Outcome Following Active Surveillance of Men with Screen-detected Prostate Cancer. Results from the Göteborg Randomised Population-based Prostate Cancer Screening Trial

Background

Active surveillance (AS) has emerged as a treatment strategy for reducing overtreatment of screen-detected, low-risk prostate cancer (PCa).

Objective

To assess outcomes following AS of men with screen-detected PCa.

Design, setting, and participants

Of the 968 men who were diagnosed with screen-detected PCa between 1995 and 2010 in the Göteborg randomised, population-based PCa screening trial, 439 were managed with AS and were included in this study. Median age at diagnosis was 65.4 yr of age, and median follow-up was 6.0 yr from diagnosis.

Intervention

The study participants were followed at intervals of 3–12 mo and were recommended to switch to deferred active treatment in case of a progression in prostate-specific antigen, grade, or stage.

Outcome measurements and statistical analysis

The end points—overall survival (OS), treatment-free survival, failure-free (no relapse after radical treatment) survival, and cancer-specific survival—were calculated for various risk groups (very low, low, intermediate, and high) with Kaplan-Meier estimates. A Cox proportional hazards model as well as a competing risk analysis were used to assess whether risk group or age at diagnosis was associated with failure after AS.

Results and limitations

Forty-five per cent of all screen-detected PCa were managed with AS, and very low-risk and low-risk PCa constituted 60% of all screen-detected PCa. Thirty-seven per cent (162 of 439) switched from surveillance to deferred active treatment, and 39 men failed AS. The 10-yr OS, treatment-free survival, and failure-free survival were 81.1%, 45.4%, and 86.4%, respectively (Kaplan-Meier estimates). Men with low-, intermediate-, and high-risk tumours had a hazard ratio for failure of 2.1 (p = 0.09), 3.6 (p = 0.002), and 4.6 (p = 0.15), respectively, compared to very low-risk tumours (Cox regression). Only one PCa death occurred, and one patient developed metastasis (both in the intermediate-risk group). The main limitation of this study is the relatively short follow-up.

Conclusions

A large proportion of men with screen-detected PCa can be managed with AS. AS appears safe for men with low-risk PCa.     

Timing of Curative Treatment for Prostate Cancer: A Systematic Review

Context

Delaying definitive therapy unfavourably affects outcomes in many malignancies. Diagnostic, psychological, and logistical reasons but also active surveillance (AS) strategies can lead to treatment delay, an increase in the interval between the diagnosis and treatment of prostate cancer (PCa).

Objective

To review and summarise the current literature on the impact of treatment delay on PCa oncologic outcomes.

Evidence acquisition

A comprehensive search of PubMed and Embase databases until 30 September 2012 was performed. Studies comparing pathologic, biochemical recurrence (BCR), and mortality outcomes between patients receiving direct and delayed curative treatment were included. Studies presenting single-arm results following AS were excluded.

Evidence synthesis

Seventeen studies were included: 13 on radical prostatectomy, 3 on radiation therapy, and 1 combined both. A total of 34 517 PCa patients receiving radical local therapy between 1981 and 2009 were described. Some studies included low-risk PCa only; others included a wider spectrum of disease. Four studies found a significant effect of treatment delay on outcomes in multivariate analysis. Two included low-risk patients only, but it was unknown whether AS was applied or repeat biopsy triggered active therapy during AS. The two other studies found a negative effect on BCR rates of 2.5–9 mo delay in higher risk patients (respectively defined as any with T ≥2b, prostate-specific antigen >10, Gleason score >6, >34–50% positive cores; or D’Amico intermediate risk-group). All studies were retrospective and nonrandomised. Reasons for delay were not always clear, and time-to-event analyses may be subject to bias.

Conclusions

Treatment delay of several months or even years does not appear to affect outcomes of men with low-risk PCa. Limited data suggest treatment delay may have an impact on men with non–low-risk PCa. Most AS protocols suggest a confirmatory biopsy to avoid delaying treatment in those who harbour higher risk disease that was initially misclassified.     

Obesity Is Associated with Risk of Progression for Low-risk Prostate Cancers Managed Expectantly

Background

Active surveillance (AS) is an expectant management strategy for prostate cancer (PCa). The impact of obesity on progression is not well characterized in this population.

Objective

To determine if obesity is associated with progression in men on AS for low-risk PCa.

Design, setting, and participants

Men undergoing AS for low-risk PCa (no Gleason pattern ≥4, three or fewer cores involved or one-third or less of the total number of cores involved, and no core with >50% cancer involvement) were identified at our institution.

Outcome measurements and statistical analysis

The outcomes were pathologic progression (defined as no longer meeting low-risk criteria on follow-up biopsy) and therapeutic progression (defined as intent to initiate active treatment). Kaplan-Meier curves and multivariable logistic regression and Cox proportional hazards models were used, with separate models for reclassification at confirmatory biopsy (first biopsy after diagnostic biopsy) and progression beyond confirmatory biopsy.

Results and limitations

In this cohort of 565 men (median follow-up: 48 mo), 124 (22%) were obese (body mass index [BMI] ≥30 kg/m²). Pathologic and therapeutic progression occurred in 168 men (30%) and 172 men (30%), respectively. No association was noted between obesity and risk of progression at the confirmatory biopsy. However, beyond confirmatory biopsy, obesity was associated with a greater probability of pathologic progression (p = 0.007) and therapeutic progression (p = 0.007) in Kaplan-Meier analyses. In adjusted Cox models, each 5-unit increase in BMI was associated with an increased risk of pathologic progression (hazard ratio [HR]: 1.5; 95% confidence interval [CI], 1.1–2.1; p = 0.02) and therapeutic progression (HR: 1.4; 95% CI, 1.0–1.9; p = 0.05). The main limitation is the retrospective design, limiting the ability to assess BMI changes over time.

Conclusions

Obesity was associated with a significantly increased risk of progression beyond the confirmatory biopsy. This suggests an increased risk of long-term biologic progression rather than solely misclassification.

Patient summary

As opposed to immediate active treatment (surgery or radiation), active surveillance (AS) involves closely monitoring low-risk prostate cancers and only using active treatment if there are signs of progression. Our study is the first to suggest that obesity is associated with a higher risk of cancer progression while on AS. Further research is needed to determine if diet and exercise can decrease the risk of cancer progression while on AS.     

Active Surveillance for Low-Risk Prostate Cancer Worldwide: The PRIAS Study

Background

Overdiagnosis and subsequent overtreatment are important side effects of screening for, and early detection of, prostate cancer (PCa). Active surveillance (AS) is of growing interest as an alternative to radical treatment of low-risk PCa.

Objective

To update our experience in the largest worldwide prospective AS cohort.

Design, setting, and participants

Eligible patients had clinical stage T1/T2 PCa, prostate-specific antigen (PSA) ≤10 ng/ml, PSA density <0.2 ng/ml per milliliter, one or two positive biopsy cores, and Gleason score ≤6. PSA was measured every 3–6 mo, and volume-based repeat biopsies were scheduled after 1, 4, and 7 yr. Reclassification was defined as more than two positive cores or Gleason >6 at repeat biopsy. Recommendation for treatment was triggered in case of PSA doubling time <3 yr or reclassification.

Outcome measurements and statistical analysis

Multivariate regression analysis was used to evaluate predictors for reclassification at repeat biopsy. Active therapy–free survival (ATFS) was assessed with a Kaplan-Meier analysis, and Cox regression was used to evaluate the association of clinical characteristics with active therapy over time.

Results and limitations

In total, 2494 patients were included and followed for a median of 1.6 yr. One or more repeat biopsies were performed in 1480 men, of whom 415 men (28%) showed reclassification. Compliance with the first repeat biopsy was estimated to be 81%. During follow-up, 527 patients (21.1%) underwent active therapy. ATFS at 2 yr was 77.3%. The strongest predictors for reclassification and switching to deferred treatment were the number of positive cores (two cores compared with one core) and PSA density. The disease-specific survival rate was 100%. Follow-up was too short to draw definitive conclusions about the safety of AS.

Conclusions

Our short-term data support AS as a feasible strategy to reduce overtreatment. Clinical characteristics and PSA kinetics during follow-up can be used for risk stratification. Strict monitoring is even more essential in men with high-risk features to enable timely recognition of potentially aggressive disease and offer curative intervention. Limitations of using surrogate end points and markers in AS should be recognized.

Trial registration

The current program is registered at the Dutch Trial Register with ID NTR1718 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1718).     

Prostate cancer antigen 3 score accurately predicts tumour volume and might help in selecting prostate cancer patients for active surveillance

Background

The optimal selection of prostate cancer (PCa) patients for active surveillance (AS) is currently being debated.

Objective

To assess the impact of urinary prostate cancer antigen 3 (PCA3) score as an AS criterion instead of and in addition to the current criteria.

Design, setting, and participants

We prospectively studied 106 consecutive low-risk PCa patients (prostate-specific antigen [PSA] ≤10 ng/ml, clinical stage T1c–T2a, and biopsy Gleason score 6) who underwent a PCA3 urine test before radical prostatectomy (RP).

Measurements

Performance of AS criteria (biopsy criteria, PCA3 score, PSA density, and magnetic resonance imaging [MRI] findings) was tested in predicting four prognostic pathologic findings in RP specimens: (1) pT3–4 disease; (2) overall unfavourable disease (OUD) defined by pT3–4 disease and/or pathologic primary Gleason pattern 4; (3) tumour volume <0.5 cm³; and (4) insignificant PCa.

Results and limitations

The PCA3 score was strongly correlated with the tumour volume in a linear regression analysis (p < 0.001, r = 0.409). The risk of having a cancer ≥0.5 cm³ and a significant PCa was increased three-fold in men with a PCA3 score of ≥25 compared with men with a PCA3 score of <25 with most AS biopsy criteria used. There was a trend towards higher PCA3 scores in patients with unfavourable and non–organ-confined disease and Gleason >6 cancers. In a multivariate analysis taking into account each AS criterion, a high PCA3 score (≥25) was an important predictive factor for tumour volume ≥0.5 cm³ (odds ratio [OR]: 5.4; p = 0.010) and significant PCa (OR: 12.7; p = 0.003). Biopsy criteria and MRI findings were significantly associated with OUD (OR: 3.9 and 5.0, respectively; p = 0.030 and p = 0.025, respectively).

Conclusions

PCA3 score may be a useful marker to improve the selection for AS in addition to the current AS criteria. With a predictive cut-off of 25, PCA3 score is strongly indicative for tumour volume and insignificant PCa.     

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.     

Outcomes of men with screen-detected prostate cancer eligible for active surveillance who were managed expectantly

Background

The incidence of small, localised, well-differentiated prostate cancer (PCa) is increasing, mainly as a result of screening. Many of these cancers will not progress, and radical therapy may lead to substantial overtreatment. Active surveillance (AS) has emerged as an alternative.

Objective

To retrospectively validate the currently used criteria for eligibility for AS.

Design, setting, and participants

For this cohort study, data from 616 men who were diagnosed with PCa between 1994 and 2007 at a mean age of 66.3 yr in four centres of the European Randomized Study of Screening for Prostate Cancer (ERSPC) were combined. All patients fit the criteria for AS (prostate-specific antigen [PSA] ≤10.0 ng/ml, PSA-density <0.2 ng/ml per ml, stage T1C/T2, Gleason score ≤3 + 3 = 6, and ≤2 positive biopsy cores), and initially they were managed expectantly. Median follow-up was 3.91 yr.

Measurements

Disease specific-, overall-, and treatment-free survival were studied. Present PSA characteristics were assessed and also compared between men who were switching to deferred active therapy during follow-up and men remaining untreated.

Results and limitations

The calculated (Kaplan-Meier) 10-yr PCa-specific survival (21 patients at risk) was 100%, which sharply contrasted with 77% overall survival. Men still alive showed favourable PSA characteristics. Although the calculated 10-yr treatment-free survival was only 43%, objective signs of progression often did not indicate the shift to radical treatment. The cohort consisted of men on AS and those on watchful waiting (WW); information on comorbidity or psychological distress was not available.

Conclusions

AS seems justified in selected men with screen-detected PCa. Prospective protocol-based AS programs are necessary to optimise selection criteria and to find the appropriate trigger points for switching to active therapy. Possible negative psychological reactions with AS against improved quality of life by withholding side-effects from radical treatment should be considered.     

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.     

A Calculator for Prostate Cancer Risk 4 Years After an Initially Negative Screen: Findings from ERSPC Rotterdam

Background

Inconclusive test results often occur after prostate-specific antigen (PSA)–based screening for prostate cancer (PCa), leading to uncertainty on whether, how, and when to repeat testing.

Objective

To develop and validate a prediction tool for the risk of PCa 4 yr after an initially negative screen.

Design, setting, and participants

We analyzed data from 15 791 screen-negative men aged 55–70 yr at the initial screening round of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer.

Outcome measurements and statistical analysis

Follow-up and repeat screening at 4 yr showed either no PCa, low-risk PCa, or potentially high-risk PCa (defined as clinical stage >T2b and/or biopsy Gleason score ≥7 and/or PSA ≥10.0 ng/ml). A multinomial logistic regression analysis included initial screening data on age, PSA, digital rectal examination (DRE), family history, prostate volume, and having had a previous negative biopsy. The 4-yr risk predictions were validated with additional follow-up data up to 8 yr after initial screening.

Results and limitations

Positive family history and, especially, PSA level predicted PCa, whereas a previous negative biopsy or a large prostate volume reduced the likelihood of future PCa. The risk of having PCa 4 yr after an initially negative screen was 3.6% (interquartile range: 1.0–4.7%). Additional 8-yr follow-up data confirmed these predictions. Although data were based on sextant biopsies and a strict protocol-based biopsy indication, we suggest that men with a low predicted 4-yr risk (eg, ≤1.0%) could be rescreened at longer intervals or not at all, depending on competing risks, while men with an elevated 4-yr risk (eg, ≥5%) might benefit from immediate retesting. These findings need to be validated externally.

Conclusions

This 4-yr future risk calculator, based on age, PSA, DRE, family history, prostate volume, and previous biopsy status, may be a promising tool for reducing uncertainty, unnecessary testing, and overdiagnosis of PCa.     

Prospective Study of Diagnostic Accuracy Comparing Prostate Cancer Detection by Transrectal Ultrasound–Guided Biopsy Versus Magnetic Resonance (MR) Imaging with Subsequent MR-guided Biopsy in Men Without Previous Prostate Biopsies

Background

The current diagnosis of prostate cancer (PCa) uses transrectal ultrasound–guided biopsy (TRUSGB). TRUSGB leads to sampling errors causing delayed diagnosis, overdetection of indolent PCa, and misclassification. Advances in multiparametric magnetic resonance imaging (mpMRI) suggest that imaging and selective magnetic resonance (MR)–guided biopsy (MRGB) may be superior to TRUSGB.

Objective

To compare the diagnostic efficacy of the magnetic resonance imaging (MRI) pathway with TRUSGB.

Design, setting, and participants

A total of 223 consecutive biopsy-naive men referred to a urologist with elevated prostate-specific antigen participated in a single-institution, prospective, investigator-blinded, diagnostic study from July 2012 through January 2013.

Intervention

All participants had mpMRI and TRUSGB. Men with equivocal or suspicious lesions on mpMRI also underwent MRGB.

Outcome measurements and statistical analysis

The primary outcome was PCa detection. Secondary outcomes were histopathologic details of biopsy and radical prostatectomy specimens, adverse events, and MRI reader performance. Sensitivity, specificity, negative predictive values (NPVs), and positive predictive values were estimated and basic statistics presented by number (percentage) or median (interquartile range).

Results and limitations

Of 223 men, 142 (63.7%) had PCa. TRUSGB detected 126 cases of PCa in 223 men (56.5%) including 47 (37.3%) classed as low risk. MRGB detected 99 cases of PCa in 142 men (69.7%) with equivocal or suspicious mpMRI, of which 6 (6.1%) were low risk. The MRGB pathway reduced the need for biopsy by 51%, decreased the diagnosis of low-risk PCa by 89.4%, and increased the detection of intermediate/high-risk PCa by 17.7%. The estimated NPVs of TRUSGB and MRGB for intermediate/high-risk disease were 71.9% and 96.9%, respectively. The main limitation is the lack of long follow-up.

Conclusions

We found that mpMRI/MRGB reduces the detection of low-risk PCa and reduces the number of men requiring biopsy while improving the overall rate of detection of intermediate/high-risk PCa.

Patient summary

We compared the results of standard prostate biopsies with a magnetic resonance (MR) image–based targeted biopsy diagnostic pathway in men with elevated prostate-specific antigen. Our results suggest patient benefits of the MR pathway. Follow-up of negative investigations is required.     

Pathologic prostate cancer characteristics in patients eligible for active surveillance: a head-to-head comparison of contemporary protocols

Background

Although the rationale for active surveillance (AS) in patients with low-risk prostate cancer is well established, eligibility criteria vary significantly across different programs.

Objective

To compare the ability of contemporary AS criteria to identify patients with certain pathologic tumor features based on the results of an extended transrectal prostate biopsy.

Design, settings, and participants

The study cohort included 391 radical prostatectomy patients who had prostate cancer with Gleason scores ≤6 on transrectal biopsy with ≥10 cores.

Intervention

Radical prostatectomy without neoadjuvant treatment.

Outcome measurements and statistical analysis

We identified patients who fulfilled the inclusion criteria of five AS protocols including those of Epstein, Memorial Sloan-Kettering Cancer Center, Prostate Cancer Research International: Active Surveillance (PRIAS), University of California, San Francisco, and University of Miami (UM). We evaluated the ability of these criteria to predict three pathologic end points: insignificant disease defined using a classical and updated formulation, and organ-confined Gleason ≤6 prostate cancer. Measures of diagnostic accuracy and areas under the receiver operating curve were calculated for each protocol and compared.

Results and limitations

A total of 75% of the patients met the inclusion criteria of at least one protocol; 23% were eligible for AS by all studied criteria. The PRIAS and UM criteria had the best balance between sensitivity and specificity for both definitions of insignificant prostate cancer and a higher discriminative ability for the end points than any criteria including patients with two or more positive cores. The Epstein criteria demonstrated high specificity but low sensitivity for all pathologic end points, and therefore the discriminative ability was not superior to those of other protocols.

Conclusions

Significant variations exist in the ability of contemporary AS criteria to predict pathologically insignificant prostate cancer at radical prostatectomy. These differences should be taken into account when making treatment choices in patients with low-risk prostate cancer.     

Predictors of Pathologic Progression on Biopsy Among Men on Active Surveillance for Localized Prostate Cancer: The Value of the Pattern of Surveillance Biopsies

Background

A better understanding of the independent predictors of disease progression for prostate cancer (PCa) patients is needed to improve the selection of ideal candidates for active surveillance (AS) and refine the surveillance regimen.

Objective

To examine the association of clinical and pathologic characteristics, as well as patterns of surveillance biopsy results, with the risk of progression in men on AS.

Design, setting, and participants

The retrospective study consisted of men with PCa who were on AS in the prospectively maintained University of California, San Francisco, institutional database from 1996 to 2011. Strict criteria for AS were prostate-specific antigen (PSA) ≤10 ng/ml, clinical stage T1 or T2, biopsy Gleason grade 6, <33% positive cores, and <50% tumor in any single core. Men were then categorized based on results of their confirmatory surveillance biopsy.

Outcome measurements and statistical analysis

Disease progression was defined as an increase in Gleason grade and/or biopsy volume beyond prespecified cut points. Serial biopsy patterns over the course of surveillance were stratified by confirmatory biopsy findings: negative, positive without progression, and positive with progression. Multivariable logistic regression models were used to evaluate predictors of progression during AS.

Results and limitations

A total of 465 men met inclusion criteria (median follow-up: 51 mo). Of these men, 23% had negative confirmatory biopsies. Only 3% of the men (1 of 30) progressed by the fourth surveillance biopsy following a biopsy pattern of negative confirmatory and negative third biopsy findings. Negative confirmatory biopsy and lower PSA density (both p < 0.01) were independently associated with decreased odds of biopsy progression at 3 yr. The main limitation of this study is its observational nature.

Conclusions

The patterns of surveillance biopsy results yield additional important information in AS. Negative confirmatory biopsy and PSA density are important independent predictors of progression on AS and may be used to better counsel men opting for AS.     

The Role of Biopsy Core Number in Selecting Prostate Cancer Patients for Active Surveillance

Background

Studies offer wide variations in inclusion criteria for active surveillance (AS) in prostate cancer (PCa), but the role of the biopsy core number has not been thoroughly assessed.

Objective

To evaluate the impact of the biopsy core number on the risk of misclassification for AS eligibility.

Design, setting, and participants

: This prospective study included 411 men eligible for AS who fulfilled at least one of four of the criteria reported in the literature groupings among a screening cohort of 2917 patients.

Intervention

All patients underwent a 21-core biopsy with cores mapped by location and acted as controls of themselves for the analysis of biopsy core number (6-, 12- and 21-core schemes). Radical prostatectomy (RP) was performed in 297 men (72%).

Measurements

The number of included patients, PCa extent on biopsy, rate of unfavorable disease in RP specimens, and biochemical recurrence-free survival were compared as a function of (1) the different criteria groupings for AS and (2) the biopsy core number (6, 12, or 21).

Results and limitations

Of the 1104 patients with PCa, the proportion eligible for AS ranged from 22.5% to 35.4% based on AS criteria. In men who fulfilled AS criteria only in a 12-core strategy, tumor length and percentage of cancer involvement on biopsy were significantly greater than in those who fulfilled AS criteria in a 21-core scheme. The rate of unfavorable disease on RP specimens was also higher in the former group, from 28.6% to 35.9% relative to AS criteria (p = 0.014, 0.044, and 0.113 in groups 2, 3, and 4, respectively).

Conclusions

Men eligible for AS based on a 21-core strategy have cancers with a lower extent of disease on biopsies and a lower risk of unfavorable disease on RP specimens regardless of how AS criteria are defined, compared with men eligible in a 12-core scheme.     

Outcomes of men on active surveillance for low-risk prostate cancer at a safety-net hospital

Purpose

To characterize demographic, disease, and cancer outcomes of men on active surveillance (AS) at a safety-net hospital and characterize those who were lost to follow-up (LTFU).

Incidence of Prostate Cancer After Termination of Screening in a Population-based Randomised Screening Trial

Background

In a previous publication from the Göteborg randomised screening trial from 2010, biennial prostate-specific antigen (PSA) screening for men ≤69 yr of age was shown to lower prostate cancer (PCa) mortality by 44%. The evidence of the optimal age to stop screening, however, is limited.

Objective

To examine the risk of PCa after the discontinuation of screening.

Design, setting, and participants

In December 1994, 20 000 men in Göteborg, Sweden, between the ages of 50 and 65 yr were randomised to a screening arm (invited biennially to PSA testing) and a control arm (not invited). At the upper age limit (average: 69 yr), a total of 13 423 men (6449 and 6974 in the screening and control arms, respectively) were still alive without PCa. The incidence of PCa hereafter was established by matching with the Western Swedish Cancer Register. Participants were followed until a diagnosis of PCa, death, or final follow-up on June 30, 2012, or for a maximum of 12 yr after the last invitation.

Outcome measurements and statistical analysis

Incidence rates and disease-free survival were calculated with life table models and Kaplan-Meier estimates. A competing risk model was also applied.

Results and limitations

Postscreening, 173 cases of PCa were diagnosed in the screening arm (median follow-up: 4.8 yr) and 371 in the control arm (median follow-up: 4.9 yr). Up to 9 yr postscreening, all risk groups were more commonly diagnosed in the control arm, but after 9 yr the rates in the screening arm caught up, other than those for the low-risk group. PCa mortality also caught up after 9 yr.

Conclusions

Nine years after the termination of PSA testing, the incidence of potentially lethal cancers equals that of nonscreened men. Considering the high PCa mortality rate in men >80 yr of age, a general age of 70 yr to discontinue screening might be too low. Instead, a flexible age to discontinue based on individual risk stratification should be recommended.     

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.     

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.     

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.