term outcomes of AS.

Patient summary

We searched the literature for articles reporting new ways to safely monitor low-risk prostate cancer for patients who have not had radical treatment. We found 30 articles. The most promising tools appear to be magnetic resonance imaging scans and various new blood markers. These may be used in the future within active surveillance regimens.     

Eleven-Year Outcome of Patients with Prostate Cancers Diagnosed During Screening After Initial Negative Sextant Biopsies

Background

The appropriate way of biopsying a prostate remains controversial. Is sextant biopsy still adequate with repeat screening?

Objective

Within the European Randomized Study of Screening for Prostate Cancer (ERSPC), lateralized sextant biopsies were applied. In this analysis we use distant end points to study the fate of prostate cancers (PCa) potentially missed by initial biopsies.

Design, setting, and participants

This retrospective study included 19 970 men ages 55–74 identified from the Rotterdam population registry and screened repeatedly for PCa between 1993 and 2005. PCa detected later in men with initially negative biopsies were considered as missed. Rescreening every 4 yr and a complete follow-up of 11 yr allowed an inventory of progressive and deadly disease in these men.

Intervention

Sextant biopsies initially, later lateralized, in screen-positive men.

Measurements

The fate of PCa potentially missed by initial sextant biopsies in terms of progression-free and PCa-specific survival were the main outcome measures. Kaplan-Meier analysis was used to evaluate differences between subgroups.

Results and limitations

In 3056 men with negative biopsies at the first screen, 287 PCa were subsequently detected. Of these 287 cases, 26 developed progressive disease and 7 died of PCa. Poor outcomes were encountered mainly in 20 interval cases. The seven PCa deaths in men with initially negative biopsies amounted to only 0.03% compared to the 0.35% PCa death rate in the whole population of 19 970 men. Limitations include the retrospective character of this analysis.

Conclusions

The number of potentially missed cancers with a poor outcome in terms of progression-free survival and deaths from PCa is very low. Despite some limitations, our data show that lateralized sextant biopsy is not obsolete if repeated screening is applied.     

Bone turnover markers as predictors of mortality risk in prostate cancer patients with bone metastases following treatment with zoledronic acid

Background

Clinical data have limited validity for predicting the survival of prostate cancer (PCa) patients with bone metastases. There is a need to improve the predictive evidence both for clinicians and patients.

Objective

To evaluate the predictive ability of serum bone markers for mortality risk in PCa patients with bone metastases.

Design, setting, and participants

We conducted a survival analysis in relation to bone markers in a subgroup of 52 patients treated with zoledronic acid (4 mg every 4 wk for 15 mo) in a prospective, multicentre trial during 2002–2005, about 4 yr after the end of the trial.

Measurements

Serum levels of total and bone-specific alkaline phosphatase, amino-terminal procollagen propeptides of type I collagen (PINP), cross-linked N-terminal (NTx) and cross-linked C-terminal telopeptides of type I collagen (ICTP), C-terminal telopeptides of type I collagen, prostate-specific antigen from the last visit of the treatment study, and clinical data were related to the overall survival (OS) status of patients in the follow-up. Univariate and multivariate Cox regression analyses with internal bootstrapping validation and concordance index calculations were performed.

Results and limitations

Out of the 52 patients followed, 34 died within a median follow-up of 13.8 mo, and 18 patients were alive at a median follow-up of 43.8 mo. The patients who died within the follow-up period had significantly higher concentrations of ICTP, NTx, and PINP than the surviving patients. Cox regression models with clinical data and bone markers showed that ICTP and PINP were most predictive for mortality risk in addition to the occurrence of skeletal-related complications and the continuation of treatment with zoledronic acid. Internal validation confirmed the reliability of the results, although the sample size was small.

Conclusions

PINP and ICTP can be considered suitable predictors for the OS of PCa patients with bone metastases.     

Potential Impact of Adding Genetic Markers to Clinical Parameters in Predicting Prostate Biopsy Outcomes in Men Following an Initial Negative Biopsy: Findings from the REDUCE Trial

Background

Several germline single nucleotide polymorphisms (SNPs) have been consistently associated with prostate cancer (PCa) risk.

Objective

To determine whether there is an improvement in PCa risk prediction by adding these SNPs to existing predictors of PCa.

Design, setting, and participants

Subjects included men in the placebo arm of the randomized Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial in whom germline DNA was available. All men had an initial negative prostate biopsy and underwent study-mandated biopsies at 2 yr and 4 yr. Predictive performance of baseline clinical parameters and/or a genetic score based on 33 established PCa risk-associated SNPs was evaluated.

Outcome measurements and statistical analysis

Area under the receiver operating characteristic curves (AUC) were used to compare different models with different predictors. Net reclassification improvement (NRI) and decision curve analysis (DCA) were used to assess changes in risk prediction by adding genetic markers.

Results and limitations

Among 1654 men, genetic score was a significant predictor of positive biopsy, even after adjusting for known clinical variables and family history (p = 3.41 × 10⁻⁸). The AUC for the genetic score exceeded that of any other PCa predictor at 0.59. Adding the genetic score to the best clinical model improved the AUC from 0.62 to 0.66 (p < 0.001), reclassified PCa risk in 33% of men (NRI: 0.10; p = 0.002), resulted in higher net benefit from DCA, and decreased the number of biopsies needed to detect the same number of PCa instances. The benefit of adding the genetic score was greatest among men at intermediate risk (25th percentile to 75th percentile). Similar results were found for high-grade (Gleason score ≥7) PCa. A major limitation of this study was its focus on white patients only.

Conclusions

Adding genetic markers to current clinical parameters may improve PCa risk prediction. The improvement is modest but may be helpful for better determining the need for repeat prostate biopsy. The clinical impact of these results requires further study.     

A panel of TMPRSS2:ERG fusion transcript markers for urine-based prostate cancer detection with high specificity and sensitivity

Background

The TMPRSS2:ERG fusion is both prevalent and unique to prostate cancer (PCa) and has great potential for noninvasive diagnosis of PCa in bodily fluids.

Objectives

To evaluate the specificity and sensitivity of the TMPRSS2:ERG fusion in urine from diverse clinical contexts and to explore potential clinical applications.

Design, setting, and participants

A total of 101 subjects were enrolled in 2008 from urologic oncology clinics to form three study groups: 44 PCa free, 46 confirmed PCa, and 11 negative prostate biopsies. The PCa-free group included females, healthy young men, and post–radical prostatectomy (RP) patients. The confirmed PCa group was composed of patients under active surveillance, scheduled for treatment, or with metastatic disease.

Measurements

Urine was collected after attentive digital rectal exam (DRE) and coded to blind group allocation for laboratory test. RNA from urine sediments was analyzed using a panel of four TMPRSS2:ERG fusion markers with quantitative polymerase chain reaction (qPCR).

Results and limitations

Our fusion markers demonstrated very high technical specificity and sensitivity for detecting a single fusion-positive cancer cell (VCaP) in the presence of at least 3000 cells in urine sediments. In clinical analysis, there were no fusion-positive samples in the PCa-free group (0 of 44 samples), while there were 16 of 46 (34.8%) fusion-positive samples in the confirmed PCa group. The fusion incidence varied significantly among the three PCa subgroups. The clinical sensitivity increased to 45.4% in cancer patients prior to treatments. The fusion markers were detected in 2 of 11 (18.2%) biopsy-negative patients, suggesting potentially false negative biopsies. This study is not prospective and is limited in sample sizes.

Conclusions

Our novel panel of TMPRSS2:ERG fusion markers provided a very specific and sensitive tool for urine-based detection of PCa. Theses markers can potentially be used to diagnose patients with PCa who have negative biopsies.     

The Evolving Role of Oestrogens and Their Receptors in the Development and Progression of Prostate Cancer

Context

Oestrogens were proven effective in the hormonal treatment of advanced prostate cancer (PCa) >60 yr ago and are still used as second-line hormonal therapy. Paradoxically, oestrogens might also be involved in the development and progression of PCa.

Objective

To examine mechanisms of how oestrogens may affect prostate carcinogenesis and tumour progression.

Evidence acquisition

Recent data obtained from animal, experimental, and clinical studies were reviewed.

Evidence synthesis

The human prostate is equipped with a dual system of oestrogen receptors (oestrogen receptor alpha [ERα], oestrogen receptor beta [ERβ]) that undergoes profound remodelling during PCa development and tumour progression. In high-grade prostatic intraepithelial neoplasia (HGPIN), the ERα is upregulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. Preliminary clinical studies with the ERα antagonist toremifene have identified the ERα as a promising target for PCa prevention. The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumour suppressor. The ERβ is generally retained in hormone-naïve PCa but is partially lost in castration-resistant disease. The progressive emergence of the ERα and the oestrogen-regulated progesterone receptor (PR) during PCa progression and hormone-refractory disease suggests that these tumours can use oestrogens and progestins for their growth. The TMPRSS2-ERG gene fusion recently reported as a potentially aggressive molecular subtype of PCa is regulated by ER-dependent signalling. TMPRSS2-ERG expression has been found to be increased by ERα agonist (oestrogens) and decreased by ERβ agonists.

Conclusions

Oestrogens and their receptors are implicated in PCa development and tumour progression. There is significant potential for the use of ERα antagonists and ERβ agonists to prevent PCa and delay disease progression. Tumours equipped with the pertinent receptors are potential candidates for this new therapeutic approach.     

What is the best way not to treat prostate cancer?

Introduction

Selective treatment approaches for prostate cancer (PCa) are warranted given the highly varied nature of the disease and the consequences associated with definitive therapy.

EAU Guidelines on Prostate Cancer. Part 1: Screening,Diagnosis, and Local Treatment with Curative Intent—Update 2013

Context

The most recent summary of the European Association of Urology (EAU) guidelines on prostate cancer (PCa) was published in 2011.

Objective

To present a summary of the 2013 version of the EAU guidelines on screening, diagnosis, and local treatment with curative intent of clinically organ-confined PCa.

Evidence acquisition

A literature review of the new data emerging from 2011 to 2013 has been performed by the EAU PCa guideline group. The guidelines have been updated, and levels of evidence and grades of recommendation have been added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews.

Evidence synthesis

A full version of the guidelines is available at the EAU office or online (www.uroweb.org). Current evidence is insufficient to warrant widespread population-based screening by prostate-specific antigen (PSA) for PCa. Systematic prostate biopsies under ultrasound guidance and local anesthesia are the preferred diagnostic method. Active surveillance represents a viable option in men with low-risk PCa and a long life expectancy. A biopsy progression indicates the need for active intervention, whereas the role of PSA doubling time is controversial. In men with locally advanced PCa for whom local therapy is not mandatory, watchful waiting (WW) is a treatment alternative to androgen-deprivation therapy (ADT), with equivalent oncologic efficacy. Active treatment is recommended mostly for patients with localized disease and a long life expectancy, with radical prostatectomy (RP) shown to be superior to WW in prospective randomized trials. Nerve-sparing RP is the approach of choice in organ-confined disease, while neoadjuvant ADT provides no improvement in outcome variables. Radiation therapy should be performed with ≥74 Gy in low-risk PCa and 78 Gy in intermediate- or high-risk PCa. For locally advanced disease, adjuvant ADT for 3 yr results in superior rates for disease-specific and overall survival and is the treatment of choice. Follow-up after local therapy is largely based on PSA and a disease-specific history, with imaging indicated only when symptoms occur.

Conclusions

Knowledge in the field of PCa is rapidly changing. These EAU guidelines on PCa summarize the most recent findings and put them into clinical practice.

Patient summary

A summary is presented of the 2013 EAU guidelines on screening, diagnosis, and local treatment with curative intent of clinically organ-confined prostate cancer (PCa). Screening continues to be done on an individual basis, in consultation with a physician. Diagnosis is by prostate biopsy. Active surveillance is an option in low-risk PCa and watchful waiting is an alternative to androgen-deprivation therapy in locally advanced PCa not requiring immediate local treatment. Radical prostatectomy is the only surgical option. Radiation therapy can be external or delivered by way of prostate implants. Treatment follow-up is based on the PSA level.     

Prostate Cancer Mortality Reduction by Prostate-Specific Antigen–Based Screening Adjusted for Nonattendance and Contamination in the European Randomised Study of Screening for Prostate Cancer (ERSPC)

Background

Prostate-specific antigen (PSA) based screening for prostate cancer (PCa) has been shown to reduce prostate specific mortality by 20% in an intention to screen (ITS) analysis in a randomised trial (European Randomised Study of Screening for Prostate Cancer [ERSPC]). This effect may be diluted by nonattendance in men randomised to the screening arm and contamination in men randomised to the control arm.

Objective

To assess the magnitude of the PCa-specific mortality reduction after adjustment for nonattendance and contamination.

Design, setting, and participants

We analysed the occurrence of PCa deaths during an average follow-up of 9 yr in 162 243 men 55–69 yr of age randomised in seven participating centres of the ERSPC. Centres were also grouped according to the type of randomisation (ie, before or after informed written consent).

Intervention

Nonattendance was defined as nonattending the initial screening round in ERSPC. The estimate of contamination was based on PSA use in controls in ERSPC Rotterdam.

Measurements

Relative risks (RRs) with 95% confidence intervals (CIs) were compared between an ITS analysis and analyses adjusting for nonattendance and contamination using a statistical method developed for this purpose.

Results and limitations

In the ITS analysis, the RR of PCa death in men allocated to the intervention arm relative to the control arm was 0.80 (95% CI, 0.68–0.96). Adjustment for nonattendance resulted in a RR of 0.73 (95% CI, 0.58–0.93), and additional adjustment for contamination using two different estimates led to estimated reductions of 0.69 (95% CI, 0.51–0.92) to 0.71 (95% CI, 0.55–0.93), respectively. Contamination data were obtained through extrapolation of single-centre data. No heterogeneity was found between the groups of centres.

Conclusions

PSA screening reduces the risk of dying of PCa by up to 31% in men actually screened. This benefit should be weighed against a degree of overdiagnosis and overtreatment inherent in PCa screening.     

Overdiagnosis and Overtreatment of Prostate Cancer

Context

Although prostate cancer (PCa) screening reduces the incidence of advanced disease and mortality, trade-offs include overdiagnosis and resultant overtreatment.

Objective

To review primary data on PCa overdiagnosis and overtreatment.

Evidence acquisition

Electronic searches were conducted in Cochrane Central Register of Controlled Trials, PubMed, and Embase from inception to July 2013 for original articles on PCa overdiagnosis and overtreatment. Supplemental articles were identified through hand searches.

Evidence synthesis

The lead-time and excess-incidence approaches are the main ways used to estimate overdiagnosis in epidemiological studies, with estimates varying widely. The estimated number of PCa cases needed to be diagnosed to save a life has ranged from 48 down to 5 with increasing follow-up. In clinical studies, generally lower rates of overdiagnosis have been reported based on the frequency of low-grade minimal tumors at radical prostatectomy (1.7–46.8%). Autopsy studies have reported PCa in 18.5–38.5%, although not all are low grade or low volume. Factors influencing overdiagnosis include the study population, screening protocol, and background incidence, limiting generalizability between settings. Reported rates of overtreatment vary widely in the literature, although contemporary international studies suggest increasing use of conservative management.

Conclusions

Epidemiological, clinical, and autopsy studies have been used to examine PCa overdiagnosis, with estimates ranging widely from 1.7% to 67%. Correspondingly, estimates of overtreatment vary widely based on patient features and may be declining internationally. Careful patient selection for screening and reducing overtreatment are important to preserve the benefits and reduce the downstream harms of prostate-specific antigen testing. Because all of these estimates are extremely population and context specific, this must be considered when using these data to inform policy.

Patient summary

Screening reduces spread and death from prostate cancer (PCa) but overdiagnoses some low-risk tumors that may not have caused harm. Because treatment has potential side effects, it is critical that not all patients with PCa receive aggressive treatment.     

Screening for Prostate Cancer in 2008 II: The Importance of Molecular Subforms of Prostate-Specific Antigen and Tissue Kallikreins

Context

Over the past decades, prostate-specific antigen (PSA), its isoforms, and other members of the tissue kallikrein family have been of continuous interest with regard to early detection and screening for prostate cancer (PCa).

Objective

This review strives to give an overview of the possible clinical utilities of these markers, focused on early diagnostics and PCa screening.

Evidence acquisition

Using the Medline database, a literature search was performed on the role of molecular subforms of PSA and other members of the tissue kallikrein family in PCa detection.

Evidence synthesis

With respect to PSA isoforms, only the combination of the various truncated forms (pPSA) shows additional value over total PSA (tPSA) and free PSA (fPSA) in PCa detection within the range of 2–10 ng/ml tPSA. At a high sensitivity for PCa, the specificity of the ratio of pPSA to fPSA (%pPSA) is, in general, better than that of the ratio of fPSA to tPSA (%fPSA), with a gain of 5–11%. The (−2)pPSA, (−4)pPSA, (−5)pPSA, (−7)pPSA, and benign PSA (BPSA) isoforms generally show no additional value over either pPSA or the existing parameters of tPSA and fPSA. Of the other members of the tissue kallikrein family, most studies on human kallikrein 2 (hK2) show an additional value of the ratio of hK2 to fPSA (%hK2) over %fPSA alone in PCa prediction. Other tissue kallikreins cannot be recommended for diagnosing PCa, due to the lack of additional value over tPSA or fPSA or to insufficient research. Regarding a prognostic role, the value of PSA subforms as well as of other members of the tissue kallikrein family is limited with regard to existing parameters.

Conclusions

pPSA and hK2 are able to improve PCa diagnosis in the range of 4–10 ng/ml tPSA over the existing variables tPSA and fPSA.     

Screening for Prostate Cancer Decreases the Risk of Developing Metastatic Disease: Findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC)

Background

Metastatic disease is a major morbidity of prostate cancer (PCa). Its prevention is an important goal.

Objective

To assess the effect of screening for PCa on the incidence of metastatic disease in a randomized trial.

Design, setting, and participants

Data were available for 76 813 men aged 55–69 yr coming from four centers of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The presence of metastatic disease was evaluated by imaging or by prostate-specific antigen (PSA) values >100 ng/ml at diagnosis and during follow-up.

Intervention

Regular screening based on serum PSA measurements was offered to 36 270 men randomized to the screening arm, while no screening was provided to the 40 543 men in the control arm.

Outcome measurements and statistical analysis

The Nelson-Aalen technique and Poisson regression were used to calculate cumulative incidence and rate ratios of M+ disease.

Results and limitations

After a median follow-up of 12 yr, 666 men with M+ PCa were detected, 256 in the screening arm and 410 in the control arm, resulting in cumulative incidence of 0.67% and 0.86% per 1000 men, respectively (p < 0.001). This finding translated into a relative reduction of 30% (hazard ratio [HR]: 0.70; 95% confidence interval [CI], 0.60–0.82; p = 0.001) in the intention-to-screen analysis and a 42% (p = 0.0001) reduction for men who were actually screened. An absolute risk reduction of metastatic disease of 3.1 per 1000 men randomized (0.31%) was found. A large discrepancy was seen when comparing the rates of M+ detected at diagnosis and all M+ cases that emerged during the total follow-up period, a 50% reduction (HR: 0.50; 95% CI, 0.41–0.62) versus the 30% reduction. The main limitation is incomplete explanation of the lack of an effect of screening during follow-up.

Conclusions

PSA screening significantly reduces the risk of developing metastatic PCa. However, despite earlier diagnosis with screening, certain men still progress and develop metastases.The ERSPC trial is registered under number ISRCTN49127736.     

Multicenter European External Validation of a Prostate Health Index–based Nomogram for Predicting Prostate Cancer at Extended Biopsy

Background

External validation of a prediction tool is mandatory to assess the tool's accuracy and generalizability within different patient cohorts.

Objective

To externally validate a previously developed Prostate Health Index (PHI)–based nomogram for predicting the presence of prostate cancer (PCa) at biopsy.

Design, setting, and participants

The study population consisted of 883 patients who were scheduled for a prostate biopsy at one of five European tertiary care centers. Total prostate-specific antigen (tPSA), free prostate-specific antigen (fPSA), and [−2]pro–prostate-specific antigen (p2PSA) levels were determined. The fPSA-to-tPSA ratio (%fPSA), p2PSA, and PHI ([p2PSA / fPSA] × √tPSA) were calculated.

Intervention

Extended initial and repeat prostate biopsy.

Outcome measurements and statistical analysis

Logistic regression models were fitted to test the predictors of PCa and to determine their predictive accuracy. A calibration plot was used to evaluate the extent of overestimation or underestimation between nomogram predictions and observed PCa rate. Decision curve analysis (DCA) provided an estimate of the net benefit obtained by using the PHI-based nomogram.

Results and limitations

Of 833 patients, 365 (41.3%) were diagnosed with PCa at extended prostate biopsy. In accuracy analyses, PHI was the most informative predictor of PCa (0.68), outperforming tPSA (0.51) and %fPSA (0.64). The predictive accuracy of the previously developed nomogram was 75.2% (95% confidence interval, 71.4–78.1). Calibration of the nomogram was good in patients at a low to intermediate predicted probability of PCa, while calibration was suboptimal, with a tendency to overestimate the presence of PCa, in high-risk patients. Finally, DCA demonstrated that the use of the PHI-based nomogram resulted in the highest net benefit. The main limitation of the study is the fact that only Caucasian patients were included.

Conclusions

At external validation, the previously developed PHI-based nomogram confirmed its ability to determine the presence of PCa at biopsy. These findings provide further evidence supporting the potential role of the nomogram in the biopsy decision pathway for European men with suspected PCa.

Patient summary

In the current study, we externally validated a Prostate Health Index–based nomogram to predict the presence of prostate cancer (PCa) at biopsy. This tool may help clinicians determine the need for a prostate biopsy in European patients with suspected PCa.     

Obesity and Prostate Cancer: Weighing the Evidence

Context

Obesity and prostate cancer (PCa) affect substantial proportions of Western society. Mounting evidence, both epidemiologic and mechanistic, for an association between the two is of public health interest. An improved understanding of the role of this modifiable risk factor in PCa etiology is imperative to optimize screening, treatment, and prevention.

Objective

To consolidate and evaluate the evidence for an epidemiologic link between obesity and PCa, in addition to examining the proposed underlying molecular mechanisms.

Evidence acquisition

A PubMed search for relevant articles published between 1991 and July 2012 was performed by combining the following terms: obesity, BMI, body mass index and prostate cancer risk, prostate cancer incidence, prostate cancer mortality, radical prostatectomy, androgen-deprivation therapy, external-beam radiation, brachytherapy, prostate cancer and quality of life, prostate cancer and active surveillance, in addition to obesity, BMI, body mass index and prostate cancer and insulin, insulin-like growth factor, androgen, estradiol, leptin, adiponectin, and IL-6. Articles were selected based on content, date of publication, and relevancy, and their references were also searched for relevant articles.

Evidence synthesis

Increasing evidence suggests obesity is associated with elevated incidence of aggressive PCa, increased risk of biochemical failure following radical prostatectomy and external-beam radiotherapy, higher frequency of complications following androgen-deprivation therapy, and increased PCa-specific mortality, although perhaps a lower overall PCa incidence. These results may in part relate to difficulties in detecting and treating obese men. However, multiple molecular mechanisms could explain these associations as well. Weight loss slows PCa in animal models but has yet to be fully tested in human trials.

Conclusions

Obesity appears to be linked with aggressive PCa. We suggest clinical tips to better diagnose and treat obese men with PCa. Whether reversing obesity slows PCa growth is currently unknown, although it is an active area of research.     

Olfactory detection of prostate cancer by dogs sniffing urine: a step forward in early diagnosis

Background

Volatiles organic compounds (VOCs) in urine have been proposed as cancer biomarkers.

Objective

To evaluate the efficacy of prostate cancer (PCa) detection by trained dogs on human urine samples.

Design, setting, and participants

A Belgian Malinois shepherd was trained by the clicker training method (operant conditioning) to scent and recognize urine of people having PCa. All urine samples were frozen for preservation and heated to the same temperature for all tests. After a learning phase and a training period of 24 mo, the dog's ability to discriminate PCa and control urine was tested in a double-blind procedure. Urine was obtained from 66 patients referred to a urologist for elevated prostate-specific antigen or abnormal digital rectal examination. All patients underwent prostate biopsy and two groups were considered: 33 patients with cancer and 33 controls presenting negative biopsies.

Measurements

During each “run,” the dog was asked to signal a cancer urine among six samples containing only one cancer urine and five randomly selected controls. Sensitivity and specificity of the test were assessed.

Results and limitations

The dog completed all the runs and correctly designated the cancer samples in 30 of 33 cases. Of the three cases wrongly classified as cancer, one patient was rebiopsied and a PCa was diagnosed. The sensitivity and specificity were both 91%.

Conclusions

This study shows that dogs can be trained to detect PCa by smelling urine with a significant success rate. It suggests that PCa gives an odor signature to urine. Identification of the VOCs involved could lead to a potentially useful screening tool for PCa.     

Is There Evidence of a Relationship between Benign Prostatic Hyperplasia and Prostate Cancer? Findings of a Literature Review

Context

More than half the male population aged >50 yr have histologic evidence of benign prostatic hyperplasia (BPH), while prostate cancer (PCa) is among the most common male cancers according to recent registry data. Understanding the aetiologies of both conditions is crucial to reduce the resulting burden of mortality and morbidity.

Objective

This review aims to examine the available data on the epidemiology, pathology, risk factors, and genetic markers involved in BPH and PCa; to discuss their clinical implications for management of both conditions; and to discuss their implications for PCa prevention. Our primary objective was to clarify the relationship between BPH and PCa by bringing together evidence from diverse areas of research.

Evidence acquisition

The primary source of data was PubMed, which was searched using Boolean strategies and by scanning lists of related articles. We also examined secondary sources from reference lists of retrieved articles and data presented at recent congresses.

Evidence synthesis

Accumulating evidence suggests that BPH and PCa share important anatomic, pathologic, and genetic links in addition to the well-established epidemiologic association between these conditions. We also found data that suggest interactions between apparently diverse factors, such as dihydrotestosterone levels and inflammation. Recent publications support the hypothesis that both BPH and PCa are part of the metabolic syndrome, while inflammation is emerging as a major contributor to the development of both BPH and PCa. Although many of the findings are preliminary and require further research, they offer new insight into the mechanisms of disease underlying the development of BPH and PCa.

Conclusions

Available data suggest that epidemiologic and pathologic links exist between BPH and PCa. Evidence of links between the conditions and contributory factors may offer common preventative strategies for BPH and PCa and common therapeutic approaches to their management.     

Age-Specific Risk of Incident Prostate Cancer and Risk of Death from Prostate Cancer Defined by the Number of Affected Family Members

Background

The thorough assessment of familial prostate cancer (PCa) risk is as important as ever to provide a basis for clinical counselling and screening recommendations.

Objective

Our aim was to determine the age-specific risks of PCa and the risk of death from PCa according to the number and the age of affected first-degree relatives.

Design, setting, and participants

The nationwide Swedish Family-Cancer Database includes a record of >11.8 million individuals and their cancers from 1958 to 2006. All men from the database with identified parents (>3.9 million individuals) were followed between 1961 and 2006. The study included 26 651 PCa patients, of whom 5623 were familial.

Measurements

The age-specific hazard ratios (HRs) of PCa and the HRs of death from PCa were calculated according to the number and age of affected fathers and brothers.

Results and limitations

The HRs of PCa diagnosis increased with the number of affected relatives and decreased with increasing age. The highest HRs were observed for men <65 yr of age with three affected brothers (HR: approximately 23) and the lowest for men between 65 and 74 yr of age with an affected father (HR: approximately 1.8). The HRs increased with decreasing paternal or fraternal diagnostic age. The pattern of the risk of death from familial PCa was similar to the incidence data.

Conclusions

The present results should guide clinical counselling and demonstrate the vast increases in risk when multiple first-degree relatives are affected.     

A Genetic Score Can Identify Men at High Risk for Prostate Cancer Among Men With Prostate-Specific Antigen of 1–3 ng/ml

Background

The diagnostic performance of a genetic score based on single nucleotide polymorphisms (SNPs) is unknown in the prostate-specific antigen (PSA) range of 1–3 ng/ml. A substantial proportion of men in this PSA span have prostate cancer (PCa), but biomarkers to determine who should undergo a prostate biopsy are lacking.

Objective

To evaluate whether a genetic risk score identifies men in the PSA range of 1–3 ng/ml who are at higher risk for PCa.

Design, setting, and participants

Men aged 50–69 yr with PSA 1–3 ng/ml and without a previous prostate biopsy were selected from the STHLM2 cohort. Of 2696 men, 49 SNPs were genotyped, and a polygenic risk score was calculated. Of these men, 860 were invited according to risk score, and 172 underwent biopsy.

Outcome measurements and statistical analysis

The risk of PCa was assessed using univariate and multivariate logistic regression analysis.

Results and limitations

PCa was diagnosed in 47 of 172 participants (27%), with Gleason sum 6 in 36 of 47 men (77%) and Gleason sum ≥7 in 10 of 47 men (21%); one man had intraductal cancer. The genetic score was a significant predictor of a positive biopsy (p = 0.028), even after adjusting for PSA, ratio of free to total PSA, prostate volume, age, and family history. There was an increase in the odds ratio of 1.60 (95% confidence interval, 1.05–2.45) with increasing genetic risk score. The absolute risk difference of positive biopsy was 19 percentage points, comparing the high and low genetic risk group (37% vs 18%).

Conclusions

A risk score based on SNPs predicts biopsy outcome in previously unbiopsied men with PSA 1–3 ng/ml. Introducing a genetic-based risk stratification tool can increase the proportion of men being classified in line with their true risk of PCa.     

EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease

Objective

Our aim was to present a summary of the 2010 version of the European Association of Urology (EAU) guidelines on the screening, diagnosis, and treatment of clinically localised cancer of the prostate (PCa).

Methods

The working panel performed a literature review of the new data emerging from 2007 to 2010. The guidelines were updated, and level of evidence and grade of recommendation were added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews.

Results

A full version is available at the EAU office or Web site (www.uroweb.org). Current evidence is insufficient to warrant widespread population-based screening by prostate-specific antigen (PSA) for PCa. A systematic prostate biopsy under ultrasound guidance and local anaesthesia is the preferred diagnostic method. Active surveillance represents a viable option in men with low-risk PCa and a long life expectancy. PSA doubling time in <3 yr or a biopsy progression indicates the need for active intervention. In men with locally advanced PCa in whom local therapy is not mandatory, watchful waiting (WW) is a treatment alternative to androgen-deprivation therapy (ADT) with equivalent oncologic efficacy. Active treatment is mostly recommended for patients with localised disease and a long life expectancy with radical prostatectomy (RP) shown to be superior to WW in a prospective randomised trial. Nerve-sparing RP represents the approach of choice in organ-confined disease; neoadjuvant androgen deprivation demonstrates no improvement of outcome variables. Radiation therapy should be performed with at least 74 Gy and 78 Gy in low-risk and intermediate/high-risk PCa, respectively. For locally advanced disease, adjuvant ADT for 3 yr results in superior disease-specific and overall survival rates and represents the treatment of choice. Follow-up after local therapy is largely based on PSA, and a disease-specific history with imaging is indicated only when symptoms occur.

Conclusions

The knowledge in the field of PCa is rapidly changing. These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice.